MANAGEMENT OF

SOME ADVERSE
EVENTS
 SOME ADVERSE EVENTS

A. Hepatitis
B. Myelosuppression
C. Peripheral Neuropathy
D. QT Prolongation
E. Depression
F. Optic Nerve Disorder

Department of Health – National TB Control Program

 The Importance Of Identification And
Management Of AEs
• Conduct education
• Prompt evaluation,
and counseling to
diagnosis and treatment
patients and family
of adverse effects are
members and
extremely important,
encourage to report
even if the adverse
any occurrence of AEs
effect is not particularly
proactively.
dangerous.
• Ask/check proactively if
• If adverse effects are not
patients have any
timely and well
clinical complaints daily
managed, there is a
higher risk of lost to
• Follow regular
follow-up, treatment
treatment monitoring
failure or can lead to
schedule by conducting
potential fatal event or
all lab/clinical
permanent disability.
examination.
GENERAL STRATEGIES FOR MANAGING ADVERSE
DRUG REACTIONS
Conduct patient
information and Adjust drug dosages
counseling
Modify the regimen
Provide
psychosocial Perform
support laboratory and
other
diagnostic
tests, as
Determine severity
recommended
of the AEs
- MILD AEs to be
managed by nurses
- MODERATE / SEVERE Refer to a specialist
AEs to be managed by
MDs
for co-morbidities

Department of Health – National TB Control Program

 SEVERITY OF ADVERSE EVENTS
Asymptomatic or mild symptoms; clinical or
1 MILD diagnostic observations only; intervention not
indicated

Minimal, local or non-invasive intervention

2 MODERATE indicated; limiting age-appropriate
instrumental ADL*
Medically significant but not immediately life-
threatening; hospitalization or prolongation of
3 SEVERE
hospitalization indicated; disabling; limiting self
care ADL**
LIFE-
4 Urgent intervention indicated
THREATENING
5 DEATH
*Instrumental Activities of Daily Living refer to preparing meals, shopping for groceries or
clothes, using the telephone, managing money, etc.
**Self care Activities of Daily Living refer to bathing, dressing and undressing, feeding self,
using the toilet, taking medications, and not bedridden.
Hepatitis
 HEPATITIS
GRADING

ADVERSE EVENT 1
MILD
2
MODERATE
3
SEVERE
4
LIFE-
5
DEATH
THREATENING

ALT (SGPT)

Hepatitis 1.1 - 2.0 - 3.0 –

>8 x
POSSIBLE <2.0 x <3.0 x 8.0 x
ANTI-TB DRUG ULN ULN ULN ULN
CAUSES: Z, H, E,
Pto/Eto, PAS,
Bdq, Cfz, Lzd AST (SGOT)

1.1 - 2.0 - 3.0 – >8 x

<2.0 x <3.0 x 8.0x
ULN
ULN ULN
ULN
This Photo by Unknown Author is
licensed under CC BY-SA
 MANAGEMENT OF HEPATITIS
GRADING

ADVERSE EVENT 1
MILD
2
MODERATE
3
SEVERE
4
LIFE-
5
DEATH
THREATENING

Hepatitis • Investigate for other causes of

POSSIBLE ANTI-TB
DRUG CAUSES: Z, hepatotoxicity (alcoholic and
H, E, Pto/Eto, PAS,
Bdq, Cfz, Lzd
non-alcoholic liver disease, viral
hepatitis or concomitant
medications).

• Laboratory and diagnostic tests

(serology tests for hepatitis A, B,
This Photo by Unknown Author is
licensed under CC BY-SA
C , hepatobiliary ultrasound)

Department of Health – National TB Control Program

 NOTES:
1. Hepatitis is characterized by nausea, vomiting,
jaundice, icteric sclera, tea colored urine, pale stool
and diminished appetite in the setting of elevated
liver function tests.
2. Mild elevation of liver enzymes, especially at
baseline, maybe related to TB rather than an
adverse effect of treatment.

3. Generally, hepatitis due to medications resolves

upon discontinuation of suspected drug.
4. In HIV coinfection, nevirapine and cotrimoxazole
can be a cause of hepatotoxicity.

Department of Health – National TB Control Program

 MANAGEMENT OF HEPATITIS
1 2 3 4
Adverse Event 55
Mild Moderate Severe Life-threatening Death
Death
2.0 - <3.0 x
ALT (SGPT) 1.1 - <2.0 x ULN 3.0 – 8.0 x ULN >8 x ULN -
ULN

2.0 - <3.0 x
AST (SGOT) 1.1 - <2.0 x ULN 3.0 – 8.0 x ULN >8 x ULN -
ULN

• Continue treatment regimen. >3x ULN AST/ALT

Patients should be followed up If patient is asymptomatic, request for
until resolution (return to Total Bilirubin, continue anti-TB
baseline results) or treatment while awaiting TB result. If
stabilization of results. TB result is >2x ULN, this is already
significant to warrant discontinuation
• If patient is asymptomatic, of treatment
continue anti-TB treatment.
Repeat liver function tests If patient has signs and symptoms of
Action weekly. hepatitis, discontinue TB treatment
immediately
Repeat ALT/AST weekly until normal

>5x ULN AST/ALT (regardless of signs

and symptoms)
Discontinue anti-tb treatment
immediately
Repeat ALT/AST weekly until normal
levels are reached or <3x ULN
MANAGEMENT OF HEPATOTOXICITY
Myelosuppression
 MYELOSUPPRESSION
Possible anti-TB drug cause: Linezolid
Other drug: AZT (Azidothymidine/Zidovudine)
Grade 4
Severity Grade 1 Grade 2 Grade 3
Life -
Grade Mild Moderate Severe
threatening
10.5 - 9.5 9.4 - 8.0 7.9 - 6.5
Anemia < 6.5 g/dL
g/dL g/dL g/dL
75,000 – 50,000 – 20,000 –
Platelets < 20,000
decreased
99,999 74,999 49,999
/mm³
/mm³ /mm³ /mm³
Absolute
1500 - 999 - 749 -
neutrophil <500/mm3
count low 1000/mm3 750/mm3 500/mm3

Department of Health – National TB Control Program

 MANAGEMENT OF MYELOSUPPRESSION

GRADING
1 2 3 4 5
ADVERSE EVENT MILD MODERATE SEVERE LIFE-THREATENING DEATH

Myelosuppression
• Investigate for other causes of
POSSIBLE ANTI-TB myelosuppression or anemia,
DRUG CAUSES: Lzd
leucopenia or thrombocytopenia
such as TB disease itself, nutritional
deficiencies, viral infections, occult
blood loss, advanced HIV/AIDS,
chronic renal insufficiency,
concomitant medications.
This Photo by Unknown Author is licensed
under CC BY-NC
• Request for other laboratory and
diagnostic tests.
 MANAGEMENT OF MYELOSUPPRESSION

GRADING

ADVERSE EVENT 1
MILD
2
MODERAT
3
SEVERE
4
LIFE-THREATENING
5
DEATH
E

Myelosuppression
• Decreas • Stop Lzd immediately.
POSSIBLE ANTI-TB e dose
DRUG CAUSES: FQ, of Lzd to • Consider blood transfusion
Cfz, Bdq, Dlm and/or erythropoietin for life
300 mg
threatening/grade 4
daily.
myelosuppression: Hb of <6.5
g/dL, ANC <500/mm3 or and/or
• Monitor platelet count of <20,000/mm3.
CBC
weekly • Reintroduce Lzd at 300 mg
until daily when toxicity level
normal decrease to Grade 1.
This Photo by Unknown Author is licensed
under CC BY-NC
levels
• Monitor CBC weekly until
are
normal levels are reached.
reached
 Myelosuppression
Possible anti-TB drug cause: Linezolid
Other drug: AZT (Azidothymidine/Zidovudine)
 How to compute for
Absolute Neutrophilic
Count:

10 x WBC (4.0) x
(neutrophils (50)
+ bands (0)
= 2000
Grade1 Grade2 Grade 3

[Link]

Department of Health – National TB Control Program

 Use of Erythropoietin (EPO)
Treatment with erythropoietin is not intended for patients who require
immediate correction of anemia (Grade 4). In this case, blood
transfusions should be considered. Whole blood count should be
repeated weekly to assess the response to treatment. Blood pressure
should be adequately controlled before initiation and monitored
during therapy. Erythropoietin treatment should in any case be
discontinued at Hemoglobin levels over 12 g/dL.
Contraindications: Erythropoietin treatment should be administered
with caution in the presence of:
 Untreated, inadequately treated or poorly controlled
hypertension , epilepsy, thrombocytosis , chronic liver
failure, hyperkalemia
Preparation and administration:
Epoetin alfa prefilled syringes of 10 000 UI or 40 000 IU/ml to be stored
in cold chain (2°C to 8°C).
Dosing Epoetin alfa: 150 IU/Kg three times a week or 450 IU/Kg once a
week subcutaneously or intravenously.
• Exclude other cause of anemia (e.g. TB itself,
iron deficiency, occult blood loss, etc.). AZT
induced anemia is more likely to be
macrocytic anemia which can be determined
by mean corpuscular volume (MCV).

• If the patient has thrombocytopenia or

neutropenia, this is more likely to be due to
linezolid.

• All patients taking linezolid should also be

receiving at least 50 mg of pyridoxine

Department of Health – National TB Control Program

 Peripheral
Neuropathy
 PERIPHERAL NEUROPATHY

▪Peripheral neuropathy is a common side

effect of MDR-TB treatment caused by drug
toxicity to the nerves of the peripheral
nervous system.

▪Signs and symptoms of peripheral

neuropathy are: numbness, tingling, burning,
or pain in the feet or hands.

▪If a patient complains of these signs and

symptoms, grading by using Brief Peripheral
Neuropathy Screening (BPNS) should be
done
Department of Health – National TB Control Program
 BRIEF PERIPHERAL NEUROPATHY
SCREENING
Step 1. Elicit Subjective Symptoms
Ask the patient to rate the severity of each symptom on a
scale from 01(mild) to 10 (most severe) for right and left feet
and legs. Enter the score for each symptom in the columns
marked R (right lower limb) and L (left lower limb).
Normal Mild --------------------------------------------------------------------------------Severe
00 01 02 03 04 05 06 07 08 09 10

Symptoms Right Left

a. Pain, aching, or burning in feet, legs
b. "Pins and needles" in feet, legs
c. Numbness (lack of feeling) in feet,
legs

Use the single highest severity score

above to obtain a total subjective sensory
neuropathy score for severity grading.
 BRIEF PERIPHERAL NEUROPATHY
SCREENING

Step 2. Grade subjective symptoms

Severity Grading of Total Score:

Grade 0 = 00 Grade 1 = 01-03 Grade 2 = 04-06 Grade 3 = 07-10

Department of Health – National TB Control Program

 PERIPHERAL NEUROPATHY
Peripheral Neuropathy
Possible anti-TB drug causes: Lzd, Cs, H, Am, S, Fq, Pto, E
Grade
Grade 4
Severity Grade 1 Grade 2 Grade 3
Life-
Grade Mild Moderate Severe
threatening

Severe
Moderate
discomfort; or Incapacitating;
Mild discomfort;
narcotic or not
discomfort; non-
Paresthesia analgesia responsive to
no treatment narcotic
required with narcotic
required analgesia
symptomatic analgesia
required
improvement

Department of Health – National TB Control Program

 MANAGEMENT OF PERIPHERAL
NEUROPATHY
GRADING

ADVERSE 1
MILD
2
MODERATE
3
SEVERE
4
LIFE-
5
DEATH
EVENT THREATENING

Peripheral
• Investigate for other causes of
Neuropathy
peripheral neuropathy such as
POSSIBLE ANTI-TB
DRUG CAUSES: Lzd, diabetes, alcoholism, vitamin
Cs, H, Am, S, FQ, deficiencies, HIV, hypothyroidism,
Pto, E uremia, concomitant medications and
manage accordingly.

• Request for laboratory and diagnostic

tests (e.g. FBS)

This Photo by Unknown Author is licensed

under CC BY-ND

Department of Health – National TB Control Program

 MANAGEMENT OF PERIPHERAL
NEUROPATHY
GRADING
ADVERSE EVENT 1
MILD
2
MODERATE
3
SEVERE
4
LIFE-
5
DEATH
THREATENING

Peripheral • Stop Lzd, high • Stop Lzd, Hhd and Cs immediately

dose H and Cs
Neuropathy immediately . • Monitor BPNS weekly until symptoms
improve to normal or stable if severity grade
POSSIBLE ANTI-TB • Monitor BPNS is high.
weekly until
DRUG CAUSES: symptoms • If symptoms improve, consider restarting Cs
Lzd, Cs, H, Am, S, improve to and Hhd. Do NOT re-introduce Lzd.
FQ, Pto, E normal.
• Increase pyridoxine to 200 mg daily.
• If smptoms
improve, • Provide symptomatic relief with ancillary
consider drugs such as gabapentin and amitriptyline.
restarting Lzd, Take caution when co-administering Lzd and
Hhd and Cs. amitryptiline due to possible occurrence of
However, re- Serotonin Syndrome. Avoid prescribing Lzd
introduce Lzd at and amitriptyline at the same time.
a lower dose of
This Photo by Unknown Author is licensed
under CC BY-ND
300 mg daily. NOTE: Peripheral neuropathy may be
irreversible. However, many patients experience
• Increase improvement when offending drugs are
pyridoxine to 200 discontinued, especially if the symptoms are
mg daily. mild.
 Peripheral Neuropathy
Possible anti-TB drug causes: Lzd, Cs, H, Am, S,
Fq, Pto, E
 SAMPLE CASE
54 y/o pt. on the 2nd month of treatment with the following regimen:
BdqLzdCfzCsPto
Complains of burning sensation in both lower extremities but more on the
right.

Step 1: Using BPNS . Elicit subjective symptoms

Normal Mild ------------------------------------------------------------------Severe
00 01 02 03 04 05 06 07 08 09 10

Right Left
a. Pain, aching, or burning in feet, legs 05 03
b. "Pins and needles" in feet, legs 04 02
c. Numbness (lack of feeling) in feet, legs 00 00
Step 2: Grade subjective symptoms
Grade 0 = 00 Grade 1 = 01-03 Grade 2 = 04-06 Grade 3 = 07-10

Grade 2 (05)
Management:
Stop Cs and Lzd. If symptoms improve, consider
restarting Cs. Do not reintroduce Lzd.
Provide symptomatic relief.
Prolonged QT Interval
 QT PROLONGATION
GRADING
ADVERSE EVENT 1 2 3 4 5
MILD MODERATE SEVERE LIFE- 5
DEAT
THREATENING Death
H

QT QTc > 501 or

Prolongation QTc QTc 481- QTc >
>60 ms
change from
POSSIBLE ANTI- 450-480 500 ms 501 ms baseline on
TB DRUG CAUSES: ms on at at least two
FQs, Cfz, Bdq, least separate
Dlm two ECGs .
separat (repeat ECG
e ECGs will be done
after
reassuring
patient to
relax for 10-15
mins)

This Photo by Unknown Author is

licensed under CC BY-SA
 MANAGEMENT OF QT PROLONGATION
GRADING

ADVERSE EVENT 1
MILD
2
MODERATE
3
SEVERE
4
LIFE-
5
DEATH
THREATENING

QT Prolongation • Investigate for other causes of

POSSIBLE ANTI-TB QTc prolongation, such as
DRUG CAUSES: FQ,
Cfz, Bdq, Dlm
concomitant medications,
hypothyroidism, electrolyte
imbalance, hypoglycemia,
cardiac diseases such as history
of syncopal episode, ventricular
arrhythmias or severe coronary
artery disease, genetic conditions.

• Request for other laboratory and

This Photo by Unknown Author is licensed
diagnostic tests (e.g. TSH, serum
under CC BY-SA
electrolytes).
Department of Health – National TB Control Program
 MANAGEMENT OF QT PROLONGATION
GRADING

ADVERSE EVENT 1
MILD
2
MODERATE
3
SEVERE
4
LIFE-
5
DEATH
THREATENING

QT Prolongation • Stop all QT prolonging drugs

immediately (Bdq, Cfz, Dlm and
Fqs).

POSSIBLE ANTI-TB • Continue • Refer patient for hospitalization

DRUG CAUSES: FQ, anti-TB and consider continuous ECG
monitoring.
Cfz, Bdq, Dlm treatment.
• Monitor ECG more frequently
• Monitor (every 2-3 days) until within
normal levels or stable.
ECG
weekly • Once QTc interval returns to
normal level, consider re-
until QTc introducing QT prolonging
reaches to drugs if it is considered critical
in the regimen.
normal
level or Note:
If a patient has syncopal attack (lightness of head),
This Photo by Unknown Author is
licensed under CC BY-SA baseline. palpitation and dizziness/weakness, refer the patient
immediately to hospital. Stop all QT prolonging drugs
until QTc reaches to normal level or baseline.
 Cardiovascular: QT Prolongation
Possible anti-TB drug causes: FQ, Cfz, Bdq,
Dlm

1
QTc on at least 2 separate ECGs done after reassuring patients to relax
after 10-15 minutes
2
Repeat ECG every 2-3 days until within normal limits
3
syncopal attacks, dizziness, weakness, chest pains, difficulty of breathing,
agitation
* ventricular arrythmias, severe coronary artery disease, genetic conditions,
valvular heart disease, rheumatic heart disease, etc
** Ondansetron, Macrolides (e.g. azithromycin), antifungals (e.g.
fluconazole), domperidone, neuropsychiatric drugs (e.g. quetiapine,
haloperidol, etc), antiretroviral (e.g. efavirenz), antimalarial (e.g
hydroxychloroquine)
 MANAGEMENT OF QT PROLONGATION

CARDIO-TOXICITY: QTC PROLONGATION

Calculation of QTc
▪Fredericia formula – best adjusted for heart rate
• QTc = Q T/ 3√ RR
• QTc = the corrected QT interval
• QT = the time between the start of the
QRS complex and the end of the T
wave
• Auto-reporting from the machine may
not be programmed with Fredericia
formula.
• Read at lead II or V5
• QT: no of small squares x 40
(e.g 9x40=360ms)
• HR: 1500/no of small squares b/t RR
(e.g. 1500/17= 88)
QT in milliseconds
[Link]
(ms) and RR interval [Link]
in seconds (s). [Link]
 Calculation of QTc
• The preferred way to calculate the QTc is
the Fredericia method (QTcF), which is
derived by dividing the QT interval by the
cubed root of the interval in seconds
between the peak of two successive R
waves (RR) read from the ECG strip.

QTc = QT
RR

Department of Health – National TB Control Program

 MANAGEMENT OF QT PROLONGATION
▪ If the patient is on bedaquiline and it is considered
critical to the regimen, consider adding the drug
back to the patient’s regimen while suspending all
other QT prolonging drugs (with the exception of
stopping ART, which should not normally be
suspended in the management of QT
prolongation).

▪ If the patient is on Delamanid and it is considered

critical to the regimen, consider adding the drug
back to the patient’s regimen while suspending all
other QT prolonging drugs (with the exception of
stopping ART, which should not normally be
suspended in the management of QT
prolongation).

Department of Health – National TB Control Program

MANAGEMENT OF QT PROLONGATION

General reminder:
All cases requiring to stop
critical drug in the regimen
(Bdq, Mfx, Lfx, Dlm) should be
discussed with the regional
TB medical advisory
committee (R-TB MAC)

Department of Health – National TB Control Program

Depression
 DEPRESSION
Possible anti-TB drugs cause: Cs,Lfx,Mfx,H,Pto
PHQ-9 Depression Proposed Treatment Actions
Score Severity
0-4 None-minimal None
Watchful waiting; repeat PHQ-9 at follow up
5-9 Mild Increase B6 to 200 mg daily
Group therapy sessions
Treatment Plan, considering counseling,
follow up and
10-14 Moderate
Pharmacotherapy
Sertraline Hcl 50 mg/tab
Active treatment with pharmacotherapy
Moderately
15-19 and/or
Severe
psychotherapy
Active treatment with pharmacotherapy
and, if severe impairment or poor response
to therapy, expedited
Severe referral to a mental health specialist for
20-27
psychotherapy and/or collaborative
management
ROUTINELY ASK FOR FIVE SIMPLE QUESTIONS

Any mood changes?

(easy irritation,
agitation, challenge to
concentration)
Any change in sleeping
pattern? (insomnia,
oversleep)
Any feeling of sadness?
Any feeling of hopelessness?
Any thought to hurt
themselves? (suicidal
ideation)
If with suicidal ideation suspend Cs immediately, refer to
psychiatrist, hospitalize patient and place under 24 hours
safety surveillance.
Department of Health – National TB Control Program
 PATIENT HEALTH
QUESTIONNAIRE – 9
 GRADING OF DEPRESSION
PHQ-9 Depression
Proposed Treatment Actions
Score Severity
0-4 None-minimal None
Watchful waiting; repeat PHQ-9 at follow up
5-9 Mild Increase B6 to 200 mg daily
Group therapy sessions
Treatment Plan, considering counseling,
follow up and
10-14 Moderate
Pharmacotherapy
Sertraline Hcl 50 mg/tab
Moderately Active treatment with pharmacotherapy
15-19
Severe and/or psychotherapy
Active treatment with pharmacotherapy
and, if severe impairment or poor response
to therapy, expedited
20-27 Severe referral to a mental health specialist for
psychotherapy and/or collaborative
management

Department of Health – National TB Control Program

PATIENT HEALTH QUESTIONNAIRE – 9
Filipino Version
PATIENT HEALTH QUESTIONNAIRE – 9
Bisaya Version
Optic Nerve Disorder
 OPTIC NERVE DISORDER
(optic neuritis)
Possible anti-TB drug causes:
Lzd, E,Eto/Pto, Cfz,rifabutin,H, S

• Optic neuritis is inflammation of the optic nerve eventually

resulting in permanent vision loss. The first sign of optic
neuritis is usually the loss of red-green color distinction. This
is best tested using the Ishihara test. Other symptoms
include central scotomas.

• Linezolid is by far the most common cause of optic neuritis

amongst all of the TB drugs. Mostly after four months of
treatment.

• Patients with diabetes are at increased risk for optic neuritis.

They should be managed with tight glucose control as a
means of prevention. Patients with advanced kidney disease
are also at increased risk for optic neuritis.
Department of Health – National TB Control Program
 OPTIC NEURITIS
GRADING

ADVERSE EVENT 1
MILD
2
MODERATE
3
SEVERE
4
LIFE-
THREATENING

Optic Neuritis Limiting Limiting Blindness

Asymptomatic
vision of the vision in the (20/200 or
; clinical or
affected affected worse)
diagnostic
POSSIBLE ANTI-TB eye (20/40 or eye (worse in the
observations
DRUG CAUSES: E, better) than 20/40 affected eye
only
Pto/Eto, Lzd, Cfz, H, S but
better than
20/200)

This Photo by Unknown Author is

licensed under CC BY-NC-ND

Department of Health – National TB Control Program

 MANAGEMENT OF OPTIC NEURITIS
GRADING
ADVERSE EVENT 1
MILD
2
MODERATE
3
SEVERE
4
LIFE-
5
DEATH
THREATENING

Optic Neuritis
POSSIBLE ANTI-TB For any sign of optic
DRUG CAUSES: E,
Pto/Eto, Lzd, Cfz,
neuritis, stop Ethambutol
H, S or Linezolid immediately.

Refer patient for

ophthalmologic
This Photo by Unknown Author is
licensed under CC BY-NC-ND consultation.

Department of Health – National TB Control Program

MANAGEMENT OF
ADVERSE DRUG
REACTIONS (FLDS)

Department of Health – National TB Control Program

 DRUG(S)
ADVERSE REACTIONS PROBABLY MANAGEMENT
RESPONSIBLE
Minor
1. Gastro-intestinal Rifampicin, Isoniazid, Give drugs at bedtime or with
intolerance Pyrazinamide small meals.
2. Mild or localized skin Any of the drugs Give anti-histamines.
reactions
3. Orange-colored urine Rifampicin Reassure the patient.
4. Burning sensation in Isoniazid Give Pyridoxine (Vit B6) 50-
the feet due to 100mg daily for treatment
peripheral neuropathy (It can also be given 10mg daily
for prevention.)
5. Arthralgia due to Pyrazinamide Give aspirin or NSAID. If
hyperuricemia persistent, consider gout and
request for uric acid
determination, manage
accordingly.
6. Flu-like symptoms Rifampicin Give antipyretics
(fever, muscle pains,
inflammation of the
respiratory tract)

Department of Health – National TB Control Program