Case Discussion 4 –

COMMON
ADVERSE DRUG
REACTIONS &
FOLLOW-UP

by
Dr. Wong Jyi Lin
Dr. Salmiah Sharif

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 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+

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 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?
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 A1
• Risk factors for ADR of antiTB drugs

Ref: CPG Mx of TB (3rd Ed.)4

AntiTB Regimen

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

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

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 A2
• Common ADRs related to antiTB drugs

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

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 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

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

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 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?

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 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

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 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.

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 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

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 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.

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

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

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 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

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 Q5
• What would be the management plan?

• What is the plan of follow-up for this

patient?

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Management of Tuberculosis
(3rd Edition)

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 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.

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A5

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

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 Case 1 (cont.)
• At one month, patient still felt lethargic,
unwell & coughing, but less than before.

• What is the next step of management?

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 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

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 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
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 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?

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 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.

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

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Management of Tuberculosis
(3rd Edition)

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Drug-Induced Hepatotoxicity
(DIH)

Yew WW et al., Respirology, 2006

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 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

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 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.
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 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

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 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?

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 A7
• Urine discoloration is commonly seen in
rifampicin usage & this may not warrant
interruption of treatment.

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

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 Case 2 (cont.)
• Patient’s liver function test is normal.

• Patient is continued with antiTB treatment

with some loratidine OM & chlorpheniramine
ON.

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 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?

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A8

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

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A8

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

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 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?

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 A9
• Optic neuritis needs to be ruled out.

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 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

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 Case 2 (cont.)
• Follow-up

Ref: CPG Mx of TB (3rd Ed.)41

 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.
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 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
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 THANK YOU

[email protected]
[email protected]

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