Active TB Drug-Safety Monitoring and Managementmohs.gov.mm/ckfinder/connector?command=Proxy&lang=en&type=… · Tin Maung Cho, Professor Win Naing, Professor Ye Tun and Professor

Active TB Drug-Safety

Monitoring and Management

(aDSM)

National TB ProgrammeDepartment of Public HealthMinistry of Health and Sports

The Republic of the Union of Myanmar

ACKNOWLEDGEMENTS 5

ABBREVIATIONS 6

INTRODUCTION 7

DEFINITIONS 9

OBJECTIVES OF aDSM 9

PURPOSE AND SCOPE of the aDSM Manual 10

ESSENTIAL ELEMENTS OF aDSM 10

LEVELS OF aDSM MONITORING 13

IMPLEMENTATION STEPS OF aDSM 14

1. Create a national coordinating mechanism for aDSM 14

2. Develop a plan for aDSM 15

3. Definemanagementandsupervisionrolesandresponsibilities 15

4. Create standard data collection materials 16

5. Train staff for collection of data 17

6. Defineschedulesandroutesfordatacollectionandreporting 17

7. Consolidate data electronically 20

8. Develop capacity for signal detection and causality assessment 20

ROLES AND RESPONSIBILITIES 20

CAUSALITY ASSESSMENT 22

SIGNAL DETECTION 25

ANNEXES 26

ANNEXA Monitoringschedule(Clinical,bacteriologicalandlaboratory)

during M-/XDR-TB treatment on new and repurposed drugs and

the shorter regimen 27

ANNEXB ProgrammaticindicatorsforaDSM(WHOGuidelines,2014) 29

ANNEXC MDR-TBTreatmentCard(DR-TBForm01)includingnewdrugs,and

new regimens 31

ANNEXD NTPFormforReportingSeriousAdverseEvent(SAE) 37

ANNEX E Severity grading scales and suggested action for common AEs 39

CONTENTS

ACKNOWLEDGEMENTS

The Ministry of Health and Sports, Myanmar would like to express its sincere thanks to Professor Tin Maung Cho, Professor Win Naing, Professor Ye Tun and Professor Yadanar Kyaw for their technicalsupportandtimeinwritingthisManual;MyanmarFoodandDrugAdministration(FDA),TBspecialistHospitalsfortheircollaborationandsupport,theWorldHealthOrganizationforitsinitiative in developing the national aDSM plan and providing technical assistance to this manual; MédecinsSansFrontières(MSF)foritscollaboration;andDr.MamelQuelapio,SeniorConsultantfromKNCVTuberculosisFoundationforhertechnicalsupportintheprocessofaDSMManualdevelopment. The development of this aDSM Manual was undertaken in 2017 with support from the USAID-funded Challenge TB project.

TheGlobalHealthBureau,OfficeofHealth,InfectiousDiseaseandNutrition(HIDN),UnitedStatesAgency for InternationalDevelopment,financiallysupports thisguide throughChal-lengeTBunderthetermsofAgreementNo.AID-OAA-A-14-00029.ThisfieldguideismadepossiblebythegeneroussupportoftheAmericanpeoplethroughtheUnitedStatesAgencyforInternationalDevelopment(USAID).ThecontentsaretheresponsibilityofChallengeTBanddonotnecessarilyreflecttheviewsofUSAIDortheUnitedStatesGovernment.

ManualforTuberculosisMedicinesandRegimens

NationalTuberculosisProgramme

5

ADR/AR Adverse drug reaction/Adverse reaction

aDSM Active TB Drug-Safety Monitoring and Management

AE Adverse event

Bdq Bedaquiline

CA Causality assessment

Cfz Clofazimine

Dlm Delamanid

DR-TB Drug-resistanttuberculosis

FDA Food and Drug Administration

Gfx Gatifloxacin

MDR-TB Multidrug-resistanttuberculosis

Mfx Moxifloxacin

NTP NationalTuberculosisProgramme

PMDT ProgrammaticManagementofDrug-ResistantTuberculosis

PV Pharmacovigilance

SAE Serious adverse event

SLD Second-line drug

TB Tuberculosis

UMC Uppsala Monitoring Centre

WHO WorldHealthOrganization

XDR-TB Extensively drug-resistanttuberculosis

ABBREVIATIONS

ActiveTBDrug-SafetyMonitoringandManagement(aDSM)


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INTRODUCTION

1WorldHealthOrganization.WHOGlobalTuberculosisReport,2016.WHO-Geneva.WHO/HTM/TB/2016.132NationalStrategicPlanforTuberculosis2016-2020,NationalTBProgramme,NTP,Myanmar.3Theuseofbedaquilineinthetreatmentofmultidrug-resistantTBWHO-Geneva.InterimPolicyGuidance,WHO-Geneva,2013. WHO/HTM/TB/2013.64 The use of delamanid in the treatment of multidrug-resistant TB WHO-Geneva. Interim Policy Guidance WHO- Geneva, 2014. WHO/HTM/TB/2014.235WHOtreatmentGuidelinesfordrug-resistanttuberculosis,2016update.WHO-Geneva,2016.WHO/HTM/TB/2016.046Active tuberculosis drug-safetymonitoring andmanagement: Framework for implementation.WHO-Geneva, 2015.WHO/HTM/TB/2015.28



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Myanmarisoneofthe30highburdencountriesforTB,multidrug-resistant(MDR)TBandTB/HIV.1

ToimplementaneffectivestrategytocombatandcontrolTB/MDR-TB,theNTPhasdevelopeda5-yearNationalStrategicPlanforTuberculosis2016-2020(NSP)2 that includes the programmatic managementofdrug-resistantTB(PMDT)asoneofthekeyinterventions.Managementofdrug-resistantTB(DR-TB)ischallengingduetoprolongedtreatmentduration,costlyregimen,andsideeffects of the drugs that lead to poor treatment adherence. New and innovative strategies are needed to address these challenges.

Recently,WHOhasapprovedtheuseofnewanti-tuberculosis(TB)medicines,Bedaquiline(Bdq)andDelamanid(Dlm)undercertainconditions.3, 4 Moreover, a shorter regimen for MDR-TB that includesrepurposeddrugs,suchasclofazimine(Cfz)andmoxifloxacin(Mfx)hasbeenapprovedandrecommendedbyWHOintheDrug-resistantTBguidelines,2016update.5 The introduction of new and repurposed TB medicines, some given at higher dosages than previously used, and somedrugswith potentially additive toxicity given in combination, prompts the importance ofactivepharmacovigilance(PV)systemforpatientsonTBtreatment.Additionally,forHIVpatientsontreatment,someofthenewTBdrugshavebeenobservedtomanifestdrug-druginteractionswith certain anti-retroviral medicines.

Toaddressthisissue,theWHOGlobalTBProgramme(WHO/GTB)andtheEssentialMedicinesProducts department drew on the input of technical partners to develop the concept of active TB drug safety monitoring and management (aDSM), defined as the “active and systematicclinicaland laboratoryassessmentofpatientswhileon treatment.” aDSMapplies topatientson treatment with new anti-TB drugs, new MDR-TB regimens, including the shorter treatment regimen, andextensively drug-resistantTB (XDR-TB) regimens.6 The purpose of aDSM is to detect,manage,andreportsuspectedorconfirmeddrugtoxicitiesinatimelyfashion.Afeedbackmechanism tocareprovidersneeds tobe inplace for theirknowledgeandneededaction forpatient management.

7ActiveTBdrug-safetymonitoringandmanagement (aDSM) for treatmentofMDR/XDR-TBusingnewor repurposeddrugsinMyanmar:Debriefing,aDSMmission,Myanmar2-6May2016,WHO.

UpontherequestoftheNTP,theTechnicalOfficer,TechnicalSupportCoordination(TSC)GlobalTBProgramme (GTB),WHO (Geneva) conducted an aDSMmission on 2-6May 2016.7 The current national PV system in Myanmar for all diseases involves spontaneous reporting of adverse events(AEs)byvoluntaryreportingofhealthcareworkers.ThishasbeenmanagedbytheFoodandDrugAdministration(FDA)/Drugcontrolsectionalthoughwithlimitedhumanresources.AnAEReportingForm(inMyanmarlanguage)isinplacebutwithlimitedimplementation,andwithnoTB-relatedAEreportssubmittedasofyet.BdqandDlmwere introduced in thecountry inMarch2016 through theEndTBproject implementedby theNTP,AungSanTBHospital andMSF-Holland. The PV system of the EndTB project is an advanced package with reporting of seriousAEs(SAEs)plusAEsofspecialinterestandclinicalsignificance(seeDefinitions).Whilean advanced package is relevant in a project or research study context, programmatic aDSM implementationwithamoresimplifiedsystemismoreappropriateintheNTPwhereresourcesare limited, in order to scale it up more widely.



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DEFINITIONS 1. Active drug-safety monitoring and management (aDSM): active and systematic

clinical and laboratory assessment of patients while on treatment. aDSM applies topatientsontreatmentwith(a)newanti-TBdrugs,suchasBdqandDlm;(b)newDR-TBregimens,suchastheshorter(or9-month)MDR-TBregimen;or(c)XDR-TBregimensonnew/repurposeddrugs,inordertodetect,manageandreportsuspectedorconfirmeddrug toxicities.

2. Adverse event (AE): any untoward medical occurrence that may present in a TB patient duringtreatmentwithapharmaceuticalproduct,butwhichdoesnotnecessarilyhaveacausal relationship with this treatment.

3. Adverse drug reaction (ADR): a response to a TB medicine that is noxious and unintended, and which occurs at doses normally used in humans.

4. Causality assessment: the evaluation of the likelihood that a TB medicine was the causativeagentofanobservedadversereaction.

5. Serious adverse event (SAE): an AE which either leads to death or a life-threatening experience;tohospitalizationorprolongationofhospitalization;topersistentorsignificantdisability;ortoacongenitalanomaly.SAEsthatdonotimmediatelyresultinoneoftheseoutcomesbutwhichrequireaninterventiontoprevent it fromhappeningareincluded.SAEs may require a drastic intervention, such as termination of the drug suspected of having caused the event.

6. AE of special interest: AE documented to have occurred during clinical trials and for which themonitoring program is specifically sensitized to report regardless of itsseriousness, severity or causal relationship to the TB treatment

7. AE of clinical significance:AE that iseithera)serious (SAE),b)ofspecial interest,c) leads toadiscontinuationorchange in the treatment,or,d) is judgedasotherwiseclinicallysignificantbytheclinician

8. Signal: reported information on a possible causal relationship between an adverseeventandaTBmedicine,therelationshipbeingunknownorincompletelydocumentedpreviously or representing a new aspect of a known association

OBJECTIVES OF aDSMTheoverallobjectivesofaDSMaretoreducerisksfromdrug-relatedharmsinpatientsonsecond-line(SL)treatmentforDR-TBandtogeneratestandardizedaDSMdatatoinformfuturepolicyupdates on the use of such medicines. aDSM aims to detect, manage, and report suspected or confirmeddrugtoxicitiesinatimelyfashion.



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PURPOSE AND SCOPE of the aDSM ManualThe purpose of this aDSM Manual is to provide a step-by-step guide to programmaticallyimplementasustainableaDSMsysteminlinewiththeWHO-recommendedaDSMFramework.8

ThisManualwillbeapplicable topatientson1) new and repurposed drugs, 2) new DR-TB regimens such as the shorter treatment regimen, and 3) XDR-TB regimens. This document willdescribethedetection,activemonitoringandmanagementofDR-TBpatientsusingclinicalandlaboratoryassessment,aswellasrecordingandreportingofSAEs.

ESSENTIAL ELEMENTS OF aDSMTherearethreeessentialelementsofaDSMtoachievetheaboveobjectives:

1. Active and systematic clinical and laboratory assessment during treatment to detect drug toxicity and AEs. There are ways to help health providers do this step.

a. Observe and listen to patients. The detection of AEs is primarily dependent upon reporting from patients, nurses, doctors, counsellors, etc. At every DOT encounter, healthworkersshouldaskthepatientandfamilymembersaboutclinicalsymptomsof common AEs including nausea, vomiting, peripheral neuropathy, skin rash, psychiatricdisturbance(headache,anxiety,depression,irritability,behaviorchange),hearingloss,jaundice,vestibulartoxicity(vertigo,ataxia,hearingloss),andsymptomsofelectrolytewasting (musclecramping,palpitations).Allhealthcareprofessionalsinvolvedmustbetrainedonadverseeventscreening.

b. Performroutine clinical assessments, e.g., for treatment adherence and tolerance, psychosocial support and consults with the psychiatrist, ophthalmologist, HIV specialist, etc. Clinical follow-up with the MDR-TB physician for all patients is at a minimum of 2 weeks after the start of MDR-TB treatment, then monthly until the treatment completion.

c. Scheduleregularlaboratoryscreening,evenifthepatienthasnospecificcomplaints,e.g.,creatinine,ECG,liverfunctiontests,etc.Regularlaboratorymonitoringdetectsoccultadverseeffects.Laboratorytestsandproceduresrelatedtotreatmentshouldbeavailableandaccessibletopatients,freeofcharge.

8Active tuberculosis drug-safetymonitoring andmanagement: Framework for implementation.WHO-Geneva, 2015.WHO/HTM/TB/2015.28



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Annex Ashowsthescheduleofclinicalandlaboratorytestsforpatientsonnewandrepurposeddrugsandtheshortertreatmentregimen(STR).AsBdqandDlm,Mfx,andCfzmay induceQTprolongation,ECGmonitoring isessential.ChallengeTBrecentlyissuedrecommendationsonthemeasurementofQTprolongation.9

2. Management of AEs in a timely manner. Early detection of signs and symptoms is key to proper management of AEs that significantly impacts patient well-being,overall treatment acceptance, and adherence. Management includes measures taken to alleviate the signs and symptoms of adverse reactions with careful individual case review, suchas:a) reassurance, ifAE isminorb) lowering thedoseof theoffendingdrug,c)stoppingthedrug,d)drugreplacement;e)providingancillarymedicationsandf)otherinterventions(surgery,transfusion,psychologicalsupport,etc.).Ancillarymedicinesshouldbeavailableandaccessibletopatients,freeofcharge.

For AEs that need additional evaluation and/or medical treatment, a treatment decision algorithm or severity grading may help clinic staff in decision-making, allowing a more objectivewayofapproachingsymptoms(Figure 1)andlaboratorytestresults(Figure 2). Themain sources of severity grading are theDivision ofMicrobiology and InfectiousDiseases (DMID) and Common Terminology Criteria for AE (CTCAE).10 A set of Severity Grading Scales using simple categories of Mild, Moderate, Severe and Life-threatening are provided in this document (Annex E) for selected common AEs (taken from the end TB Guide for TB patient management11).

Figure 1: Serverity grading of a symptom (vomiting)10, 12

Condition term Grade 1 Grade 2 Grade 3 Grade 4

Vomiting 1 episode in 24 hours 2-5 episodes in 24 hours

>6 episodes in 24 hours or needing IV fluids

Physiologic conse-quences requiring hospitalizationorrequiring parementer-al nutrition

9GuidanceonrequirementsforQTcmeasurementinECGmonitoringwhenintroducingnewdrugsandshorterregimensforthetreatmentofDrug-resistantTuberculosis,ver0.4,25Apr2017.USAID,KNCVTuberculosisFoundation,ChallengeTB.http://www.challengetb.org/publications/tools/pmdt/Guidance_on_ECG_monitoring_in_NDR.pdf10 version 5.0; date, 14-Nov-2016, DMID Nov 2007 and CTCAE v.4.03 14-Jun-2010.https://www.google.com.ph/search?q=D-MID+Severity+grading&oq=DMID+Severity+grading&aqs=chrome..69i57.18194j0j7&sourceid=chrome&ie=UTF-8 (ac-cessed4Apr2017)11 End TB clinical and programmatic guide for patient management with new TB drugs, ver 3.3, 25/11/2016. Partners in Health, IRD, MSF, UNITAID 12 Clinical monitoring of AEs and management of adverse drug reactions, Multi-partner training package on active TB drug safetymonitoringandmanagement(aDSM),July2016



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Generaldefinitionsapplyforparametersnot included inthegivenseveritygradingforspecificsignsandsymptomsofthedifferentorgansystemsintheDMIDandCTCAEcitedabove.

Certain references for clinical management of AEs are available. The PMDT CompanionHandbook, 201413 contains comprehensive guidance on the management of various AEs commonly encountered during MDR-TB treatment. The relevant parts of the Handbook areenumeratedbelow.

Figure2. Severity grading of a laboratory test result (SGPT level)10, 11

Condition term Grade 1 Grade 2 Grade 3 Grade 4

Alanine Aminotrans-ferase(ALTorSGPT)Increased

1.1 - < 2.0 x ULN 2.0 - <3.0 x ULN 3.0 - 8.0 x ULN >8 x ULN

Table 1. General definitions for parameters of AEs not provided in theDMID and CTCAE table11

Grade 1 MILD Grade 2 MODERATE Grade 3 SEVEREGrade 4

LIFE-THREATENINGTransient or mild discomfort (<48hours)

No medical intervention/therapy required

Mild to moderate limitation in activity - some assis-tancemaybeneeded

No or minimal medical in-tervention/therapy required

Marked limitation in activity, some assistance usually required

Medical intervention/thera-pyrequired,hospitalizationpossible

Extreme limitation in activ-ity,significantassistancerequired

Significantmedicalinter-vention/therapy required, hospitalizationorhospicecareprobable

132014CompanionHandbooktotheWHOGuidelinesfortheprogrammaticmanagementofdrug-resistantTB.WHO-HQ.WHO/HTM/TB/@014.11http://apps.who.int/iris/bitstream/10665/130918/1/9789241548809_eng.pdf

Table 2. Parts of the WHO Companion Handbook providing clinical guidance

2014 WHO Companion Handbook

Topic

Chapter 11 Management of adverse effects and pharmacovigilance

Annex A4.1.5 “How-to”guideontheuseofBdqinMDR-TBtreatmentMonitoringandmanagingpatientsreceivingBdq

Annex A4.2.5 “How-to”guideontheuseofDlminMDR-TBtreatmentMonitoringandmanagingpatientsreceivingDlm

Annex 7 Managementofelectrolyteimbalance

Annex 8 Management strategy for hearing loss



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14 EndTB clinical and programmatic guide for the patient management with new TB drugs, version 3.3, 25/11/2016. Part-ners in Health, Medecins sans Frontieres, IRD, UNITAID

The EndTB clinical and programmatic guide for the patient management with new and repurposed TB drugs14 also provides management guidance for peripheral neuropathy, myelosuppression, prolongedQTinterval(examplebelow),opticneuritis,hepatitis,hearingloss,acutekidneyinjury,hypokalemia, hypomagnesemia, and hypothyroidism.

Figure 3. Severity grading and management of QT prolongation11, 13

Severity grade

Grade 1MILD

Grade 2MODERATE

Grade 3SEVERE

Grade 4LIFE-THREATENING

Prolongation ofQTcF

QTcF450-480ms QTcF481-500ms QTcF>501msonatleast2 separate ECGs

QTcF>501or>60mschangefrombaselineand Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia

Action Monitor closely; at least weekly ECG untilQTcFhasreturned tograde 1 or less

Monitor more closely; at least weekly ECG; check electrolytes and Replenish as needed

Stop the suspected causativedrug(s).Hospitalizeandrepleteelectrolytes asnecessary.

Stop the suspected causativedrug(s).Hospitalizeandrepleteelectrolytes as necessary.

3. Standardized data should be systematically collected and reported for any detectedSAE.ThesewilleventuallybeusedtocharacterizethetypesofSAEs,assessthesafetyof treatment, and inform future policy on the use of these medicines.

LEVELS OF aDSM MONITORINGThereare three levels of aDSMmonitoring thatmaybeused in programsdepending on thehumanresourcecapacity,namely:

1. Core package: requires monitoring and reporting of all SAEs*

2. Intermediate package: includes SAEs and AEs of special interest*

3. Advanced package:includesallAEsofclinicalsignificance*

*Seeabovefordefinition

The NTP in Myanmar will implement the core package of aDSM and, therefore, will monitor and report only SAEs.However,as resourcesbecomeavailableandas theNTPdecides,aDSMmaybeexpandedtoincludemonitoringofotherAEsthatareofclinicalsignificanceorofspecialinterest to the programme, as part of comprehensive aDSM.



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IMPLEMENTATION STEPS OF aDSMThere are 8 WHO recommended steps in the programmatic implementation of aDSM.4 Ideally, all8stepsareinplacebeforepatientsareenrolledintreatmentwithnewdrugsandregimensincluding the shorter treatment regimen and the XDR-TB regimens. However, this may not always befeasible.Steps4and5arethemostessential tobe inplacebeforeanypatientenrolmentoccurs.

1. Create a national coordinating mechanism for aDSM.

TheNationalCoreCommitteeforaDSM(NCCA)ofMyanmarwascreatedon6th May 2016 duringtheWHOaDSMmission. IthastheresponsibilityofoversightandcoordinationofaDSMactivitiesat thenational level. It iscomposedofmemberswithscientificandclinical expertise for MDR-TB care and for management and communication, such as fundingandadvocacy.Theywillbetrainedondrugsafetymonitoring,includingcausalityassessment.

Table 3. Key steps in implementing aDSM

1 Create a national coordinating mechanism for aDSM

2 Develop a plan for aDSM

3 Definemanagementandsupervisionrolesandresponsibilities

4 Create standard data collection materials

5 Train staff for collection of data

6 Defineschedulesandroutesfordatacollectingandreporting

7 Consolidate aDSM data electronically

8 Develop(oruseexisting)capacityforsignaldetectionandcausalityassessment



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Table 4. National Core Committee for aDSM (NCCA)

Agency Representative(s)

1. Drug Control Section, Food and Drug Administration(FDA)

Director

2. Clinical Professors* Professor & Head, Dept of Respiratory Medicine, University of Medi-cine 1, University of Medicine 2, University of Medicine Mandalay

3. NTP National Program Manager

4. TB Specialist Hospitals – Department of Medical Services

Medical Superintendents of Aung San TB Hospital and Patheingyi Hospital

Partners*:

5. MSF(Holland)

6. WHO

7. FHI360

Note: * The aDSM Workshop in March 2017 specified the clinical professors to include 2 from Yangon and 1 from Mandalay; FHI360 was added to the list of partners.

2. Develop a plan for aDSM.

The National aDSM Implementation Plan15 of Myanmar was drafted with the assistance of WHO following an assessment of the country situation and a wide consultation with all relevantstakeholders.IthasbeenendorsedbytheNTPandapprovedbytheNCCA.TheplanclearlydescribedwhatshouldbedoneineachofthestepsinaDSMimplementation.Financial support for the implementation of the plan is through the NTP /FDA or other stakeholders.

3. Define management and supervision roles and responsibilities.

The NCCA will exercise national oversight and coordination of aDSM activities through regularcoordinationmeetingsamongitsmembers(6monthlyandadhoc,whenneeded).A tentative pre-agreed schedule for meetings is recommended, e.g., the 3rd Wednesday of themonth,soastokeepthisinthecalendarofthemembers.TheNTPaDSMFocalPointwith support from CTB or any other partners will arrange the NCCA meetings including sendingofinvitationstomembersandprovidingminutesofthemeeting.

WithNTPbeingaleadmemberoftheNCCA,theNTP Program Manager will designate an NTP aDSM Focal Person to coordinate aDSM activities together with partners, and ensure that the key steps are in place prior to the start of patient enrolment. The FDA

15 Annex 3. National aDSM Implementation Plan of Assessment on Drug safety monitoring and management for the treat-ment of DR-TB using new and repurposed drugs Myanmar, 2-6 May 2016, WHO.



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Director will likewise designate an FDA aDSM Focal Person to work together with the NTP aDSM Focal Person in coordinating aDSM activities. The current NTP and FDA aDSMFocalPersonshavebeentrainedonPVduringtheAsia-PacificPVCourseinIndiain January 2017.Other opportunities for training should further strengthen the capacity of NCCAmembers.

The Clinical ProfessorswhoaremembersoftheNationalDR-TBExpertCommittee,andotherdesignatedmembers,willprovideclinicaladviceforAEsthatcannotbemanagedintheMDR-TBCentres,andwillberesponsibleforcausalityassessment,afterundergoingtrainingbyexpertsinthisfield.

Monitoring and supervision of the programmatic implementation of aDSM is an important task for the NCCA. The committee will oversee the monitoring of the two essential indicatorsoutoffouraDSMindicatorssuggestedbyWHO(Annex B).Thetwoessentialindicators,namelya)coverage(rateofenrolledpatientscoveredbyaDSM);andb)SAErate among patients treated andmonitored for aDSMwill be used tomonitor aDSMprogrammatic implementation given the current limited resources.

4. Create standard data collection materials

WHO,theClintonHealthAccessInitiative(CHAI),andotherpartnerswillprovidesupportin data collection and M & E.

TheformsrelatedtoaDSMareasfollows:

a. Modified NTP MDR-TB Treatment Card (DR-TB Form 01) (Annex C)

The six-page NTPMDR-TB Treatment Card, based on theWHO recommendedtemplate, is the standard card used for all DR-TB patients enrolled in treatment. For aDSMpurposes,somerevisionshavebeenmadeontheoriginalTreatmentCard,whichareasfollows:

• Page1: Addedabbreviationsfornewandrepurposeddrugs;modifiedtableforDST

• Page2: Provided 4 columns for liver function tests (LFT) [bilirubin, alkalinephosphatase, aspartate aminotransferase (AST) and alanineaminotransferase(ALT)]

• Page3: Providedseparate tables; thefirst table (ascontinuationof the tableonpage2),3columnsforelectrolytes,addedcolumnsforalbuminandlipase,andanewtableforECG/QTc,andaudiometryforfollow-up.

• Page4: addedonecolumnforfollow-upmonthandyear(mm-yy).



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• Page5: Updatedthecolumnheadingwithnewandrepurposeddrugs;anewtabletorecordtheissues,discussionanddecisionbyExpertPanel.

• Page6: Included a comment box, outcome categories with new categories(moved to either conventional regimen or individualized regimen);added a table to record patients’ information during 2 years aftercompletion of treatment.

b. Form for Reporting of Serious Adverse Event

This form is a simplified version of theMSFSAEFormdeveloped byWHOwithinputsfromtheNCCAmembers,andisnowbeingusedbythefocalMSF-HdoctorfortheEndTBProjectinAungSanTBSpecialistsHospital(ASTSH).ThisformistobefilledoutbytheMDR-TBHospitalphysicianeverytimeanSAEisdetectedduringthecourseoftreatment.ThisformwillbeusedtoalerttheNTPandtheNCCA,andwill also be sent to theRegion/StateDR-TBCommittee for their information andclinical inputs. TheReporter/ the attending (on duty) clinician from theHospital /MDR-TBcentrewillenterallavailableinformationatthetimeofreporting,andwillsubmittheformwithin24hoursfromSAEdetection.AllothermissinginformationinthisformwillbefilledoutandtransmittedtotheNCCAwithin72hours.

Fornow,alldatacollectionformsarepaper-based,andshouldbekepton-site,andfiledforelectronicdataentryinthefuture(whenanaDSMelectronicdatabaseisdeveloped).

5. Train staff for collection of data

Thetrainingwillcover,mostimportantly,datacollection(whichhappensbothinthehospitalwhenthepatientisstillconfined,andintheout-patientsettingafterdischarge),reportingflow, as well as the basics of aDSM, clinical monitoring and management, causalityassessment, and signal detection. Training participants will include those involved in direct patient care, in providing clinical advice, performing causality assessment and signaldetection,andinsupervisionandmonitoringofbothhospitalizedandambulatoryphases of treatment.

6. Define schedules and routes for data collection and reporting

UnderthecoreaDSMpackage,reportingismainlyforSAEsdetectedandidentifiedwhileontreatmenteitherintheMDR-TBhospitalorinthecommunityduringtheambulatoryphase.

A. ThehospitalorMDR-TBCentresubmitstheSAEReportingForm(Annex D) within 24 hours of SAE detectionbyemailtothefollowing:



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a. Region/StateDR-TBCommittee:This is to inform theCommitteeof theSAE,andtoseektechnicalassistance,beitforprogrammaticorclinicalmanagementpurposes.

b. NCCA:TheNTPProgramManagerneedstoknowtheSAE,andwillsupervisetheNTPaDSMFocalPoint(whoiscopyfurnishedwiththeSAEForm)inquicklyreviewing the entries of the SAE Form for completion, consistency and accuracy.

B. TheNTPaDSMFocalPointverifieswiththehospitalreporteranyunclearinformation.Within 72 hours,all information in theSAEFormmusthavebeencompletedandreceivedbytheNTPaDSMFocalPoint.

C. TheNPTaDSMFocalPointwill forwardthecompletedSAEFormbyemail tothefollowing:

a. Clinical Professors who aremembers of the NCCA and the National DR-TBExpertCommitteeandtotheothermembersoftheNCCAfortheirinformation,their review and clinical inputs, if and when necessary.

b. AllmembersofNCCA

c. The FDA Director with a copy furnished to the FDA aDSM Focal Point. The Director and/or theFDAFocalPointmayask questions or clarification to theNTPaDSMFocalpointabouttheSAE.

d. The Department of Medical Services

D. The NTP aDSM Focal Point will then schedule and convene a meeting among the Clinical Professors to perform causality assessment on the SAE within 15 days from SAE detection.

E. TheNTPaDSMFocalPointentersthedatatotheNationalaDSMDatabasewithin72hoursassoonasalldetailsareverifiedfromthehospitalorMDR-TBCenter.

F. TheNTPaDSMFocalPoint transmits the data to theGlobal aDSMDatabase [email protected].

G. TheGlobalaDSM teamwillmakeverifications to theNTPaDSMFocalPoint, asneed,andwillenterthedatatotheGlobalDatabase.Feedbackwillbegiventothecountry, after a certain agreed period of time.

H. Two-way communication is maintained between the FDA and the Department ofMedicalServices,andbetweentheNTPandDepartmentofMedicalServices.



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Figure 4. Reporting Flow for SAE, Myanmar



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National Core Committee for aDSM (NCCA)

Global aDSM database• ReviewsentriessentbytheNTPandverifiesunclearinformation

• EntersdataintotheglobalaDSMdatabase

FDA Director and FDA aDSM Focal point

• Reviews the SAE Form and

discusses concerns with

NTP aDSM Focal Point

Department ofMedical Services

Clinical Professors/Expert Committee,

MSF & others• Provide clinical input, as

needed

• Perform Causality

Assessment

Region/State DR-TB Committee• Provides immediate programmatic

& clinical input, as needed

Hospital/MDR-TB Center(Districtlevelandabove)•IdentifiesSAEandfillsouttheSAEForm

NTP ProgramManager and aDSM

Focal Point• Reviews the SAE Form for

completion, consistency

andaccuracyandverifies

with hospital reporter

• Entersdatatothedatabase

• Transmitsdatatoglobal

aDSMdatabase

All NCCA Members• Provide oversight to aDSM activities

• Meet regularly to discuss aDSM concerns

7. Consolidate data electronically

TheClintonHealthAccessInitiative(CHAI)forDR-TBpatients isassistingtheNTPincreatinganationalelectronicdatabaseforDR-TBpatients.TheelementsoftheaDSMdatabaseare tobe incorporated into thisDR-TBDatabase, rather thanbedevelopedindependentlyasaseparateone.ThecreationoftheelectronicaDSMdatabaseshouldnotduplicatetheworkbeingdonefortheexistingdatabases,andshouldbeinteroperablewiththeexistingdatamanagementsystem.TheelectronicaDSMdatabasewillensurestandardizationandsafekeepingofdata.

Thepaper-basedSAEForm received by theNTP should be entered regularly to theNational Database by theNTP Focal Point in a format linkedwith theGlobal aDSMDatabasesharingthesamekeyvariablestofacilitatedatatransmissionandcontributionofthedatafromthecountrytotheGlobalDatabase.

AlistofkeyvariablestobecollectedfortheWHOcentralaDSMdatabaseandadatadictionarymay be found at http://www.who.int/tdr/research/tb_hiv/adsm/en/. It collectsanonymizedindividualpatientdataforallSAEsfromPMDT.WHOandCTBarehelpingfacilitatethelinkbetweenthegroupworkingontheNationalDatabasewiththeGlobalDatabase.

Management of data in electronic form is necessary and will facilitate sharing of data as wellasgenerationofindicatorsandanalysisthatwillbeusefultoassessthecoverageofaDSMactivitiesandtosummarizetheoverallAEexperienceofmonitoredpatients.

8. Develop capacity for signal detection and causality assessment

TheultimatepurposeofsystematicdatacollectionwithinaDSMis toenablecausalityassessment for the SAEs, determine the frequency and rates of occurrence and detect signals.ClinicalexpertsinM/XDR-TBmanagementmayattempttoestablishrelationshipsbetween drugs andADRs; however, performing causality assessment is a separateprocess requiring expertise. The physicians involved in M/XDR care will undergo training on causality assessmentwhichwill enable them to conduct causality assessment foreverySAEreported.Signaldetectionwillbeafunctionthatwillberequestedfromexternalexperts.

ROLES AND RESPONSIBILITIESThe roles and responsibilities in aDSM focus on key stakeholders involved in the clinicalmanagementandpublichealthmanagement forDR-TBpatientsat thenational, regionalandhospitallevels.ThesearediscussedinStep#2aboveandsummarizedinthenext2tables.



20

aDSM Component Lead responsibility

Formation of national aDSM coordination mechanism NTP, FDA, Expert Committee

Development of the aDSM Implementation Plan NTP with support from WHO

Tools for data collection NTP with support from WHO

Development of aDSM Manual NTP with support from FHI360

Training plan for all staff involved in aDSM NTP with support from FHI360

Collection of data Hospital sites/ MDR-TB centres

Communication, coordination and follow up of all data collected from the sites NCCA(NTPaDSMFocalPoint)

Data review NCCA(NTPaDSMFocalPoint)

TransferofcleanedandvalidateddatatoGlobalDatabases NTP aDSM Focal Point

Causality assessment NCCA(ClinicalProfessors)

Analysedataandprovidefeedbacktohealthcentresandclinicians NCCA through causality assessment, and NTP

Table5. Responsibilities for aDSM implementation

ThetablebelowsummarizesthestepsandtimelinesforSAEreportinginMyanmar

Table 6. Summary of steps and timelines for SAE reporting, Myanmar

STEP Event description Action taken Responsible party Forms sent to Time frame

STEP 1 SAE event detected

SAE Form filledoutandsubmitted

Hospital(treating)physician

NTP aDSM Focal Point [email protected](to send to NTP Program Manager)

Within 24 hours or 1 working day of SAE detection

STEP 2 SAE Report Form received at the national level

SAE Form completed with all details, upon verificationwiththe hospital/MDR-TB Centre reporter; meeting for CA scheduled


Clinical Professors and all membersoftheNCCAincludingFDA, and to the Department of Medical Services

Within 72 hours of SAE detec-tion for initial reporting, then follow-up

STEP 3 SAE entry to National Database

All entries of SAE Form en-tered to National aDSMDatabase


NationalaDSMDatabase Within 72 hours of SAE detection

STEP 4 Clinical Professors’meeting andcausality consensus

Meeting conducted for CA, and Causality consensus made

NCCA Clinical Professors and other designated partners

NTP Within 15 days of SAE detection or during month-ly meeting

STEP 5 CA reportcompleted

FeedbacktotheNTP and the hospital


[email protected]

Within 30 days of SAE



21

CAUSALITY ASSESSMENTCausality assessment (CA) is an integral part of clinical management. In TB, evaluating thelikelihoodthataTBmedicinewasthecausativeagentofanobservedadversereactionformspart of clinical evaluation. While the details of the systematic method of conducting CA may not befamiliartothepractitioner,theoverallapproachisnottoodifferentfromtheclinicalpracticefollowed when evaluating any patient on treatment.16

CAinvolvesmakinganattributionordescribingtherelationshipbetweentheAEandanexposurebyaphysicianoranyotherhealthcareprofessionalwiththerightexpertisewhichformspartofclinicalmonitoringandmanagement.Thisdeterminationmustberecordedbothinthepatient’smedicalrecordaswellasinacasereportform.ForaDSM,CAshouldbemadeprimarilyatthecountry levelandbyconsulting the relevantdatasourcesclose towhere theeventoccurred.AttributingarelationshiprequiresasystematicprocessandisoneofthemainreasonswhydataarecollectedinaDSM.CAoncedoneattributesalevelofcertaintybetweentheeventandtheexposure, ranging from certain to unrelated.

CAisconductedbytheClinicalprofessorsoftheNCCA,whoalsocomprisetheNationalDR-TBExpertCommittee,withtheparticipationofotherdesignatedmembers.CAshouldbeconductedusing a systematic tool provided later in this section, involving inputs from the panel of experts beyondthetreatingphysician.ThestepsindoingCAareasfollows:

- The hospital site provides all details relevant to the SAE to the national level (within 24 hourstotheNTPandFDAaDSMfocalpoints)

- The hospital site will forward all other details to the NTP aDSM Focal Point (within 72 hoursfromSAEdetection)intheCaseSummarysectionoftheSAEForm,includingthefollowingkeydataelements:

a) medicalhistory(includingconcomitantdisease),

b) otherriskfactors(socialfactors,alcoholuse,substanceabuse,etc.),

c) detailsofdrugstaken:names,doses,routes,

d) startandstopdatesandindicationsforuse,

e) descriptionofadverseevent,includingclinicaldescription,baseline,monthlyandadhoclaboratoryresults,anddateofonset/endand

f) evolutionofevent,severity,seriousness,andoutcome.

- The NTP aDSM Focal Point forwards the completed SAE Form to the Clinical Professors andallwhoareinvolvedinCA,andotherNCCAmembers

16aDSMtrainingpackage(trainingslidespreparedbyKNCVTuberculosisFoundation,ManagementSciencesforHealth(SIAPS),MédecinssansFrontières,WorldHealthOrganization/GlobalTBProgrammeSpecialProgrammeforResearchandTraininginTropicalDiseases(TDR)atWHOHeadquarters,July2016http://www.who.int/tdr/research/tb_hiv/adsm/training_adsm/en/((accessedon2Feb2017)



22

- The NTP aDSM Focal Point schedules a CA meeting within 15 days from SAE detection.

- Priortothemeeting,eachmemberoftheCAteamwillindividuallyreviewtheSAEFormguidedbytheWHO-UppsalaMonitoringCentre(UMC)CausalityAlgorithmortheNaranjoADRprobabilityscale.

- DuringtheCAmeeting, the individualCAswillbeconsidereduntilaNCCA Causality Consensus is arrived.

The goal for CA is to decrease inter-individual differences in the assessment of a given event, classifythelikelihoodofarelationshipbetweenthedrugandtheevent,andimprovescientificevaluation.CAcannotprovetheconnectionbetweenthedrugandtheAE,norcanitquantifythecontributionofadrugtothedevelopmentoftheAE.AEsarerarelyspecifictothedrug,andoftencasereportsinvolvesuspectedadversedrugreactionsthatmayneverbeproven.

SomequestionstoasktoguidetheprocessofCAincludethefollowing:

1. Isthereaconvincingrelationshipbetweenthemedicineandtheevent?

2. Didthemedicineactuallycausetheevent,orwasitcausedbyotherTBmedicines,ormedicinesforotherdiseases,orbydrug-druginteraction?

3. IstheAEtheeffectoftheTBdiseaseitselforofaco-morbidity?

SomeofthecriteriatoguidetheprocessofCAincludethefourbelow:

1. Theassociationintimebetweenthedrugadministrationandtheevent.

2. Thepharmacologyandpharmacokinetics:includingpreviousknowledgeofsideeffects,features of the event, site of reaction, dose-response effects (dose reduction; effect of re-exposure);aswellasknownactionsofthedrug.

3. Medical plausibility: including characteristic signs and symptoms, laboratory tests,pathologicalfindings

4. Likelihood or exclusion of other causes

There are instruments for the systematic performance of CA, namely the WHO-Uppsala Monitoring Centre (UMC) algorithm (Table 7) and the Naranjo ADR probability scale, but country preference is the UMC algorithm.

The WHO-UMC algorithmhasbeendevelopedasapracticaltoolfortheassessmentofcasereports,andisbasicallyacombinedassessmenttakingintoaccounttheclinical-pharmacologicalaspectsofthecasehistoryandthequalityofthedocumentationoftheobservation.SincePVisparticularly concerned with the detection of unknown and unexpected adverse reactions, other criteria such as previous knowledge and statistical chance play a less prominent role in the system. The various causality categories are listed in Table7.17

17TheuseoftheWHO-UMCsystemforstandardisedcasecausalityassessment.TheUppsalaMonitoringCentrehttps://www.who-umc.org/media/2768/standardised-case-causality-assessment.pdf(accessed20May2017)



23

Tabl

e 7.

The

WHO

-UM

C Cl

assi

ficati

on S

yste

m fo

r cau

salit

y as

sess

men

t

Cau

salit

y te

rmD

efini

tion

Ass

essm

ent c

riter

ia*

Cer

tain

Cle

arly

cau

sed

by th

e ex

posu

reTh

ere

is c

lear

evi

denc

e to

sug

gest

a c

ausa

l rel

atio

nshi

p an

d ot

her p

ossi

ble

cont

ribut

ing

fact

ors

can

be ru

led

out.

• • • • •

Eventorlaboratorytestabnormality,w

ithp

laus

ible

tim

e re

latio

nshi

p to

dru

g in

take

Can

notbeexplainedbydiseaseorotherdrugs

Res

pons

e to

with

draw

al p

laus

ible

(pha

rmac

olog

ical

ly, p

atho

logi

cally

)Eventdefinitivepharmacologicallyorphenomenologically(i.e.,anobjective

andspecificmedicaldisorderorarecognizedpharmacologicalphenomenon)

Re-

chal

leng

e sa

tisfa

ctor

y, if

nec

essa

ry

Probable/Likely

Like

ly to

be

rela

ted

to th

e ex

posu

re

Ther

e is

evi

denc

e to

sug

gest

a li

kely

cau

sal r

elat

ions

hip

and

the

influ

ence

of o

ther

fact

ors

is u

nlik

ely.

• • • •


ith re

ason

able

tim

e re

latio

nshi

p to

dr

ug in

take

Unl

ikel

ytobeattributedtodiseaseorotherdrugs

Res

pons

e to

with

draw

al c

linic

ally

reas

onab

leR

e-ch

alle

nge

not r

equi

red

Possible

May

be

rela

ted

to th

e ex

posu

re

Ther

e is

som

e ev

iden

ce to

sug

gest

a c

ausa

l rel

atio

nshi

p (e

.g.

beca

use

the

even

t occ

urs

with

in a

reas

onab

le ti

me

afte

r adm

in-

istra

tion

of th

e tri

al m

edic

atio

n).

How

ever

, the

influ

ence

of o

ther

fa

ctor

s m

ay h

ave

cont

ribut

ed to

the

even

t (e.

g. th

e pa

tient

’s

clin

ical

con

ditio

n, o

ther

con

com

itant

trea

tmen

ts).

• • •


ithre

ason

able

tim

e re

latio

nshi

p to

dr

ug in

take

Couldalsobeexplainedbydiseaseorotherdrugs

Informationondrugwithdraw

almaybelackingorunclear

Unl

ikel

yD

oubt

fully

rela

ted

to th

e ex

posu

re

Ther

e is

littl

e ev

iden

ce to

sug

gest

ther

e is

a c

ausa

l rel

atio

nshi

p (e

.g. t

he e

vent

did

not

occ

ur w

ithin

a re

ason

able

tim

e af

ter a

d-m

inis

tratio

n of

the

stud

y re

gim

en).

Ther

e is

ano

ther

reas

onab

le

expl

anat

ion

for t

he e

vent

(e.g

. the

pat

ient

’s c

linic

al c

ondi

tion,

ot

her c

onco

mita

nt tr

eatm

ent).

• •


ith a

tim

e to

dru

g in

take

that

mak

es

a re

latio

nshi

p im

prob

able(butnotim

possible)

Dis

ease

or o

ther

dru

gs p

rovi

de p

laus

ible

exp

lana

tions

Con

ditio

nal o

r Unclassified

Ther

e is

insu

ffici

ent i

nfor

mat

ionabouttheADRstoallowfor

an a

sses

smen

t of c

ausa

lity.

• • •

Eventorlaboratorytestabnormality

Mor

e da

ta fo

r pro

per a

sses

smen

t nee

ded,

or

Add

ition

al d

ata

unde

r exa

min

atio

n

Unassessable

orUnclassifiable

ThereisinsufficientinformationabouttheADRstoallowforan

asse

ssm

ent o

f cau

salit

y an

d N

O M

OR

E is

exp

ecte

d.• • •

Rep

ort s

ugge

stin

g an

adv

erse

reac

tion

Cannotbejudgedbecauseinformationisinsufficientorcontradictory

Datacannotbesupplementedorverified

*Allpointsshouldbereasonablycom

pliedwith



24

SIGNAL DETECTIONAsignal isa reported informationonapossiblecausal relationshipbetweenanAEandaTBmedicine. Either the relationship was previously unknown or incompletely documented (e.g. a newaspectofaknownassociation)

Signal detection is an important process to improve knowledge on the new TB medicines and complete the safety profile of a new drug.WhenmonitoringAEs, it is important to lookbeyondalreadyknownadversereactionsandbiologicalpathways.Previouslyunknownorrareassociationsmayoccur,especiallyfornewandrepurposeddrugs.ReportsofAEstotheglobalaDSMDatabaseisexpectedtoimprovethelikelihoodofpickingupmoresignals.

Asignalisworthinvestigatingwhenthedataqualityisreliable,severalreportsshowacredibleand strong relationship betweenevent and drug, and the event is of sufficient importance orinterest (either to require regulatory action, to require advice to prescribers, or for scientific /clinicalpurposes).

Thefeaturesofasignalincludethefollowing:a)usually>1eventwithasimilar,strongrelationshiptoamedicine(“certain”or“probable“).Eventscodedas“possible”canbeusedassupportingevidence;b)aclusterofunexpecteddeathscodedas“possible”formsanexceptiontothegeneralruleandwillneedtobetakenseriously;c)occasionally,asingleevent(“certain”or“probable”)-notableforitsseverity,seriousnessordistinctiveness.

Signaldetectioncanaddknowledgetothedrugsafetyprofileofanagentwhichdescribesthebenefits,risksandtoxicityofagivenTBdrugorregimen,specifyinganyknownorlikelysafetyconcerns, contraindications, cautions, preventive measures and other features that the user shouldbeawareoftoprotectthehealthofaTBpatient.



25

ANNEXES

AnnexA Clinical, bacteriological and laboratorymonitoring duringMDR-TB treatmentRR-/MDR-TB patients

Annex B Programmatic indicators of aDSM

AnnexC MDR-TBTreatmentCard(DR-TBForm01)modifications

AnnexD NTPFormforReportingSeriousAdverseEvent(SAE)

Annex E Severity Grading Scales and suggested action of selected common AEs



26

ANN

EX A

–M

onito

ring

sche

dule

(Clin

ical

, bac

terio

logi

cal a

nd la

bora

tory

) dur

ing

M-/

XDR-

TB tr

eatm

ent o

n ne

w a

nd

repu

rpos

ed d

rugs

and

the

shor

ter r

egim

en18

Eval

uatio

n/Te

stB

asel

ine

Inte

nsiv

e ph

ase

(IP)

Con

tinua

tion

phas

e (C

P)Fo

llow

-up

afte

r tre

atm

ent

com

plet

ion

for 2

yea

rs

C L I N I C A L

Clin

ical

eva

luat

ion

(sym

ptom

s,

sideeffects&PE)

√DailyateveryDOTencounter;monthlybyMDRphysician

Mon

thly

M

onth

s 3,

6 &

12,

and

as

need

ed

Wei

ght

√M

onth

ly

Mon

thly

M

onth

s 6

& 1

2

Aud

iom

etry

√Monthlywhileoninjectable

Monthlywhileoninjectable;3&6

monthpost-injectable

No

need

Visual(S

nellen’sandIshihara

chart)

If on

long

-term

E a

nd/

orLzd

Whe

n in

dica

ted

Whe

n in

dica

ted

No

need

12-le

ad E

CG

√

Wee

k 2,

4, th

en m

onth

ly, a

nd a

d ho

c1M

onth

ly, a

nd a

d ho

c if

on B

dq o

r Dlm,MfxandCfz

1

No

need

Note:SpecialattentioninpatientsreceivingmorethanoneQTprolongingdrugs(B

dq,D

lm,M

fx,

Lfx,Cfz)orw

ithlowalbum

in(<

3,4g/dl)

Che

st X

-ray

√

Eve

ry 6

mon

th, a

nd a

d ho

cE

very

6 m

onth

, and

ad

hoc

Mon

ths

6 &

12,

and

as

clin

ical

ly in

dica

ted

B A C T E R I O L O G I C

Sm

ear

√M

onth

ly

Mon

ths

6 &

12

Cul

ture

√M

onth

ly

Mon

ths

6 &

12

Xpe

rt® M

TB/R

if√

If cl

inic

ally

indi

cate

d

SL-

LPA

√Incaseof+cultureafterconversion,andbaselineshow

ednoresistancetoFQandSLI

Whe

n cu

lture

+ a

nd R

R-T

B

byXpertorMDR-TBby

DS

T

DS

T (H

, R, M

fx, L

fx, K

m, A

m,

Cm),ifculturepositive

√Incaseof+culturebymonth3oftreatment,orreversion

In c

ase

of re

vers

ion

Whe

n cu

lture

+

18 G

ener

ic p

rogr

amm

atic

and

clin

ical

gui

de fo

r th

e in

trodu

ctio

n of

new

dru

gs a

nd s

horte

r re

gim

ens

for

the

treat

men

t of

multi-/extensivelydrug-resistanttuberculosis,ver0.19,20Feb2017(U

SAID,K

NCV,ChallengeTB

)



27

Eval

uatio

n/Te

stB

asel

ine

Inte

nsiv

e ph

ase

(IP)

Con

tinua

tion

phas

e (C

P)Fo

llow

-up

afte

r tre

atm

ent

com

plet

ion

for 2

yea

rs

L A B O R A T O R Y

Hem

oglobin,W

hitebloodcells

IfonLzd

Ifindicated.IfonLzd,weeklyonmonth1,thenmonthlyorifindicated.IfonZidovudine,m

onthly

initi

ally

then

if in

dica

ted

If in

dica

ted

Pla

tele

tsIfindicated,especiallyifonLzd

Cre

atin

ine5


Every1-3weeksinHIV-infected,diabeticsandotherhigh-riskpatients

If in

dica

ted

Pot

assi

um5


RepeatifanyECGabnormalitiesdevelopwhileonBdqorD

lmEvery1-3weeksinHIV-infected,diabeticsandotherhigh-riskpatients

If in

dica

ted

Ser

um m

agne

sium

and

ca

lciu

m

If hy

poka

lem

ia is

pre

sent

If on

Bdq

or D

lmIf

hypo

kala

emia

is p

rese

nt.

MonthlyifonBdqorD

lm.R

epeatifanyECGabnormalitiesdevelop

Whe

n in

dica

ted

Liverenzym

es(AST/SGPT,ALT/S

GOT)

2√

Mon

thly

and

as

clin

ical

ly in

dica

ted

for D

MA

t lea

st q

uarte

rly a

nd a

s cl

inic

ally

in

dica

ted

for D

M

If cl

inic

ally

indi

cate

d

Glu

cose

√

MonthlyifelevatedatbaselineandifreceivingGfx

If in

dica

ted

Thyr

oid-

stim

ulat

ing

horm

one

(TSH)3

√Atm

onths3and6,ifwithEto(w

ithorw

ithoutPAS),thenifclinicallyindicated

Serum

album

in

√E

very

2 m

onth

s if

on D

lmW

hen

indi

cate

dW

hen

indi

cate

d

Ser

um L

ipas

e/am

ylas

eSpecialattentiontopatientsreceivingBdq,Lzd,D

4T,ddIorddc,andbasedonriskfactors

Lact

ic a

cid

Whe

n in

dica

ted

Forw

orkupoflacticacidosisinpatientsonLzdandARTorLzdandMetformin

HbsAgandanti-HCV

If ris

k fa

ctor

s ar

e pr

esen

t

HIV

√R

epea

t, if

indi

cate

dR

epea

t, if

indi

cate

d

CD4count(ifHIV+)

√A

ccor

ding

to N

atio

nal A

IDS

Pro

gram

gui

delin

es

Pre

gnan

cy te

st

(forchildbearingwom

en)

√R

epea

t, if

indi

cate

dR

epea

t, if

indi

cate

d

1 ECG-adhocforsuspectedrhythm

andconductiondisturbances

2 LFTs-Periodicmonitoring(every1-3months)forp

atientsonprolongedZ,andpatientsatriskof,orwithsym

ptom

sof

hepatitis.M

onthlyifHIV-positive,a

ndifonBdq.M

onitorevery1-2weeksfo

rthefirstm

onth,thenevery1-4weeksfo

rpa

tient

s w

ith v

iral h

epat

itis.

Dis

cont

inue

sus

pect

ed d

rug

if LF

Ts a

re >

3X th

e up

per l

imit

of n

orm

al L

FTs,

and

2X

the

uppe

r lim

itofbilirubin.



28

ANN

EX B

– P

rogr

amm

atic

indi

cato

rs fo

r aDS

M (W

HO G

uide

lines

, 201

4)

CLA

SSIM

POR

-TA

NC

E

IND

ICAT

OR

N

UM

BER

AN

D

NA

ME

CA

LCU

LATI

ON

STR

ATIF

ICAT

ION

EXPR

ESSE

D

AS

DAT

A SO

UR

CES

LEVE

LPE

RIO

D O

F A

SSES

SMEN

TN

OTE

S

Cov

erag

e(process)

Ess

entia

l1)TargetR

R/

MD

R-T

B p

atie

nts

incl

uded

in c

ohor

t ev

ent m

onito

ring

Num

berator:Num

ber

of T

B c

ases

sta

rted

on ta

rget

trea

tmen

t in

clud

ed in

aD

SM

du

ring

the

perio

d of

as

sess

men

t.Denom

inator:N

umber

of T

B c

ases

sta

rted

on ta

rget

trea

tmen

t du

ring

the

perio

d of

as

sess

men

t and

who

wereeligiblefora

aDS

M.

Non

eAbsolute

numbers,

prop

ortio

n

Num

berator:

aDS

M re

gist

er.

Denom

inator:

Sec

ond-

line

TB tr

eatm

ent

regi

ster

.

National:NTP

an

d na

tiona

l ph

arm

a co

vigi

lanc

e centre(N

PV)

3 m

onth

sTobecomputed

durin

ng th

e pe

riod

of

recr

uitm

ent

butnotinthe

post

-trea

tmen

t observation

phas

e

Com

plet

enes

s (process)

Opt

iona

l2)Timeto

stop

ping

targ

et

drug

The

diffe

rent

in d

ays

betweenthedateof

star

t of t

reat

men

t with

a

targ

et d

rug

and

the

date

of t

he s

topp

ing

the

targ

et d

rug.

The

ca

lcul

atio

n is

don

e fo

r eachmem

berofthe

coho

rt.

Rea

son

for

stop

ping

Num

ber

of p

atie

nts

incl

uded

in th

e ca

lcul

atio

n;

med

ian

inte

rval

and

in

terq

uarti

le

rang

e in

day

s

aDS

M re

gist

erNational:NTP

&

NP

V12

mon

ths

Stratifyby

reas

on fo

r st

oppi

ng (e

.g.

succ

ess,

die

d,

treat

men

t fai

led,

lo

ss to

follo

w

up, e

xclu

sion

cr

iterio

n de

velo

ping

af

ter s

tart

of

treat

men

t suc

h aspregnancy).

Ser

ious

ad

vers

e ev

ents

Ess

entia

l (but

Stratifica-

tion

optitonal)

3)RR-/M

DR-TB

patie

nts

incl

uded

in

aD

SM

with

any

se

rious

adv

erse

ev

ent

Num

berator:Num

ber

of T

B c

ases

incl

uded

in

aD

SM

dur

ing

the

perio

d of

ass

essm

ent

with

one

or m

ore

serio

us a

dver

se

even

ts.

Denom

inator:N

umber

of T

B c

ases

incl

uded

in

aD

SM

dur

ing

the

perio

d of

ass

essm

ent.

By

orga

n gr

oup;

byoutcome

Absolute

numbers,

prop

ortio

n

Num

berator:

aDS

M re

gist

er.

Denom

inator:

aDS

M re

gist

er.

NTP

& N

PV

3 m

onth

sTobecomputed

durin

g th

e pe

riod

of p

atie

nt

recr

uitm

ent

and

durin

g th

e po

st tr

eatm

ent

observation

phas

e. In

dica

te

outc

ome

(dea

ths,

ho

spita

lisat

ions

, disability)



29

CLA

SSIM

POR

-TA

NC

E

IND

ICAT

OR

N

UM

BER

AN

D

NA

ME

CA

LCU

LATI

ON

STR

ATIF

ICAT

ION

EXPR

ESSE

D

AS

DAT

A SO

UR

CES

LEVE

LPE

RIO

D O

F A

SSES

SMEN

TN

OTE

S

Adv

erse

re

actio

ns

asso

ciat

ed

with

targ

et

treat

men

t

Opt

iona

l5)Timeto

deve

lopm

ent o

f A

DR

s as

soci

ated

w

ith th

e ta

rget

tre

atm

ent

The

diffe

renc

e in

day

s betweenthedate

of s

tart

of th

e ta

rget

tre

atm

ent a

nd th

e da

te

ofthefirstdetected

onse

t of t

he A

DR

attributedtoit

By

orga

n gr

oup

Num

ber

of A

DR

s in

clud

ed in

the

calc

ulat

ion;

m

edia

n in

terv

al a

nd

inte

rqua

rtile

ra

nge

in d

ays

aDS

M re

gist

eraD

SM

cen

tre6

mon

ths

Tobecomputed

durin

g th

e pe

riod

of p

atie

nt

recr

uitm

ent

and

durin

g th

e po

st-tr

eatm

ent

observation

phas

e. T

he

calc

ulat

ion

is d

one

for

each

reac

tion

attributedtothe

targ

et tr

eatm

ent;

the

sam

e pa

tient

may

ha

ve s

ever

al

AD

Rs

com

pute

d (th

e un

it of

m

easu

rem

ent

is th

e A

DR

and

notthepatients);

if a

parti

cula

r A

DR

recu

rs

in th

e sa

me

patie

nt d

urin

g th

e aD

SM

it is

no

t cal

cula

ted

agai

n. O

nly

to

bereported

afte

r cau

salit

y as

sess

men

t (e

.g.

dech

alle

nge,

rechallenge)

sugg

ests

the

targ

et tr

eatm

ent

as th

e ca

usat

ive

agen

t (ce

rtain

, probableor

possible).



30

ANN

EX C

-MDR

-TBT

reat

men

t Car

d (D

R-TB

For

m 0

1) in

clud

ing

new

dru

gs, a

nd n

ew re

gim

ens



31

Nam

e: __

____

____

____

____

____

____

____

____

____

____

____

____

____

____

__

Sex:

M

F

Age:

____

___ D

ate

of b

irth

: ___

___/

____

___/

____

____

Initi

al w

eigh

t (kg

): __

____

____

Hei

ght (

cm):

____

____

_

Site

: P

ulm

onar

y

Ext

ra-p

ulm

onar

y

Bot

h

If ex

tra-

pulm

onar

y, sp

ecifi

c site

: ___

____

____

____

____

____

____

____

Addr

ess:

____

____

____

____

____

____

____

____

____

____

____

____

____

____

__

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

____

phon

e: __

____

____

____

____

____

____

____

____

____

____

____

____

____

____

__

MDR

-TB

Initi

atio

n Ce

nter

: ___

____

____

____

____

____

____

____

____

___

DC S

ite/C

ente

r: __

____

____

____

____

____

____

____

____

____

____

____

____

Nam

e of

DOT

Pro

vide

r: __

____

____

____

____

____

____

____

____

____

___

DOT

Supe

rvis

or: _

____

____

____

____

____

____

____

____

____

____

____

____

Date

of X

-per

t Res

ult :

____

____

____

____

____

____

____

____

____

____

___

No

Regi

stra

tion

gro

up1

New

2N

on-c

onve

rter

IR

R

R3

Trea

tmen

t afte

r los

s to

follo

w u

p

IR

R

R4

Trea

tmen

t afte

r fai

lure

of t

reat

men

t

IR

R

R5

Rela

pse

IR

R

R6

Trea

tmen

t afte

r MDR

-TB

trea

tmen

t6.

1 St

anda

rd R

egim

en

LFU

Fai

lure

R

elap

se6.

2 Ot

her R

egim

en

LFU

Fai

lure

R

elap

se7

Othe

rs (a

. Unk

now

n re

gim

en/o

utco

me

of p

revi

ousl

y tr

eate

d TB

b

. pat

ient

who

doe

s not

fit i

n re

gist

ratio

n gr

oup

1-6)

MD

R-TB

Tre

atm

ent C

ard

(DR-

TB F

orm

01)

Prev

ious

tube

rcul

osis

trea

tmen

t epi

sode

s

Prev

ious

Tow

nshi

p TB

N

o./t

owns

hip

Star

t dat

e (i

f un

know

n, p

ut

year

)

Regi

men

(in

drug

abb

re

-via

tion

s)

Out

com

e

Used

seco

nd-li

ne d

rugs

pre

viou

sly?

Y

es

No

If ye

s, sp

ecify

: ___

____

____

____

____

____

____

____

____

____

____

____

____

_

Dru

g ab

brev

iatio

nsFi

rst-

line

drug

sSe

cond

-line

dru

gs

H=

Ison

iazi

dR=

Rifa

mpi

cin

E= E

tham

buto

lZ=

Pyr

azin

amid

eS=

Str

epto

myc

in(T

h= T

hioa

ceta

zone

)

Am=

Amik

acin

Cm=

Capr

eom

ycin

Ipm

= Im

ipen

emM

pm =

Mer

open

emLf

x= L

evof

loxa

cin

Mfx

= M

oxifl

oxac

inEt

o= E

thio

nam

ide

Cs=

Cycl

oser

ine

PAS

= P-

amin

osal

icyl

ic N

aBd

q =

Beda

quili

ne

Dlm

= D

elam

anid

Lz

d =

Line

zolid

Cf

z =

Clof

azim

ine

Amx/

Clv

= Am

oxic

illin

/Cla

vula

nate

Stan

dard

Tre

atm

ent R

egim

en 6

-8 (A

mk

Z Lf

x Et

o Cs

)/ 1

2-14

(Z L

fx E

to C

s) 6

-8 (A

mk

Z Lf

x Et

o Cs

PAS

)/ 1

2-14

(Z L

fx E

to C

s PAS

) O

ther

Reg

imen

(Spe

cify

……

……

……

……

......

......

……

….)

X-pe

rt re

sult:

NI

TRR

TIN

= N

o M

TB, I

= In

valid

/ N

o re

sult,

T =

MTB

det

ecte

d, R

R =

Rif r

esis

tant

,TI

= M

TB (+

)/bu

t Rif

resi

stan

t is i

nval

id o

r N

o re

sult

Dat

eS

HR

EPZ

APt

o/Et

oK

m/

Amk

CmFq

(

)

HIV

info

rmat

ion

HIV

test

ing

done

:

Y

N

u

nkno

wn

Date

of t

est

____

/___

_/__

___

Res

ults

:St

arte

d on

ART

: Y

N

D

ate

____

/___

_/__

___

Star

ted

on C

PT:

Y

N

Dat

e __

__/_

___/

____

_AR

T= a

ntir

etro

vira

l the

rapy

; CP

T =

co-t

rim

oxaz

ole

prev

entiv

e th

erap

y

Diab

etes

Mel

litus

Yes

No

NATI

ONA

L TU

BERC

ULO

SIS

PRO

GRAM

ME

MDR

TB

regi

stra

tion

num

ber:

____

____

____

____

____

____

____

____

_

Date

of r

egis

trat

ion:

____

/___

_/__

___

R=re

sist

ant,

S=su

scep

tible

, C=c

onta

min

ated



32

Mon

th

No.

Sput

um Sm

ear M

icros

copy

Cultu

reUr

eaSe

rum

Crea

tinin

eLi

ver F

unct

ion T

est

CPSe

rum

Uric

Acid

TSH

Date

Sam

ple N

o.Gr

adin

gDa

teSa

mpl

e No.

Grad

ing

Biliru

binAl

Phos

ASTALT

Diag

nosis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

CXR

Resu

lts



33

Mon

th

No.

Date

Seru

m El

ectro

lytes

Bloo

d Su

gar

Albu

min

Lipa

seK+

Mg++

Ca++

Diag

nosis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

Wee

kNo

.Da

teEC

G fin

ding

sQT

c (m

s)Au

diog

ram

Find

ings

Rt Ea

rLt

Ear

Diag

nosis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26



34

ADM

INIS

TRAT

ION

OF D

RUGS

(one

line

per

mon

th):

Mth No

.m

m-y

yDa

ysW

eigh

t(k

g)1

23

45

67

89

1011

1213

1415

1617

1819

2021

2223

2425

2627

2829

3031

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

Mar

k in t

he bo

xes:

√ = d

irectl

y obs

erve

d, N

= no

t sup

ervis

ed, Ø

= dr

ugs n

ot ta

ken



35

MDR-T

B RE

GIME

N (d

ate tr

eatm

ent s

tarted

and d

osag

e (mg

), fre

quen

cy of

dose

, cha

nge o

f dos

age,

and c

essa

tion o

f dru

gs):

Da

teH

ZE

S/Am

/Cm

FQ(

)Et

oCs

Lzd

Cfz

Bdq

Dlm

PAS

Imp/

Mpm

Amx/

Clv

Com

men

ts,SA

E (Y/

N)

(od =

Onc

e a da

y, bd

= 12

hour

ly: m

ornin

g and

even

ing do

ses)

DR-T

B Co

mm

ittee

/ Pan

el Di

scus

sion a

nd D

ecisi

ons

Date

Issue

s and

Disc

ussio

nDe

cisio

n



36

Outco

me (

circle

one)

Date

Cure

d

Comp

leted

Faile

d

Died

Lost

to fol

low up

Not e

valua

ted

Move

d to c

onve

ntion

al Re

gimen

Move

d to i

ndivi

duali

zed R

egim

en

6th m

onth

Follo

w up

afte

r com

plet

ion o

f tre

atm

ent

Date

Smea

rCu

lture

CXR

Clinic

al

12th

mon

th Fo

llow

up af

ter c

ompl

etio

n of t

reat

men

tDa

teSm

ear

Cultu

reCX

RCli

nical

18th

mon

th Fo

llow

up af

ter c

ompl

etio

n of t

reat

men

tDa

teSm

ear

Cultu

reCX

RCli

nical

24th

mon

th Fo

llow

up af

ter c

ompl

etio

n of t

reat

men

tDa

teSm

ear

Cultu

reCX

RCli

nical

Com

men

ts

ANNEX D – NTP Form for Reporting Serious Adverse Event (SAE)



37

National Tuberculosis ProgramMinistry of Health and Sports (MYANMAR)

Date of Report ( / / ) All dates must be filled in as (dd/mm/yyyy)

Give date of follow-up SAE form last sent ( / / )

Full Name Age (yrs) Date of Birth

pre/XDR/MDR -TB registration number Sex M / F Is patient pregnant Yes No

Treatment Center Weight (Kg) Height (cm)

Address and phone number

2. Details of Serious Adverse Event

Why is the event considered serious?⃝ Death Life Threatening Hospitalization OR prolongation of hospitalization OR ICU/HDU

⃝ Persistent/ Significant disability ⃝ Congenital Abnormality Others ( specify )…………………………………

3. Suspected Medicine (s)

4. Action Taken 5. Outcome of Serious Adverse Event

⃝ Recovered/ resolved

⃝ Recovering/ resolving

⃝ Recovered with sequelae

⃝ Not recovered/ not resolved

⃝ Died

⃝ Unknown

Description of Event

Date

Form for Reporting of Serious Adverse Event

Is this report a new event? Yes No Give date when initial SAE form sent ( / / )

1. Patient Details

LMP ( / / )

( / / )

Continues √Date stoppedDate startedTotal daily doseName (Generic name)

Date Event Started - ( / / )

Provisional Diagnosis ……………………………………………………………………………

⃝ Unknown

Responsible Drug

⃝ Medicine withdrawn

⃝ Dose reduced

⃝ Dose not changed

⃝ Dose interupped



38

National Tuberculosis ProgramMinistry of Health and Sports (MYANMAR)

Batch No

MM Reg: no

Expiry Date

⃝ IHD Hypertension Other Heart Disease (specify)…………………….. DM Renal disease

⃝ Viral Hepatitis Alcoholic Hepatitis Other Liver Disease (specify)…………………. Peptic Ulcer/ Gastritis

⃝ HIV Opportunistic Infection(s) (specify)……………………………... Last CD4/VL & date ……………………………...

⃝ Bronchial Asthma COPD Other Lung Disease (specify)…………………….. Other (specify) …………………

⃝ None

8. Concomitant Medicine (s)

Name of Reporter ………………………………………….

Address ……………………………………..

Designation ……………………………………………….. email …………………………………………………………

Signature ………………………….. Date ……………………………. Tel no. ……………………………….

9. Relevant Laboratory/ Investigation Results(s) - Clinical

Laboratory Test Date done Normal Value (unit) Patient's result (unit) Comment

Date started Date stopped Continues √Name (Generic name) Total daily dose

7. Co-morbidities

10. SOURCE OF REPORT

6. Details of suspected drug Drug 1 Drug 2 Drug 3

Brand Name (formulation/ dosage form)

Generic Name

Name of manufacturer, country of origin

Anne

x E

- Sev

erity

gra

ding

scal

es a

nd su

gges

ted

actio

n fo

r com

mon

AEs

Seve

rity

grad

eG

rade

1

Mild

Gra

de 2

Mod

erat

eG

rade

3Se

vere

Gra

de 4

Life

- thr

eate

ning

1. P

erip

hera

l neu

ropa

thy

Poss

ible

ant

i-TB

dru

g ca

uses

:Lzd,Cs,H,S,Km,Cm,H,FQ,Pto/Eto,E.P

ossi

ble

othe

r cau

ses:

d4T

, ddI

Pare

sthe

sia

(Bur

ning

, tin

glin

g, e

tc.)

Mild

dis

com

fort;

no

treat

men

t re

quire

d; a

nd/o

r BP

NS

(Brie

f PeripheralN

europathyScreen)

subjectivesensoryneuropathy

scor

e 1-

3 on

any

sid

e.

Mod

erat

e di

scom

fort;

non

-nar

cotic

an

alge

sia

requ

ired;

and

/or B

PN

S


scor

e 4-

6 on

any

sid

e.

Sev

ere

disc

omfo

rt; o

r nar

cotic

an

alge

sia

requ

ired

with

sym

ptom

-at

ic im

prov

emen

t; an

d/ o

r BP

NS


scor

e 7-

10 o

n an

y si

de.

Inca

paci

tatin

g; o

r not

re

spon

sive

to n

arco

tic a

nalg

esia

Act

ion

StopCsandLzd.Ifsym

ptom

sim

prov

e, c

onsi

der r

esta

rting

thes

e drugs.ConsiderrestartingLzdata

low

er d

ose

(300

mg

daily

or

600mgthriceweekly).

If C

s is

not

ess

entia

l to

the

regi

men

con

side

r sus

pend

ing

the

drug

.

StopCsandLzd.Ifsym

ptom

sim

prov

e, c

onsi

der r

esta

rting

Cs.

DonotreintroduceLzd.

Pro

vide

sym

ptom

atic

relie

f

Sam

e as

Gra

de 2

.Sa

me

as G

rade

2.

2. M

yelo

supp

ress

ion

(ane

mia

, thr

ombo

cyto

peni

a, o

r neu

trop

enia

) Po

ssib

le a

nti-T

B d

rug

caus

es:Lzd.P

ossi

ble

othe

r cau

ses:AZT,cotrim

oxazole

Ane

mia

10.5

- 9.

5 g/

dL9.

4 - 8

.0 g

/dL

7.9

- 6.5

g/d

L<

6.5

g/dL

Plat

elet

s de

-cr

ease

d75

,000

– 9

9,99

9/m

m³

50,0

00 –

74,

999/

mm

³20

,000

– 4

9,99

9/m

m³

< 20

,000

/mm

³

Abs

olut

e ne

utro

-ph

il co

unt l

ow15

00 -

1000

/mm

399

9 - 7

50/m

m3

749

- 500

/mm

3<5

00/m

m3

Act

ion

Mon

itor c

aref

ully,

and

con

side

r reductionofdoseofLzd(300mg

dailyor600mgthriceweekly).

Mon

itor c

aref

ully,

and

con

side

r reductionofdoseofLzd(300mg

dailyor600mgthriceweekly);in

case

of G

rade

2 n

eutro

peni

a, s

top

Lzdimmediately.IncaseofGrade

2 an

emia

, con

side

r ery

thro

poie

tin

(EPO).Restartatreduceddose

once

toxi

city

has

dec

reas

ed to

G

rade

1.

StopLzdimmediately.Incaseof

Gra

de 3

ane

mia

, con

side

r EP

O.

Res

tart

at re

duce

d do

se o

nce

toxi

city

has

dec

reas

ed to

Gra

de 1

.

Stop

Lzd

imm

edia

tely

.C

onsi

der h

emot

rans

fusi

on o

r EP

O. R

esta

rt a

t red

uced

dos

e on

ce to

xici

ty h

as d

ecre

ased

to

Gra

de 1

.



39

Seve

rity

grad

eG

rade

1

Mild

Gra

de 2

Mod

erat

eG

rade

3Se

vere

Gra

de 4

Life

- thr

eate

ning

3. P

rolo

nged

QT

inte

rval

Poss

ible

ant

i-TB

dru

g ca

uses

:Cfz,B

dq,M

fx,D

lm,andLfx(amildQTprolongingdrug)

Poss

ible

oth

er c

ause

s:Otherdrugs,e.g.,erythrom

ycin,clarithrom

ycin,quinidine,ketoconazole,fluconazole,antipsychotics(allhavesom

erisk,includinghaloperidol,

chlorpromazineandrisperidone),m

anyanti-nauseadrugs(ondansetron/granisetron,dom

peridone),m

ethadone,andsom

eanti-retrovirals);geneticcausessuchas

longQTsyndrome;hypothyroidism

Prol

onge

d Q

TcF

QTcF450–480ms.

QTcFinterval481–500ms.

QTcF>

=501ms

with

out s

igns

/ sym

ptom

s of

ser

ious

ar

rhyt

hmia

.

QTc

F>=

501

or>6

0 m

s ch

ange

from

bas

elin

e an

d on

e of

the

follo

win

g:

Tors

ade

de p

oint

es o

r po

lym

orph

ic v

entr

icul

ar

tach

ycar

dia

or s

igns

/sym

ptom

s of

ser

ious

arr

hyth

mia

.A

ctio

nM

onito

r mor

e cl

osel

y; a

t lea

st

weeklyECGuntilQTcFhas

retu

rned

to le

ss th

an g

rade

1.

Rep

lete

ele

ctro

lyte

s as

nec

essa

ry.

Mon

itor m

ore

clos

ely;

at l

east

weeklyECGuntilQTcFhas

retu

rned

to le

ss th

an g

rade

1.

Rep

lete

ele

ctro

lyte

s as

nec

essa

ry.

Sto

p th

e su

spec

ted

caus

ativ

e drug(s).Hospitalizeandreplete

elec

troly

tes

as n

eces

sary

.

Stop

the

susp

ecte

d ca

usat

ive

drug

(s).

Hos

pita

lize

and

repl

ete

elec

trol

ytes

as

nece

ssar

y.

4. O

ptic

ner

ve d

isor

der (

optic

neu

ritis

)Po

ssib

le a

nti-T

B d

rug

caus

es:Lzd,E,Eto/Pto,Cfz,rifabutin,H,S.P

ossi

ble

othe

r cau

ses:

ddI

Opt

ic n

erve

di

sord

erA

sym

ptom

atic

; clin

ical

or

diagnosticobservationsonly

Lim

iting

vis

ion

of th

e af

fect

ed e

ye

(20/40[6/12]orbetter)

Lim

iting

vis

ion

in th

e af

fect

ed e

ye

(worsethan20/40[6/12]butbetter

than20/200[6/60])

Blin

dnes

s (2

0/20

0[6/

60] o

r w

orse

) in

the

affe

cted

eye

Act

ion

StopLzdimmediatelyifthereare

any

susp

icio

ns o

f opt

ic n

eurit

is. D

o no

t res

tart

it.


any

susp

icio

ns o

f opt

ic n

eurit

is. D

o no

t res

tart

it.


any

susp

icio

ns o

f opt

ic n

eurit

is. D

o no

t res

tart

it.

Stop

Lzd

imm

edia

tely

if th

ere

are

any

susp

icio

ns o

f opt

ic

neur

itis.

Do

not r

esta

rt it

.5.

Hep

atiti

sPo

ssib

le a

nti-T

B d

rug

caus

es:Z

,Lzd,Cfz,Bdq.P

ossi

ble

othe

r cau

ses:

unk

now

n

ALT

(SG

PT)

1.1

– 3.

0 x

uppe

r lim

it of

nor

mal

(ULN

)>3

.0 –

5.0

x U

LN>5

.0 –

20.

0 x

ULN

>20.

0 x

ULN

AST

(SG

OT)

1.1

– 3.

0 x

ULN

>3.0

– 5

.0 x

ULN

>5.0

– 2

0.0

x U

LN>2

0.0

x U

LNA

ctio

nC

ontin

ue tr

eatm

ent r

egim

en.

Patientsshouldbefolloweduntil

resolution(returntobaseline)or

stabilizationofAST/ALTelevation.

Con

tinue

trea

tmen

t reg

imen

. Patientsshouldbefolloweduntil

resolution(returntobaseline)or

stabilizationofAST/ALTelevation.

Sto

p al

l dru

gs, i

nclu

ding

ant

i- TB

dr

ugs;

mea

sure

LFT

s w

eekl

y.Treatmentm

aybereintroduced

afte

r tox

icity

is re

solv

ed.

Stop

all

drug

s, in

clud

ing

anti-

TB

drug

s; m

easu

re L

FTs

wee

kly.

Trea

tmen

t may

be

rein

trod

uced

af

ter t

oxic

ity is

reso

lved

.



40

Seve

rity

grad

eG

rade

1

Mild

Gra

de 2

Mod

erat

eG

rade

3Se

vere

Gra

de 4

Life

- thr

eate

ning

6. A

cute

kid

ney

inju

ry

Poss

ible

ant

i-TB

dru

g ca

uses

: S,K

m,A

m,C

m. P

ossi

ble

AR

T ca

uses

:Tenofovir(TDF)-rare

Acu

te k

idne

y In

jury

Cre

atin

ine

leve

l inc

reas

e of

>0

.3 m

g/dL

; cre

atin

ine

1.5-2.0xabovebaseline

Creatinine2-3xabovebaseline

Cre

atin

ine

>3 x

baselineor>4.0m

g/dL;

hospitalizationindicated

Life

-thre

aten

ing

cons

eque

nces

; di

alys

is in

dica

ted

Act

ion

Considerstoppinginjectable

until

cre

atin

ine

has

retu

rned

to

baseline.Considerrestartingthe

injectableatlow

erfrequency

(e.g.,MWF).

Stopinjectableuntilcreatininehas

returnedtobaseline.Consider

restartingtheinjectableatlow

er

frequency(e.g.,MWF)or

substitutewithanon-nephrotoxic

drug

.

Stopinjectableuntilcreatininehas

returnedtobaseline.Consider

restartingtheinjectableatlow

er

frequency(e.g.M

WF)orsubstitute

with

a n

on- n

ephr

otox

ic d

rug.

Stop

inje

ctab

le u

ntil

crea

tinin

e ha

s re

turn

ed to

bas

elin

e. C

on-

side

r res

tart

ing

the

inje

ctab

le a

t lo

wer

freq

uenc

y (e

.g. M

WF)

or

subs

titut

e w

ith a

non

- nep

hro-

toxi

c dr

ug.

7.

Hyp

okal

emia

and

hyp

omag

nese

mia

Po

ssib

le a

nti-T

B d

rug

caus

es: C

m,K

m,A

m,S

. Pos

sibl

e A

RT

caus

es:T

DF(rare)

Hyp

okal

emia

3.4

- 3.0

mE

q/L

2.9

- 2.5

mE

q/L

2.4

- 2.0

mE

q/L

or in

tens

ive

repl

acem

ent t

hera

py o

r hospitalizationrequired

< 2.

0 m

Eq/L

or a

bnor

mal

po

tass

ium

with

par

esis

, ile

us o

r lif

e-th

reat

enin

g ar

rhyt

hmia

Act

ion

Continueinjectable.S

tartoral

pota

ssiu

m re

plac

emen

t the

rapy

. C

heck

ser

um m

agne

sium

and

re

plac

e if

nece

ssar

y.


tart

aggr

essi

ve o

ral p

otas

sium

re

plac

emen

t the

rapy

. Rep

lace

m

agne

sium

as

nece

ssar

y.


tartIV

pota

ssiu

m re

plac

emen

t the

rapy

in

addi

tion

to o

ral.

Rep

lace

mag

-ne

sium

and

oth

er e

lect

roly

tes

as

nece

ssar

y.

Stop

inje

ctab

le te

mpo

raril

y.

Star

t IV

pota

ssiu

m re

plac

emen

t th

erap

y in

add

ition

to o

ral.

Rep

lace

mag

nesi

um a

nd o

ther

el

ectr

olyt

es a

s ne

cess

ary.

Hyp

omag

nese

-m

ia0.

60-0

.70

mm

ol/L

0.45

-0.5

9 m

mol

/L0.

30-0

.44

mm

ol/L

<0.3

0 m

mol

/L

8. H

ypot

hyro

idis

m

Pos

sibl

e an

ti-TB

dru

g ca

uses

: Eto

/Pto

, PA

S. P

ossi

ble

AR

T ca

uses

: d4T

Hyp

othy

roid

ism

Asy

mpt

omat

ic; c

linic

al o

r diagnosticobservationsonly;

inte

rven

tion

not i

ndic

ated

Sym

ptom

atic

; thy

roid

repl

acem

ent

indi

cate

d; li

miti

ng iA

DL

(inst

rum

en-

talactivitiesofdailyliving)*

Sev

ere

sym

ptom

s; li

miti

ng s

elf-

careADL*hospitalizationindicated

Life

-thre

aten

ing

cons

eque

nces

; ur

gent

inte

rven

tion

indi

cate

d

Act

ion

Con

tinue

ant

i-TB

dru

gs.

Con

tinue

ant

i-TB

dru

gs. S

tart

thyr

oxin

e.C

ontin

ue a

nti-T

B d

rugs

. Sta

rt th

yrox

ine.

Stop

all

anti-

TB d

rugs

. Sta

rt

thyr

oxin

e.



41

*https://w

ww.payingforseniorcare.com

/longtermcare/activities-of-daily-living.html#title2

Seve

rity

grad

eG

rade

1

Mild

Gra

de 2

Mod

erat

eG

rade

3Se

vere

Gra

de 4

Life

- thr

eate

ning

8. H

earin

g lo

ss

Po

ssib

le a

nti-T

B d

rug

caus

es: S

,Km

,Am

,Cm

,Clr.

Pos

sibl

e ot

her c

ause

s: n

one.

Hea

ring

loss

Adu

lt en

rolle

d in

mon

itorin

g program(ona1,2,4,3,6and8kH

zaudiogram):thresholdshiftof

15 -

25 d

B a

vera

ged

at

2 co

ntig

uous

test

freq

uenc

ies

in a

t leastoneearorsubjectivechange

intheabsenceofa

Gra

de 1

Thr

esho

ld s

hift.

Ped

iatri

c (o

n a

1, 2

, 4,3

, 6 a

nd

8kH

zaudiogram):thresholdshift

>20dB

at8kHzinatleastone

ear.

Adu

lt en

rolle

d in

mon

itorin



>25

dB a

vera

ged

at 2

con

tiguo

us

test

freq

uenc

ies

in a

t lea

st o

ne e

ar.

Adu

lt no

t enr

olle

d in

mon

itorin

g program:hearinglossbuthearing

aid

or in

terv

entio

n no

t ind

icat

ed;

limiti

ng in

stru

men

tal A

DL.

Pediatric(ona1,2,3,4,6and8kH

zaudiogram):thresholdshift

>20dB

at4kHzandaboveinat

leas

t one

ear

.

Adu

lt en

rolle

d in

mon

itorin



>25

dB a

vera

ged

at 3

con

tigu-

ous

test

freq

uenc

ies

in a

t lea

st

one

ear;

ther

apeu

tic in

terv

entio

n in

dica

ted.

Adu

lt N

ot e

nrol

led

in m

onito

ring

program:hearinglosswithhearing

aid

or in

terv

entio

n in

dica

ted;

lim

it-in

g se

lf-ca

re A

DL.

Ped

iatri

c (o

n a

1, 2

, 3, 4

, 6 a

nd

8kH

zaudiogram):hearingloss

sufficienttoindicatetherapeutic

inte

rven

tion,

incl

udin

g he

arin

g aids):Thresholdshift>20dBat

3kH

zandaboveinatleastone

ear;

addi

tiona

l spe

ech-

lang

uage

re

late

d se

rvic

es in

dica

ted.

Adu

lts: p

rofo

und

bila

tera

l he

arin

g lo

ss (T

hres

hold

>8

0 dB

HL

at 2

kH

z an

d ab

ove)

; no

n-se

rvic

eabl

e he

arin

g Pe

diat

ric: a

udio

logi

c in

dica

tion

for c

ochl

ear i

mpl

ant a

nd

addi

tiona

l spe

ech-

lang

uage

re

late

d se

rvic

es in

dica

ted.

Act

ion

Continueinjectable.

Considerdecreasinginjectable

frequ

ency

if fu

rther

hea

ring

loss

is

a co

ncer

n. In

itiat

e di

scus

sion

with

patientaboutrisksandbenefitsof

theinjectable.C

onsiderreplacing

injectableagentwith

a no

n- o

toto

xic

TB d

rug.

DoNOTsubstituteasingledrug

repl

acem

ent i

f the

trea

tmen

t is

faili

ng, a

dd a

dditi

onal

TB

dru

gs.

Con

side

r sto

ppin

g or

dec

reas

ing

injectablefrequency(e.g.M

WF).

Dis

cuss

with

pat

ient

the

risks

and

benefitsoffurtherinjectableuse.

In m

ost c

ases

of G

rade

3 h

earin

g losstheinjectableshouldbe

stop

ped

and

repl

aced

with

a

non-

otot

oxic

TB

dru

g.DoNOTsubstituteasingledrug

repl

acem

ent i

f the

trea

tmen

t is

faili

ng, a

dd a

dditi

onal

TB

dru

gs.

Con

side

r con

tinue

inje

ctab

le

if to

lera

ted

by th

e pa

tient

. (In

ca

ses

of c

ompl

ete

hear

ing

loss

, so

me

clin

icia

ns w

ill c

ontin

ue

the

inje

ctab

le a

gent

as

the

dam

age

is a

lread

y do

ne).

Con

side

r sus

pens

ion

of th

e in

ject

able

if o

ngoi

ng u

se

cont

ribut

es to

wor

seni

ng ti

nni-

tus

or v

estib

ular

dis

turb

ance

s (o

r if s

ome

hear

ing

mig

ht b

e st

ill

pres

erve

d). A

dd a

dditi

onal

TB

dr

ugs

as n

eede

d.

Source:EndTBClinicalandProgram

maticGuideforpatientmanagem

entw

ithnew

TBdrugs,ver3.3,25/11/2016,PartnersinHealth,IRD,M

SFandUNITAID



42

40dB

Slig

ht/M

ild41

-60

dBM

oder

ate

61-8

0 dB

Seve

reO

ver 8

1 dB

Prof

ound

Difficultyhearingandunderstand

-in

g so

ft sp

eech

, spe

ech

from

a

dist

ance

, or s

peec

h ag

ains

t a

backgroundofnoise

Difficultyhearingregularspeech,

even

at c

lose

dis

tanc

e.

May

onl

y he

ar v

ery

loud

spe

ech

or

loud

sou

nds

in th

e en

viro

nmen

t, suchasafiretrucksirenoradoor

slam

min

g. M

ost c

onve

rsat

ion

spee

ch is

not

hea

rd.

May

per

ceiv

e lo

ud s

ound

s as

vi

brat

ions

In th

e ca

se o

f mod

erat

e he

arin

g lo

ss, t

he ra

nge

for c

hild

ren

is 3

1-60

dB

.

WHO

Cla

ssifi

catio

n gr

adin

g sc

ale

for h

earin

g lo

ss



43

Documents

Active TB Drug-Safety Monitoring and Managementmohs.gov.mm/ckfinder/connector?command=Proxy&lang=en&type=… · Tin Maung Cho, Professor Win Naing, Professor Ye Tun and Professor