aDSM 8th June 2020 active drug safety.pptx

adsm tuberculosis

1. Dr.C.Padmapriyadarsini Deputy Director (Sr.GD) ICMR-National Institute for Research in Tuberculosis, Chennai, India

2. active Drug Safety Monitoring and M anagement ( aDSM ) Spontaneous reporting no active measures are taken to look for adverse effects other than the encouragement of health professionals and others to report safety concerns Targeted reporting variant of spontaneous reporting. It focuses on capturing ADRs in a well-defined group of patients on treatment. Active surveillance (or proactive) safety surveillance means that active measures are taken to detect adverse events. This is achieved by active follow-up after treatment

3. Adverse events (AE): Any untoward medical occurrence that may present during treatment with a pharmaceutical product, but which does not necessarily have a causal relationship with this treatment Adverse drug reactions (ADR): a response* to a medicine which is noxious and unintended, and which occurs at doses normally used** in humans * Response = a causal relationship between a medicine and an adverse event is at least a reasonable possibility ** a n error which occurs during the prescribing, dispensing and/or use of a medication is called a medication error

4. Serial testing / screening for AEs aDSM : cohort-based approach Drug start Drug exposure Death Success Loss to f/u Change of treatment Success f/u after treatment Serious AE Other event

5. Adverse event of clinical significance: an AE that is either ( i ) serious, (ii) of special interest, (iii) leads to a discontinuation or change in the treatment Adverse event of special interest: an AE documented to have occurred during clinical trials and for which the monitoring programme is specifically sensitized to report regardless of its seriousness, severity or causal relationship to the TB treatment

6. Serious Adverse Events (SAEs) A  serious adverse event  is any event that : • Is fatal • Is life-threatening • Is permanently/significantly disabling • Requires or prolongs hospitalization • Causes a congenital anomaly • Other medically important condition Three basic points: Is it Severe? Is it Expected? Is it Related?

7. Severity of Adverse Events MILD (GRADE 1) Causes minimal discomfort & not interfere with everyday activities Resolves without treatment Event not resulting in disability / incapacity MODERATE (GRADE 2) Causes Sufficient discomfort & interferes with normal activity, Requires treatment Event not resulting in disability / incapacity SEVERE (GRADE 3) Extreme distress, causing significant impairment of functioning or incapacitation. Prevents normal everyday activities Requires treatment/ hospitalization Event resulting in temporary & mild disability / incapacity LIFE THREATENING (GRADE 4) Potentially life threatening. Prevents basic self-care activities Requires treatment/ hospitalization Event may result in permanent impairment/ persistent disability / incapacity. DEATH (GRADE 5) Death

8. Expectedness of Adverse events An Adverse event may be expected , i.e., an event related to the use of study agent that has been previously observed (according to the package insert) An unexpected adverse event is an event that is not consistent in nature and / or severity with those included in the package insert

9. Relatedness of adverse events : Casuality Causal relationship: the association between an exposure (A) and an event (B) in which A precedes and causes B. This may refer to the causal association between an exposure to a TB medicine and the occurrence of an adverse reaction Causality assessment: the evaluation of the likelihood that a TB medicine was the causative agent of an observed adverse reaction

10. Assessment Criteria

11. Certain Probable Possible Unlikely Temporal time relationship Definite pharmacological Unlikely due to concomitant medications/ illness + ve de-challenge + ve re-challenge WHO UMC scale-category Rechallenge - necessary

12. Certain Probable Possible Unlikely Temporal time relationship Unlikely to be attributed to disease/concomitant medications/ illness Definite pharmacological + ve de-challenge WHO UMC scale-category Rechallenge - not necessary

13. Certain Probable Possible Unlikely Temporal time relationship could also be explained to disease or concomitant medications/ illness de-challenge information lacking/ unclear WHO UMC scale-category could also be explained by disease or other drug s

14. Certain Probable Possible Unlikely Temporal time relationship - doubtful/questionable but not impossible Could also be explained due to disease or concomitant medications WHO UMC scale-category

15. WHO UMC Causality Categories Conditional/Unclassified AE- More data for proper assessment needed or additional data under examination Unaccessible /Unclassifiable AE- Cannot be judged because of insufficient or contradictory information Report cannot be supplemented or verified

16. Category Description Certain/ Very Likely Listed as an adverse reaction Alternative explanations- Cannot be reasonably explained Relationship in time- very suggestive e.g. Confirmed by Dechallenge and Rechallenge Probable Might be due to the use of the drug Alternative explanation- less likely Relationship in time suggestive, e.g. Confirmed by Dechallenge Possible Might be due to the use of the drug Alternative explanation- inconclusive Relationship in time- reasonable Unlikely/ Doubtful Alternative explanation- more likely, and/or Relationship in time- suggests causal relationship is unlikely Conditional/ Unclassified An adverse reaction about which more data is essential for a proper assessment or Additional data are under examination. Causality criteria

17. MONTH CLINICAL CONSULTATION WEIGHT SMEAR CULTURE DST CXR LFT CR, K TSH AUDIO-METRY HIV TESTING 0 (baseline) √ √ √ √ √ √ √ √ √ √ √ 1 Every two weeks Every two weeks √ √       √   √ repeat if indicated 2 √ √       √   √ 3 √ √       √   √ 4 √ √ √ √ If culture positive     √   √ 5 √ √ √ √     √   √ 6 √ √ √ √     √   √ 7 √ √ √ √     √   √ 8 √ √ √ √     √   √ 9 √ √ √ Every two months     If on injectable   If on injectable 10 √ √ √       11 √ √ √       12 √ √ √       until completion √ monthly monthly       To be adapted for shorter regimen

18. Assessing & Managing Adverse Events during MDR-TB Treatment

19. Classes of Anti TB Drugs recommended for treatment of DR-TB GROUPS & STEPS DRUG Group A: Include all three medicines Levofloxacin OR Moxifloxacin Lfx // Mfx Bedaquiline Bdq Linezolid Lzd Group B: Add one or both medicines Clofazimine Cfz Cycloserine OR Terizidone Cs // Trd Group C: Add to complete the regimen and when medicines from Group A and B cannot be used Ethambutol E Delamanid Dlm Pyrazinamide Z Imipenem- cilastatin OR Meropenem Ipm-Cln / m pm Amikacin ( OR Streptomycin) Am ( S) Ethionamide ( OR Prothionamide ) Eto // Pto p - aminosalicylic acid PAS

20. Rapid Communication: December 2019 (Key changes to Consolidated Guidelines on Rx of DR-TB ) Shorter all-oral bedaquiline containing MDR TB regimen 9-12 months 4-6 Bdq *- Lfx / Mfx-Eto-Cfz -E-Z- Hh / 5 Lfx / Mfx - Cfz -Z-E All Oral longer regimen refers to a regimen with a total duration of 18-20 months designed using the priority grouping of medicines recommended by WHO BPaL regimen is defined as a novel treatment regimen lasting 6-9 months and composed of bedaquiline, pretomanid and linezolid as used in the Nix-TB study by the TB Alliance

21. Principles of designing a WHO recommended All oral longer MDR TB regimen In MDR/RR TB patients on longer regimens, All three Group A agents ( Lfx / Mfx , Bdq &Lzd) and One Group B agent ( Cfz &Cs) should be included to ensure that treatment starts with at least four TB agents likely to be effective, and that at least three agents are included for the rest of the treatment after Bdq is stopped. If only one or two Group A agents are used, both Group B agents are to be included. If the regimen cannot be composed with agents from Groups A and B alone, Group C agents are added to complete it. [ All oral longer reg eg . 18-20 Bdq (6) Lfx Lzd # Cfz Cs] # Reduce Lzd to 300 mg/day after 6 to 8 months.

22. COMMON OR RELEVANT ADVERSE EFFECTS OF DRUG-RESISTANT TB THERAPY Nausea/vomiting Abdominal pain Visual disturbances Diarrhoea Anorexia Seizures Arthralgia Gastritis Hypothyroidism Dizziness/vertigo Peripheral neuropathy Psychosis Hearing disturbances Depression Suicidal ideation Headache Tinnitus Hepatitis (hepatotoxicity) Sleep disturbances Allergic reaction Renal failure (nephrotoxicity) Electrolyte disturbances Rash QT prolongation

23. Management of Adverse events Proper management of adverse effects begins with pre treatment patient education. Before starting treatment the patient should be instructed in detail about the potential adverse effects that could be produced by the prescribed drug regimen, and if and when they occur, to notify a health-care provider. Early detection and Close monitoring of signs and symptoms is key to proper management of adverse drug reactions that significantly impacts: Patient well-being, Overall treatment acceptance, Adherence. Keeping in mind : we treat the patient not the lab result

24. Training of all the health staffs will be done to identify and manage ADRs Treatment supporter to be trained and will monitor and record all the adverse events routinely Depending on the severity of ADRs the following actions may be indicated: If the adverse effect is mild and not serious, continuing the treatment regimen, with the help of ancillary drugs if needed, is often the best option. Reducing the dosage of the offending drug or terminating the offending drug is another method of managing adverse effects. Psychosocial support

25. Severity grading: ( DMID ) Adult Toxicity Table) Management of AEs Grade 1 - MILD Grade 2 - MODERATE Grade 3 - SEVERE Grade 4 – LIFE-THREATENING Transient or mild discomfort (<48 hours); no medical intervention/therapy required Mild to moderate limitation in activity - some assistance may be needed; no or minimal medical intervention/ therapy required Marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalization possible Extreme limitation in activity, significant assistance required; significant medical intervention/therapy required, hospitalization or hospice care probable Condition term Grade 1 Grade 2 Grade 3 Grade 4 Alanine Aminotransferase (ALT or SGPT) Increased 1.1 - <2.0 x ULN 2.0 – <3.0 x ULN 3.0 – 8.0 x ULN > 8 x ULN Condition term Grade 1 Grade 2 Grade 3 Grade 4 Vomiting 1 episode in 24 hours 2-5 episodes in 24 hours >6 episodes in 24 hours or needing IV fluids Physiologic consequences requiring hospitalization or requiring parenteral nutrition

26. CASE I Perform causality assessment of the given case using WHO UMC scale A 25 years female patient was diagnosed with MDR-TB . Known diabetic on treatment. On 14/7/201 8 , the following treatment was started as per DST; Tablet Bedaquiline 400mg oral OD Inj. Kanamycin 750mg IM OD Tablet Ethambutol 1200mg oral OD Tab. Ethionamide 750mg oral OD Tablet Cycloserine 750mg oral OD Tab. Pyrazinamide 1500 mg oral Tablet Linezolid 600 mg oral OD Tab. Pyridoxine 100mg oral OD On 19/7/201 8 Patient complained of blurring of vision . Ophthalmic examination fundoscopy was normal. Bedaquiline and Ethambutol were suspected, however both were continued. On 25/7/201 8 ; Patient doing well and no complains. All treatment continued.

27. Key -1 Blurring of vision- suspected drug ethambutol and bedaquiline Time relationship between drug administration and event- Pharmacological characteristics- Medical plausibility/acceptable- Exclusion of other causes- Dechallenge - Rechallenge - Causality- Yes Yes Yes No info Not done Not done Possible

28. Visual disturbances Visual disturbances Prevalence (DR TB patients) Lzd is by far the most common cause of optic neuritis - 18% of patients in trials, mostly after 4 months of treatment. How to detect? Visual acuity, color testing Common causes Age, cataract, use of Lzd, Emb , Eto / Pto , Cfz , rifabutin , H, S, ddI How to manage? Rule out other causes, discontinue or lower dose of E and/or Lzd Additional tests/precautions Examination of optic nerve ! Diabetes !

29. How to detect visual disturbances?

30. How to manage visual disturbances? endTB Clinical Guideline, MSF&PIH, version 3.2

31. During 16 th week follow up, he c/o pricking and numbness over bilateral great toe > 2week Tingling over entire feet but sensation was intact Pain increasing in intensity & unable to walk normally or hold footwear LZD 600mg witheld . Neurologist opinion obtained and diagnosed as large fiber sensory motor peripheral neuropathy. NCS finding : latency increased in lateral peroneal nerve other conductions are within normal limits. Treatment given : T.Pregabalin75mg OD / T.pyridoxine 100mg OD / T.Amitriptyline 25mg OD Linezolid dose reduced to 300mg. Patient on follow-up . Case 2 29 years old male, non-alcoholic , non-diabetic, unemployed - Diagnosed with Pre XDR TB (3+ smear & MGIT positive ) - started on BDQ & LZD containing regimen on 16.11.2019

32. Key - 2 Peripheral Neuropathy - suspected drug Linezolid Time relationship between drug administration and event- Pharmacological characteristics- Medical plausibility/acceptable- Exclusion of other causes- Dechallenge - Rechallenge - Causality- Yes Yes Yes Yes Yes Not done Probable At 24 th week c/o blurring of vision ????

33. Peripheral neuropathy Peripheral neuropathy Prevalence (DR TB patients) up to 30% of patients More common with comorbidities such as HIV, DM, alcohol use How to detect? Symptomatic Subjective neuropathy scale: ACTG Brief Peripheral Neuropathy Testing Common causes Lzd, hINH , Cs, Pto / Eto , alcohol S, Km, Cm, FQ, E, d4T, ddI How to manage? Consider discontinuation of Lzd, INH, Cs. Physical therapy; sturdy shoes; Amytriptylline ; Pregabaline Additional tests/precautions Prevention: pyridoxine for all patients on INH, Lzd, Cs. Additional testing: alcohol screening, examine extremities for lesions, sores, loss of function.

34. How to detect peripheral neuropathy?

35. How to detect peripheral neuropathy?

36. How to manage peripheral neuropathy? endTB Clinical Guideline, MSF&PIH, version 3.2

37. How to manage peripheral neuropathy? Often improved when offending drugs are suspended, especially if symptoms are mild. Neuropathy with Lzd is common after prolonged use and often extremely painful and irreversible. Lzd should be immediately stopped and not reintroduced when ≥grade 2. Consider additional anti-TB drugs to reinforce the regimen. Symptomatic relief : NSAIDs or acetaminophen may help alleviate symptoms. Tricyclic antidepressant: start amitriptyline 25 mg at bedtime (max dose 150 mg daily) Carbamazepine may be effective in relieving pain and other symptoms Pregabalin 50 – 100 mg every 8 hrs (max dose 300mg/day) At least 50 mg of prophylactic pyridoxine daily. endTB Clinical Guideline, MSF&PIH, version 3.2

38. Case 3 40 years non-diabetic, non-alcoholic, male with Pulmonary XDR-TB Started on Rx with BDQ and LZD containing regimen on 05/08/2019 During 10 th week follow-up, c/o breathlessness on exertion & fatigue since 2 weeks Physical examination revealed moderate pallor and mild pedal edema Blood count done which revealed Hb : 6.6 gm/ dL Patient was hospitalized - Linezolid withheld temporarily Two unit of packed cell volume was transfused with three days apart Improved and discharged at request from hospital Repeat hemoglobin showed 8.4 gm/ dL . Linezolid reintroduced at 300mg/ day BL 2 ND WK 4 TH WK 6 TH WK 8 TH WK 10 TH WK 12 TH WK 16 TH WK 20 TH WK 24 TH WK 10.1gm/dl 10.5 9.7 8.8 8.2 6.6 8.4 9.7 12.8 11.6

39. Key - 3 Myelosuppression (Anemia) - suspected drug Linezolid Time relationship between drug administration and event- Pharmacological characteristics- Medical plausibility/acceptable- Exclusion of other causes- Dechallenge - Rechallenge - Causality- Yes Yes Yes No Yes Not done Possible

40. Myelosuppression Myelosuppression Prevalence (DR TB patients) 18% of patients in a trial with Lzd More common in patients with comorbidity, including HIV, alcohol use How to detect? Complete blood count, hemoglobin, platelets, white blood cells Common causes TB, Lzd, HIV, ART (AZT), alcohol (low platelets) How to manage? Iron supplementation, decrease dose of Lzd, transfusion or EPO if indicated, discontinue other medications. Additional tests/precautions Prevention: vitamin B6 Additional tests: Pregnancy testing, other co-morbidities, alcohol screening, investigation for possible hemorrhage.

41. endTB Clinical Guideline, MSF&PIH, version 3.2 How to manage myelosuppression?

42. How to manage myelosuppression? Rule out : Acute blood loss (occult GI bleeding from a peptic ulcer ) Other causes of anemia (nutritional , iron-deficiency, etc.) are possible, but less likely to occur in the middle of treatment, especially if the patient is clinically improving. Stop the causative drug immediately. Monitor full blood counts regularly . Monthly is not enough if severe myelosuppression occurs. Hospitalize the patient and consider transfusion or erythropoietin if the myelosuppression is severe. Consider erythropoietin (if accessible) for anemia Grade 2 or 3. Consider additional anti-TB drugs to reinforce the regimen.

43. Case- 4 20 years female patient was diagnosed with MDR-TB. She is UPT negative for pregnancy test. On 23/7/2019, the following treatment was started as per DST; On 23/07/2019 Tablet Bedaquiline 400mg oral OD Tablet Ethambutol 800mg oral OD Tablet Moxifloxacin 400 mg oral OD Tablet Cycloserine 750mg oral OD Tablet Linezolid 600 mg oral OD Tablet Clofazamine 200 mg oral BD Lab Values: Total WBC- 26.10 Hb - 9.6 Billirubin T- 0.98 ALT-84 AST-33.3 ALP- 95.20 Amylase- 60.9 Lipase- 53.4 Creatinine-0.66 Glucose-108 TSH-3.4 ECG (QTc- 270 msec) Urea- 15.20 Serum Na+- 139.8mmol/l; Serum K+- 4.46mmol/l; Serum Calcium- 6.11mmol/l; Serum Mg- 2.14 mEq /L

44. On 26/7/2019 QTc observed was 500 msec. Bedaquiline, Clofazamine and moxifloxacin were suspected and witheld (BL QTc recorded was 270 msec).   On 29/7/19 Bedaquiline was started again. The value of QTc was 280 msec.   On 01/8/2019 Clofazamine was also reintroduced and the QTc was 278 msec.   On 04/8/2019 Moxifloxacin was reintroduced and the QTc was 480msec. Moxifloxacin was then stopped and QTc was 320 msec.   On 07/8/2019 Patient doing well and no complains. Rest all treatment continued

45. Key - 4 QTc Prolongation suspected drugs- Bedaquiline , Clofazamine & Moxifloxacin Time relationship between drug administration and event- Pharmacological characteristics- Medical plausibility/acceptable- Exclusion of other causes- Dechallenge - Rechallenge - Causality- Yes Yes Yes Not Likely, Serum electrolytes deranged- etiology not convincing Positive Positive Certain, [Step wise rechallenge confirmed the causality to certain] Calcium is maintained within 8.5 to 10.5 mg/dl (4.3 to 5.3 mEq /L or 2.2 to 2.7 mmol/L ) Magnesium is maintained at 1.7 to 2.2 mg / dL (1.4–2.0 mEq / L or 0.85 to 1.10 mmol/L).

46. QT prolongation QT prolongation Prevalence (DR TB patients) Can occur in up to 10% of patients How to detect? ECG Common causes Mfx , Bdq , Cfz , Dlm , Lfx // Hypothyroidism Many other drugs: e.g . erythromycin, clarithromycin, quinidine, ketoconazole, fluconazole, Antipsychotics (all have some risk including haloperidol, chlorpromazine and risperidone), Many anti-nausea drugs (ondansetron/ granisetron , domperidone ), Methadone , Some antiretrovirals. Genetic causes such as long QT syndrome; How to manage? Assess for symptoms, repeat to confirm, review all medications; if >500 msec and does not correct, d/c BDQ Additional tests/precautions Potassium, TSH

47. How to detect QT prolongation? endTB Clinical Guideline, MSF&PIH, version 3.2  

48. The ECG machine should be calibrated to ensure that the following voltage and speeds apply: endTB Clinical Guideline, MSF&PIH, version 3.2 How to detect QT prolongation ? 1 small squares in EGG = 40 ms 1 large box of squares=200ms

49. endTB Clinical Guideline, MSF&PIH, version 3.2 You can count on the ECG display and gets the value for RR and QT? How much are QT here ? How to detect QT prolongation? Abnormal values: Males: > 450 ms Females > 470 ms Abnormal QTc: Repeat ECG and calculations

50. endTB Clinical Guideline, MSF&PIH, version 3.2 QTcF can be calculated using the formula… OR you just use the nomogram. Can you find QTcF for the example? How to detect QT prolongation ?

51. How to manage QT prolongation? endTB Clinical Guideline, MSF&PIH, version 3.2

52. Stop all QT prolonging drugs immediately . ART usually not stopped unless the patient is severely unstable. Hospitalize and consider continuous ECG monitoring for Grade 3 and above. Hospitalization should occur in a facility capable in the management of Torsades de Pointes / arrhythmia. Check a TSH and treat any hypothyroidism found. Check electrolytes and manage. endTB Clinical Guideline, MSF&PIH, version 3.2 How to manage QT prolongation?

53. Checking and repleting serum electrolytes: Serum potassium (K + ), ionized calcium (ionized Ca ++ ), and magnesium (Mg ++ ) should be obtained in case of prolonged QT. Abnormal electrolytes are most commonly due to injectable and should be corrected . If low K + is detected, urgent management with replacement and frequent repeat K + test (daily or multiple times a day) to document K + is improving. If K + is low, always check Mg ++ and Ca ++ , and compensate as needed. If unable to check, consider oral empiric replacement doses of Mg ++ and Ca ++ . endTB Clinical Guideline, MSF&PIH, version 3.2 How to manage QT prolongation? Once stable (QTcF <450 and normal electrolytes), drugs can be added back: Mfx  consider using Lfx instead. Cfz  consider suspending it permanently if not critical to the regimen. Bdq or Dlm  if considered critical to the regimen, consider adding back to the regimen while suspending all other QT prolonging drugs

54. Hepatitis Hepatitis Prevalence (DR TB patients) Up to 25% How to detect? Symptomatic, screening (transaminases) Baseline : screen for hepatitis B and C Common causes Viral hepatitis, alcohol, NVP, any of the TB medications Can be very difficult to decide causative agent in multidrug regimen ! cotrimoxazole in HIV patients ! How to manage? Discontinue medications and serially reintroduce Additional tests/precautions Consider serum bilirubin, alcohol screening, hepatitis B and C serology, liver ultrasonography

55. How to manage hepatitis? endTB Clinical Guideline, MSF&PIH, version 3.2

56. Dosage of DR-TB drugs for adults 1 For H mono/poly resistant TB; 2 For adult more than 60 yrs of age, dose of SLI should be reduced to 10mg/kg (max up to 750 mg) 3 In patient of PAS with 80% weight/volume the dose will be changed to 7.5gm (16-29Kg); 10 gm (30-45 Kg); 12 gm (46-70 Kg) and 16 gm (>70 Kg ) 4 drugs can be given in two divided doses in a day in the event of intolerence S.No Drugs 16-29 Kgs 30-45 Kgs 46-70 Kgs >70 Kgs 1 Rifampicin(R) 1 300mg 450mg 600mg 600mg 2 High dose H ( H h ) 300 mg 600 mg 900 mg 900 mg 3 Ethambutol (E) 400 mg 800 mg 1200 mg 1600 mg 4 Pyrazinamide(Z) 750 mg 1250 mg 1750 mg 2000 mg 5 Kanamycin(Km) 2 500 mg 750 mg 750 mg 1000 mg 6 Capreomycin (Cm) 500 mg 750 mg 750 mg 1000 mg 7 Amikacin (Am) 500 mg 750 mg 750 mg 1000 mg 8 Levofloxacin(Lfx) 4 250 mg 750 mg 1000 mg 1000 mg 9 Moxifloxacin (Mfx) 4 200 mg 400 mg 400 mg 400 mg 10 High Dose Mfx (Mfx h ) 4 400mg 600mg 800mg 800mg 11 Ethionamide(Eto) 4 375 mg 500 mg 750 mg 1000 mg 12 Cycloserine(Cs) 4 250 mg 500 mg 750 mg 1000 mg 13 Na-PAS (60% weight/vol) 3,4 10 gm 14 gm 16 gm 22 gm 14 Pyridoxine(Pdx) 50 mg 100 mg 100 mg 100 mg 15 Clofazimine (Cfz) 50 mg 100 mg 100 mg 200 mg 16 Linezolid (Lzd) 300 mg 600 mg 600 mg 600 mg 17 Amoxyclav(Amx/Clv) (In child: WHO 80mg/Kg in 2 divided doses) 875/125 mg BD 875/125 mg BD 875/125 mg (2 morning +1 evening) 875/125 (2 morning +1 evening) 18 Bedaquiline (Bdq) Week 0–2: Bdq 400 mg daily Week 3–24: Bdq 200 mg 3 times per week

57. Missing Bedaquiline doses & Reload after interruption Initia l 2 weeks of BDQ course and returns to resume the treatment: If interruption is up to 7 days: BDQ containing regimen will be continued to complete the doses and the duration of treatment will be extended to complete IP.. If interruption is more than 7 consecutive days BDQ course will be re-loaded (started afresh) and a sputum sample will be collected for culture. 3-24 weeks of BDQ course and returns to resume the treatment: If interruption is up to 1 month: BDQ containing regimen will be continued to complete the doses If interruption is more than 1 months: BDQ will be permanently discontinued. Such patients will be given an outcome of “Lost to follow up” (LTFU) based on the duration of LTFU culture isolate must be stored for BDQ DST in future

58. Hypokalaemia Hypokalemia Prevalence (DR TB patients) Up to 15% More common in patients with vomiting, diarrhea, alcohol use How to detect? Serum K+ Common causes Injectables (TDF rarely) How to manage? Replete potassium, replete magnesium, ensure hydration, encourage dietary intake of K+ (banana, orange, etc.) In cases refractory to replacement therapy, amiloride 5 to 10 mg PO daily or spironolactone 25 mg PO daily Additional tests/precautions Consider checking calcium if there is QT prolongation, alcohol screening.

59. How to manage hypokalaemia? endTB Clinical Guideline, MSF&PIH, version 3.2

60. How to manage hypokalemia ? Monitor electrolytes frequently in case of vomiting/diarrhea and when using injectables . Start oral or IV rehydration immediately until volume is normal. Replete K+ and Mg++. Hypokalemia may be refractory if concurrent hypomagnesemia is not corrected. If Mg++ cannot be checked, give empiric oral replacement therapy in all cases of hypokalemia with magnesium gluconate 1000 mg twice daily. Check ECG in patients with significant electrolyte disturbances. Drugs that prolong the QT interval should be discontinued in patients with evidence of QT interval prolongation. Electrolyte abnormalities are reversible upon discontinuation of injectable, it may take weeks or months to normalize under maintained replacement therapy. endTB Clinical Guideline, MSF&PIH, version 3.2

61. Hypothyroidism endTB Clinical Guideline, MSF&PIH, version 3.2 How to detect? TSH levels (! High TSH = hypo- thyroidism ) How to manage? Thyroid replacement therapy Precaution QTc interval

62. Gastritis & abdominal pain Suspected agent(s): Cfz , FQs, H, E, and Z Suggested management strategies if symptoms are associated and consistent with gastritis (epigastric burning or discomfort, sour taste in mouth associated with reflux) initiate medical therapy with the use of H2-blockers (ranitidine 150 mg twice daily or 300 mg once daily) or proton-pump inhibitors (omeprazole 20 mg once daily) which should be avoided along with Bdq Avoid use of antacids as they decrease absorption of FQ For severe abdominal pain, stop suspected agent(s) for 1-7 days lower the dose of the suspected agent, if this can be done without compromising the regimen / discontinue suspected agent if this can be done without compromising regimen

63. Nausea and Vomiting : 3 Step approach to manage Step 1: Adjust medication and conditions without lowering overall dose . Give Eto / Pto at night; Eto or PAS twice or thrice daily; light snack (biscuits, bread, rice, tea) before medication; and Step 2: Start antiemetic(s) like Metoclopramide 10 mg, 30 minutes before anti- TB medication; Ondansetron 8 mg, 30 minutes before anti-TB drugs and again eight hours after. Ondansetron can either be used on its own or with metoclopramide (if ondansetron is not available, promethazine can be used.) For refractory nausea give 24 mg, 30 minutes before the dose. Step 3 : Decrease dose of suspected drug by one weight class (except Bdq / Dlm ) if this can be done without compromising the regimen. It is rarely necessary to suspend the drug completely .

64. D rugs are replaced according to their efficacy, no demonstrable resistance, prior use, side-effects profile and background resistance to the replacement drug in the country Regimen should preferably be fully oral. However, in certain circumstances, an Injectable may have to be used for the need of efficacy and side-effect profile. Dlm and Am will not be used in the final 12 months of treatment. One group A drug will be replaced by two group C drugs. Though Imp- Cln is 4 th in the sequence of drugs of group C, it will only be used as the last resort for designing the regimens, operational issues of a Peripherally Inserted Central Catheter (PICC) placement for the entire duration of its use, need for admission to a NDR TBC. Replacement Principles

65. Sequence of Replacement Drugs In case of Adverse drug reaction / Poor tolerance / Documented resistance / Contraindication or Non-availability of any component drug of the combination regimen Add drug in the order of sequence : Cs, H h E, Bdq * (in RR-TB patients also where a WHO recommended regimen could not be formed), PAS, Amx -clv. Shorter MDR TB regimen If there is a need for stopping/replacing any drug, stop the regimen and evaluate the patient to switch to all oral longer regimen.

66. Conclusions Adverse events are common and are to be expected during treatment for DR-TB Routine monitoring is important for all patients on MDR-TB treatment; aDSM is the systematic way of achieving this Early recognition and optimal management of adverse events is key to ensuring better treatment outcomes Standard scales can help with severity ratings and finding the appropriate management option Health care providers need to be trained and supported to provide appropriate care – including management of adverse reactions – to patients

67. Thank You