1. Case Discussion 4 – COMMON ADVERSE DRUG REACTIONS & FOLLOW-UP by Dr. Wong Jyi Lin Dr. Salmiah Sharif 1

2. Case 1 73 year-old man PTB in 2009 - completed treatment Coughing for 3 months since November 2012 CXR noted to have some evidence of worsening Repeat Sputum AFB x 1: 3+ 2

3. Case 1 (cont.) Started on SHERZ, while waiting for sputum TB C+S Past history of: – Hepatitis B infection with normal liver function test (LFT) – Weight - 55 kg Q1. Does the patient have any risk factors for adverse drug reactions? 3

4. A1 Risk factors for ADR of antiTB drugs 4 Ref: CPG Mx of TB (3 rd Ed.)

5. AntiTB Regimen 5 Ref: CPG Mx of TB (3 rd Ed.)

6. Q2 What other adverse events should the patient & doctors watch out for? 6

7. A2 Common ADRs related to antiTB drugs 7 Ref: CPG Mx of TB (3 rd Ed.)

8. Case 1 (cont.) 2 weeks after treatment: – Complained that cough still persistent – Loss of appetite & dizziness – Left foot pain + swollen + redness – Wished to stop medication as thinking that medication did not help his symptoms 8

9. Q3 When a patient complains of side effects & wishes to stop medication: – What are the considerations in formulating a management plan? 9

10. What are the issues here? Issue 1 : Is antiTB treatment really necessary? Is the diagnosis correct? Issue 2 : Are the symptoms due to side effects of antiTB drugs & is there a need to withhold the drugs? 10

11. A3. Issue 1 Is the diagnosis correct? Is this PTB? – Rapid LPA To differentiate between Tuberculosis and Non- tuberculosis mycobacteria To look for drug resistance Results in 2 weeks time 11

12. Issue 2 Are the symptoms due to the adverse effect of antiTB drugs? – An adverse drug reaction (ADR) is an expression that describes harm associated with the use of given medication at a normal dosage during normal use. 12

13. A3. Issue 2 Timing of Adverse Event For antiTB treatment, most of ADRs occur within early stage of the treatment compared to the later stage (52.5% experience ADRs within 20 days, 7.5% in 21 - 40 days, 22.5% within 41 - 60 days & 17.5% in >60 days after starting treatment). Kishore PV et al., Pa J Pharm Sci., 2008 13

14. Classification of Adverse Events ADRs which are troublesome but not serious such as nausea, tiredness, pruritus & minor rashes. These can be treated symptomatically without necessarily having to interrupt treatment. Most of these will resolve spontaneously even when treatment is continued. ADRs which need immediate discontinuation of treatment such as severe skin reactions [ Steven- Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) & Drug Rash with Eosinophilia & Systemic Symptoms (DRESS)] & hepatitis. 14

15. Q4: What are the helpful investigations to decide whether interruption of antiTB treatment is necessary? 15

16. A4 Helpful investigations: – Full blood count – Liver function test – Renal profile – Se. uric acid 16

17. Case 1 (cont.) Noted: – FBC - normal – ALT - 79 U/L or 2x ULN – Bilirubin - normal – Albumin – 36 g/L – RP - normal – Se. Uric Acid - 600 umol/L 17

18. Q5 What would be the management plan? What is the plan of follow-up for this patient? 18

19. Management of Tuberculosis (3 rd Edition) 19

20. Case 1 (cont.) AntiTB drugs were continued & patient was informed the importance of compliance to them & side effects to look for. Patient was started on NSAIDs for gout symptoms. 20

21. 21 Ref: CPG Mx of TB (3 rd Ed.) A5

22. Case 1 (cont.) At one month, patient still felt lethargic, unwell & coughing, but less than before. What is the next step of management? 22

23. Case 1 (cont.) Patient was continued on antiTB treatment, but now switched back to EHRZ in view of clinical improvement. On follow-up at 2 months: still complained of worsening lethargy & coughing had occasional nausea no rashes 23

24. Case 1 (cont.) Patient came to A&E at Day 70 antiTB treatment complaining of generalised weakness & unable to walk. Noted to be confused for 2 weeks. Smear AFB: 3+ LFT – TB: 200 umol/L – DB: 180 umol/L – ALT: 400 U/L – AST: 320 U/L – Albumin: 22 g/L – INR: 2.3 24

25. Case 1 (cont.) In view of presence of symptoms & abnormal liver function test – Anti TB was withheld After stopping antiTB treatment, patient’s symptoms improved. – Q6. What is the next step of management? 25

26. A6 Subsequently, if the TB disease is of low severity in terms of radiographic extent, bacillary load & infectiousness, antiTB treatment can be withheld until liver chemistry recovers & patient’s symptoms resolve. Timing of restarting treatment also depends on whether hepatotoxicity sets in during the initial or the continuation phase of treatment and the amount of treatment received prior to the onset of such toxicity. 26 Ref: CPG Mx of TB (3 rd Ed.)

27. Management of Tuberculosis (3 rd Edition) 27

28. Drug-Induced Hepatotoxicity (DIH) 28 Yew WW et al., Respirology, 2006

29. AntiTB-induced liver injury (ATLI) Compared with those without ATLI, ATLI patients have a 9.3-fold risk (95% CI 5.7 to 15.1) of unsuccessful antiTB treatment outcomes & a 2.1-fold risk (95% CI 1.2 to 3.6) of prolonged intensive treatment phase. Shang P et al., PLoS ONE, 2011 29

30. Summary of Case 1 Hepatotoxicity is the most common adverse drug reaction to antiTB treatment. In patients with risk factors, liver function test should be monitored regularly & frequently. AntiTB drugs should be stopped when the ALT is 3x ULN in symptomatic patients & 5x ULN in asymptomatic patients. AntiTB drugs can be rechallenged once LFT normalises. Not all abnormal LFT is due to antiTB drugs. 30

31. Case 2 33 year-old lady New case of PTB, smear +ve, advanced disease on CXR, RVD status –ve Presented with coughing Started on antiTB treatment in December 2012 – Weight 45 kg – Given rifampicin 450 mg, isoniazid 250 mg, pyridoxine 10 mg, pyrazinamide 1000 mg & ethambuthol 1200 mg 31

32. Case 2 (cont.) Complained of pruritus & orange-coloured urine one day after starting antiTB treatment No nausea or vomiting, some degree of lethargy On examination: normal physical findings Q7. What is the next step of management? 32

33. A7 Urine discoloration is commonly seen in rifampicin usage & this may not warrant interruption of treatment. 33 Ref: CPG Mx of TB (3 rd Ed.)

34. Case 2 (cont.) Patient’s liver function test is normal. Patient is continued with antiTB treatment with some loratidine OM & chlorpheniramine ON. 34

35. Case 2 (cont.) Day 4 treatment, patient started to develop some rashes. Otherwise status quo. She was reassured & antiTB continued. 2 weeks later: Rashes worsened & became generalised Started to have painful mouth ulcers & lethargy Q8. What is the next step of management? 35

36. A8 36 Ref: CPG Mx of TB (3 rd Ed.)

37. A8 37 Ref: CPG Mx of TB (3 rd Ed.)

38. Case 2 (cont.) Patient had been successfully rechallenged with rifampicin & isoniazid, & was subsequently commenced on HER regimen. 6 weeks later, rashes improved but patient started to complain of blurring of vision & numbness. Q9. What is the main concern here? 38

39. A9 Optic neuritis needs to be ruled out. 39

40. Case 2 (cont.) Extensive eye review was normal Ethambutol dose reduced to the recommended dose of 20 mg/kg If there was optic neuritis, ethambutol should be discontinued 2 weeks later, patient’s medication was switched to antiTB maintenance regimen No more complain of blurring of vision after that 40

41. Case 2 (cont.) Follow-up 41 Ref: CPG Mx of TB (3 rd Ed.)

42. Summary of Case 2 Minor rashes are not a contraindication to continue with antiTB drugs. However, patients need to be followed-up for more severe skin reactions. Ethambutol-induced optic neuritis is rare but patients should be instructed to seek medical help early if there are suggestive symptoms. 42

43. Take Home Messages Adverse drug reactions – Should be taken seriously – Stopping or changing of regimen may not be necessary in all cases – For those with adverse events leading to change in regimen, follow-up is necessary as treatment failure is higher Follow-up is necessary during treatment to look for side effects of antiTB drugs 43

44. 44 THANK YOU  wongjl@srwk.moh.gov.my wongjl@srwk.moh.gov.my  drmayasharif@yahoo.com drmayasharif@yahoo.com