Clinical and Programmatic Guide for Patient Management with New TB Drugs. Version 4.0

Transcription

1 Clinical and Prgrammatic Guide fr Patient Management with New TB Drugs Versin 4.0

2 Ntice This guide is designed t give guidance t the endtb sites n the use f new TB drugs bedaquiline and delamanid. It is intended t be a resurce fr physicians and ther health care prfessinals invlved in the endtb. Every effrt pssible has been made t ensure that the material presented here is accurate, reliable, and in accrd with current standards. It is the respnsibility f the individual physician r ther health care prfessinal t use his/her best medical judgment in determining apprpriate patient care r treatment. Yur use f this guide is prvided n an "as-is" basis withut warranty f any kind, and nne f the entities listed abve represent r warrant that the infrmatin cntained herein is cmplete r accurate r free frm errr. By chsing t use this guide, yu acknwledge and agree t the terms f this disclaimer. Updated versins f this guide are psted at Future versins will als be available in Spanish, French and Russian. If reprducing part r all f this guide, please reference with the apprpriate versin and date: endtb Cnsrtium. endtb Clinical and Prgrammatic Guide fr Patient Management with New TB Drugs. Versin 4.0; January Versin 4.0, January 2018 Page 2 f 69

3 Table f Cntents Table f tables... 5 Acknwledgements... 6 List f abbreviatins Intrductin Gruping f anti-tb drugs used fr the treatment f RR and MDR-TB Eligibility Eligibility criteria fr bedaquiline r delamanid New and repurpsed drugs t be used in endtb Cautins and warnings Cntraindicatins fr new and repurpsed drugs Drug-drug interactins Overlapping txicities Regimen design Step-by-step directins fr regimen design Operatinal research n shrter standardized regimens using the new and repurpsed TB drugs Interpretatin f phentypic and gentypic DST results Hw t chse between bedaquiline and delamanid Dsing f new and repurpsed drugs Duratin f bedaquiline and delamanid Off-label use f new and repurpsed TB drugs Children Pregnancy r lactatin Extrapulmnary TB Special ppulatins Patient cnsent Patient cnsent Example f medicatin guide and patient cnsent fr the clinical use f bedaquiline and delamanid Mnitring schedule Mnitring schedule fr patient fllw-up Drug safety Scpe f safety data cllectin and definitins Recrding, medical assessment and ntificatin f adverse events Clinical management f adverse events f interest Peripheral neurpathy Versin 4.0, January 2018 Page 3 f 69

4 7.3.2 Myelsuppressin (anemia, thrmbcytpenia, r neutrpenia) Prlnged QT interval Optic nerve disrder (ptic neuritis) Elevated liver enzymes (hepattxicity) Hearing impaired Acute kidney injury Hypkalemia Hypthyridism Frequent adverse events References Versin 4.0, January 2018 Page 4 f 69

5 Table f tables Table 1 Medicines recmmended fr the treatment f rifampicin-resistant and multidrugresistant TB (adapted frm WHO 2016 treatment guidelines fr DR-TB) Table 2 Cntraindicatins fr new and repurpsed drugs * Table 3 Pssible drug-drug interactins with the new TB drugs Table 4 Pssible drug-drug interactins between antiretrvirals and the new TB drugs Table 5 Nn-TB drugs that have ptential verlapping txicities with the new TB drugs Table 6 The building steps fr M/XDR-TB regimens Table 7 Examples f pssible regimens Table 8 Dsing f new and repurpsed drugs in adults Table 9 Treatment f children with new and repurpsed drugs Table 10 Treatment f pregnant r lactating wmen with new and repurpsed drugs Table 11 Treatment f extrapulmnary TB with new and repurpsed drugs Table 12 Special ppulatins Table 13 Mnitring schedule Table 14 General definitin f severity Table 15 Causality categries definitin Table 16 Clinical management f peripheral neurpathy accrding t severity grading Table 17 Clinical management f myelsuppressin accrding t severity grading Table 18 Clinical management f prlnged QT interval accrding t severity grading Table 19 Clinical management f ptic nerve disrder accrding t severity grading Table 20 Clinical management f elevated liver enzymes accrding t severity grading Table 21 Clinical management f hearing impairment accrding t severity grading Table 22 Clinical management f acute kidney injury accrding t severity grading Table 23 Clinical management f hypkalemia accrding t severity grading Table 24 Clinical management f hypmagnesemia accrding t severity grading Table 25 Ptassium replacement therapy Table 26 Magnesium replacement therapy Table 27 Clinical management f hypthyridism accrding t severity grading Versin 4.0, January 2018 Page 5 f 69

6 Acknwledgements This guide and endtb are generusly supprted by Unitaid. Unitaid is a unique funding mechanism engaged in finding new ways t prevent, treat and diagnse HIV/AIDS, tuberculsis and malaria mre quickly, mre cheaply and mre effectively. It takes game-changing ideas and turns them int practical slutins that can help accelerate the end f the three diseases. Website: Cre Writing Team: KJ Seung Michael Rich Francis Varaine Cntributrs and Reviewers: Cathy Hewisn Alex Telnv Charles Ssnk Uzma Khan Nathalie Lachenal Lrenz Guglielmetti Versin 4.0, January 2018 Page 6 f 69

7 List f abbreviatins adsm ACTG AE ADL ALT Am Amx ART ARV AST AZT Bdq BMI BPNS BSA Cfx Clv Cm Cln CNS Cs CTCAE CYP d4t DAA ddi DIP Dlm DMID DR-TB DST E ECG ECOG EFV EMA EMR endtb EPO Et FDA FQ GI H H h HIV Ipm IRD Km Lfx LLN active TB Drug-Safety Mnitring and Management AIDS Clinical Trial Grup Adverse Event Activities f daily living Alanine amintransferase Amikacin Amxicillin Anti-retrviral therapy Anti-retrviral Aspartate amintransferase Zidvudine Bedaquiline Bdy Mass Index Brief Peripheral Neurpathy Screen Bdy Surface Area Clfazimine Clavulanate Capremycin Cilastatin Central Nervus System Cyclserine Cmmn Terminlgy Criteria fr Adverse Events Cytchrme P450 Stavudine Direct-acting Antivirals Didansine Distal interphalangeal Delamanid Divisin f Micrbilgy and Infectius Diseases Drug-resistant Tuberculsis Drug Susceptibility Testing Ethambutl Electrcardigram Eastern Cperative Onclgy Grup Efavirenz Eurpean Medicines Agency Electrnic medical recrd Expand New Drugs fr TB Erythrpietin Ethinamide United States Fd and Drug Administratin Flurquinlne Gastrintestinal Isniazid High-dse isniazid Human Immundeficiency Virus Imipenem Interactive Research and Develpment Kanamycin Levflxacin Lwer Limit f Nrmal Versin 4.0, January 2018 Page 7 f 69

8 Lzd MCV MDR MDR-TB Mfx Mfx h MSF MTB/RIF MWF NCI NIAID NTP NVP Ofx PAS PIH Pt PO PV QTcF S SAE SL SLD SSRI TB Trd TDF TSH ULN WHO XDR XDR-TB Z Linezlid Mean Crpuscular Vlume Multidrug-resistance Multidrug-resistant Tuberculsis Mxiflxacin High-dse mxiflxacin Médecins Sans Frntières Mycbacterium Tuberculsis/Rifampicin Mnday-Wednesday-Friday Natinal Cancer Institute Natinal Institute f Allergy and infectius Diseases Natinal Tuberculsis Prgram Nevirapine Oflxacin Para-Aminsalicylic Acid Partners In Health Prthinamide Per s Pharmacvigilance QT interval Fridericia s crrectin Streptmycin Serius Adverse Event Secnd Line Secnd Line Drug Selective Sertnin Re-uptake Inhibitr Tuberculsis Terizidne Tenfvir Thyrid Stimulating Hrmne Upper Limit f Nrmal Wrld Health Organizatin Extensive Drug Resistance Extensively Drug-resistant Tuberculsis Pyrazinamide Versin 4.0, January 2018 Page 8 f 69

9 1 Intrductin Tw new anti-tb drugs have been granted cnditinal medical apprval by stringent regulatry authrities, bedaquiline by the FDA (2012) 1 and EMA (2013) 2 and delamanid by EMA (2013). T gain full apprval, the drug manufacturers have been required t perfrm Phase III trials in the next few years t demnstrate efficacy and safety. Otsuka has recently reprted interim results f the Phase III study f Delamanid trial 213. Janssen has nt registered a phase III trial fr bedaquiline althugh it frms part f several regimens under investigatin in ther studies (endtb, TB PRACTECAL, NiX-TB, Next, STREAM 2). In additin t the tw new TB drugs, in 2016, tw repurpsed drugs, linezlid and clfazimine were elevated by the Wrld Health Organizatin (WHO) t cre secnd-line medicines fr MDR- TB treatment. There is als evidence frm clinical studies that supprts the use f carbapenems (imipenem/cilastatin and merpenem) fr the treatment f MDR-TB in certain circumstances. Under the funding mechanism f Unitaid, endtb aims t increase uptake f the new TB drugs and repurpsed TB drugs thrugh a number f initiatives. A main activity f the prject is give access t new TB drugs and regimens t a large chrt f patients acrss multiple cuntries wh are receiving clse mnitring and pharmacvigilance. The bjective f this guide is t prvide guidance t physicians wh are managing the care f MDR-TB patients enrlled in endtb. This guide is nt meant t replace WHO guidelines r NTP guidelines; it aims at cmplementing the natinal guidelines if they have nt yet incrprated new TB drugs r updating them if already incrprated. The guide is meant t be used as a template and t be adapted by NTPs and prjects, as lng as the adaptatins remain cnsistent with WHO recmmendatins. This guide prvides the fllwing instructins t aid the clinician: Identifying wh needs new TB drugs. Hw t build a MDR regimen with the new TB drugs. Implementing clse mnitring f patients fr respnse t treatment and fr ptential adverse events. The endtb prject emplys active pharmacvigilance fr adverse events, including ptential reactins t a new TB drug which are yet t be described, thrugh immediate ntificatin f serius adverse events t central pharmacvigilance unit. This guide includes prtcls n the grading and management f adverse events. 1 FDA website [nline]. Available at: Anti- InfectiveDrugsAdvisryCmmittee/ucm htm 2 EMA website [Online]. Available frm: medicines/human/medicines/002552/human_med_ jsp&mid =WC0b01ac058001d124. Versin 4.0, January 2018 Page 9 f 69

10 2 Gruping f anti-tb drugs used fr the treatment f RR and MDR-TB In 2016, the WHO regruped the TB medicines being used fr rifampicin-resistant TB (RR-TB) and MDR-TB. Bedaquiline and delamanid were placed in the anti-tb drug Grup D by the WHO: "Add-n agents (nt part f the cre MDR-TB regimen)". Because the new TB drugs have the mst evidence f efficacy, Grup D2 is priritized ver D1 and D3. Repurpsed drugs such as the Grup C drugs linezlid and clfazimine and Grup D3 drugs (imipenem/cilastatin and merpenem) als play an imprtant rle in building an effective regimen. This guide addresses hw t use bth new and repurpsed drugs in the treatment f MDR-TB. See Sectin 4.1 fr a step-by-step guide fr building an MDR-TB regimen. Table 1 Medicines recmmended fr the treatment f rifampicin-resistant and multidrugresistant TB (adapted frm WHO 2016 treatment guidelines fr DR-TB) Grup A: Flurquinlnes Grup B: Secnd-line injectable agents Grup C: * Other cre secnd-line agents Levflxacin Mxiflxacin Amikacin Capremycin Kanamycin Ethinamide / Prthinamide Cyclserine / Terizidne Linezlid Clfazimine Lfx Mfx Am Cm Km Et / Pt Cs / Trd Lzd Cfz D1 Pyrazinamide Ethambutl High-dse isniazid Z E H h Grup D: Add-n agents (nt part f the cre MDR-TB regimen) D2 D3 Bedaquiline Delamanid p-aminsalicylic acid Imipenem-cilastatin Merpenem Ertapenem Amxicillin-clavulanate Bdq Dlm PAS Ipm/Cln Mpm Epm Amx/Clv Carbapenems and clavulanate are meant t be used tgether; clavulanate is nly available in frmulatins cmbined with amxicillin. Versin 4.0, January 2018 Page 10 f 69

11 3 Eligibility 3.1 Eligibility criteria fr bedaquiline r delamanid There are tw grups f patients eligible fr the use f bedaquiline r delamanid: The first eligibility grup is fr any patient that des nt have five likely effective drugs frm Grups A, B r C with at least ne frm grup A and ne frm grup B at the start f treatment. Cmmn situatins fr the first eligibility criteria include: a. XDR-TB (resistance t a flurquinlne and at least ne injectable). b. Pre-XDR-TB (resistance t a flurquinlne r t at least ne secnd-line injectable, but nt bth). c. Patients with tw r mre f the Grup C drugs (Et/Pt, Cs, Lzd, Cfz) cmprmised. d. Cntact with a patient with a strain with resistance pattern f a, b, c. e. Patients unable t tlerate MDR-TB drugs necessary fr cnstructin f the regimen (fr example, ttxicity due t an injectable agent, psychsis due t cyclserine, r nnretractable nausea and vmiting due t ethinamide). f. Patients wh meet the utcme definitin f "failure" f an MDR-TB regimen by WHO 2013 definitins. The secnd eligibility grup includes any patient wh has a high risk f unfavrable utcme fr whm a strnger regimen is recmmended: a. Patients with extensive r advanced disease (X-ray demnstrating cavitary disease, bilateral lesins, r extensive parenchymal damage r multiple system invlvement). b. Patients with increased likelihd f acquisitin f additinal resistance, treatment failure, r death due t c-mrbidities r ther cnditins (drug cntraindicatin, patients with lw bdy mass index (BMI), HIV, diabetes). c. Patients cming frm catchment areas that have pr MDR-TB treatment utcmes despite gd prgrammatic cnditins (e.g. sites with extensive secnd-line drug resistance backgrund). Patients shuld have a sputum sample cllected fr secnd-line DST at the time f starting treatment with new TB drugs. Secnd-line DST is imprtant because the secnd-line resistance pattern can affect the design f the treatment regimen. Of nte, based n the abve criteria, secnd-line DST is nt a requirement fr the use f new drugs. Sme patients may be treated with new drugs withut secnd-line DST, based n a clinical histry that a regimen with five likely effective drugs including a flurquinlne and an injectable is nt pssible; intlerance t a key secnd-line anti-tb drug; r have a high risk f unfavrable utcme. MDR-TB prgrams with success rates belw 80% shuld cnsider redesigning their standardized and individualized regimens t include the new and repurpsed TB drugs. This is especially true fr prgrams with pr treatment utcmes despite strng prgram management and patient supprt. See Sectin 4.1 n cnstructing an MDR-TB regimen fr mre infrmatin. 3.2 New and repurpsed drugs t be used in endtb New drugs (Grup D2): Bedaquiline (Bdq) Delamanid (Dlm) Versin 4.0, January 2018 Page 11 f 69

12 Repurpsed drugs: Linezlid (Lzd) (Grup C). Clfazimine (Cfz) (Grup C). Carbapenems (Grup D3). Imipenem/cilastatin (Ipm/Cln) r merpenem (Mpm) are the tw mst cmmnly used. It is recmmended t cmbine the carbapenem, an antibitic in the beta-lactam class, with clavulanic acid, a beta-lactamase inhibitr. Clavulanic acid des nt exist in pill by itself frm a quality-assured supplier, s amxicillin/clavulanate (Amx/Clv) is recmmended. Merpenem has the mst data published in the frm f case series. It is usually dsed three times daily. Ertapenem (Epm) is als a carbapenem with anti-tb activity and can be dsed nce daily. There is little experience with ertapenem t date 3,4 and shuld nly be cnsidered when the use f Ipm/Cln r Mpm is nt pssible. Evidence suggests Amxicillin/Clavulanate (Amx/Clv) (Grup D3) is at best weakly effective, and shuld nt be used alne withut the carbapenem. 3.3 Cautins and warnings Cntraindicatins fr new and repurpsed drugs There are n abslute cntraindicatins fr the use f any drug in the treatment f MDR- and XDR-TB, a disease that pses serius risk f death r debilitatin t the patient if treated inadequately. Hwever, there are relative cntraindicatins fr the use f the new and repurpsed drugs. If the clinician judges that the ptential benefits utweigh the ptential risk, treatment may prceed with cautin. The endtb Central Medical Cmmittee is always available fr case-by-case advice. Table 2 Cntraindicatins fr new and repurpsed drugs * Drug Relative cntraindicatins Remarks/Precautins All drugs Knwn hypersensitivity t the drug A histry f anaphylaxis r severe drug reactin like Stevens-Jhnsn syndrme is an abslute cntraindicatin. Bdq, Dlm Baseline ECG demnstrating a QTcF > 500 ms (repeated); r Histry f syncpal episdes, ventricular arrhythmias r severe crnary artery disease Use with cautin if QTcF > 450/470 ms in male/female patients. Weekly ECG mnitring and serum electrlyte screening shuld be perfrmed if Bdq r Dlm is being used despite a cardiac cntraindicatin. Dlm may prlng the QT interval less than Bdq. Bdq Severe hepatic failure Cautin in patients with severe hepatic impairment. Bdq, Dlm, Lzd Severe renal failure Cautin in patients with severe renal impairment. 3 Tiberi S, D Ambrsi L, De Lrenz S, et al. Ertapenem may be useful fr MDR/XDR-TB t simplify administratin f carbapenem when the patient is at hme. Eur Respir J 2016; 47: van Rijn SP, van Altena R, Akkerman OW, van Slingen D, van der Laan T, de Lange WC, et al. Pharmackinetics f ertapenem in patients with multidrug-resistant tuberculsis. Eur Respir J 2016; 47(4): Versin 4.0, January 2018 Page 12 f 69

13 Ipm/Cln, Mpm, Epm Patients with central nervus system disrders Use with cautin as carbapenems have been assciated with seizures. * See Table 10 fr safety during pregnancy Drug-drug interactins Table 3 Pssible drug-drug interactins with the new TB drugs Drugs Examples/ntes Efavirenz* Strng/mderate inducers f cytchrme P450 may decrease bld levels f Bdq Rifamycins: Rifampicin Rifapentine Rifabutin Phenytin Carbamazepine Avid use with Bdq Phenbarbital St. Jhn s Wrt Strng/mderate inhibitrs f cytchrme P450 may increase bld levels f Bdq Ritnavir-bsted PIs* Oral azle antifungals (can be used up t tw weeks): Itracnazle Flucnazle Macrlide antibitics ther than azithrmycin : Clarithrmycin Erythrmycin Avid use with Dlm First-line standard anti-tb therapy (isniazid, rifampicin, ethambutl, pyrazinamide) First line anti-tb therapy with fixed dse cmbinatin f HREZ appears t decrease levels f Dlm in early studies. The mechanism is nt clear. * See Table 4 fr a cmplete list f ART interactins. All fur ral azles inhibit CYP3A4; itracnazle and psacnazle are mre ptent inhibitrs than flucnazle r vricnazle. 5 Azithrmycin des nt inhibit CYP isenzymes but des prlng the QT interval s may want t be avided fr this reasn. Fr a mre cmprehensive list f drugs that affect and are affected by the cytchrme P450 system, see the Drug Interactins webpage f the Department f Medicine f Indiana University ( 5 Brüggemann RJ, Alffenaar JC, Blijlevens NM, et al. Clinical relevance f the pharmackinetic interactins f azle antifungal drugs with ther cadministered agents. Clin Inf Dis 2009; 48(10): Versin 4.0, January 2018 Page 13 f 69

14 Table 4 Pssible drug-drug interactins between antiretrvirals and the new TB drugs Drugs Instructins ARVs t avid with Bdq Efavirenz (EFV) (Using EFV with Bdq will result in lw levels f Bdq) Substitute nevirapine (NVP) r integrase inhibitr instead f EFV. Allw a 5 day washut f EFV if pssible (substitute NVP n day 1 and then start MDR regimen 5 days later). If patient is critically ill with MDR-TB, n washut perid is necessary. When switching back t EFV after ending treatment with Bdq, this can be dne immediately after Bdq is stpped. Ritnavir cntaining prtease inhibitrs (PIs) (Using ritnavir with Bdq will result in high levels f Bdq) If pssible, use an ARV regimen with n PI. One pssible slutin is t substitute the PI with an integrase inhibitrs (INSTIs), e.g. dlutegravir (DTG) r raltegravir (RAL). If a ritnavir-cntaining PI must be used, check ECG every tw weeks. ARVs t avid with Dlm Nne Dlm has very little drug-drug interactins with ARVs and n extra drug mnitring r regimen adjustment is needed Overlapping txicities Every effrt shuld be made t avid the use f drugs with verlapping txicities. Hwever, there may be circumstances where n ther ptin is available and the ptential benefits utweigh the risks. Fr example, a fragile mental health patient with a high risk f suicide that must have linezlid in the regimen (n ther anti-tb drug ptins) culd require a sertninergic medicatin. Psychiatric drugs are cmmnly used in MDR-TB patients fr the treatment f cyclserineinduced psychsis r reactive depressin. The anti-psychtics in particular are well-knwn t prlng the QT interval. It is the respnsibility f the TB physician t understand the effects and side effects f psychiatric drugs, and t mnitr MDR-TB patients taking these drugs carefully, even if the patient is referred t a psychiatrist. Finally, a number f cardiac drugs are listed in this table. Cardiac drugs are used in MDR-TB patients fr a number f incrrect reasns, such as t "prevent" arrhythmia, t treat cardiac symptms, r t decrease the QT interval. In fact, there is n cardiac drug that can cunteract r "prtect" frm QT prlngatin. Cardiac rhythm-cntrlling and rate-cntrlling drugs shuld therefre nly be used fr clear indicatins. Sinus tachycardia is ften a physilgic respnse t ther pathlgies. It shuld be viewed as a symptm, nt as a cardiac disrder. Fr example, betablckers shuld nt be used t treat sinus tachycardia in TB patients. 7 6 Mallikaarjun S, Wells C, Petersen C, Paccaly A, Shaf SE, et al. Delamanid cadministered with antiretrviral drugs r antituberculsis drugs shws n clinically relevant drug-drug interactins in healthy subjects. Antimicrb Agents Chemther, 2016; 60(10): endtb Medical Review Bard. Beta-blcker use in MDR-TB patients, ver January Versin 4.0, January 2018 Page 14 f 69

15 Table 5 Nn-TB drugs that have ptential verlapping txicities with the new TB drugs Drugs Examples/ntes Oral azle antifungals (can be used up t tw weeks): Ketcnazle Itracnazle Flucnazle Macrlide antibitics: Azithrmycin Clarithrmycin Erythrmycin Avid with Bdq, Dlm Drugs that cause QT prlngatin r affect the heart rhythm * Antipsychtics (all have sme risk), including: Halperidl Risperidne Many anti-nausea drugs, fr example: Ondansetrn Granisetrn Dmperidne Chlrprmazine Methadne Cardiac drugs that may affect the heart rhythm, fr example: Amidarne Beta-blckers Digxin Quinidine Sertnin re-uptake inhibitrs (SSRIs): fluxetine, parxetine Avid with Lzd Medicines that increase sertnin levels Tricyclic antidepressants: amitriptyline, nrtriptyline Sertnin 5-HT1 receptr agnists MAO inhibitrs: phenelzine, iscarbxazid Other sertninergic agents: meperidine, buprpin, r buspirne, quetiapine * This is nt a cmprehensive list. Dctrs shuld infrm themselves abut ptentially QT-prlnging drugs that their MDR-TB patients may be taking (see CredibleMeds.rg). 8 8 Wsley RL, Black K, Heise CW, Rmer K. CredibleMeds.rg: What des it ffer? Trends Cardivasc Med, pii: S (17) Versin 4.0, January 2018 Page 15 f 69

16 4 Regimen design 4.1 Step-by-step directins fr regimen design The design r cnstructin f a regimen with new TB drugs is dne accrding t WHO interim guidelines fr bedaquiline (2013) and delamanid (2014), and is cnsistent with new WHO recmmendatins prduced in 2016 fr drug-resistant TB and updated guidelines fr bedaquiline (2017). The WHO 2016 guidelines fr DR-TB revised the hierarchy f drug gruping used t treat rifampicin-resistant TB (Grups A t D). "The cnventinal regimen is designed with at least five effective TB medicines during the intensive phase, including pyrazinamide and fur cre secnd-line TB medicines - ne chsen frm grup A, ne frm grup B, and at least tw frm grup C (cnditinal recmmendatin, very lw certainty in the evidence). If the minimum f effective TB medicines cannt be cmpsed as abve, an agent frm grup D2 and ther agents frm D3 may be added t bring the ttal t five." 9 The definitin f an "effective TB medicine" includes bth labratry DST results and the patient's TB treatment histry, including the TB cntact histry. In shrt, clinical judgement is ften necessary t decide whether a specific drug cunts as an effective TB medicine. An anti-tb drug is cnsidered likely t be effective if: 1. The drug has nt been used in a regimen that failed t cure the individual patient. 2. DST perfrmed n the patient s strain indicates that it is susceptible t the drug. 3. N knwn resistance t drugs with high crss-resistance. Fr example, resistance t kanamycin is highly assciated with amikacin resistance. 4. N knwn clse cntacts with resistance t the drug. 5. Drug resistance surveys demnstrate that resistance t the drug is rare in patients with similar TB histry. 10 This is particularly imprtant fr drugs fr which DST is nt rutinely perfrmed. The hierarchy f the building steps is based n evidence f effectiveness f the drug against TB, ptential adverse effects, and the likely backgrund resistance in MDR-TB strains. Table 6 The building steps fr M/XDR-TB regimens Steps Grup Drugs Step 1: Assess the need fr bedaquiline r delamanid: Use Bdq r Dlm in the regimen fr any patient with risk f a pr utcme as detailed in sectin 3.1.2, including patients cming frm catchment areas that have pr MDR-TB treatment utcmes (success < 80%) despite gd prgrammatic cnditins. D2 Bdq Dlm 9 WHO. Treatment guidelines fr DR-TB: 2016 update (WHO/HTM/TB/ ) Table 1, p WHO. Cmpanin handbk t the WHO guidelines fr the prgrammatic management f DR-TB (WHO/HTM/TB/ ) Sectin Versin 4.0, January 2018 Page 16 f 69

17 In sme patients, Bdq r Dlm may be added as a sixth drug in the regimen in rder t maximize the prbability f having five effective drugs (alternatively, Bdq r Dlm can be cunted as ne f the five effective drugs in the regimen). Bdq r Dlm are the first chice in case f cnfirmed r suspected resistance t secnd-line drugs (e.g. XDR r pre-xdr) r intlerance r cntraindicatins t ther secnd-line TB drugs. Bdq and Dlm can be used in the same regimen. Cnsider using bth Bdq and Dlm in all cases f FQ-resistant strains. Add bth D2 drugs if needed t reach five effective drugs in the regimen. Bdq r Dlm are the first chice when substituting anther drug fr the injectable. Step 2. Use a later generatin flurquinlne (FQ). Avid Mfx if pssible when using multiple QT-prlnging drugs. If there is nly lw-level resistance t the FQ, the use f high-dse Mfx (Mfx h ) can be cnsidered; in this case, this drug shuld nt be cunted as effective. Because f their excellent activity against MDRTB and their relatively gd side effect prfile, FQ may still be used in patients when effectiveness is uncertain, but nt cunted as an effective drug. A Lfx Mfx Step 3. Add a secnd-line injectable. Due t high rates f adverse events, injectable are ften nt used unless they are likely t be effective and can be prperly mnitred. When the effectiveness is uncertain (fr example susceptible DST but previusly used in a regimen that did nt cure the patient) the risks and benefits f inclusin in the regimen shuld be discussed with the patient." If a secnd-line injectable is added, clse mnitring f hearing, renal functin and electrlytes is indicated (stp the injectable fr Grade 1 hearing lss r Grade 1 renal txicity). If clse mnitring cannt be dne, use alternative drugs. Avid the injectable in children, the elderly, and HIV patients. B Am Cm Km Step 4. Add tw r mre cre secnd-line drugs. Lzd is cnsidered very effective, but has a high incidence f AEs. If Et/Pt r Cs/Trd have been used in the patient's regimen previusly withut success, they are rarely used due t high rates f adverse events. If they are used in such patients, they shuld nt be cunted as effective drugs. C Lzd Cfz Et / Pt Cs / Trd Step 5. Cnsider first-line drugs. First-line TB drugs are generally f limited utility because they have been used befre, but they can be cnsidered in sme cases. In many cuntries, the prevalence f Z resistance amng MDR-TB strains is significant. In such situatins, Z can be added t the regimen but nt cunted as ne f the 5 effective drugs. If DST demnstrates resistance t Z frm a reliable labratry, cnsider nt adding it t the regimen. In such cases, it shuld nt be cunted as an effective drug. D1 Z H h E Versin 4.0, January 2018 Page 17 f 69

18 High-dse H shuld never be cunted as a likely effective drug. Avid high-dse H with Lzd because f ptential additive txicity f neurpathy. Step 6. Add Grup D3 drugs. Add Grup D3 drugs until there are 5 likely effective drugs in the regimen. When the carbapenems are used, it is advised t als use clavulanate (clavulanic acid). D3 PAS Ipm/Cln Mpm Epm The abve steps d nt make use f the drugs streptmycin r thiacetazne. Given the unclear rle f streptmycin r thiacetazne in imprving efficacy f MDR regimens and the adverse events assciated with these drugs, many clinicians leave these drugs ut cmpletely when designing MDR regimens. If n ther ptins are available, these drugs might be cnsidered fr use in an MDR-TB regimen: Streptmycin is ften resistant in MDR-TB strains and there is almst always an alternative injectables. Use streptmycin nly with dcumented susceptibility, meets criteria fr likely effective, unable t use secnd-line injectable agents, the patient has n histry f injectable ttxicity, and there are n ther ptins t reach five effective drugs in the regimen. Thiacetazne is a weak bacteristatic drug and likely has minimal effect n MDR-TB. It shuld be used nly in HIV-negative patients. It is nt cunted it as a likely effective drug. Table 7 Examples f pssible regimens Patient type Patient is very sick in severe cnditin r with extensive lung damage but has never been treated fr MDR-TB befre ("Simple MDR"; SLD resistance is unlikely). Patients cming frm catchment areas that have pr MDR-TB treatment utcmes despite gd prgrammatic cnditins (e.g. sites with extensive secnd-line drug resistance backgrund). Patient has resistance t injectables n DST r experiencing (r at high risk fr experiencing) ttxicity, r nephrtxicity. Typical MDR Regimen * plus new and repurpsed drugs Typical MDR Regimen plus Dlm r Bdq Typical MDR Regimen plus Dlm r Bdq Typical MDR Regimen with Bdq r Dlm substituted fr the injectable. Lzd can be added if Et/Pt, Cs/Trd r Z is unlikely t be effective r effectiveness is unknwn. Examples Bdq-Lfx-Km-Pt-Cs-Z Dlm-Lfx-Km-Pt-Cs-Z Bdq-Lfx-Km-Pt-Cs-Z Dlm-Lfx-Km-Pt-Cs-Z Bdq-Lfx-Pt-Cs-Z Dlm-Lfx-Pt-Cs-Z Dlm-Lfx-Lzd-Pt-Cs-Z Patient has FQ resistance n Typical MDR Regimen with n FQ plus Bdq-Lzd-Km-Pt-Cs-Z Versin 4.0, January 2018 Page 18 f 69

19 DST. Dcumented XDR-TB Or Patient failed treatment with typical MDR regimen and likely has resistance t injectables and the flurquinlnes ("prbable XDR"). tw f the fllwing: Bdq/Dlm/Lzd. All three can be added if there is ther resistance in additin t the FQ High-dse Mfx can be used in case f lw-level FQ resistance but shuld nt be cunted as an effective drug. Any Grup A-C drugs thught t still be effective plus three t fur Grup D drugs. In the case f failure f an MDR regimen, Et/Pt, Cs and Z usually cannt be cnsidered likely effective. High-dse Mfx can be used in case f lw-level FQ resistance. Bdq-Lzd-Km-Pt-Cs-Z-Mfx H Bdq-Dlm-Km-Pt-Cs-Z Bdq-Dlm-Lzd-Km-Z Bdq-Dlm-Lzd-Cfz-Cs-PAS Bdq-Dlm-Lzd-Cfz-Et-Cs Bdq-Dlm-Lzd-Cfz-Cs-PAS- Mfx H Bdq-Dlm-Lzd-Cfz-Et-Cs- Ipm/Cln-Amx/Clv * "Typical MDR Regimen" means the 2016 WHO-recmmended MDR regimen which is typically cmpsed designed with at least five effective TB medicines during the intensive phase, including pyrazinamide and fur cre secnd-line TB medicines ne chsen frm grup A, ne frm grup B, and at least tw frm grup C. Examples are nt cmprehensive. Always refer t "hw t build a regimen" principles. 4.2 Operatinal research n shrter standardized regimens using the new and repurpsed TB drugs Sme prgrams may chse t cnduct peratinal research using shrter standardized regimens with new and repurpsed TB drugs. Standardized regimens shuld nly be implemented under peratinal research cnditins, with a research prtcl and additinal ethical apprval, enhanced mnitring and analysis and disseminatin f results. A study prtcl template fr mdified shrter MDR-TB regimens using new and repurpsed TB drugs is available frm the Glbal Drug-resistant TB Initiative (GDI) website ( and assistance in adapting the prtcl t lcal cntexts can be requested. Examples f shrter standardized MDR-TB regimens with new and repurpsed TB drugs which culd be used under peratinal research cnditins include: 9 Bdq-Lzd-Mfx-Z 9 Bdq-Cfz-Lzd-Lfx-Z 9 Bdq-Dlm-Lzd-Lfx-Z 9 Dlm-Cfz-Lzd-Lfx-Z 9 Dlm-Cfz-Mfx-Z Examples f shrter standardized XDR-TB regimens with new and repurpsed TB drugs which culd be used under peratinal research cnditins include: 9 Bdq-Dlm-Lzd-Cfz The abve regimens have the advantage f being part f planned endtb clinical trials. Treatment utcmes and adverse events must be reprted. Psitive (r negative) results f peratinal research n the abve regimens can eventually be validated by the endtb clinical trials. Versin 4.0, January 2018 Page 19 f 69

20 4.3 Interpretatin f phentypic and gentypic DST results Drug Ntes H Resistance t H is classified as either high-level (MIC >2 µg/ml) r lw-level (MIC µg/ml) resistance. A katg mutatin cnfers high-level resistance t H; inha cnfers lw-level resistance t H. Sme clinicians will use high-dse H when if DST shws lw-level resistance, but there is very limited clinical evidence t supprt this practice. Z Sequencing f the pnca gene may be helpful in determining pyrazinamide resistance. Phentypic testing Z can be dne in qualified labratries. FQ A gyra mutatin cnfers high-level resistance acrss the class f FQ. FQ (including Mfx H ) is shuld nt be used in such cases. The definitins f lw- and high-level resistance are based n the latest expert cnsultatin and are subject t change: Lw-level resistance t the FQ is defined as resistance in MGIT t Ofx at 2.0 mg/l r Lfx at 1.0 mg/l r Mfx at 0.25 mg/l) but susceptible t high-level Mfx at 1.0 mg/l (cut-ff values differ in Lwenstein Jensen (LJ), Middlebrk 7H10 and 7H11 medium). Mfx H may be used in such cases, but shuld nt be cunted as an effective drug. High-level resistance t the FQ is defined as resistance t Mfx in MGIT at 1.0 mg/l. Mfx H is unlikely t be effective in such cases. Injectable An rrs mutatin is thught t cnfer crss-resistance t all injectables, including mderate resistance t Cm. An eis prmtr mutatin is thught t cnfer lw-level resistance t Km, Am, and Cm. Sme clinicians will use Am r Cm in the presence f the eis prmtr mutatin while thers are f the pinin that the side effect prfile and the lw level resistance assciated with the eis mutatin des nt justify the use f Am r Cm if ther drugs are available. In such cases, Am r Cm shuld nt be cunted as an effective drug. Et/Pt The inha mutatin cnfers crss-resistance t H and Et/Pt; katg mutatin cnfers resistance t H but nt t Et/Pt. If inha mutatin is present, then Et/Pt shuld nt be used. In the absence f inha mutatin, the clinical histry shuld be taken int cnsideratin, since there are ther mutatins that cnfer resistance t Et/Pt (e.g. etha) that are nt tested in cmmercially available LPA. Phentypic testing t Et/Pt can be dne in qualified labratries. Cs, PAS Phentypic testing f PAS and Cs/Trd can be dne in qualified labratries. Hwever, labratries utside f the supranatinal labratry netwrk are increasingly pting nt t d these tests because f difficulty in btaining reliable results. Versin 4.0, January 2018 Page 20 f 69

21 Lzd, Cfz, Bdq, Dlm Phentypic testing f these drugs is limited t supranatinal labratries and generally cnsidered reliable. The clinical significance f these results, hwever, is still unclear. 4.4 Hw t chse between bedaquiline and delamanid Factrs t be taken in cnsideratin when deciding between bedaquiline and delamanid: There is currently mre experience with the use f bedaquiline 11,12,13,14 in the treatment f XDR-TB than there is fr delamanid 15. Delamanid's excellent safety prfile was cnfirmed in the phase III clinical trial. There was als quicker culture cnversin in sme f the analyses, but n significant effect n final treatment utcme. Bedaquiline has nt cmpleted its phase III clinical trial. Delamanid has less drug-drug interactin with ART and ther drugs metablized by the cytchrme P450 enzymes like CYP3A4. There is theretical crss-resistance between clfazimine and bedaquiline. 4.5 Dsing f new and repurpsed drugs Table 8 Dsing f new and repurpsed drugs in adults Drug Suggested dsing* Remarks Bdq (100 mg tablets) 400 mg nce daily fr 2 weeks, then 200 mg 3 times per week afterwards. Minimum 48 hurs between dses after the first 2 weeks. Dlm (50 mg tablets) 100 mg twice daily (200 mg ttal daily dse). 7 days per week. Lzd (600 mg tablets) 600 mg nce daily fr duratin f treatment 7 days per week is preferred, althugh many prgrams use 6 days a week dsing. Alternative dsing regimens fr patients with adverse effects: 600 mg thrice weekly (MWF), r 300 mg daily. 11 Guglielmetti L, Jaspard M, Le Du D, Lachatre M, Marigt-Outtandy D, et al. Lng-term utcme and safety f prlnged bedaquiline treatment fr multidrug-resistant tuberculsis. Eur Respir J 2017; 49(3): Ndjeka N, Cnradie F, Schnippel K, Hughes J, Bantubani N, et al. Treatment f drug-resistant tuberculsis with bedaquiline in a high HIV prevalence setting: an interim chrt analysis. Int J Tuberc Lung Dis 2015; 19(8): Pym AS, Diacn AH, Tang SJ, Cnradie F, Danilvits M, et al. Bedaquiline in the treatment f multidrugand extensively drug-resistant tuberculsis. Eur Respir J 2016; 47(2): Udwadia ZF, Ganatra S, Mullerpattan JB. Cmpassinate use f bedaquiline in highly drug-resistant tuberculsis patients in Mumbai, India. Eur Respir J 2017; 49(3). 15 Hewisn C, Ferlazz G, Avaliani Z, Hayrapetyan A, Jnckheere S, et al. Six-mnth respnse t delamanid treatment in MDR TB patients. Emerg Infect Dis 2017; 23(10). di: /eid Versin 4.0, January 2018 Page 21 f 69

22 Cfz (50, 100 mg gel capsules) 200 mg nce daily fr 2 mnths, fllwed by 100 mg daily fr duratin f treatment 7 days per week is preferred, althugh many prgrams use 6 days a week dsing fr cnvenience. Ipm/Cln** (ne vial has Ipm 500 mg and Cln 500 mg) and ther carbapenems Ipm/Cln: 1 g IV twice daily (based n the Ipm cmpnent); tw vials administered as a minute infusin twice daily (ttal f fur vials daily). Minimum f 10 hurs between infusins. Mpm: 2 g IV three times a day. Epm: 2 g IV nce daily. 7 days per week during hspitalizatin r at the start f treatment: 6 days per week during the ambulatry phase is allwed. The first dse always in health care setting supplied with anti-shck kit. Duratin depends n the number f effective drugs in the regimen. At least 4 effective drugs after culture cnversin until the end f treatment is strngly advised. Sme patients with highly resistant strains may require Ipm/Cln fr the entire duratin f treatment. Amx/Clv 875/125 tablets r 1000/200 pwder fr injectin If dsing as adjunctive therapy with a carbapenem: Dse based n the clavulanic acid cmpnent, 125 mg 60 minutes rally befre the IV infusin f the carbapenem. Or 200 mg IV 30 minutes befre the IV infusin f the carbapenem. Amx/Clv shuld be added when a carbapenem is being used. A carbapenem is the preferred beta-lactam antibitic when ne is indicated; hwever, if a carbapenem is nt available, sme prgrams may chse t use Amx/Clv instead. If dsing as a Grup 5 drug in the regimen withut a carbapenem, dse based n the amxicillin cmpnent (max daily dse is 3000 mg f amxicillin): Adults and children: 80 mg/kg/day f amxicillin cmpnent in 2 divided dses. * All duratins are the full length f the MDR-TB treatment unless therwise nted. ** Patients n Ipm/Cln require lng-term access t central veins because f twice daily IV injectins. Implantable access systems such as "Prt-a-cath" are the preferred ptin: While nt required t receive imipenem, the placement f a Prt-a-cath makes lng-term injectin f imipenem mre cnvenient, mre hygienic, and less damaging t peripheral veins than relying n repeated twice-daily injectins f imipenem. Prt-a-cath insertin is a minr surgical prcedure that needs 30 min t 1 hur. Stitches are remved n pst-perative day Typically the delivery f fluids and medicatins is dne thrugh a special nn-cring needle inserted thrugh the skin and changed nce per week, ideally taken ut n Saturday evening and replaced n Mnday mrning s that the patient can have a day withut the needle (t have a shwer and wash hair as the site is nt suppsed t get wet when the needle is inserted). 4.6 Duratin f bedaquiline and delamanid One f the mst cmmn misunderstandings amng clinicians is that bedaquiline and delamanid can nly be prescribed fr 24 weeks. In fact, these drugs shuld be prescribed fr a minimum f 24 weeks, and may be extended until the entire length f treatment. Versin 4.0, January 2018 Page 22 f 69

23 The endtb patients are ften heavily previusly treated and DST shws extensive drug resistance. There is n need t stp bedaquiline and delamanid if these the nly last safe and effective drugs. Ding s risks reversin even after culture cnversin. 16 Other studies have shwn gd safety f prlnged use f bedaquiline 17 and endtb pharmacvigilance thrugh 2017 have nt demnstrated any unexpected safety cncerns fr either bedaquiline r delamanid. Treatment shuld therefre be extended at the clinical discretin f the prescribing dctr under apprpriate mnitring. Cmmn reasns fr extending bedaquiline r delamanid lnger than 24 weeks include: Less than five effective drugs in the regimen if Bdq r Dlm is stpped. Late r slw respnse t treatment. Fr example, the patient is slw t sputum cnvert (still strngly smear r culture psitive after mnth 2), has slw reslutin f TB symptms, r has extensive lung damage. The cnsent frms fr bedaquiline r delamanid have been mdified t cnsent t 24 weeks r mre f treatment. There is n need t seek a secnd signed cnsent fr extended use f bedaquiline r delamanid. The extended use f bedaquiline and delamanid shuld be discussed with the patient in all cases; it is always recmmended t dcument such discussins in the medical chart. 4.7 Off-label use f new and repurpsed TB drugs Off-label use is defined as use fr indicatin, dsage frm, dse regimen, ppulatin r ther use parameter nt mentined in the apprved labeling. It may als include using f the medicine in an age grup, in a dsage r in a frm f administratin different frm the ne f riginal apprval. A number f MDR-TB drugs, such as flurquinlnes, sme secnd-line injectable agents, clfazimine and linezlid, have been "repurpsed" fr use in TB and are used rutinely as fflabel. As is the case fr many TB drugs, ff-label use is ften recmmended in WHO guidelines. Fr example, delamanid is recmmended by WHO fr children lder than six years. Hwever, such practice is currently ff-label until the Eurpean Medical Agency updates the registratin f delamanid. Furthermre, the lack f a WHO recmmendatin is nt synnymus with ff-label use. The cncmitant use f bedaquiline and delamanid tgether is nt regarded as ff-label, since bth drugs are being used accrding t their indicatins. 18 Clinicians shuld cnsult experts when treating difficult cases. Cuntries ften have set up MDR- TB cmmittees r "cnsilia" fr this purpse. The endtb Medical Cmmittee is available t give advice t any clinician, whether r nt they wrk at an endtb site. 16 Sinha A, Tassew Y, Khusainva Z, et al. Effectiveness f TB treatment regimens cntaining bedaquiline with repurpsed drugs fr drug-resistant tuberculsis in the Chechen Republic, Russian Federatin. Abstract OA [Online] [Cited 2017 May 16]. Available frm: 17 Guglielmetti L, Jaspard M, Le Du D, Lachatre M, Marigt-Outtandy D, et al. Lng-term utcme and safety f prlnged bedaquiline treatment fr multidrug-resistant tuberculsis. Eur Respir J 2017; 49(3): pii: WHO. WHO best-practice statement n the ff-label use f bedaquiline and delamanid fr the treatment f multidrug-resistant tuberculsis (WHO/HTM/TB/ ). WHO: Geneva, Versin 4.0, January 2018 Page 23 f 69

24 4.7.1 Children Table 9 Treatment f children with new and repurpsed drugs 19 Drugs Experience t date Dsing Bdq Dlm Lzd Cfz Ipm/Cln Enrllment in clinical trials is nging. There is als experience in cmpassinate and prgrammatic use in children. 20 Studies f the pharmackinetics f Bdq in children are nt yet cmpleted. N recmmendatin by the WHO. Enrllment in clinical trials is nging. There is als experience in cmpassinate and prgrammatic use in children. Dlm pharmackinetics in lder children (6-17 years) has been studied by the manufacturer. Dlm is recmmended by WHO fr use in this age grup based n this data. 21 Study f pharmackinetics f Dlm in yunger children is nging. There is experience with prgrammatic use in children. The pharmackinetics f Lzd has been studied in children in multiple clinical trials, but nt in children with TB. There is experience with prgrammatic use in children bth in TB and leprsy. Pharmackinetics f clfazimine in children has nt been studied. Pharmackinetics f imipenem and have been studied in children (including premature infants). > 12 years and > 33 kg: 400 mg daily fr 14 days fllwed by 200 mg three times a week (same as adult dse) < 12 years r < 33 kg: crrect dse is unknwn, but 6 mg/kg fr 2 weeks, then 3 mg/kg afterwards may be tried. > 35 kg: 100 mg twice daily (same as adult dse) kg: 50 mg twice daily < 20 kg: crrect dse is unknwn, but 3-4 mg/kg may be tried. >= 12 years: 10 mg/kg nce daily < 12 years: 10 mg/kg twice daily 2-3 mg/kg daily r every ther day fr a maximum daily dse f 100 mg (gelcaps cannt be split) 3 mnths t <3 years: 25 mg/kg/dse 3-12 years: 15 mg/kg/dse 19 Harausz EP, Garcia-Prats AJ, Seddn JA, et al. Sentinel Prject n Pediatric Drug-Resistant Tuberculsis. New and repurpsed drugs fr pediatric multidrug-resistant tuberculsis. practice-based recmmendatins. Am J Respir Crit Care Med 2017; 195(10): Achar J, Hewisn C, Cavalheir AP, et al. Off-label use f bedaquiline in children and adlescents with multidrug-resistant tuberculsis. Emerg Infect Dis 2017; 23(10). 21 WHO. The use f delamanid in the treatment f multidrug-resistant tuberculsis in children and adlescents: interim plicy guidelines (WHO/HTM/TB/ ). WHO: Geneva, Versin 4.0, January 2018 Page 24 f 69

25 4.7.2 Pregnancy r lactatin In MDR-TB patients wh are pregnant, the main bjective is t design a regimen that is effective and likely t cure the mther. The highest risk t bth mther and fetus is frm inadequately treated MDR-TB. While drugs with identified teratgenic risks may be nt primary chices, the ptential teratgenic impact f these drugs shuld be cnsidered in perspective f the risks t the mther/baby/family/cmmunity f nt treating the mther with an apprpriate regimen. The fllwing table summarizes the limited evidence abut the safety f new and repurpsed TB drugs in pregnant and lactating wmen. Little is knwn abut the safety f ther MDR-TB drugs as well, but drugs like injectables and ethinamide are generally avided during pregnancy. Table 10 Treatment f pregnant r lactating wmen with new and repurpsed drugs Drugs Bdq Dlm Lzd Cfz Ipm/Cln US FDA safety class B Nt yet assigned an FDA safety class. C C C Summary Animal studies have nt revealed any evidence f harm t the fetus r any effects n fertility in females; sme males treated with high dses failed t prduce ffspring. There are n cntrlled data in human pregnancy. 22 Pharmackinetic data in rats treated with dses 1-2 times the human clinical dse have shwn 6- t 12-fld higher bedaquiline cncentratins in milk than the maximum cncentratins bserved in maternal plasma. In rabbits reprductive studies, embry-fetal txicity was bserved at maternally txic dsages. Avid in pregnancy; hwever the benefits in patients with n ther ptins may utweigh the risks. Pharmackinetic data in animals have shwn excretin f delamanid /metablites int breast milk. In lactating rats, the Cmax fr delamanid in breast milk was 4-fld higher than that f the bld. Animal studies have failed t reveal evidence f teratgenicity, but embryfetal txicity was bserved at materntxic dses. Placental transfer f this drug and/r its metablites was bserved in rats. There are n cntrlled data in human pregnancy. There are n studies f clfazimine use in pregnant wmen. Few cases f clfazimine use during pregnancy have been reprted in the literature. Embryfetal txicity studies were cnducted in rats, rabbits and mice. In mice, clfazimine-induced embrytxicity and fettxicity was evident. Develpmental txicity studies with imipenem and cilastatin sdium (alne r in cmbinatin) administered t mnkeys, rabbits, rats, and mice revealed n evidence f teratgenicity. Hwever, an imipenem-cilastatin dse f 40 mg/kg given t pregnant mnkeys by blus intravenus injectin caused significant maternal txicity including death and embryfetal lss. 22 Jaspard M, Elefant-Amura E, Melni I, De Mntglfier I, Veziris N, et al. Bedaquiline and linezlid fr extensively drug-resistant tuberculsis in pregnant wman. Emerg Infect Dis 2017; 23(10). di: /eid Versin 4.0, January 2018 Page 25 f 69

26 It is nt knwn whether imipenem-cilastatin sdium is excreted in human milk. *A=Safety established using human studies; B=Presumed safety based n animal studies; C=Uncertain safety, n human studies and animal studies shw an adverse effect; D=Unsafe, evidence f risk that may be justifiable under certain clinical circumstances Extrapulmnary TB Table 11 Treatment f extrapulmnary TB with new and repurpsed drugs Drugs Recmmendatins Bdq Dlm Lzd Cfz Ipm/Cln Mpm Very limited experience with Bdq in TB meningitis r TB stemyelitis. One patient with meningitis had undetectable levels f Bdq in CSF. 23 Drug is prtein bund and likely has lw penetratin int the CSF. Very limited experience with Dlm in TB meningitis r TB stemyelitis. Drug is prtein bund and likely has lw penetratin int the CSF. Excellent bne and sft-tissue penetratin; cmmnly used fr stemyelitis due t gram-psitive bacteria. Cfz has been used extensively t treat leprsy lesins in sft tissue, thugh it is unclear if this means that bne and sft tissue penetratin is adequate. Bth Ipm/Cln and Mpm reach measurable cncentratins in CSF, but Mpm is thught t be less neurtxic (seizures). Bth drugs have been used t treat stemyelitis caused by ther bacteria. 4.8 Special ppulatins Table 12 Special ppulatins Situatin Recmmendatins HIV Antiretrviral therapy (ART) shuld be given t any HIV c-infected MDR-TB patient withut delay. ART can be started as sn as MDR-TB treatment is tlerated usually within a few days. The risk f immune recnstitutin syndrme can be mitigated by designing an apprpriate MDR-TB regimen. Bedaquiline has imprtant interactins with ART that will affect the chice f ART (see sectin 3.3.2). 23 Akkerman OW, Odish OF, Blhuis MS, et al. Pharmackinetics f bedaquiline in cerebrspinal fluid and serum in multidrug-resistant tuberculus meningitis. Clin Inf Dis 2016; 62(4): Versin 4.0, January 2018 Page 26 f 69

27 Chrnic renal insufficiency Hepatitis C Bedaquiline and delamanid are nt renally excreted and n dse adjustment is required in mild/mderate renal insufficiency. There is n data n the use f either f these drugs in patients with severe renal impairment. N dse adjustment f linezlid is required in patients with renal impairment; hwever, the tw primary metablites f linezlid accumulate in patients with renal impairment and the clinical significance f this is unknwn. N dse adjustment f clfazimine is required in patients with renal impairment. MDR-TB is strngly crrelated with hepatitis C infectin in many cuntries. Active hepatitis C is a risk factr fr MDR-TB treatment failure. Direct-acting antivirals (DAA) are well-tlerated when given with MDR-TB treatment. Versin 4.0, January 2018 Page 27 f 69

28 5 Patient cnsent 5.1 Patient cnsent After prviding the patient educatin material t the patient, cnsent in patients starting new TB drugs must be btained. The cnsent prcess will ensure the patient is: Aware f the nvel nature f the new TB drug; Appreciates the reasn why the drug is being prpsed t be included in their treatment regimen; Recgnizes the pssible benefits and ptential harms, including the uncertainty that surrunds utcmes. In the case f bedaquiline, the infrmed cnsent will be dcumented with a signature f the patient. In the case f delamanid, the infrmed cnsent will be dcumented with a signature frm the patient (r if allwed by lcal standards patient cnsent can be verbal). Fr patients cnsidered minr r incapacitated by natinal law, cnsent frm the legal representative is additinally required. 5.2 Example f medicatin guide and patient cnsent fr the clinical use f bedaquiline and delamanid. Belw are examples a medicatin guide and cnsent fr bedaquiline and delamanid. All patients shuld be infrmed f the risks and benefits f the new TB drugs befre treatment. Patients shuld nt be cerced int taking the new TB drugs. The infrmatin in the examples belw shuld be prvided t the patient in a ne-n-ne setting. If the patient is illiterate all parts f the medicatin guide shuld be read and explained t the patient. The patient shuld be given the pprtunity t ask questins and take adequate time befre making a decisin n whether r nt t cnsent t treatment with new TB drugs. Versin 4.0, January 2018 Page 28 f 69

29 MEDICATION GUIDE AND CONSENT FOR BEDAQUILINE What is the mst imprtant infrmatin I shuld knw abut bedaquiline? Bedaquiline is a drug used t treat multidrug-resistant tuberculsis (MDR-TB) lungs in peple with limited treatment ptins. MDR-TB is a serius disease that can result in death, and fr which there are few treatment chices. It is imprtant t cmplete the full curse f treatment f bedaquiline and yur ther TB medicines and nt skip dses. Skipping dses may decrease the effectiveness f the treatment and increase the likelihd that yur TB disease will nt be treatable by bedaquiline r ther medicines. It is nt knwn if bedaquiline is safe in: Children under 18 years. In pregnancy. In frms f TB that is nt drug-resistant r nt in the lungs. In patients with heart, kidney, liver r ther health prblems. Befre yu take bedaquiline, tell yur healthcare prvider if: Yu have had an abnrmal heart rhythm r ther heart prblems. Anyne in yur family has r has had a heart prblem called cngenital lng QT syndrme. Yu have liver r kidney prblems r any ther medical cnditins, including HIV infectin. Yu are pregnant r plan t becme pregnant. It is nt knwn if bedaquiline will harm yur unbrn baby. Yu are breastfeeding r plan t breastfeed. It is nt knwn if bedaquiline passes int breast milk. Yu and yur healthcare prvider shuld decide if yu will take bedaquiline r breastfeed. Yu are taking any prescriptin and nnprescriptin medicines, vitamins and herbal supplements. Hw shuld I take bedaquiline? Bedaquiline must always be taken with ther medicines t treat TB. Yur healthcare prvider will decide which ther medicines yu shuld take with bedaquiline. Always take bedaquiline with a light meal (nt heavy in fat). Swallw the tablets whle with water. Take bedaquiline fr a minimum f 24 weeks (6 mnths). Yu may be prescribed lnger than 6 mnths by yur clinician wh will discuss this with yu unless therwise prescribed by yur clinician. Week 1 and Week 2: Take 400 mg (4 tablets) nce a day, 7 days a week. Week 3 t Week 24 (r end f prescribed duratin): Take 200 mg (2 tablets) thrice a week. Fr example, yu may take bedaquiline n Mnday, Wednesday and Friday f every week. Versin 4.0, January 2018 Page 29 f 69

30 Yu will need t take yur ther TB medicines fr lnger than 24 weeks, and at least fr 20 mnths in ttal (the injectable drug is usually given fr up t 8 mnths). Yur treatment will be prvided under directly bserved treatment (DOT), with a patientcentred apprach, which means that a healthcare prvider will accmpany yu during the treatment. D nt skip bedaquiline dses. If yu skip dses, r d nt cmplete the ttal prescribed treatment f bedaquiline yur treatment may nt wrk as well and yur TB may be harder t treat. If fr sme reasn yu miss a dse, infrm the persn respnsible fr yur treatment right away, they will tell yu what t d. What shuld I avid while taking bedaquiline? Yu shuld nt drink alchl while taking bedaquiline. What are the pssible side effects f bedaquiline? Serius heart rhythm changes. Tell yur health-care prvider right away if yu have a change in yur heartbeat (a fast r irregular heartbeat), r if yu faint. Yur heart will be mnitred peridically with a machine that checks that the heart rhythm is nrmal. Liver prblems (hepattxicity). Liver txicity can present in many ways. Tell yur dctr f symptms such as nausea r vmiting, stmach pain, fever, weakness, itching, unusual tiredness, lss f appetite, light clured bwels, dark clred urine, yellwing f yur skin r yellwing f the white f yur eyes. Other side effects f bedaquiline include nausea, jint pain, headache, an abnrmal labratry test assciated with damage t the pancreas, cughing up bld, chest pain, lss f appetite, and/r rash. It is pssible that it may als cause sme prblems that we are nt aware f. Hwever, yu will be fllwed clsely fr any unwanted effects r any prblems. Other medicines t decrease the symptms f the side effects r reactins may als be given. Always tell yur health-care prvider f any side effects r prblems yu are having. Smetimes because f side effects bedaquiline r ther drugs may need t be stpped. What mnitring tests d I need while n bedaquiline? Yu will need the same mnitring test that all patients n MDR-TB treatment need. In additin, yu will need heart mnitring, extra bld tests fr the liver and yur electrlytes. Talk t yur health-care prvider n the schedule f all yur mnitring tests and regular dctr visits. General infrmatin abut the risks versus the benefits f taking bedaquiline RISK: It is pssible that yu will be at greater risk than yu wuld therwise be f certain side effects due t the drug. It is pssible that a side effect culd be serius and even result in death. BENEFIT: There is a greater chance that yu will be cured f tuberculsis than if yu did nt take the medicine. Yu will pssibly als becme better very much sner than if yu Versin 4.0, January 2018 Page 30 f 69

31 nly tk the standard medicines fr treatment f resistant TB. Als, it is less likely that the drugs yu are taking will develp resistance if yu are taking bedaquiline. Cnfidentiality and sharing infrmatin Because bedaquiline is a new drug fr which we have limited experience we are cllecting infrmatin n patients taking them. The infrmatin that we cllect frm yu will be kept cnfidential and n ne but the clinical staff will be able t see yur medical infrmatin. Any infrmatin cllected t help us better use the drug in patients will be unlinked t yur name (made annymus) befre we share r analyse it. Right t refuse r withdraw Yu d nt have t agree t take bedaquiline if yu d nt wish t d s, and refusing t accept the drug as part f yur treatment schedule will nt affect yur treatment at this clinic in any way. Yu will still have all the benefits that yu wuld therwise have at this clinic. If yu agree t take bedaquiline, yu may als at any pint after yu start wish t stp withut lsing any f yur rights as a patient here. Yur treatment at this clinic will nt be affected in any way. Cntact persn If yu have any questins, yu may cntact any f the fllwing persns: Name. Title. Phne. Name. Title. Phne. Name. Title. Phne. Name f respnsible physician: Name f clinic/hspital/institutin: Versin 4.0, January 2018 Page 31 f 69

32 Statement frm the patient: TREATMENT CONSENT I have read the prvided Medicatin Guide, r it has been read t me. I have had the pprtunity t ask questins abut it and any questins that I have asked have been answered t my satisfactin. I cnsent t receive bedaquiline fr treating the drug-resistant tuberculsis disease that I am suffering frm. Print Name f Patient: Signature f Patient: Date: (Day/mnth/year) If illiterate, a literate witness must sign. (If pssible, this persn shuld be selected by the participant and shuld have n cnnectin t the care prviders). Patients wh are illiterate shuld include their thumbprint. Statement frm the witness: I have witnessed the accurate reading f the cnsent frm t the ptential recipient f bedaquiline, and the individual has had the pprtunity t ask questins. I cnfirm that the individual has given cnsent freely. Print name f witness: AND Thumbprint f patient Signature f witness: Date: (Day/mnth/year) Statement frm the persn taking cnsent: I cnfirm that the participant was given an pprtunity t ask questins abut the treatment, and all the questins asked by the participant have been answered crrectly and t the best f my ability. I cnfirm that the individual has nt been cerced int giving cnsent, and the cnsent has been given freely and vluntarily. A cpy f this infrmed cnsent frm has been prvided t the participant. Print name f persn taking the cnsent: Signature f persn taking the cnsent: Date: (Day/mnth/year) Versin 4.0, January 2018 Page 32 f 69

33 MEDICATION GUIDE AND CONSENT FOR DELAMANID What is the mst imprtant infrmatin I shuld knw abut delamanid? Delamanid is a drug used t treat multidrug-resistant tuberculsis (MDR-TB) lungs in peple with limited treatment ptins. MDR-TB is a serius disease that can result in death, and fr which there are few treatment chices. It is imprtant t cmplete the full curse f treatment f delamanid and yur ther TB medicines and nt skip dses. Skipping dses may decrease the effectiveness f the treatment and increase the likelihd that yur TB disease will nt be treatable by delamanid r ther medicines. It is nt knwn if delamanid is safe in: Children under 6 years. In pregnancy. In frms f TB that is nt drug-resistant r nt in the lungs. In patients with heart, kidney, liver r ther health prblems. Befre yu take delamanid, tell yur healthcare prvider if: Yu have had an abnrmal heart rhythm r ther heart prblems. Anyne in yur family has r has had a heart prblem called cngenital lng QT syndrme. Yu have liver r kidney prblems r any ther medical cnditins, including HIV infectin. Yu are pregnant r plan t becme pregnant. It is nt knwn if delamanid will harm yur unbrn baby. Yu are breastfeeding r plan t breastfeed. It is nt knwn if delamanid passes int breast milk. Yu and yur healthcare prvider shuld decide if yu will take delamanid r breastfeed. Yu are taking any prescriptin and nnprescriptin medicines, vitamins and herbal supplements. Hw shuld I take delamanid? Delamanid must always be taken with ther medicines t treat TB. Yur healthcare prvider will decide which ther medicines yu shuld take with delamanid. Always take delamanid with a light meal (nt heavy in fat). Swallw the tablets whle with water. Take delamanid fr a minimum f 24 weeks (6 mnths) unless therwise prescribed by yur clinician. Take 100 mg (2 tablets) early in the mrning and again 100 mg (2 tablets) in the evening, every day f the week (including the weekends). Yu will need t take yur ther TB medicines fr lnger than 24 weeks, and at least fr 20 mnths in ttal (the injectable drug is usually given fr up t 8 mnths). Versin 4.0, January 2018 Page 33 f 69

34 Yur treatment will be prvided under directly bserved treatment (DOT), with a patientcentred apprach, which means that a healthcare prvider will accmpany yu during the treatment. D nt skip delamanid dses. If yu skip dses, r d nt cmplete the ttal prescribed treatment f delamanid yur treatment may nt wrk as well and yur TB may be harder t treat. If fr sme reasn yu miss a dse, infrm the persn respnsible fr yur treatment right away, they will tell yu what t d. What shuld I avid while taking delamanid? Yu shuld nt drink alchl while taking delamanid. What are the pssible side effects f delamanid? Serius heart rhythm changes. Tell yur health-care prvider right away if yu have a change in yur heartbeat (a fast r irregular heartbeat), r if yu faint. Yur heart will be mnitred peridically with a machine that checks that the heart rhythm is nrmal. Other side effects f delamanid include nausea, vmiting, and dizziness. Other imprtant adverse drug reactins are anxiety, paraesthesia, and tremr. Tell yur dctr f symptms such as nausea r vmiting, dizziness, anxiety, itching, r tremr. It is pssible that it may als cause sme prblems that we are nt aware f. Hwever, yu will be fllwed clsely fr any unwanted effects r any prblems. Other medicines t decrease the symptms f the side effects r reactins may als be given. Always tell yur health-care prvider f any side effects r prblems yu are having. Smetimes because f side effects delamanid r ther drugs may need t be stpped. What mnitring tests d I need while n delamanid? Yu will need the same mnitring test that all patients n MDR-TB treatment need. In additin, yu will need heart mnitring, extra bld tests fr the liver and yur electrlytes. Talk t yur health-care prvider n the schedule f all yur mnitring tests and regular dctr visits. General infrmatin abut the risks versus the benefits f taking delamanid RISK: It is pssible that yu will be at greater risk than yu wuld therwise be f certain side effects due t the drug. It is pssible that a side effect culd be serius and even result in death. BENEFIT: There is a greater chance that yu will be cured f tuberculsis than if yu did nt take the medicine. Yu will pssibly als becme better very much sner than if yu nly tk the standard medicines fr treatment f resistant TB. Als, it is less likely that the drugs yu are taking will develp resistance if yu are taking delamanid. Cnfidentiality and sharing infrmatin Because delamanid is a new drug fr which we have limited experience we are cllecting infrmatin n patients taking them. The infrmatin that we cllect frm yu will be kept cnfidential and n ne but the clinical staff will be able t see yur medical infrmatin. Versin 4.0, January 2018 Page 34 f 69

35 Any infrmatin cllected t help us better use the drug in patients will be unlinked t yur name (made annymus) befre we share r analyse it. Right t refuse r withdraw Yu d nt have t agree t take delamanid if yu d nt wish t d s, and refusing t accept the drug as part f yur treatment schedule will nt affect yur treatment at this clinic in any way. Yu will still have all the benefits that yu wuld therwise have at this clinic. If yu agree t take delamanid, yu may als at any pint after yu start wish t stp withut lsing any f yur rights as a patient here. Yur treatment at this clinic will nt be affected in any way. Cntact persn If yu have any questins, yu may cntact any f the fllwing persns: Name. Title. Phne. Name. Title. Phne. Name. Title. Phne. Name f respnsible physician: Name f clinic/hspital/institutin: Versin 4.0, January 2018 Page 35 f 69

36 Statement frm the patient: TREATMENT CONSENT I have read the prvided Medicatin Guide, r it has been read t me. I have had the pprtunity t ask questins abut it and any questins that I have asked have been answered t my satisfactin. I cnsent t receive delamanid fr treating the drug-resistant tuberculsis disease that I am suffering frm. Print Name f Patient: Signature f Patient: Date: (Day/mnth/year) If illiterate, a literate witness must sign. (If pssible, this persn shuld be selected by the participant and shuld have n cnnectin t the care prviders). Patients wh are illiterate shuld include their thumbprint. Statement frm the witness: I have witnessed the accurate reading f the cnsent frm t the ptential recipient f delamanid, and the individual has had the pprtunity t ask questins. I cnfirm that the individual has given cnsent freely. Print name f witness: AND Thumbprint f patient Signature f witness: Date: (Day/mnth/year) Statement frm the persn taking cnsent: I cnfirm that the participant was given an pprtunity t ask questins abut the treatment, and all the questins asked by the participant have been answered crrectly and t the best f my ability. I cnfirm that the individual has nt been cerced int giving cnsent, and the cnsent has been given freely and vluntarily. A cpy f this infrmed cnsent frm has been prvided t the participant. Print name f persn taking the cnsent: Signature f persn taking the cnsent: Date: (Day/mnth/year) Versin 4.0, January 2018 Page 36 f 69

37 6 Mnitring schedule 6.1 Mnitring schedule fr patient fllw-up Patient shuld underg apprpriate fllw-up at baseline, during and after treatment, including clinical evaluatin, bacterilgical and labratry testing as described in the fllwing table. The baseline visit refers t the beginning f the treatment with new TB drugs: this can ccur at any mment during the treatment curse f drug-resistant TB. The mnitring schedule shuld be applied t patients receiving any treatment regimen cntaining new TB drugs, regardless f the cmpsitin f the regimen. Additinal remarks: The labratry and ECG fllw-up shuld be cntinued at mnthly intervals fr all the duratin f treatment with bedaquiline and/r delamanid (i.e. fr lnger than 6 mnths in case f treatment prlngatin beynd 24 weeks) Mre frequent mnitring may be advisable in specific categries f patients, including elderly peple, patients infected with HIV, affected by HBV- r HCV-related hepatitis, diabetes mellitus, with mderate t severe hepatic r renal impairment, r receiving specific drug cmbinatins (i.e. bedaquiline and delamanid) In case f electrlyte disturbances r ECG abnrmalities, mre frequent mnitring shuld be perfrmed as described in the chapter n clinical management f adverse events f interest (Sectin 7.3.7) Mre frequent albumin dsing (i.e. mnthly) may be indicated during treatment with delamanid in specific cases, i.e. in patients with Grade 2 r wrse Hypalbuminemia (<30 g/l) at baseline, r in patients experiencing QT interval prlngatin as described in Sectin If sputum culture psitive at Mnth 4 f treatment, baseline and Mnth 4 respiratry specimens shuld be sent t the Supranatinal Reference Labratry t perfrm cmprehensive first- and secnd-line DST (if pssible). Table 13 Mnitring schedule Clinical evaluatin Baseline Visit Week 2 Mnth 1 Mnth 2 Mnth 3 Mnth 4 Mnth 5 Mnth 6 While n injectable* Vital signs X X X X X X X Mnthly Until end f treatment Perfrmance status X X X End f treatment Brief peripheral neurpathy screen X X X X X X X Mnthly X X Audimetry X X X X X X X Mnthly X Psttreatment mnth 6 Versin 4.0, January 2018 Page 37 f 69

38 Baseline Visit Week 2 Mnth 1 Mnth 2 Mnth 3 Mnth 4 Mnth 5 Mnth 6 While n injectable* Until end f treatment End f treatment Visual acuity and clrblindness screen X X X X X X X Mnthly X X Outcme cnsultatin X X Assessment and fllw-up f adverse events (Sectin 6) X X X X X X X X At each scheduled /unscheduled visit Weight X X X X X X X X Mnthly X Bacterilgical testing Smear X X X X X X X Mnthly X X Culture X X X X X X X Mnthly X X Xpert MTB/RIF X Hain GenType MTBDRsl (sme sites) X If smear- r culture-psitive Culture-based first-line DST X If smear- r culture-psitive Culture-based secnd-line DST (sme sites) X If smear- r culture-psitive Labratry testing ECG X X X X X X X X X X Full Bld Cunt X X X X X X X X Mnthly X Urea, creatinine X X X X X X X Mnthly X Serum electrlytes (ptassium) X X X X X X X Mnthly X Liver functin tests (AST, ALT) X X X X X X X Mnthly X TSH X X every 3 mnths Hepatitis Bs Antigen Hepatitis C Antibdy HbA1c (repeated every 3 mnths if elevated) Pregnancy test X X X X X Psttreatment mnth 6 X Versin 4.0, January 2018 Page 38 f 69

39 HIV serstatus CD4 (repeated every 6 mnths if HIV+) HIV VL (repeated every 6 mnths if HIV+) Baseline Visit X X X Week 2 Mnth 1 Mnth 2 Mnth 3 Mnth 4 Mnth 5 Mnth 6 While n injectable* Until end f treatment Chest X-Ray X X X * Injectable = kanamycin, amikacin, capremycin. End f treatment Psttreatment mnth 6 Versin 4.0, January 2018 Page 39 f 69

40 7 Drug safety 7.1 Scpe f safety data cllectin and definitins Pharmacvigilance is in place t ensure timely detectin and prper transmissin f infrmatin relating t drug safety, especially adverse events. An adverse event (AE) is defined as any untward medical ccurrence in a patient administered a pharmaceutical prduct and that des nt necessarily have a causal relatinship with this treatment. An AE can therefre be any unfavrable and unintended sign (including an abnrmal labratry finding), symptm, r disease temprally assciated with the use f a medicinal prduct, whether r nt related t this medicinal prduct. All patients, irrespectively frm treatment allcatin, are mnitred and assessed clinically fr AEs (including lab abnrmalities) at all visits during treatment (see als visit schedule in sectin 6). Systematic symptmatic screening and referral fr ptential AEs is a mandatry part f scheduled and unscheduled visits. In additin, the evlutin and utcme f the previusly recrded AEs shuld be systematically assessed. Labratry screening fr hematlgic and bichemical abnrmalities and ECG fr mnitring f the QT length are cnducted at specific visits during treatment (see als visit schedule in sectin 6) and mre frequently as needed. Safety data cllectin starts at time f first MDR TB treatment administratin in the frame f the endtb prgram. Each AE is fllwed-up until reslutin r stabilizatin. 24 Safety data cllectin in the frame f endtb is limited t the fllwing elements: AEs f clinical significance, including: Serius Adverse Events (SAEs) defined as any untward medical ccurrence that, at any dse: Results in death, Requires hspitalizatin r prlngatin f hspitalizatin, Results in persistent r significant disability/incapacity, Is life-threatening; life-threatening in this cntext refers t a reactin in which the patient was at risk f death at the time f the reactin; it des nt refer t a reactin that hypthetically might have caused death if mre severe, Is a cngenital anmaly r a birth defect, Is therwise medically significant; Medical and scientific judgment shuld be exercised in deciding whether ther situatins shuld be cnsidered serius reactins, such as imprtant medical events that might nt be immediately life threatening r result in death r hspitalizatin but might jepardise the patient r might require interventin t prevent ne f the ther utcmes listed abve. Suspected transmissin f an infectius agent (e.g. pathgenic r nn-pathgenic) via drug is always cnsidered an SAE. AEs f interest, defined as all AEs regardless f their seriusness, severity r causal relatinship t the MDR TB treatment, pertaining t the fllwing medical cnditins: 24 Reslutin, return t pre-treatment status; stabilizatin, n further deteriratin r imprvement expected. Versin 4.0, January 2018 Page 40 f 69

41 Peripheral neurpathy, Myelsuppressin (anemia, thrmbcytpenia, r neutrpenia), Prlnged QT interval, Optic nerve disrder (ptic neuritis), Hepatitis, Hearing impaired, Acute kidney injury, Hypkalemia, and Hypthyridism. Adverse events leading t treatment discntinuatin r change in drug dsage, defined as all AEs regardless f their seriusness, severity, r causal relatinship t the MDR TB treatment, leading t a discntinuatin f MDR TB treatment, including permanent and temprary treatment interruptin, r changes in drug(s) dsage(s) r drug regimen, as decided by the clinician. Adverse events judged as therwise clinically significant, defined as all AEs regardless f their seriusness, severity, r causal relatinship t the MDR TB treatment, nt pertaining t ne f the abve-mentined categry but cnsidered f clinical significance by the treating physician. Pregnancy must be avided during MDR-TB treatment and effective cntraceptin is recmmended. If despite all precautins, a patient is fund t be pregnant, the pregnant patient shuld be referred t receive the lcal, standard f MDR-TB treatment fr pregnant wmen. All pregnancies (including pregnancies f partners f male patients) shuld be fllwed-up until an utcme is knwn. Infants brn frm expsed pregnancies shuld be fllwed-up until they reach 12 mnths f age. Medicatin errrs defined as unintended mistakes in the prescribing, dispensing and administratin f a medicine that culd cause harm t a patient (e.g. wrng drug prescribed, verdse) must be managed n a case by case basis. Hspitalizatin shuld be cnsidered as apprpriate. The clinician is respnsible fr apprpriately managing AEs, drug-expsed pregnancies, and ptential medicatin errrs in accrdance with the lcal standards f care and fr referring the patient t the apprpriate specialist if needed. He/she shuld additinally assess the benefit f the cntinuatin f the current TB treatment in the light f the whle clinical picture: weighing treatment cntinuatin benefits vs. the risks (including AEs, pregnancy expsure, abnrmal lab results, etc.). Specific clinical management suggestins are available in sectin 7.3 fr AEs f interest. 7.2 Recrding, medical assessment and ntificatin f adverse events Recrding and ntificatin f adverse events ccurs as fllws: Immediate transmissin (within 24 hurs f awareness) f Serius Adverse Events (as defined in sectin 7.1), drug-expsed pregnancies and medicatin errrs (with r withut assciated AEs/SAEs) t the pharmacvigilance (PV) unit (PVunit.GVA@geneva.msf.rg) as recrded using the SAE r Pregnancy Reprt Frm. Rutine recrding f all ther AEs (nn-serius) using the AE Frm/AE Lg. Versin 4.0, January 2018 Page 41 f 69

42 Upn recrding, all SAEs and AEs shuld be graded fr severity accrding t the prvided Severity Grading Scale (grades ). Fr thse AEs nt described in the Severity Grading Scale, the general definitin f clinical severity shuld apply. Table 14 General definitin f severity Grade 1 Mild Grade 2 Mderate Grade 3 Severe Grade 4 Lifethreatening Transient r mild discmfrt (<48 hurs); n medical interventin/therapy required. Mild t mderate limitatin in activity * - sme assistance may be needed; n r minimal medical interventin/ therapy required. Marked limitatin in activity *, sme assistance usually required; medical interventin/therapy required, hspitalizatins pssible. Extreme limitatin in activity *, significant assistance required; significant medical interventin/therapy required, hspitalizatin r hspice care prbable. *The term activity cvers basic self-care functins such as bathing, dressing, tileting, transfer/mvement, cntinence and feeding; but als usual scial and functinal activities r adaptive tasks and desirable activities, such as ging t wrk, shpping, cking, use f transprtatin, pursuing a hbby, etc. All AEs shuld additinally be evaluated t determine their causal relatinship with MDR TB treatment (including MDR TB drugs and ther drugs as apprpriate), using the standard terms as displayed in the table belw. This evaluatin shuld take int accunt all ther pssible causal factrs (e.g. medical histry, risk factrs, past drug use, cncmitant prcedures, TB prgressin). Table 15 Causality categries definitin Causality categry Related Descriptin There is a reasnable pssibility that the AE may be related t the drug(s). Elements in favur f a reasnable causal relatinship include: A favurable tempral relatinship, A psitive dechallenge and/r rechallenge, A plausible pharmaclgical/bilgical mechanism f actin (whether prven r ptential), Previus knwledge f similar reactin with the drug(s), r N ther evident cause (e.g. previus disease, ther drugs). There is insufficient infrmatin t evaluate the causal relatinship between the AE and the expsure. Cnservatively, the AE shuld be cnsidered related t the drug(s) until a prper assessment is feasible (i.e. upn fllw-up). Nt related There is n reasnable pssibility that the AE is related t the drug(s). This implies that there is a plausible alternative cause fr the AE that better explains the ccurrence f the AE r that highly cnfunds the causal relatinship between the drug(s) and the AE. 25 The scale includes all terms frm the Natinal Institute f Allergy and infectius Diseases (NIAID) Divisin f Micrbilgy and Infectius Diseases (DMID) grading system and a selectin f relevant terms frm the Natinal Cancer Institute (NCI) Cmmn Terminlgy Criteria fr Adverse Events (CTCAE) r ther scales. Versin 4.0, January 2018 Page 42 f 69

43 A dedicated pharmacvigilance guideline fr endtb details all prcesses relating t pharmacvigilance describing hw SAE/Pregnancy Reprt Frms shuld be cmpleted and prviding further guidance n severity and causality assessment. A Data Management plan details the recrding f clinical infrmatin (nn-serius AEs, lab values) in the clinical practice database. In case f severity grading questins, please als refer t the "Frequently Asked Questins n the severity grading scale". 7.3 Clinical management f adverse events f interest Peripheral neurpathy Pssible anti-tb drug causes: Lzd, Cs/Trd, H, S, Km, Cm, H, FQ, Pt/Et, E. Pssible ther causes: d4t, ddi. Peripheral neurpathy is a cmmn side effect f MDR-TB treatment caused by drug txicity t the nerves f the peripheral nervus system. All patients taking isniazid shuld receive 50 mg f pyridxine daily; all patients taking Cs/Trd shuld receive 50 mg f pyridxine daily fr every 250 mg f Cs/Trd. Peripheral neurpathy is extremely cmmn in patients taking linezlid. In ne clinical trial f linezlid, 55% f the patients experienced clinically significant peripheral neurpathy. Skin punch bipsies, nerve cnductin studies r ther specialized tests are the gld standard but are nt necessary fr a diagnsis. Accrding t the ACTG Brief Peripheral Neurpathy Screen (BPNS), a patient can be diagnsed with peripheral neurpathy if he/she reprts typical symptms (numbness, tingling, burning, pain) plus decreased vibratin sense in the big tes r decreased ankle tendn reflexes. When assessing the patient's symptms with the BPNS (See Step 1 f the BPNS descriptin), assess whether his/her symptm is suggestive f neurpathic pain. Althugh difficult t define and variable fr each individual, neurpathic pain is ften described as "burning", "electric", "tingling", and "shting" in nature. It can vary frm a cnstant pain t intermittent sharp shting pains. As described, the pain is mst ften present withut assciated stimulatin, but can be exacerbated by stimuli. After a diagnsis f peripheral neurpathy, the subjective sensry neurpathy scre frm the BPNS (See Step 1 f the BPNS descriptin) shuld be used fr grading (Table 16). Table 16 Clinical management f peripheral neurpathy accrding t severity grading Severity grade* Grade 1 Mild Grade 2 Mderate Grade 3 Severe Grade 4 Lifethreatening Paresthesia (Burning, Tingling, etc.) Mild discmfrt; n treatment required; and/r BPNS subjective sensry neurpathy scre 1-3 n any side. Mderate discmfrt; nnnarctic analgesia required; and/r BPNS subjective sensry neurpathy scre 4-6 n any side. Severe discmfrt; r narctic analgesia required with symptmatic imprvement; and/r BPNS subjective sensry neurpathy scre 7-10 n any side. Incapacitating; r nt respnsive t narctic analgesia Actin Stp Cs/Trd, highdse H, and Lzd. If Stp Cs/Trd, highdse H, and Lzd. If Same as Grade 2. Same as Grade 2. Versin 4.0, January 2018 Page 43 f 69

44 Severity grade* Grade 1 Mild Grade 2 Mderate Grade 3 Severe Grade 4 Lifethreatening symptms imprve, cnsider restarting these drugs. Cnsider restarting Lzd at a lwer dse (300mg daily r 600 mg thrice weekly). If Cs/Trd r highdse H are nt essential t the regimen, cnsider suspending these drugs. symptms imprve, and if the drugs are essential t the regimen, cnsider restarting Cs/Trd r high-dse H. D nt reintrduce Lzd. Prvide symptmatic relief as described belw. * Reference: NIAID Divisin f Micrbilgy and Infectius Diseases, severity scale, Nv Suggested management strategy: Many patients experience imprvement when ffending drugs are suspended, especially if the symptms are mild. The neurpathy assciated with linezlid is cmmn after prlnged use and ften extremely painful and irreversible. Fr this reasn, linezlid shuld be immediately stpped and nt reintrduced when symptmatic neurpathy develps (grade 2 r abve). Cnsider additinal anti-tb drugs t reinfrce the regimen. In HIV cinfected patients, avid use f d4t r ddi in cmbinatin with cyclserine/terizidne r linezlid because f an increased risk f peripheral neurpathy. Symptmatic relief: Nn-steridal anti-inflammatry drugs r acetaminphen may help alleviate symptms. Tricyclic antidepressants have als been used successfully. Start amitriptyline 25 mg at bedtime. The dse may be increased t a maximum f 150 mg daily fr refractry symptms. If pssible, the c-administratin f amitriptyline and Lzd shuld be avided due t ptential risk f sertnergic syndrme. Carbamazepine may als be effective in relieving pain and ther symptms f peripheral neurpathy. Carbamazepine is a strng inducer f CYP3A4 and shuld nt be used with bedaquiline r delamanid. ACTG Brief Peripheral Neurpathy Screen (BPNS): Step 1. Grade Subjective Symptms Ask the subject t rate the severity f each symptm n a scale frm 01 (mild) t 10 (mst severe) fr right and left feet and legs. Enter the scre fr each symptm in the clumns marked R (right lwer limb) and L (left lwer limb). Nrmal Mild Severe Symptms R L Versin 4.0, January 2018 Page 44 f 69

45 a. Pain, aching, r burning in feet, legs b. "Pins and needles" in feet, legs c. Numbness (lack f feeling) in feet, legs Use the single highest severity scre abve t btain a subjective sensry neurpathy scre. Subjective Sensry Neurpathy Scre Severity grade Step 2. Evaluate Perceptin f Vibratin Cmpress the ends f a 128-Hz tuning frk just hard enugh that the sides tuch. Place the vibrating tuning frk n a bny prminence n the subject's wrist r hand t be sure that he/she can recgnize the vibratin r "buzzing" quality f the tuning frk. Again, cmpress the ends f the tuning frk just hard enugh that the sides tuch. Immediately place the vibrating tuning frk gently but firmly n the tp f the distal interphalangeal (DIP) jint f ne great te and begin cunting the secnds. Instruct the subject t tell yu when the "buzzing" stps. Repeat fr the ther great te. The diagram belw illustrates where t place the tuning frk (adapted frm Internatinal Wrking Grup n the Diabetic Ft, Practical guidelines n the management and preventin f the diabetic, 2007). Vibratin perceptin Result Scre Felt > 10 secnds Nrmal 0 Felt 6-10 secnds Mild lss 1 Felt <5 secnds Mderate lss 2 Nt felt Severe lss 3 Step 3. Evaluate Deep Tendn Reflexes With the subject seated, the examiner uses ne hand t press upward n the ball f the ft, drsiflexing the subject's ankle t 90 degrees. Using a reflex hammer, the examiner then strikes the Achilles tendn. The tendn reflex is felt by the examiner's hand as a plantar flexin f the ft, appearing after a slight delay frm the time the Achilles tendn is struck. Use reinfrcement by having the subject clenching his/her fist befre classifying the reflex as absent. Versin 4.0, January 2018 Page 45 f 69

46 Ankle reflexes Scre Absent 0 Hypactive 1 Nrmal deep tendn reflexes 2 Hyperactive 3 Clnus 4 A diagnsis f peripheral neurpathy can be made with the cmbinatin f a subjective neurpathy grade greater than 0 and at least ne bilateral bjective finding (abnrmal vibratry sense r abnrmal deep tendn ankle reflex). Hwever, nly the subjective sensry neurpathy scre BPNS step 1) is used fr grading Myelsuppressin (anemia, thrmbcytpenia, r neutrpenia) Pssible anti-tb drug causes: Lzd. Pssible ther causes: AZT, ctrimxazle. The mean crpuscular vlume (MCV) may be helpful t assess whether anemia is nrmcytic versus micrcytic versus macrcytic. Macrcytic anemia is mre likely t be due t AZT, but AZT can als induce a nrmcytic anemia. If the patient has thrmbcytpenia r neutrpenia, this is mre likely t be due t linezlid. AZT can d this, but it is rarer. Myelsuppressin is very cmmn in patients receiving linezlid. In ne clinical trial f linezlid, apprximately 18% f patients taking linezlid experienced clinically significant myelsuppressin. Acute bld lss (ccult GI bleeding frm a peptic ulcer) can cause anemia. Other causes f anemia (TB, irn-deficiency, etc.) are pssible, but less likely t ccur in the middle f treatment, especially if the patient is clinically imprving. Table 17 Clinical management f myelsuppressin accrding t severity grading Severity grade* Grade 1 Mild Grade 2 Mderate Grade 3 Severe Grade 4 Lifethreatening Anemia g/dl g/dl g/dl < 6.5 g/dl Platelets decreased 99,999-75,000 /mm³ 74,999-50,000 /mm³ 49,999-20,000 /mm³ < 20,000 /mm³ White bld cells decreased <LLN - <3,000-2,000/mm 3 <2,000-1,000/mm 3 < 1,000 /mm 3 3,000/mm 3 Abslute neutrphil cunt lw /mm /mm /mm 3 <500/mm 3 Actin Mnitr carefully, and cnsider reductin f dse f Lzd (300mg daily r 600 mg thrice Mnitr carefully, and cnsider reductin f dse f Lzd (300mg daily r 600 mg thrice weekly); in case f Grade 2 neutrpenia, Stp Lzd immediately. In case f Grade 3 anemia, cnsider EPO. Restart at reduced dse nce txicity has decreased t Grade 1. Stp Lzd immediately. Cnsider hemtransfusin r EPO. Restart at reduced dse nce txicity has Versin 4.0, January 2018 Page 46 f 69

47 Severity grade* Grade 1 Mild Grade 2 Mderate Grade 3 Severe Grade 4 Lifethreatening weekly). stp Lzd immediately. In case f Grade 2 anemia, cnsider EPO. Restart at reduced dse nce txicity has decreased t Grade 1. decreased t Grade 1. Reference: NIAID Divisin f Micrbilgy and Infectius Diseases, severity scale, Nv Suggested management strategy: 1. Stp the causative drug immediately. 2. Mnitr full bld cunts regularly. 3. Cnsider erythrpietin fr anemia Grade 2 r Hspitalize the patient and cnsider transfusin r erythrpietin if the myelsuppressin is severe. 5. Cnsider additinal anti-tb drugs t reinfrce the regimen. Erythrpietin (EPO) Treatment with erythrpietin is nt intended fr patients wh require immediate crrectin f anemia (Grade 4). In this case, bld transfusins shuld be cnsidered. Whle bld cunt shuld be repeated weekly t assess the respnse t treatment. Bld pressure shuld be adequately cntrlled befre initiatin and mnitred during therapy. Erythrpietin treatment shuld in any case be discntinued at Hemglbin levels ver 12 g/dl. Cntraindicatins Erythrpietin treatment shuld be administered with cautin in the presence f: Untreated, inadequately treated r prly cntrlled hypertensin Epilepsy Thrmbcytsis Chrnic liver failure Hyperkalemia Presentatin Epetin alfa prefilled syringes f UI r IU/ml t be stred in cld chain (2 C t 8 C). Dsing Epetin alfa: 150 IU/Kg three times a week r 450 IU/Kg nce a week subcutaneusly r intravenusly Prlnged QT interval Pssible anti-tb drug causes: Cfz, Bdq, Mfx, Dlm, Lfx. Pssible ther causes: Many ther drugs can cause QT prlngatin (e.g. erythrmycin, clarithrmycin, quinidine, ketcnazle, flucnazle, antipsychtics (all have sme risk including Versin 4.0, January 2018 Page 47 f 69

48 halperidl, chlrprmazine and risperidne), many anti-nausea drugs (ndansetrn/granisetrn, dmperidne), methadne, and sme antiretrvirals); genetic causes such as lng QT syndrme; hypthyridism. Check an ECG if the patient has clinical symptms (tachycardia, syncpe, palpitatins, r weakness r dizziness) f carditxicity. Check the QT interval and rule ut an arrhythmia. The QTc will be calculated using the Fridericia's frmula which crrects fr the heart rate and has been shwn t be mre accurate at slwer r faster heart rates than ther crrectin frmulae: Where: QTcF = the crrected QT interval QTcF = QT 3 RR QT = the time between the start f the QRS cmplex and the end f the T wave RR = the time between the start f ne QRS cmplex and the start f the next QRS cmplex The ECG machine shuld be calibrated t ensure that the fllwing vltage and speeds apply: Versin 4.0, January 2018 Page 48 f 69

49 Obtain the 12-lead ECG: Prcedure fr measuring RR and QT interval Ensure that the 12-lead ECG is perfrmed in a relaxed patient t avid artifacts. Use the apprpriate electrdes and clean the patient s skin if necessary. Ensure the sweep speed is set t 25 mm/sec. This will allw fr standard calibratin and measurement f the QT interval. Measure the RR and QT intervals manually (Figure 1 illustrates the intervals): The QT interval shuld be measured manually, preferably by using ne f the limb leads that best shws the end f the T wave n a 12-lead ECG. Often, leads II r V5 may best shw the end f the T wave. Try t measure the QT interval in these leads first. If the end f the T wave is nt well seen in leads II r V5, then the clinician shuld use their best judgment t assess which lead best shws the end f the T wave. The QT interval shuld be measured frm the beginning f the QRS cmplex t the end f the T wave. If the rhythm is irregular (i.e. atrial fibrillatin), the QT interval shuld be averaged ver 3 t 5 beats. Calculate the QTcF fr each f the 3 t 5 beats, and then calculate the arithmetic average QTcF f the beats. U waves pssibly crrespnding t the late replarizatin f cells in the mid mycardium shuld be included in the measurement nly if they are large enugh t seem t merge with the T wave. The figure belw illustrates hw t determine the start f the Q wave and end f the T wave by drawing a baseline and a tangent line n the back side f the T wave. Each 1 mm (small) hrizntal bx crrespnds t 0.04 secnd (40 msec), with heavier lines frming larger bxes that include five small bxes and hence represent 0.20 sec (200 msec) intervals. Cunt the number f bxes that make up the QT interval and then multiply the number f bxes by 40 msec. if the start f the Q wave Versin 4.0, January 2018 Page 49 f 69

50 r the end f the T wave fall in the middle f the bx, estimate it t the nearest ¼ f a bx. Crrect the QT interval fr the heart rate: Fr standardizatin, we will be using the Fridericia frmula t crrect fr heart rate. The Fridericia frmula perfrms better at lwer and higher heart rates than ther crrectin methds. The QTcF can als be determined by using a calculatr and using the frmula in Sectin 6.3.3; hwever, it is recmmended fr clinicians t use the ther methds as it is less prne t errr. One way is t use the QTcF nmgram belw. Even simpler and quicker than the nmgram are several applicatins available n mbile phnes (e.g. Andrid, iphne) that are designed t calculate the QTcF with a minimum f effrt, fr example, the QTc Calculatr fr Andrid phnes (Ggle Play). These applicatins require the user t enter the QT interval and the RR interval, after which the QTc will be calculated accrding t several frmulas. The crrect units shuld be selected (e.g. mm r msec), as well as the crrect frmula. Cmpare the crrected value measured manually with what the ECG machine prduces (if the ECG machine has the functin f autmatically calculating the crrected QT interval). If there is a difference f mre than 20 ms repeat the manual measurement. The manual measurement serves as the "gld standard". Recrd RR interval, heart rate, and the QTcF interval in the patient s chart: The RR interval is measured in secnds. Recrd the heart rate frm the ECG machine if it prduces it autmatically r determined it by measuring the RR interval and dividing int 60. (HR = 60/RR interval in secnd). Recrd the QTcF interval as calculated by the instructins abve. Heart rate (beats per minute) Hw t use the QTcF Nmgram Identify the patient s HR r RR interval n the tp f the table. Identify the measured QT (uncrrected) interval n the left f the table. Find the crrespnding calculated QTcF in the cell belw the HR (r RR) and t the right f the QT interval. Recrd the calculated QTcF in the endtb ECG frm Versin 4.0, January 2018 Page 50 f 69

51 QT interval (msec) R-R interval (sec) Table 18 Clinical management f prlnged QT interval accrding t severity grading Severity grade* Grade 1 Mild Grade 2 Mderate Grade 3 Severe Grade 4 Lifethreatening Electrcardigram QT Crrected Interval Prlnged QTcF ms # QTcF ms # QTcF >= 501 ms withut signs/symptms f serius arrhythmia # QTcF >= 501 r >60 ms change frm baseline and ne f the fllwing: Trsade de pintes r plymrphic ventricular tachycardia r signs/symptms f serius arrhythmia # Actin Mnitr mre clsely; at least weekly ECG until QTcF has returned t less than grade 1. Replete electrlytes as necessary. Mnitr mre clsely; at least weekly ECG until QTcF has returned t less than grade 1. Replete electrlytes as Stp the suspected causative drug(s). Hspitalize and replete electrlytes as necessary. Stp the suspected causative drug(s). Hspitalize and replete electrlytes as necessary. Versin 4.0, January 2018 Page 51 f 69

52 Severity grade* Grade 1 Mild Grade 2 Mderate necessary. Grade 3 Severe Grade 4 Lifethreatening * NCI Cmmn Terminlgy Criteria fr Adverse Event, v Jun # When multiple ECGs are recrded n a same day, average f the QTcF measures shuld be used t determine the grade. Checking and repleting serum electrlytes: Serum ptassium (K + ), inized calcium (inized Ca ++ ), and magnesium (Mg ++ ) shuld be btained in the event a prlnged QT interval is detected. Abnrmal electrlytes are mst cmmnly due t the injectable and shuld be crrected. Whenever a lw ptassium is detected it shuld trigger urgent management with replacement and frequent repeat ptassium testing (ften daily r multiple times a day) t dcument the ptassium is mving in the crrect directin. If ptassium is fund lw, always check magnesium and inized calcium and cmpensate as needed. (If unable t check, cnsider ral empiric replacement dses f magnesium and calcium). In patients receiving delamanid, serum albumin shuld be btained and repeated mnthly in the event a prlnged QT interval is detected. Suggested management strategy: Stp all QT prlnging drugs immediately. ART is usually nt stpped unless the patient is severely unstable. Hspitalize and cnsider cntinuus electrcardiac mnitring fr Grade 3. Hspitalizatin shuld ccur in a facility capable in the management f Trsades de Pintes arrhythmia. Check electrlytes and manage as described abve. Check TSH and treat any hypthyridism fund. Once stable (QT CF interval belw 450 and nrmal electrlytes), critical QT prlnging anti- TB drugs can be added back: If the patient is n any nn-tb drugs that are prlng the QT interval cnsider suspending them. If the patient was n mxiflxacin cnsider using levflxacin instead. If the patient was n clfazimine cnsider suspending it permanently if nt critical t the regimen. If the patient is n bedaquiline and it is cnsidered critical t the regimen, cnsider adding the drug back t the patient s regimen while suspending all ther QT prlnging drugs (with the exceptin f stpping ART, which shuld nt nrmally be suspended in the management f QT prlngatin). If the patient is n delamanid and it is cnsidered critical t the regimen, cnsider adding the drug back t the patient s regimen while suspending all ther QT prlnging drugs (with the exceptin f stpping ART, which shuld nt nrmally be suspended in the management f QT prlngatin) Optic nerve disrder (ptic neuritis) Pssible anti-tb drug causes: Lzd, E, Et/Pt, rifabutin, H, S. Versin 4.0, January 2018 Page 52 f 69

53 Pssible ther causes: ddi. Optic neuritis is inflammatin f the ptic nerve eventually resulting in permanent visin lss. The first sign f ptic neuritis is usually the lss f red-green clr distinctin. This is best tested using the Ishihara test. Other symptms include central sctmas. Linezlid is by far the mst cmmn cause f ptic neuritis amngst all f the TB drugs. In a clinical trial f linezlid, 18% f patients eventually develped ptic neuritis, mstly after fur mnths f treatment. Patients with diabetes are at increased risk fr ptic neuritis. They shuld be managed with tight glucse cntrl as a means f preventin. Patients with advanced kidney disease are als at increased risk fr ptic neuritis. Table 19 Clinical management f ptic nerve disrder accrding t severity grading Severity grade* Grade 1 Mild Grade 2 Mderate Grade 3 Severe Grade 4 Lifethreatening Optic nerve disrder Asymptmatic; clinical r diagnstic bservatins nly Limiting visin f the affected eye (20/40 [6/12] r better) Limiting visin in the affected eye (wrse than 20/40 [6/12] but better than 20/200 [6/60]) Blindness (20/200 [6/60] r wrse) in the affected eye Actin Stp Lzd immediately if there are any suspicins f ptic neuritis. D nt restart it. Stp Lzd immediately if there are any suspicins f ptic neuritis. D nt restart it. Stp Lzd immediately if there are any suspicins f ptic neuritis. D nt restart it. Stp Lzd immediately if there are any suspicins f ptic neuritis. D nt restart it. *NCI Cmmn Terminlgy Criteria fr Adverse Event, v Jun Suggested management strategy: D nt restart the suspected causative drug (linezlid r ethambutl). Refer patient t an phthalmlgist fr immediate evaluatin and management. Optic neuritis generally imprves fllwing cessatin f ffending drug, if it can be stpped early enugh. Cnsider additinal anti-tb drugs t reinfrce the regimen Elevated liver enzymes (hepattxicity) Pssible anti-tb drug causes: Z, H, Cfz, PAS, Et/Pt, Bdq, FQ, Amx/Clv. Pssible ther causes: viral hepatitis (A, B, C), NVP, many ther drugs. Hepatitis is characterized by nausea, vmiting, jaundice, scleral icterus, tea-clred urine, pale stl, and diminished appetite in the setting f elevated liver functin tests. Mild elevatin f liver enzymes, especially at baseline, may be related t TB rather than an adverse effect f treatment. Generally hepattxicity due t medicatins reslves upn discntinuatin f suspected drug. In HIV cinfectin, ctrimxazle can be a cause f hepattxicity. Versin 4.0, January 2018 Page 53 f 69

54 NVP hepattxicity usually ccurs shrtly after expsure, accmpanied by flu-like symptms with r withut rash. It can als happen late as an islated hepatitis withut cnstitutinal symptms. Patients wh experience NVP hepattxicity shuld nt be rechallenged. Table 20 Clinical management f elevated liver enzymes accrding t severity grading Severity grade* Grade 1 Mild Grade 2 Mderate Grade 3 Severe Grade 4 Lifethreatening ALT (SGPT) >ULN 3.0 x ULN > x ULN > x ULN >20.0 x ULN AST (SGOT) >ULN 3.0 x ULN > x ULN > x ULN >20.0 x ULN Actin Cntinue treatment regimen. Patients shuld be fllwed until reslutin (return t baseline) r stabilizatin f AST/ALT elevatin. Cntinue treatment regimen. Patients shuld be fllwed until reslutin (return t baseline) r stabilizatin f AST/ALT elevatin. Stp all drugs, including anti-tb drugs; measure LFTs weekly. Treatment may be reintrduced after txicity is reslved. Stp all drugs, including anti-tb drugs; measure LFTs weekly. Treatment may be reintrduced after txicity is reslved. * NCI Cmmn Terminlgy Criteria fr Adverse Event, v Jun Reintrductin f anti-tb drugs: Reintrduce anti-tb drugs nce liver enzymes return t baseline. Anti-TB drugs shuld be reintrduced in serial fashin by adding a new medicine every three t fur days. The least hepattxic drugs shuld be added first, while mnitring liver functin tests after each new expsure. Cnsider suspending the mst likely ffending drug permanently if it is nt essential t the regimen. This is ften the case fr pyrazinamide if it is less likely t be effective by clinical histry. Cnsider additinal anti-tb drugs t reinfrce the regimen Hearing impaired Pssible anti-tb drug causes: S, Km, Am, Cm, Clr. Pssible ther causes: nne. Hearing impaired is a disrder characterized by partial r cmplete lss f the ability t detect r understand sunds resulting frm damage t ear structures. The injectables can cause damage f the hearing apparatus f the inner ear, including the cchlea, vestibule, semicircular canals, and cranial nerve VIII. Symptms include hearing lss and tinnitus, as well as vestibular symptms such as disequilibrium and visin prblems. Hearing lss is cmmnly bserved in patients receiving large cumulative dses f injectables. Capremycin may be mildly less ttxic than the aminglycsides. Hearing lss and vestibular dysfunctin are generally nt reversible upn discntinuatin f therapy. Sme degree f hearing lss ccurs with mst patients taking an injectable, but highfrequency lss may nt significantly affect the patient's quality f life. Versin 4.0, January 2018 Page 54 f 69

55 Sme patients may chse t tlerate significant hearing lss t achieve a higher chance f cure. This shuld be discussed between the patient and a physician trained in MDR-TB. Cntinuing the injectable in such situatins almst always results in permanent hearing lss and smetimes cmplete deafness. Patients with previus expsure t aminglycsides may have already sustained a degree f hearing lss. These patients are at the highest risk f incurring further ttxicity. In such patients, audimetry may be helpful in guiding therapy t prevent further damage. Cncmitant use f fursemide, particularly in the setting f renal insufficiency, may exacerbate ttxic effects f the injectables. Versin 4.0, January 2018 Page 55 f 69

56 Table 21 Clinical management f hearing impairment accrding t severity grading Severity grade* Grade 1 Mild Grade 2 Mderate Grade 3 Severe Grade 4 Life-threatening Hearing Impaired Adults Enrlled n a Mnitring Prgram (n a 1, 2, 4, 3, 6 and 8 khz audigram): threshld shift f db averaged at 2 cntiguus test frequencies in at least ne ear r subjective change in the absence f a Grade 1 Threshld shift. Pediatric (n a 1, 2, 4, 3, 6 and 8 khz audigram): threshld shift >20 db at 8 khz in at least ne ear. Adult enrlled in mnitring prgram (n a 1, 2, 3, 4, 6 and 8 khz audigram): threshld shift f >25 db averaged at 2 cntiguus test frequencies in at least ne ear. Adult nt enrlled in mnitring prgram: hearing lss but hearing aid r interventin nt indicated; limiting instrumental ADL. Pediatric (n a 1, 2, 3, 4, 6 and 8 khz audigram): threshld shift >20 db at 4 khz and abve in at least ne ear. Adult enrlled in mnitring prgram (n a 1, 2, 3, 4, 6 and 8 khz audigram): threshld shift f >25 db averaged at 3 cntiguus test frequencies in at least ne ear; therapeutic interventin indicated. Adult Nt enrlled in mnitring prgram: hearing lss with hearing aid r interventin indicated; limiting self care ADL. Pediatric (n a 1, 2, 3, 4, 6 and 8kHz audigram): hearing lss sufficient t indicate therapeutic interventin, including hearing aids): Threshld shift >20 db at 3 khz and abve in at least ne ear; additinal speech-language related services indicated. Adults: prfund bilateral hearing lss (Threshld >80 db HL at 2 khz and abve); nnservicable hearing Pediatric: audilgic indicatin fr cchlear implant and additinal speech-language related services indicated. Actin Cnsider decreasing injectable frequency (e.g. MWF). Cnsider replacing the injectable with a nnttxic drug. Cnsider replacing injectable with a nn-ttxic TB drug. Decrease injectable frequency (e.g. MWF) if injectable is essential. Replace injectable with a nn-ttxic TB drug. Decrease injectable frequency (e.g. MWF) if injectable is essential. In cases f cmplete hearing lss, sme clinicians will cntinue the injectable as the hearing lss is irreversible. Cnsider suspensin f the injectable if sme hearing might be still preserved r if it is causing ther reversible symptms such as tinnitus r vestibular disturbances. *NCI Cmmn Terminlgy Criteria fr Adverse Event, v Jun Versin 4.0, January 2018 Page 56 f 69

57 Suggested management strategy: Perfrm a mnthly assessment f hearing lss and balance. Audimetry is helpful in detecting early high-frequency hearing lss that the patient may nt even be aware f. If the patient is experiencing hearing lss, stp the injectable and replace it with a nnttxic drug. If there is n ther nn-ttxic drug available r effective, cnsider decreasing the dsing frequency f the injectable t tw t three times a week. Even when nn-ttxic drugs are nt available, stpping the injectable can be cnsidered based n the patient's desire t maintain hearing. If mderate r severe vertig, tinnitus (ringing in the ears) r vestibular disturbances arise, with r withut significant hearing lss, cnsider decreasing frequency r stpping the injectable agent. Surce: Auditry Neurscience: Making sense f Sund. Accessed June 2013, Ntes n audigram: This audigram represents high-frequency hearing lss, which is ften the first sign f auditry txicity due t injectables. The patient with this audigram culd still hear cnversatins. Frequencies arund 2,000 Hz are the mst imprtant fr understanding cnversatins; the patient has nly mderate hearing lss in this area. Often patients d nt ntice hearing lss abve 4,000 Hz. An audigram that demnstrates hearing lss as illustrated abve is a gd example f a situatin where suspending (r substituting) a different anti-tb drug is indicated; this can prevent further lss f hearing. Versin 4.0, January 2018 Page 57 f 69