Republic of the Philippines

Department of Health
OFFICE OF THE SECRETARY

__
December 1, 2023

DEPARTMENT CIRCULAR
No. 2023 - 0552

FOR . ALL UNDERSECRETARIES AND ASSISTANT SECRETARIES;

CENTERS FOR
DIRECTORS OF BUREAUS, SERVICES AND
DEVELOPMENT; MINISTER __OF HEALTH _-

HEALTH

___
AUTONOMOUS REGION IN__ MUSLIM
BANGSAMORO
AGENCIES;
MINDANAO; HEADS OF ALL DOH ATTACHED
EXECUTIVE DIRECTORS OF SPECIALTY HOSPITALS; CHIEFS
SANITARIA__AND
OF MEDICAL CENTERS, HOSPITALS,
GOVERNMENT
INSTITUTES; PARTNERS FROM NATIONAL
NON-GOVERNMENT
AGENCIES, DEVELOPMENT PARTNERS,
ORGANIZATIONS, MEDICAL _AND ALLIED HEALTH
SOCIETIES, CIVIL SOCIETY
PROFESSIONAL
ORGANIZATIONS, AND ALL OTHERS CONCERNED

Advisory on the 2023 Key Updates to the Current

Drug-Resistant
SUBJECT :
Tuberculosis Treatment Guidelines

The Department of Health (DOH) hereby issues the 2023 Key Updates to the Current
Treatment Guidelines for the Programmatic Management of Drug-Resistant
Tuberculosis (PMDT).
2022-0018 or the “Development and
This Department Circular shall support AO
and provide supplementary
Utilization of the Omnibus Health Guidelines per Life Stage”
issued through DC 2022-0344 or the
guidelines to each Section IV of the OHG per Lifestage
specifically on the use of
“Dissemination of the Omnibus Health Guidelines per Lifestage”,
this issuance updates the Chapter 3.2 of the
drug-resistant tuberculosis regimens. Likewise,
existing NTP Manual of Procedures 6" Edition.

For compliance and widest dissemination.

By Authority of the Secretary of Health:

MARIA ROSARIO S. VERGEIRE, MD, MPH,

Undersecjetary of Health
CESO
II
Public Health Service Team

Sta. Cruz, 1003 Manila e Trunk Line 651-7800

local 1113, 110
Building 1, San Lazaro Compound, Rizal Avenue, httn://www.doh.gov.oh: e-mail dohosec(@doh.gov.oh
@ URL:
direct Line: 711-9502: 711-9503 Fax: 743-1829
 2023 Key Updates to the Current Treatment Guidelines for the Programmatic
Management of Drug-Resistant Tuberculosis (PMDT)

I Background

On December 15, 2022, the WHO issued the “WHO

consolidated guidelines on tuberculosis.
This includes the
Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update’.
updated and detailed recommendations on the
use of a 6-month treatment regimen composed
the 9-month short
of bedaquiline, pretomanid, linezolid and moxifloxacin (BPaLM) and
and 18-month longer regimens in eligible RR/MDR-TB patients.

In this regard, the 6-month treatment regimen composed of

BPaLM shail be
included as the
with fluoroquinolone-susceptible RR/MDR-
primary standardized regimen for eligible patients DRTB. This
TB and BPal as preferred regimen for eligible patients with FQ-resistance
the
memorandum shall provide instructions to the Centers for
Health Development (CHDs),
in the delivery of services
Provincial/City Health Offices (PHO/CHO) and healthcare workers
the Current Treatment
for drug-resistant TB. Please refer to Annex A. Key Updates to
Tuberculosis for detailed
Guidelines for the Programmatic Management of Drug-Resistant
information on the technical guidelines.

I. Capacity Building and Cascading

Office
The DPCB, in collaboration with Lung Center of the Philippines — Project Management
for developing the training
(LCP-PMO), partners and technical experts, shall be responsible
Delivery of TB Services (DOTS) Phase
module and conducting the orientation of Integrated
2 mentors prior to the roll-out of the new regimens. Cascading to all DRTB services providing
iDOTS Phase 2 strategy. The
facilities shall be done through the mentoring activities of the
the CHDs on the schedule of these
DPCB along with partners will be coordinating with
capacity building activities.

Ill. Recording and Reporting

The DPCB shall lead the updating of the Integrated Tuberculosis Information System (ITIS)
and the paper forms to reflect the changes accordingly, in coordination with the Knowledge
and Epidemiology Bureau (EB).
Management and Information Technology Service (KMITS)
The use of new and updated forms shall commence in 2024, while interim instructions on the’

use of the current forms shall be released through an advisory.

Memorandum
‘Drug-resistant tuberculosisis
a mandatorily notifiable disease as per Department
transition of reporting to a weekly
No. 2023-0070. A separate advisory shall be provided on the
basis.

IV. Active Drug Safety Monitoring and Management (aDSM)

while on treatment using
Active and systematic clinical and laboratory assessment of patients
new anti-TB drugs and novel regimens shall be
continued to ensure patient safety and reduced
aDSM data to assist in policy
risk from drug-related harms, and to generate standardized
 aDSM shall be implemented
enhancement and guideline updates in DR-TB treatment.
6th Edition, as stipulated in AO
following unaffected provisions in NTP Manual of Procedures
2016-0040 Revised Policies and Guidelines on the Implementation
of the Programmatic
2020-0025 Policy and Guidelines on the
Management of Drug-Resistant TB (PMDT), AO
and Management (aDSM) of the National
Implementation of Active Drug Safety Monitoring Guidelines on the
Tuberculosis Control Program (NTP), DM 2017-0281 Implementing
DM 2020-0074 Implementation
Programmatic Management of Drug-Resistant TB (PMDT),
Tuberculosis, DM 2020-0177
of the Key Changes to the Treatment of Drug-Resistant
Monitoring and
Reiteration of Policy on the Implementation of Active TB Drug Safety
System (PViMS).
Management, and utilizing the Pharmacovigilance Monitoring
that all facilities providing
For the regions implementing iDOTS Phase 2, CHDs shall ensure
PViMS through the Pharmaceutical
full cascade of DR-TB care shall be issued access to the
the Regional TB Medical
Division (PD); also ensure that referrals from iDOTS facilities to
warranted.
Advisory Committee (R-TBMAC) are facilitated, if

The full guideline can be found atthis link: https://bit.ly/2023 DRTB-TreatmentGuideline:

Tuberculosis
1.Annex A. Treatment Algorithm Management of Drug-Resistant
2. Annex B. Types of RR/MDR-TB and Pre-XDR-TB treatment regimens
based on Xpert
3. Annex C. Guide on deciding appropriate treatment regimen
XDR/MTB or results
LPA

D. Recommended Schedule of Baseline, Routine and Post-treatment

4. Annex
Monitoring Examinations for DR-TB Patients
5. Annex E. Clinical Management of Some Adverse Events
of Special Interest (AES!)
6. Annex F. WHO weight-based dosing of medicines
used in multidrug-resistant TB

Regimens, adults and children

§
Annex A. Key Updates to the Current Treatment Guidelines for the
Programmatic Management of Drug-Resistant Tuberculosis
SECTION I. Rifampicin-resistant/Multidrug-resistant/Pre-extensively drug-resistant
Tuberculosis (RR/MDR/Pre-XDR-TB)
above. in Individuals 14 years old and

A. Assign ing the Appropriate Treatment Regimen

1. The shorter all-oral 6-month treatment
regimen (BPaLM/BPaL) composed of
bedaquiline, pretomanid, linezolid (600 mg) and moxifloxacin (BPaLM)
be the preferred standardized regimen for eligible
shall
patients with
fluoroquinolone-susceptible RR/MDR-TB. Patients diagnosed with pre-XDR-
TB shall have the shorter all-oral 6-month treatment
regimen composed of
bedaquiline, pretomanid and linezolid (600 mg) or BPaL as the preferred
standardized regimen. Refer to Annex B for the list
Patients with fluoroquinolone-susceptible RR/MDR-TB who
of updated regimens.
are
not eligible for
the BPaLM shall be checked for eligibility to the 9-month standardized short
all-oral regimen (SSOR) either linezolid (Lzd) or prothionamide (Pto) variation.
Those deemed not eligible for the aforementioned standardized
regimens shall
be referred to the Regional TB Medical Advisory Committee (R-TB MAC)
design of an Individualized Treatment
for
Regimen (ITR).
Individuals less than 14 years old diagnosed with RR/MDR-TB
evaluated for eligibility to the standardized all-oral treatment
shall
be
regimens
recommended for age below 14 years old. (Please see Section
in Individuals below 14 years old)
I.
RR/MDR-TB
Patients who are pregnant or breastfeeding shall be referred to the R-TB MAC
for evaluation of eligibility to Lzd-containing SSOR regimen or to ITR. Offer
both SSOR, if eligible, and the designed ITR.
Once an adult patient who
is not pregnant or breastfeeding is diagnosed with
RR/MDR-TB evaluate eligibility to receive BPaLM/BPaL by
reviewing the
exclusion criteria in Box A.

Box A. Exclusion Criteria for BPaLM/BPaL (if

NOT GIVE BPaLM/BPaL)
YES
to any
of the following, DO

1. TB involving the central nervous system, osteoarticular and disseminated

(miliary) TB
Known allergy to any of the component drugs
More than one month exposure to bedaquiline, linezolid,
pretomanid or
delamanid, unless resistance is ruled out through DST, or less than 1 month
exposure but with confirmed resistance to bedaquiline, linezolid, pretomanid or
delamanid
Close contact of a patient who had failed treatment with MDR-TB treatment
regimen containing bedaquiline, linezolid, pretomanid or delamanid
Risk of toxicity or intolerance to any drugs in BPaLM/BPaL
regimen as
manifested by:
 a. Presence of severe life-threatening anemia (hemoglobin level of less
to

than 8 g/dL)
Pre-existing severe to life-threatening peripheral neuropathy (Grade 3-4)
c. History of chronic active hepatitis or with liver enzyme levels five times
greater than the upper limit of normal!
d. History of heart disease (heart failure, myocardial infarction, cardiac
conduction abnormality, arrhythmia)
e. QTcF > 500ms?
6. Pregnant, breastfeeding or women of reproductive age not willing to use
contraception during the treatment course of BPaL.M/BPaL regimen

6. In cases of possible fluoroquinolone resistance (e.g., history of >4 weeks of

fluoroquinolone use or close contact with a person infected with a
fluoroquinolone-resistant strain), it is best to use the BPaLM regimen until DST
for fluoroquinolones becomes available. Mfx may be omitted
upon
confirmation of fluoroquinolone resistance or in case of Mfx intolerance, and
the regimen may be continued as BPaL**. No dose recount
or regimen restart
is needed.
7. Ifany of the exclusion criteria above is YES or
present, the patient is ineligible
to receive BPaLM/BPaL. Check eligibility to receive 9-Month Standardized
Short All-Oral Regimen (SSOR).

Box B, Exclusion Criteria for SSOR (9-Month Standardized Short All-Oral

Regimen) If YES any to of
the general exclusions, DO NOT GIVE SSOR
General Exclusions:
1. Extensive? or disseminated TB
(miliary) or severe/intractable extrapulmonary
TB (¢.g., TB meningitis, bone/oint TB, pericardial TB)
2. Confirmed resistance to Bdq, Lfx/Mfx, Cfz, Pto or Lzd
3. Previous exposure to Mfx/Lfx, Bdq, Cfz, Pto or Lzd for >1 month (unless
proven
susceptible)
4. Close contact of a patient who had failed treatment with MDR-TB
treatment
regimen containing Lfx/Mfx, Bdq, Cfz, Pto or Lzd

at
"
Patients with liver enzymes levels 3x greater than upper limit of normal (ULN) were excluded from both the
ZeNix-TB
trial and TB-PRACTECAL trials because bedaquiline and
pretomanid are both associated with increases in liver enzymes -
this may be considered a relative contraindication and may
still opt to monitor until liver function tests LFTs drop to <or less
than 3x ULN with advice from TB MAC. Otherwise, these patients will be
eligible straightaway to longer regimen with no
hepatotoxic agents (WHO Operational Handbook on DR-TB, p.14)
2
Caution should be taken in patients with a known
history of cardiac disease. Populations of concern include those with a
baseline corrected QT interval by Fridericia (QTcF) of more than 450
ms, history of cardiac disease with syncopal episodes,
significant arrhythmias, personal or family history of congenital QTc prolongation, torsade de
pointes (tdP), bradyarrhythmia,
or cardiomyopathy. Although bedaquiline and moxifloxacin can prolong QTe, of serious adverse events and mortality
reports
are rare. (WHO Operational Handbook on DR-TB, p.13) If >460 ms, withhold only non-essential
QT prolonging meds, e.g.,
anti-histamines and do more frequent ECG monitoring, and refer to TB
3 Presence MAC) - OH, Web annex, page 76
of bilateral cavitary disease or extensive parenchymal damage on chest X-ray
** Re-classify diagnosis
to Pre-XDR-TB retaining the same case holding and regimen number
 Risk of toxicity or intolerance to any drugs
5.
in
the regimen as manifested by:
a. History of heart disease (heart failure, myocardial infarction, cardiac
conduction abnormality, arrhythmia)
b. QTcF > 500ms
c. History of chronic active hepatitis or AST/ALT >5 times elevated
d. History of chronic renal insufficiency (Creatinine clearance <20
ml/min)
For Lzd variation:
6.
Hemoglobin < 8g/dL
Evidence of severe peripheral neuropathy, or
7.
any sign or suspicion of optic
neuritis, at baseline assessment
For Pto variation:
8. DST results with mutations* conferring both Pto/Eto
resistance (low H -res) and
high H-resistance

8. If mone of the general exclusion criteria are present, check eligibility of the
patient to receive either the Lzd variation or the Pto variation.
9. Ifnot eligible to receive the SSOR, consult the R-TB MAC
of an Individualized Treatment Regimen (ITR). for
composition

B. Initiating the Treatment Regimen

1. Perform pretreatment evaluation and baseline
2.
tests. (Please see Annex D)
Check for possible drug-drug interactions that may
potentially occur to any of
the first-line and second-line drugs. (Please see Annex 3B the
of NTP MOP 6%
Edition)
3. For patients whom the exclusion criteria for BPal.M/BPaL
are “NO” or absent,
the following treatment shall be offered:

Box C. BPaLM/BPaL Regimen Composition and Duration

Bdq (100 mg tablet) 400 mg daily for 2 weeks, then 200 mg 3 times
per week
for 24 weeks
OR
200 mg daily for 8 weeks, then 100 mg daily for 18
weeks
Pa (200 mg tablet) 200 mg once daily for 6 months (26 weeks)
Lzd (600 mg tablet) 600 mg once daily for 6 months (26 weeks)
Mfx (400 mg tablet) 400 mg once daily for 6 months (26 weeks)

Dose modifications for Bdg, Mfx, and Pa are not allowed.

Mfx cannot be substituted with Lfx.
e Fluoroquinolone-susceptible patients can be started on the BPaLM for 6 months
(26 weeks).

4 inhA
and katG mutations
 e In case of fluoroquinolone resistance identified after treatment initiation, Mfx
may be discontinued and the regimen continued as BPaL for 6 months (26
weeks) or 9 months (39 weeks).
e Incase of intolerance to Mfx (e.g., cardiotoxicity) during the course treatment,
of
Mfx may be omitted and the regimen may be continued as BPaL for 6 months
(26 weeks) or 9 months (39 weeks).
e BPaLM shall be given for a maximum duration of 6 months. BPaL
may be
extended only to 9 months (39 weeks from start of therapy) if TB culture (TBC)
remains positive at month 4 (16 week) OR there
is
lack of clinical response
(based on clinical judgment of the treating physician) between months 4 and
Physician’s clinical assessment and other monitoring parameters like smear
6.
microscopy (SM) and comparative chest x-ray (CxR) may be used if TBC result
is not available at 6 months (26 weeks).
e Temporary cessation of the full regimen is allowed for suspected drug-related
toxicity. Reintroduction of the
full regimen can be considered after a cessation
of no more than 14 days of consecutive interruption or up to a cumulative 4
weeks of nonconsecutive treatment interruption.
e Missed doses of >7 days of the whole BPaL.M/BPaL shall be compensated
by
extending the treatment duration for the number of missed doses. However,
missed doses of Lzd alone need not be compensated. Individuals who switch
from BPaLM to BPaL shall consider their treatment start date the
same as the
date BPaLM was initiated, because the treatment continued with three effective
drugs during the entire treatment period.
e Further considerations on Lzd dosing are as follows:
© Any dose modification of Lzd shall not be allowed in the first 9 weeks of
treatment. However,
if
the patient manifests toxicity or intolerance to Lzd
during this duration, the patient should be reassessed for eligibility to
continue treatment or shift to a new regimen upon the advice of the TB
MAC.
© IfLzd is permanently discontinued during the first 9 weeks of treatment,
discontinue the entire regimen and consult with the TB MAC
for
switching
to SSOR or
new regimen
ITR. Dose count must be restarted after switching to an entire

© Dose reduction (to 300 mg) after the first 9 weeks of treatment
may be done
in the presence of adverse events. (Please see Section C:
Monitoring
Treatment)
Table C.1. Timing of dose reduction and modification of Lzd

It is preferred to continue Lzd at 600 mg

daily for the entire duration of BPaLM/BPaL; however, if
there is significant toxicity (depending on the severity of specific AESIs) associated with
Lzd, including
optic neuritis, peripheral neuropathy or myelosuppression, the following modifications
are possible:
4
Regimen 1-9 weeks of >9-18 weeks of >18-26 weeks of >27-39 weeks
treatment treatment treatment
BPaLM 600 mg
daily, If not tolerated, If necessary, Lzd Regimen cannot be
ideally continued Lzd may be may be omitted extended for the

BPaL
throughout the
regimen duration
reduced to 300 mg
daily until the end
| until the end of
treatment with
BPaLM

without any dose of treatment, or Bdq, Pa +Mfx

Regimen may be
extended for the
modification resumed anytime
to 600 daily,
remaining to BPaL, if
necessary.
mg
complete the Lzd may continue
as tolerated, but regimen; or Lzd at the tolerated
ideally not
omitted.
may be restarted
anytime at either
dose, or stopped
not tolerated.
if
600 mg or 300 mg

Reference: WHO Operational Handbook on TB

daily, as
tolerated.
Module 4 DRTB Treatment 2022 Update
page 18

e If either Bdq or Pa needs to be permanently discontinued, the entire

BPaLM/BPaL regimen should be discontinued.

For Fq-susceptible patients whom BPaLM cannot

4.
be given but who areeligible
for the SSOR, and whose baseline assessment shows no evidence of
myelosuppression (Hgb < 8g/dL), no evidence of severe peripheral
neuropathy, and no sign or suspicion of optic neuritis, the following
treatment shall be offered:

Box D. SSOR: 9-Month Standardized Short All-Oral

Regimen (Lzd variation)
Composition and Duration

4-6 Bdqis) - Lzd,2) - Lfx - Cfz - Z - E - HdH /5 Lfx - Cfz-Z,- E

Initial Phase: 4-6 Bdqis) - Lzd) - Lfx - Cfz - Z - E- HdH
Maintenance Phase: 5 Lfx - Cfz-Z-E

e Bdqis given for6 months, but may be extended to

9 months* if the initial phase
of the regimen is
extended from to
6 months because of positive sputum smears
at month 4 of treatment.
e Bdq
shall
be given with an initial loading dose of 400mg daily for first 2 the
weeks, followed by 200mg for 3 days a week (with at least 48 hours between

*Off-label use requiring consent. Safety profile of Bdq use beyond 6 months was available to the GDG 2019
 doses) thereafter.
©
is
If one dose of Bdq missed in the 2-week loading phase, the missed dose
does not need to be made up and the daily dosing schedule can be
continued.
© Ifone dose of Bdq is missed in the maintenance phase but is remembered
within the 48-hour dosing period, the dose should be administered
as soon
as possible, and the next dose adjusted to be taken 48 hours later. Resume
usual thrice a week dose schedule thereafter.
© If Bdqis interrupted for >2 weeks (but <8 weeks) during the maintenance
phase of dosing, the drug should be reloaded at the higher daily dose for
7 days before resuming the thrice-weekly dosing schedule.
© If Bdqis interrupted for <2 consecutive weeks during the maintenance
phase, no reloading is required.
©
IfBdq is interrupted for >8 consecutive weeks, the patient and treatment
plan should be reassessed because the patient will no longer be
eligible to
continue or restart the 9-month all-oral regimen.
e Lzd is only given for 2 months. If Fq resistance is not yet ruled-out, missed Lad
doses can be added on to the end of the 2-month period if Lzd is well
tolerated.
For cases where Fq susceptibility has been confirmed, no need to make
up for
the missed Lzd doses.
e Ifeither Z or E (only one) is discontinued due to intolerance, adverse
event or
confirmed resistance, the regimen may continue without
necessitating to switch
to a longer regimen.
e Ifboth Z and E are discontinued due to intolerance, adverse event
or confirmed
resistance, shift to ITR.
e Ifresistance to Pto or HdH (only one) is confirmed, the regimen
may continue
without necessitating to switch to a longer regimen
If resistance to both Pto and HdH
is confirmed, shift to ITR
If any other drugs of the SSOR regimen (Bdq/Lfx/Cfz/HdH) are discontinued
due to intolerance or adverse events, shift to ITR.
© Lzd dose (600 mg) should not be reduced to less than the recommended
dose to
reduce severity of adverse effects. If full dose
months of treatment, then the patient
is not tolerated during the first 2
may be switched to Pto variation
(provided patient is not pregnant) or refer to TB MAC
for ITR without Lzd.

5. Women who are pregnant or breastfeeding should be assessed for eligibility to

the 9-month SSOR with Lzd. If not eligible, refer to the TB MAC
Women who are for
pregnant and breastfeeding should not receive the 9-month
ITR.
SSOR
Pto variation.
6. Ifthe patient is not pregnant/not breastfeeding, and
if baseline assessment shows
evidence of myelosuppression (Hgb < 8g/dL), severe peripheral
neuropathy, or
any sign or suspicion of optic neuritis, the Pto variation may
be offered:
4
E
Box E. SSOR: 9-Month Standardized Short All-Oral Regimen
(Pto variation)
Composition and Duration

4-6 Bdqis) - Lfx - Cfz - Z- E - HdH - Pto /5 Lfx -Cfz-Z-E

Initial Phase: 4-6 Bdqs) - Lfx - Cfz - Z - E - HdH - Pto
Maintenance Phase: 5 Lfx - Cfz-Z-E

e All seven drugs are given for 4 months, with the possibility of
extending to 6
months if the patient’s sputum smear remains positive at the end of 4"
or 5th
month.
e Pto and HdH are
dropped between 4 to 6 months (depending on smear status at
month 4).
©
Bdqis given for 6 months but may be extended to 9 months
of theregimen is extended from to
6 months because of positive sputum smears
if
the initial phase

e
at months
If Pto
4
or 5 of treatment.
is not tolerated,, then the patient
may be switched to Lzd variation or
refer to TB MAC for ITR without Pto.

7. Ifboth Lzd and Pto after being used

alternatively are not tolerated, shift to ITR.
8. Dosages of the different anti-TB
drugs in the SSOR regimen shall be determined
based on the latest WHO recommended dosages by weight band for medicines
used in MDR-TB regimens. For 9-month SSOR containing Pto:
a. Start Pto in two divided doses (morning and evening) if total daily dose
is >250 mg for the first 2 weeks treatment.
b. Once tolerance to Pto has improved, change Pto
of
dosing to once daily
after 2 weeks.
c. Advise patients to take Pto only after light meals.
9. IfbothZ and are
discontinued due to intolerance, adverse events, or confirmed
resistance, shit to ITR.
10. ITR should be offered when the BPaLM
or SSOR cannot be used, or if the
patient presents with drug intolerance, adverse reactions, additional resistance
to, or lack of response to
the shorter regimens. The stepwise approach, following
the priority order based on the revised classification of regimen
preferred, and must be composed of
components,
at least four likely effective drugs® at the
is
start of treatment and
11. Collect three (3) sputum specimens: one
at least three for
(1)
the rest of the treatment.
for first-line and second-
specimen
line LPA or Xpert MTB/XDR two and (2)
specimens for SM and TBC and
phenotypic drug susceptibility testing (pDST) as part of the baseline tests.
12. Take appropriate action based on results of DST.

C. Monitoring Treatment Response

SWHO Grouping of medicines recommended for

use in longer MDR-TB regimens, NTP MOP6.
 1. Response to treatment should be monitored on the basis of monthly clinical
assessment, monthly sputum SM and TBC.
2. In case of discordant results between LPA/Xpert MTB/XDR
DST, follow the worse result (i.e., that with more drug and phenotypic
resistance) and consult
the case with the TB MAC for regimen revision, if needed. For imhA and katG
mutation results using LPA or Xpert MTB/XDR,
see Table of ANNEX C.
More frequent monitoring based on the physician’s clinical
judgment may be
advisable in specific situations, such as, but not limited to, the
following cases:
a. Elderly
b. PLHIV
c. Diagnosed with hepatitis (caused by Hepatitis B virus or Hepatitis C
virus)
d. Diabetes mellitus
¢. Moderate to severe hepatic or renal impairment
f. Anemia at any grade
. Baseline visual disturbances (e.g. glaucoma, cataract, or color blindness)
All patients receiving shorter regimens should be followed
up for clinical
reassessment 6 months and 12 months post-treatment, to monitor for potential
relapse.

D. Active Drug Safety Monitoring and Management (aDSM)

[refer to Annex E for
management of some Adverse Events]
1. For breastfeeding patients, exercise
caution and monitor infants due to breast
milk deposition of Bdq (e.g., cardiotoxicity, hepatotoxicity). This
applies all to

Bdq-containing regimens.
Brief Peripheral Neuropathy Screening (BPNS) and Visual Acuity (Snellen) &
Color Vision Test (Ishihara) must be done
every 2 weeks during
of treatment and then monthly for all Lzd containing regimens. the first month

ECG monitoring for any signs of QT prolongation should be done

intervals (or more frequently, if warranted) for the duration of the at monthly
treatment,
including cases of treatment prolongation.
AST and ALT should be monitored monthly (or more frequently, if
warranted)
to check for possible hepatotoxicity.
Appropriate action shall be taken in cases of adverse drug reactions,
poor
bacteriological or clinical response to treatment, or acquired resistance to drugs
in the regimens.
Report all serious adverse events (SAEs) or adverse events of special interest
(AESIs) through the Pharmacovigilance Monitoring System (PViMS).
In case PViMS is not accessible, use the FDA Suspected Side Effects Reporting
Form. The paper report shall be submitted to the Center for Health
Development
(CHD) NTP Coordinator and National Drug Policy Compliance Officer
(NDPCO). This shall be later entered into PViMS by NDPCO
0025, s2020).
(refer to AO-
Through PViMS or paper format, submit the report within two working days or
48 hours from the occurrence of the event or immediately
upon receipt of the
information.
Manage alladverse events accordingly and promptly regardless of severity and
seriousness.
E. Assigning Treatment Outcome
1. After completion of treatment
or if
the patient is
discharged from the program,
assign the appropriate treatment outcomes for DR-TB patients based on the
following definitions:

Outcome Definition
Treatment A patient whose treatment regimen needed to be terminated
or
failed permanently changed to a new regimen or treatment strategy, due
to any of the following:
¢ Noclinical and/or bacteriological response to appropriate
treatment regimen. Examples:
©
Bacteriologic reversion or lack of bacteriologic
conversion by month 4 (BPaLM);
© Lack of smear conversion or presence of culture
reversion during the extended months 7-9 of BPaL
correlated clinically;
© Lack of evidence of at least two negative cultures
by the end of an extended intensive phase (six
months) of the SSOR
© [SSOR] persistent positive sputum smear at 6th
month during the extension of initial phase;
© [ITR] Bacteriologic reversion? anytime after 6
months of treatment
e Toxicity or intolerance to a drug in the regimen
(pharmacologic failure)
© More than 2 weeks consecutive treatment
interruption of all medicines in the BPaLM
regimen
© More than 4 weeks cumulative nonconsecutive
treatment interruption of all medicines in the
BPaLM/BPaL regimen
© Permanent discontinuation
of any of the other
drugs of the SSOR (Bdq/Lfx/Lzd/Pto/Cfz/HdH)
or to both Z and E
e Evidence of acquired resistance to key medicines in the
regimen

Cured A patient with bacteriologically confirmed RR/MDR-TB at the

beginning of treatment who has completed treatment, with
evidence of bacteriological conversion® (two or more consecutive
negative cultures taken at least 7 days apart) and no evidence of
failure.
 Treatment A patient who completed treatment with clinical improvement
completed whose outcome does not meet the definition for CURED,
and
without evidence of
failure.

Died A patient who died for any reason before starting treatment
or
during the course of treatment.

Lost to follow- A patient who did not start treatment or whose treatment
was
up interrupted for 2 consecutive months more. or
Not evaluated A patient for whom no
treatment outcome was assigned.

2. Record the treatment outcome and update patient record on ITIS.

3. Issue the certificate of completion of treatment and advise
patients on post-
treatment follow-ups.

*Bacteriologic reversion: at least two consecutive cultures taken on different occasions least 7
at
positive either after bacteriologic conversion or in patients without bacteriologic confirmation
days apart are
of TB
>Bacteriologic conversion: bacteriologically confirmed TB with at least two
consecutive negative cultures taken
on different occasions at least 7 days apart
SECTION
II.
Rifampicin-resistant/Multidru g-resistant/Pre-extensively Drug-resistant
Tuberculosis (RR/MDR/Pre-XDR TB) in
Individuals below 14 years old
All cases for treatment initiation shall be presented to the TB MAC.
1.
Initiation of
treatment shall be in accordance with the regimen and dosage based on latest WHO
guidelines. Refer to Annex B for the list of updated regimens.
2. A regimen consisting of 4-5 drugs
initially and at least 3 likely effective drugs after
discontinuation of Bdq or Lzd (dueto intolerance) shall be given forthe entire treatment
duration, with composition as follows:

Box F. RR/MDR-TB regimen for Children

FQ — susceptible DRTB FQ - resistant DRTB or Pre-XDR-TB

(FQ-S) (FQ-R)

e
Bdgq

- Lfx - Lzd - Cfz (Cs/DIm) Bdgq - Lzd - Cfz - Cs (DIm/PAS)

Determine severity or extensiveness of disease. Severe or extensive disease in

children is usually defined by the presence of any of the following:
° Extrapulmonary TB other than lymphadenopathy (peripheral nodes or
intrathoracic lymph node TB without airway obstruction)
Complicated TB pleural effusion (with empyema or pneumothorax)
Positive TB bacteriology (smear, Xpert MTB/RIF or other WHO-
recommended RDT, or culture)
Cavitary, bilateral disease, or miliary pattern as evaluated on chest
x-ray
Presence of comorbid conditions or disease such as severe malnutrition
[presence of oedema of both feet regardless of the grade or severe wasting
(weight-for-height) Z score below negative 3 or mid-upper arm
circumference below 115 mm] or advanced immunosuppression.
e Determine treatment duration:
© 9-12 months for non-severe/non-extensive disease depending on clinical
progress as assessed by physician
° 15-18 months for severe or extensive disease.
e Appropriate dosing, precaution, and strict monitoring must be observed on
theuse
of Lzd. In cases where BPNS andvisual tests are difficult to perform and
hematological side effects are likely, replacing Lzd with an alternative likely
effective drug (e.g., drugs in parentheses) may be considered.

3. In children without microbiological confirmation of TB disease or rifampicin

resistance, the choice of regimen should consider the following:
a. Drug resistance pattern of the isolate obtained from the most likely index
case.
Age-appropriateness of prescribed medication
aes
Drug tolerance and adverse drug reactions
Availability of pediatric formulations
4.
of
Treatment monitoring for children shall compose the following:
a. Bacteriological monitoring (SM, culture) of sputum for pulmonary TB
or
specimen of affected extrapulmonary site, if feasible
b. Clinical monitoring
° Resolution of TB signs and symptoms
° Monthly weight gain and growth
to
° Baseline chest x-ray and follow up chest X-ray at six months
check for resolution of lesions in case of pulmonary TB
° Follow-up scans (CT scan/MRI scan/ultrasound) at six months
for intrathoracic or EPTB diagnosed by imaging
Healing of other EPTB lesions (e.g., cold abscess)
 SECTION III. Rifampicin-susceptible and Isoniazid-resistant TB
1. Inpatients with confirmed rifampicin-susceptible, isoniazid -resistant tuberculosis (Hr-
TB), treatment with rifampicin, ethambutol, pyrazinamide and levofloxacin is
recommended for a duration of 6 months:

Box G. Hr-TB Regimen Composition and Duration

6 (A) RZE - Lfx

e Lfx must be given for 6 months and
is
the preferred quinolone.® If single
dose formulation of RZE is
not available, fixed-dose combination of HRZE can
be used instead. When Hr-TB is diagnosed after the start of the regimen for DS-
TB, the companion medicines (HRZE) would end up being given for more than
6 months, thus treatment duration for Hr-TB shall be based
on the completion of
6 months oftreatment containing the Lfx in the regimen.
e Prolongation of treatment in patients with cavitary disease and with persistent
positivity on sputum smearnot satisfying the criteria for treatment failure should
be referred to TB MAC and may be managed on a case-by-case basis.

2. Do not give Lfx in

the following circumstances’:
a. Rifampicin resistance cannot be tested
b. Documented resistance or known intolerance to
fluoroquinolones
c. Pre-existing QT prolongation®
3. Monthly clinical assessment and treatment monitoring
by SM at months 5 and 6 shall
be done to check for treatment response. Culture with smear microscopy, at least in the 2,
last month of treatment, is recommended.
ap Non-response to treatment should be investigated with rapid molecular test and DST.
For post-treatment follow-up follow the same schedule in Annex D.

it still
8
Exposure to Mfx decreases markedly when is combined with Rifampicin (WHO OH on DR-TB, 2022 update, p.66)
"If fluoroquinolones cannot be used, patient may be’treated with 6(H)RZE
8
Baseline ECG for those with risk
Annex B. Types of RR/MDR-TB and Pre-XDR-TB treatment regimens
The treatment regimens shall only be offered to eligible patients if all of the drugs in the
regimen are available and accessible.

Regimen Duration
Regimen Name Type of DR-TB Remarks
and Composition*

BpaLM/BPaL RR-TB 6 months (26 weeks):

MDR-TB
Bedaquiline- Pre-XDR-TB Bdq-Pa-Lzd (600 mg)
Pretomanid- -Mfx
Linezolid-
Moxifloxacin

SSOR RR-TB and MDR- 4-6 months:

TB
9-11 month Lfx-Bdqc6)-Cfz-
standardized (Lzd(2/Pto)-E-Z-HdH
short all-oral
regimen 5 months:
Lfx-Cfz-Z-E
CTR FQ-S RR-TB Bdq - Lfx - Lzd - Cfz| Present the case at TB
MDR-TB
Child Treatment
(Cs/DIm) MAC. Duration may last
between 9-12 months and
Regimen FQ — 15-18 months dependent
susceptible on disease
DRTB

CTR FQ-R Pre-XDR-TB Bdq Lzd -

- Cfz- Cs} Present the case at TB
(Dim/PAS) MAC. Duration may last
Child Treatment between 9-12 months and
Regimen for FQ 15-18 months dependent
— resistant
on disease
DRTB

Hr-TB Rifampicin- 6 months

susceptible,
6-month mono- | Isoniazid-resistant (H)RZE-Lfx
Hr-TB Regimen TB (Mono-Hr)
 Individualized Retreatment RRTB, 18-20 months Present the case at TB
Treatment MDR-TB, and Pre- MAC andfollow advice
Regimen (ITR) XDR-TB cases not Construct at least 4-5 for the regimen design
eligible to any of likely effective drugs.
the standardized
regimen
and XDR-TB

*Bdq=Bedaquiline, E=Ethambutol, Cfz=Clofazimine, Cs=Cycloserine, Dlm=Delamanid, HdH or Hh=high dose

Isoniazid,
Lfx=Levofloxacin, Lzd=Linezolid, Mfx=Moxifloxacin, PAS= P-aminosalicylic acid; Pto=Prothionamide
Annex C. Guide on deciding appropriate treatment regimen based on LPA
or Xpert XDR/MTB results

+/- +/- Continue BPaLM/BPaL

BPaLM/
BPaL
Continue BPaLM/BPaL but drop Mfx
+/~- +/- and continue dose count. Reclassify
diagnosis to Pre-XDR-TB

+/- +/- Continue SSOR Lzd

SSOR
Lzd

+/- +/- Shift to ITR and restart dose count

- . Continue SSOR Pto

SSOR
Pto + . Continue SSOR Pto

Continue SSOR Pto

 Shift to ITR. Continue dose count
within 1 month of treatment initiation.
if
- + + Restart dose count
more than 1
if shifting to ITR is
month from treatment
initiation

+ +/- +/- Shift to ITR. Restart dose count.

_ +/- +/- Continue CTR FQ-S.

CTR FQ-
S

+ +/- +/. Shift to CTR FQ-R. Restart dose

count

Review initial regimen and revise if

TTR +/- +/- +/- needed in consultation with TB MAC

"High-level resistance to H (katG mutation) is interpreted only with the

following results:
*lusing LPA: “Resistance Detected — High Level”
*2-using Xpert MTB/XDR: “Resistance DETECTED”
"Complete cross-resistance between Pto and Eto. Below DST results of H confers
to Pto resistance (inhA)
-LEPA: “Resistance Detected ~ Low Level”
»2.Xpert MTB/XDR: “Low Resistance DETECTED”
 Annex D. Recommended Schedule of Baseline, Routine and Post-treatment
Monitoring Examinations for DR-TB Patients

Examination Baseline 2nd week Monthly End of 6 and 12

from start Treatment months
of post-
treatment treatment
(for Lzd
containing
regimens)

Clinical evaluation by physician including

weight
V V V J V

Bacteriologic tests

Smear microscopy
V V J J
TB culture*
V V V V
Drug susceptibility testing If culture positive at month 4 of
remains
First- and second-line Xpert XDR or
LPA J treatment, case of culture reversion, or
in
culture positivity during post-treatment
Phenotypic DST
.
v ff-up

Diagnostic tests

Chest X-ray
V V Vv

Electrocardiogram Vv V
(Regimen contains Cfz, Bdq, Mfx, Dim, Pa, and Lfx)
JV V

Visual acuity and color vision

(Regimen contains Lzd and E)
V V V V

Brief peripheral neuropathy screening

(Regimen contains Lzd, H, Cs, Trd, Lfx, Mfx, and Am)
V V J V

Mental health screening (PHQ-9)

. v v Jv
rcs orhdtt-
containing)

Blood chemistry/ Hematology/ Immunologic tests

ALT and AST”

(Regimen contains Z, H, Pa, Bdq, Eto/Pto,Cs/Trd, and PAS)
V J V V
CBC
(Regimen contains Lzd, Mpm, H, and Pa)
Jv
J
FBS or HbAIC
V

Serum K*
V

Creatinine
V V
(If Am or S-
containing)

TSH
V
(if Pto or PAS
containing)

Albumin
(Regimen contains Dim)

Pregnancy test (for women of reproductive V

age)

HIV screening
V

HBV and HCV‘ test

V

*Every other month after month

6 of treatment with ITR
“For any elevation of LFTs, request for Total Bilirubin
“In case of hypokalemia check serum Ca and
Mg
“Desirable or as necessary,
e.g, patient is known to have hepatitis
Annex E. Clinical Management of Some Adverse Events of Special Interest
(AESD
General strategies for managing adverse events (AEs):

1. Conduct a thorough clinical history and physical examination.

2. Checkfor other potential causes of the AE. Request or perform additional laboratory
and other diagnostic tests, as needed to determine potential cause.
oS)
Follow the recommended actions based on the severity grade of the AE.
4. Adjust drug dosage as long
it
as will not compromise the effectiveness of the
regimen; check allowed dose modification for the drug
5. Modify the regimen to ensure effectiveness and safety; check if modification
in
allowed
is
the regimen, and follow guide on Table C.1. regarding Lzd modification.
6. Provide relevant information and counsel the patient.
7. Refer to the TB Medical Advisory Committee for difficult or challenging cases.
8. Refer to a specialist for concomitant uncontrolled or unmanageable co-morbidities
and adverse events.
9. Provide psychosocial support.

A. PERIPHERAL NEUROPATHY (Lzd, H, Cs/Trd, Lfx, Mfx, Am)

Adverse event Grade 1 Grade 2 Grade 3 Grade 4

Paresthesia: a Mild Moderate Severe Incapacitating;
disorder discomfort: no discomfort: non- discomfort: or or not
characterized by treatment narcotic narcotic responsive to
functional required; and/or analgesia ** analgesia *** narcotic
disturbances of BPNS required; and/or required with analgesia***
sensory neurons subjective BPNS subjective symptomatic
resulting in sensory sensory improvement;
abnormal neuropathy neuropathy score and/or BPNS
culaneous score 1-3 on 4-6 on any side subjective
sensations of any side sensory
tingling, neuropathy
numbness score 7-10 on
pressure, cold, any side
and/or warmth

Regimens: Actions to be taken:

BPaLM/BPaL* Reduce dose of Consider drug Permanently stop Lzd.
Lzd to 300 holiday of Lzd OR
mg/day and for 1-2 weeks; if Drug holiday of Lzd for 1-2
monitor weekly. symptoms weeks. If
there is reversion to
If symptoms improve, restart baseline, may restart Lzd at 300
improve, may Lzd at a lower mg/day provided it does not revert
resume to 600 dose of 300 back to Grade 3 or 4. Otherwise,
mg/day, as mg/day or at permanently stop Lzd.
tolerated. 600 mg/day, as
OR tolerated. If
Consider a drug symptoms
holiday of Lzd worsen, stop
for 1-2 weeks, Lzd
and if symptoms permanently.
improve, restart
Lzd at a lower
dose of 300
mg/day, or at
600 mg/day, as
tolerated.

SSOR with Consider a drug

Lzd*, HdH holiday of Lzd
Consider a drug up to 3
holiday of Lzd_ cumulative
up to 3 doses and/or
cumulative HdH
for 1-2
doses and/or weeks. If
HdH
for 1-2 symptoms
If restart
weeks Sotand
Lzd and/or HdH
Stop Lzd and/or HdH permanently
symptoms
at the same
4
on shift to ITR.
improve, restart
Lzd and/or HdH dose.
at the same
dose. Ifsymptoms
worsen, stop
Lzd and/or HdH
permanently
then shift ot
ITR.

ITR with Lzd, Considerdmg Considerdrug Permanently stop Lzd, HdH and/or
HdH, Cs holiday of the holiday of the Cs
 the suspected suspected agent
agent for 1-2 for 1-2 weeks; if OR
weeks; if symptoms
symptoms improve, restart Drug holiday of the suspected
improve, restart
HdH and/or Cs
HdH
and/or Cs agent for 1-2 weeks. If there
at the same reversion to baseline, may restart
is
at the same dose, and Lzd at HdH and/or Cs the same dose,
dose, and Lzd at a lower dose of and/or Lzd at 300 mg/day
at
a lower dose of 300 mg/day, or provided it, does not revert to
300 mg/day, or
at 600 mg/day,
at 600 mg/day,
as tolerated. If
Grade or 4. Otherwise,
permanently stop the drugs.
3
as tolerated. symptoms
worsen, stop the
drug(s)
permanently.

TB
in
References: Clinical Guidefor the Introduction of BPal. regimen the Philippines under Operational Research,
Clinical and Programmatic Guide for Patient Management with New TB Drugs, version
January 2022 and End
4.0, January 2018, WHO Operational
Handbook, December 2022
*Any modification of Lad is allowed only after 9 weeks of Lzd 600 mg/day.
**Non-narcotic analgesics: weaker non-prescription drugs generally given for headaches, muscular aches
origin. Examples. aAspirin, acetaminophen (no anti-inflammatory effect); Nonsteroidal anti-inflammatory
and painsof inflammatory
drugs (NSAIDs), e.g., ibuprofen,
naproxen, or prescription Cox-2 inhibitors (e.g., Celebrex).
***Narcotic (or opioid) analgesics or opiates: strong drugs for moderate to severe
pain that induce tolerance and drug dependence.
Examples. morphine, synthetic narcotic drugs, such as methadone; tramadol; oxycodon,
fentanyl
“May allow only
up to 3 accumulated missed doses of Lad butresumeat 600 mg/day and add the missed doses at the end of the 2-month
period. No dose reduction of Lzd is allowed. Shift to another regimen, if not tolerated.
 B. (Lzd,
MYELOSUPPRESSION Mpm, H, Pa)

Myelosuppression Grade 1 Grade 2 Grade 3 Grade 4

Anemia 10.5 -9.5 g/dL 9.4 -8.0 g/dL 7.9-6.5 g/dL <6.5 g/dL

Platelets decreased 75-000 nnn?

ie 9 - 30,000
he 9 - 20,000
< 20,000 /mm?

WBC decreased <LLN -—

<3,000 — 2,000/ <2,000 - 1,000 < 1,000 Amm?
3,000/mm?3 mm? /mam3

ANC 1500 -
999 —750/mm> 749 -500/mm3 < 500/mm?
1000/mm3

Regimens: Actions to be taken:

BPaLM/BPaL* Monitor Drug holiday Drug holiday
carefully, do Monitor for Lzd for 1-2 for Lzd for 1-2
ITR with Lzd weekly CBC carefully, do weeks and weeks.
and consider weekly CBC consider Hospitalize the
reduction of and consider erythropoietin patient and
Lzd dose to
300 mg daily.
reduction of
Lzd dose to 300
|
therapy
available.
if consider blood
transfusion or
mg daily Restart at a erythropoietin
reduced dose of therapy if
Lzd 300 available.
For Grade 2
mg/day once Restart at a
neutropenia, toxicity has reduced dose of
stop Lzd. decreased to Lzd 300 mg/day
Restart at lower Grade 1 or once toxicity
dose once consider has decreased to
toxicity has stopping Lzd_ Grade 1 or
reduced to
permanently. consider
baseline.
stopping Lzd
permanently.
SSOR with Lzd** Monitor
Monitor
.
Drug holiday Drug holiday
carefully, do
carefully, do forLzd forup for Lzd for up
weekly CBC. to 3 to 3
weekly CBC.
cummulative cummulative
 For Grade 2 doses and doses.
neutropenia, consider Hospitalize the
stop Lzd. erythropoietin patient and
therapy if consider blood
available. transfusion or
erythropoietin
therapy if
available.
References: Clinical Guidefor the Introduction ofBPaL regimen
TB
in the Philippines under Operational Research, January 2022 and End
Clinical and Programmatic Guide for Patient Management with New TB
Drugs, version 4.0, January 2018, WHO Operational
Handbook, December 2022
*Dose reduction of Lzdis allowed only after 9 weeks of Lzd 600 mg/day. Temporary or permanent discontinuation
when there are only 8 weeks remaining
of Lzd is allo wed only
in the treatment course (or after 18 weeks of 600 mg/day).
Note: A decreasein haemoglobin level of 10% or more after4 weeks of treatment may
**May allow upto 3 accumulated missed doses
help to identify thoseat high risk fors evere anaemia
of Lzd but resume at 600 mg/day and add themissed doses the end of the 2 -month period.
No dose reduction of Lad is allowed. Shift to another regimen, if not tolerated. at
 C. OPTIC NEURITIS (Lzd, E)

Adverse event Grade 1 Grade 2 Grade 3 Grade 4

Adverse event

Optic nerve Asymptomatic Symptomatic; Limiting vision Blindness

disorder: or mild moderate in the affected [20/200 (6/60)
symptoms; decrease in eye; VA worse or worse] in the
a disorder clinical or visual acuity than 20/40 affected eye
characterized by diagnostic (VA) [20/40 (6/12) but better
involvement of observations (6/12) or better] than 20/200
the optic nerve only or unable or drop of 2 (6/60) or drop
(2"4 cranial to read 4 or lines on VA of >2 lines on
nerve) more plates in (Snellen) chart VA (Snellen)
the color vision or unable to chart or unable
test read 4 ormore_ to read 4 or
plates in color more plates in
vision test color vision test

Regimens: Actions to be taken:

BPaLM/BPaL Discontinue Lzd and/or E immediately regardless of severity grade for

SSOR with Lzd optic neuritis, and must refer patient to an ophthalmologist as soon as
restart if optic neuritis is confirmed or unless there is an
not
Do
(& B) possible,
alternative diagnosis.
ITR with Lzd
and E
Reference: Clinical Guide for the Introduction of BPaL regimen in the Philippines under Operational Research, January 2022
 D. HEPATOTOXICITY
(Z, H, Pa, Bdq, Eto/Pto, Cs/Trd, PAS )

Adverse Grade 1 Grade 2 Grade 3 Grade 4

event

ALT >ULN-3X ULN >3X-5X ULN >5X-20X ULN >20K ULN

(SGPT)

AST (SGOT
>ULN-3X ULN_ >3X-5X ULN >5X-20X ULN >20X ULN

Regimens: Actions to be taken:

Continue If withoutsigns
Regardless of treatment and symptoms,
regimen regimen with continue
routine treatment
monitoring regimen, and
schedule. monitor
ALT/AST every
two weeks until
reversion to
Grade 1.
BPaLM/ Continue If with signs and Regardless of signs and symptoms,
BPaL treatment symptoms, interrupt the entire regimen
regimen with mterrupt the (interruption allowed for < 2
routine entire regimen consecutive weeks or < 4 non-
monitoring (interruption consecutive weeks cumulative).
schedule. allowed for < 2 Treatment may be reintroduced
consecutive after
weeks or <4 non- toxicity is resolved or ALT/AST
consecutive returned to Grade 1 with close
weeks ALT/AST monitoring.
cumulative).
Treatment may be
reintroduced after
toxicity is
resolved or
ALT/AST
retumed to Grade
1 with close
 ALT/AST
monitoring.
SSOR Continue If with signs
treatment symptoms, stop
and Regardless of symptoms, stop
TB and non-TB drugs. Monitor
all
ITR regimen with all TB and non- ALT/AST weekly.
routine TB drugs. Treatment may be
reintroduced
monitoring Monitor after toxicity is resolved or
schedule. ALT/AST ALT/AST retumed to Grade 1,
weekly. following drug
Treatment may be reintroduction/rechallenge
reintroduced after guidelines.
toxicity is
resolved or
ALT/AST
returned to Grade
1, following drug
reintroduction/rec
hallenge*
guidelines.
References: Clinical Guide for the Introduction of BPaL regimen in the
Philippines under Operational Research, January 2022 and End TB Clinical and
Programmatic Guide for Patient Mana gement with New TB Drugs, version 4.0,
*Reintroduce anti-TB drugs once liver e nzymes return to baseline. Anti-TB January 2018, WHO Operational Handbook, December 2022
drugs should be reintroduced in a serial fashion by adding a new medicine
days. The least hepatotoxic drugs shoul d be added first, while every 3-4
monitoring ALT/AST after each new exposure. Where applicable, consider
likely offending drug permanently
it. ‘5 not essential to the regimen.
if suspending the most
{|
E. QT PROLONGATION (Cfz, Bdg, Mfx, Dim, Pa, Lfx)
Adverse event Grade 1 Grade 2 Grade 3 Grade 4

QT QT cF 450-480 QTcF 481-500 QTcF >500 ms QTcF >500 or

prolongation ms ms on at least two >60 ms change
separate ECGs from baseline
at least 30 and Torsade de
minutes apart pointes or
without polymorphic
signs/symptoms ventricular
of serious tachycardia or
arrhythmia* signs/symptoms
of serious
arrhythmia

Regimens: Actions to be taken:

Regardless of Monitor more closely (at least

regimen weekly ECG) until QTcF has Consider Hospitalize as
returned less than grade
to
1. hospitalization soon as possible
and replete and replete
electrolytes as__|
electrolytes as
necessary; necessary;
address other address other
identified identified
cause(s). Repeat cause(s). Repeat
ECG
in 24-48
hours until
ECG
in 24-48
hours until
QTcF is <500
ms.
QTcF

ms.
is<500

BPaLM/BPaL Monitor more closely (at least May interrupt Interrupt the
weekly ECG) until QTcF has the entire entire regimen
returned less than grade 1.
to
regimen for <2
(allowed for <2 consecutive
consecutive weeks
or<4
weeks or <4 non-consecutive
non-consecutive weeks
 weeks cumulative.
cumulative). Reintroduce the
Reintroduce the regimen when
regimen when
QTcF is <500
QTcF
is <500 m
with close ECG
ms with close monitoring.
ECG
monitoring.
SSOR Monitor more closely (at least May
stop the Stop the
weekly ECG) until QTcF has suspected suspected
returned less than grade
to
1. causative causative
drug(s) and shift drug(s) and shift
to another to another
regimen. regimen.
Monitor more closely (at least
ITR
May
stop the Stop the
weekly ECG) until QTcF has suspected suspected
returned to less than grade 1. causative causative
drug(s). drug(s).
Reintroduce Reintroduce
crucial drug(s) crucial drug(s)
when QTcF
is
back to baseline
when QTcF is
back to baseline
or change to or change to
other agent(s). other agent(s).
Reference: End TB Clinical and Programmatic G uide
for Patient Management with New TB Drugs, version 4.0, January 2018
Note: When multiple ECGs are recorded on the s ame day,
average of the QTcF measures should be used to determine the grade.
 Annex F. WHO weight-based dosin g of medicines used in multidrug-resistant TB Regimens, adults and
children?

Formulation
Group. A (tablets,
diluted in 3-<5kg’ |
5-<7kg 7~<10 kg. 10-<16:kg 16-<24 kg 24-<30 kg|:30-< 36 kg: 36-<46
medicines
10 mL of water, kg 46-<56 kg |56-<70 kg| 270 kg Comments
.

as applicable)
Levofloxacin 100 mg dt 1 15 2 3 —
(Lfx) (10 mg/mL)
5 mL
(0.5 dt)
250 mgtab
(25 mg/mL)
2 mL? 5 mL (0.5 tab)° L5 2

500 mg tab
15
750 mg tab
Moxifloxacin
(Mix)
100 mg
dt
(10 mg/mL)
4mL 8 mL 15

400 mg tab 1 mt? 2m? 3mL? Sm 7.5mb 1

(40 mg/mL) (0.5 tab)® (0.75 tab)°
Standard dose

dose‘
tab
400 mg high
lor1.s L5 1.5 or2
 Formulation

in:
Sf pe
aronps
ne|
diluted |
3-<5kg 5-<7kg | 7-<10 kg 10-<16 kg | 16-<24 kg 24~<30 kg 30-<36 kg | 36~-<46 kg |
46-<56 kg S6-<70kg| 270 kg |Comments
medicines
OEE
|

10 mL of water,
asapplicable)
-

. :
.
oe pene eps et
plein pe
Bedaquiline 20mg dt 0 to <3 months: 1.5 od 0 to 3to 10 od for 2 weeks; then 20 od for 2 weeks; then -
(Bdq) (2 weeks); <3 months: <6 months: 5 od M/W/F 10 od M/W/F
1.5 0d for 3 od for
ren weky fr 2 weeks;
then
2 weeks;
then 1 od
2 3 months: 3 od for 0.5 od M/W/F
2 weeks; M/W/F >
then 1 od M/W/F for 3to 6 months:
22 weeks <6 months:| 6 od for
3 od for 2 weeks;
2 weeks; then 3 od
then 1 od M/AW/F
M/W/F
26 months:
4 od for
2 weeks;
then 2 od
M/W/F
100 mg tab 0 to <3 months: 3 mL 0 to 3 to 2 od for 2 weeks; then 4 od for 2 weeks; then 2 od M/W/F
od for 2 weeks; <3 <6 1 od M/W/F
(10 mg/mty? months months
then 1 mL od M/W/FI .
od for od for
= 3 months: 6 mL od 2 weeks; 2 weeks;
for 2 weeks; then 1 mL then 2 mL
then 2 ml od MAW/F° od M/W/F? od M/W/F°
3 to 2
<6 months: 6 months:
6mL 12 mL
od for od for
2 weeks; 2 weeks;
then 2 mL then 6 mL
od M/W/F? od M/W/F*
2
6 months:
8 mL
od for
2 weeks;
then 4 mL
od M/w/FP
100 mg tab
(10 mg/mL}
- 200 mq daily (od) for 8 weeks; then
100 mg dose daily (od)
is
Dasing scheme for
BPaLM/BPal regimen
(>14 years).
—
as op
i
Sere s
Se
Formulation
Group A (tablets, unk se | ee p

Opes
ee
me divin es.
diluted in 38S kg] 5-<7 kg
feo
se

7-<10 kg 10-<16 kg 16-<24'kg 24-<30 kg

10 mL-of water,
|

|= ae
ne
pees ve
Linezolid
(Lzd)
:
as applicable)
20 mg /mL susp 2mt 4 mb
ree
6 mL
et
8 mL
nae
11 mL 14 mb
oes

150 mg dt 25
(15 mg/mL)
mL 5 mb
(0.5 dt)
1
2
600 mg tab - 1.25 ml? 2.5 mt°
(60 mg/mL)
5 mL
(0.5 tab)®* 5 mL 7.5 mt 1 1
(0.5 tab)’ (0.75 tab)?

sreeg [Formulation 3-<Skg S-<7kg 7-<10kg |10-<16 kg 16-<24 kg 24~<30 ky 30-<36 kg 36-<46 kg 46-<56 kg
|

g.. |Comments
a
|
|

Clofazimine 50 mg cap or 1 M/F 1 M/W/F 1 2

~ )

(Cfz) tab’ 2 For children <24 kg, the

use of the 50 mg tab
100
tab
mg
cap or ~ 1M/F 1 MW/F 1 1 is preferred.

Cycloserine
or terizidone
125 mg mini 2m? 4mL® 1 2 3 4 4 -
cap (Cs)
(Cs/Tz) (12.5 mg/mL)
250 mg cap
(25 mg/mL)
ims 2m? Sm? 1 2 2 2 3

mediines [Formulation 3-5 kg"

|
5-<7.kg* 7-<10 kg |10-<16 kg 16+<24 kg 24-<30 kg 30-<36 kg 36-<46 kg 46~<56 kg 56-<70 kg
|

|
270 kg) |Comments...
Ethambutol 100 mg dt (10 ma/ 5mL 1 2
(E or EMB) mL) (0.5 dt)
3 4 - - -
400 mg tab 1S mL 3m? 4mL> 6 mL 1 15 2 3 4
(40 mg/mL)
Delamanid 25 mg dt lod <3 months: 1 od 1 bd 2 morning
(Dim)
23 months: 1 bd
2 bd -
evening 1
50 mg tab" (5 mg/ 5 mL <3 months: 5
me 5 mL 10 ml (1 tab) morning 1bd 2 bd
ml) (05 (0.5 tab) od
o
tab)
23 months: 5 mL
(0 2b) 5 ml (0.5 tab) evening

(0.5 tab) bd®

 er a
Pyrazinamide
(Z or PZA)
|
Formulation
150 mg dt (15 mg/|
ml)
3-<5 kg"
5 ml
(0.5 dt)
5-<7-kg*
1 2
|
7-<10 kg 10-<16 kg} 16-<24 kg 24-<30kg 30-236
3 5
|

=
kg
| |
36-<46 kg 46-256kq|56-<70kg} 270kg
—
|Comments
=
400 mg tab 2.5 mL” mL 7.5 mb 1 25
5S
2 3
(40 mg/mL) 4 5
(0.5 tab)’ (0.75 tab)?

500 mg tab 2 mL? 5 mL (5 mL)? 1 15 2 25 3

(50 mg/mL) 4

Imipenem- 500 mg + Not used in patients aged <15

cilastatin 500 mg powder years (use meropenem) 2 vials (1g + 1g) bd Only to be used with
(Ipm/Cln) for injection, vial clavulanic acid.
(10 mL)
Meropenem 1g powder for 1 mL
tid 2 ml tid 4mL tid 6 tid 9mLtid 11 tid
(Mpm) injection, vial
mL ml 1 vial tid or 2 vials bd Only to be used with
(20 mL) clavulanic acid.

Amikacin
(Am)
500 mg/2 mL
solution for - 3-4 mL 4m 4mL Recommended only in
injection, ampoule adults aged >18 years.
Streptomycin 1g powder for -
(Sm) injection, vial Calculate according to the difution Recommended only in
used adults aged >18 years.
Ethionamide 125 mg dt(Eto) 3 mb? 7m? 1 2 3 4
or Prothion- (12.5 mg/mL) - Although once daily dose
amide (Eto/ advised, two divided
Pto) 250 mg tab
(25 mg/ml)
- 3 mu ; > mt
(0.5 tab)>
1 2 3 4
doses canbe also given
to improve tolerance.

P-aminosal- PAS sodium salt

03gbd
icylic acid (equivalent to 4 g
0.75g bd igbd 2g bd 3g bd 3.5 g bd
4gbd 4-6 g bd Usually given in
(PAS) PAS acid) sachet divided doses.
 onees Formulation 3-<Skg
|

S-<7kg |.7~<10kg 10-<16 kg 16-<24 kg |

24~-<30 kg |
30-<36 kg| 36=<46 kg: ‘A6-<56 kg 56-<70 | kg” Comments
Isoniazid! 50 mg/5 soln 5 mL
(INH or H)
mb 9 mL 15 mL 20 mL - - - Pyridoxine is always
(high dose) given with high-dose
[100 mgdtortab 5mL 1 15 2 4
(10 mg/ml) (0.5 dt)
3 4 45 - isoniazid in children
(1-2 mg/kg) and in
people at risk of side-
effects (e.g. those with
HIV or malnutrition). In
infants, pyridoxine may
be given as part of a
multi-vitamin syrup.
300 mg tab - 15
1
15 2
Clavulanic tid
acid! (as
62.5 mg clavulanic
acid as amoxicillin/
1.5 mt tid 2 ml 3 mL
tid 5 mL
tid 8&mLtid 10 mL
tid 10 mL bd or tid - Only available in
amoxicillin/ clavulanate combination with
clavulanate) (250/62.5 ma), amoxicillin. To be given
(Amx/clav) powder for oral with each dose of
solution, 5 mL imipenem/cilastatin (bd)
125 mg clavulanic or meropenem (tid).
acid as amoxicillin/
- 1 tid 1 bd
or tid
clavulanate
(500/125 mg) tab
Pretomanid 200 mg tab
(Pa) - 1 Currently only used
as part of the BPaLM/
BPaL regimens.

bd: two times a day; BPaL: bedaquiline, pretomanid and linezolid; BPaLM:
bedaquiline, pretomanid, linezolid and moxifloxacin; cap: capsule, DR-TB: drug-resistant TB; dt: dispersible tablet;
Development Group; HIV: human immunodeficiency virus; kg: g: gram; GDG: Guideline
kilograrn; MDR-TB: multidrug-resistant TB; MDR/RR-TB: multid
or
M/W/F: Monday, Wednesday and Friday; od: once daily; soln: solution; susp: suspension; tab: tablet; TB: tuberculosis;
rug- rifampicin-resistant TB; mg: milligram; mL: millilitre; M/F: Monday Friday; and
tid: three times a day; WHO: World Health Organization.
*
Dosing guidance is based on currently available data and may be revised once additional data
ar e available. Dosages were established by the GDGs for the WHO guidelines on DR-TB treatment (2018 and 2020
updates), the WHO Global Task Force on the Pharmacokinetics and Pharmacodynamics (PK/PD) of TB
medicines and the expert consultation on dosing convened by WHO in October 2021,
meeting on child and adolescent TB in June 2021. following the GDG
Doses for children and
young adolescents weighing <46 kg were revised according to Annex 6 of the 2022 WHO operational handbook
adolescents (153), which was informed by an expert consultation on dosing convened on tuberculosis — Module 5: Management
by WHO in October 2021 (154). They are based on the most recent re views and best
of
tuberculosis in children and
MDR/RR-TB. For certain medicines the
dosages were informed by pharmacokinetic modelling results based on the principle of allometric
practices in the treatment (paediatric) of
scaling and mati uration (155). Due to the pharmacokinetic properties of
certain medicines the doses proposed may exceed the mg/kg/day
ranges shown here
weight band and for bedaquiline and delamanid is based on currently available data and
in
order to achieve blood concentrations similar to target levels in an
average adult patient. The guidance for the 3-<5 kg
may be revised when new data become available.
°
Dissolving of crushed adult tablets or capsule content in 10 mL of water
is required for admini stering this dose. The number of ml the table reflects the dose to provide. This avoids fractioning solid formulations,
in
although bioavailability of the dissolved, crushed adult tablets is uncertain (use of
dispersible tablets is preferred).
“The higher dose may be used except when there is risk of toxicity; levels
are expected to be lowered because of pharmacokinetic interactions, malabsorption or other
reasons; or the strain has low-level drug resistance,
 *
Bedaquiline adult tablets (100 mg) crushed and suspended in water have been shown to be bioequivalent to tablets swallowed whole.
crushed and suspended in water. Vigorous stirring/shaking is needed prior to administering the 100 mg tablet

using dt to dose children

*
When the 600 mg tab and the 150 mg
weighing 16 to <24 kg, the dose in mg/kg will exceed 10-12
in 10 mL water. mg/kg and clinicians may opt to administer 1.5 dt or 4 mL of the 600 mg tab dispersed

"Clofazimine tablets are technically not dispersible but

they do slowly (this takes approximately 5 minutes) dissolve in water (5 mL and 10 mL
stirred prior to administration. The 100 mg soft gel capsule for
the 50 mg and 100 mg tablets, respectively). The suspension should
is
be
difficult to swallow for young children and therefore
countries are strongly encouraged to make the 50 mg
‘In children weighing 3 to <7 kg doses are lower than tablet formulation available.
previously recommended. This is because of relatively high
when co-administering cycloserine with delamanid. exposures associated with risk of neuropsychiatric adverse events, which
is
especially concerning
"
Delamanid adult tablets (50 mg) crushed and
‘Amikacin and streptomycin may be used in adults
suspended in water have been shown to
be bioequivalent to tablets swallowed whole.
aged 18 years or more, in
situations where an effective regimen cannot otherwise be
designed using oral agents, when susceptibility is demonstrated and when
adequate measures are
in place to monitor for adverse events. Given
the profound impact that hearing loss can have on the acquisition of
language and the ability to learn at school, the use of injectable agents
amikacin is 15~20 mg/kg and for streptomycin it is 20-40
mg/kg for children aged 2 years and older. To determine the dosing for infants and children
consulted and a lower mg/kg dose used to compensate for immature clearance. aged beiow 2 years, a paediatric DR-TB expert should be
/ These
medicines are only recommended as a
Co-administration with lidocaine is
advised to reduce pain at the injection site (156).

in adults (isoniazid).
companion agent (amoxicillin/clavulanic acid) or are not included in Groups
a
A, B and C, because of lack of data from the latest analysis on longer MDR-TB regimens
Specific comments on dosing children with medicines used in second-line MDR-TB
regimens:
* For
dosing of premature and low birth weight infants weighing <3 kg, advice should be
sought from a paediatric DR-TB expert.
* For
dosing of infants weighing 3 to <S kg, a paediatric DR-TB expert should be consulted
whenever possible.
* The
use of child-friendly, dispersible tablets in infants and young children is preferred
over manipulating adult tablets or administering or manipulating capsules. Where
on dissolving the dispersible formulation in 10 mL. of water and administering the number applicable, the dosing provided is based
immediately and the remainder of the 10 mL should be discarded.
of
mL (aliquots). The number of mL in the table reflects
the dose to provide. The dissolved solution should be used
* For some weight bands, dosing
is
indicated with both child-friendly, dispersible formulations
and adult formulations. If adult formulations are used, the table
provides the dose using aliquots
fractions where applicable (if
the fraction is 0.5 or more). Aliquots refer to the volume to administer
after crushing and dissolving the tablet in 10 mL of water.
in mL and tablet

See the detailed description of individual TB medicines in Web Annex 1.