Pharmacovigilance of Drug
Resistant Tuberculosis Medicine
Presented by N. Misra, Pharmacy Manager, KDHC
at the AWACC Conference held on the 19/20th November 2015
Background
• Drug resistance is a major threat to global
tuberculosis (TB) care and control.
• WHO estimates that around 480,000 new
multidrug-resistant tuberculosis (MDR-TB) cases
occurred in 2013.
• Current treatment regimens for drug-resistant TB
are complex, lengthy, toxic and expensive.
Background
• Only about half of DR-TB patients started on
treatment globally are reported to be treated
successfully,
• largely due to a high frequency of death and loss to
follow-up, commonly associated with adverse drug
reactions
• and high costs of treatment.
Background
• In addition, emergence of strains with additional
resistance to fluoroquinolones and/or injectable
second line drugs (aminoglycosides or
Capreomycin), rendering their treatment even
more difficult,
• with recourse only to highly toxic drugs
Pharmacovigilance
Pharmacovigilance (PCV) is the “science and activities
relating to the detection, assessment, understanding and
prevention of adverse effects or any other drug-related
problem” (WHO)
• “Pharmakon” (Greek) = Medicinal Substance
• “Vigilia” (Latin) = To keep watch
Objectives of PCV
• Improve patient care, public health and safety
• Encourage safe, rational and appropriate use of
drugs
• To recognize, at the earliest possible stage , the
adverse effects that a drug may induce, so that the
risk (unfavourable result) never becomes
disproportionate to benefit (favourable results)
PCV IS……
• An arm of patient care and must be
incorporated into clinical care of the patient
routinely.
• Aims to balance the risk – benefit ratio.
• Saves Lives
Why increased focus of PCV for DR
TB Medicine?
• The increasing use of complex regimens for DR TB globally,
including repurposed medicine and Group 5 medicine
(unproven safety and efficacy);
• the concomitant use of antiretroviral therapy in patients
with HIV-associated TB, and
• the release of new classes of medicines to treat TB on the
market (Bedaquiline and Delaminid)
DRUG RESISTANT TB TX
Treatment consists
• Daily injections for 6 months
• A large number of tablets (15 – 20)
that is taken for 18 – 24 months.
Overlapping Toxicities of TB medicine
Side Effect
Offending Drug
Nausea and Vomiting
Ethionamide, PAS, CFZ, BDQ, LZD
Hearing loss and Ototoxicity
Kanamycin, Capreomycin, Amikacin
Peripheral Neuropathy
Terizidone, Linezolid, High dose INH
Electrolyte Disturbances
Capreomycin, Kanamycin, BDQ
Renal Toxicity
Capreomycin, Kanamycin, BDQ, CFZ,
Arthralgia, arthritis, osteo-articular Pyrazinamide, Moxifloxacin, Levofloxacin, Linezolid
pain
Skin reactions
Several agents – CFZ, LZD
Liver Toxicity and Hepatitis
PZA, Moxi, Levo, Ethio, PAS, INH, CFZ, BDQ
Seizures
Terizidone, high dose INH, Moxi, Levo
Psychosis
Terizidone, high dose INH, Moxi, Levo, Ethio
Hypothyroidism
PAS, Ethio
DRUG RESISTANT TB TX
• High Co-infection rate – ARVs + TB medicine
• Co-morbidities
• Adjuvant Drugs to treat Side Effects
PROVINCIAL INDICATOR DATASET DHIS
• Number of patients on ARVs that have been reported to
have experienced AMEs
RELATIVELY GOOD DATA - TSR
• Number of spontaneous AME reports submitted – exclude
ARVs
INCOMPLETE, INACCURATE AND SPARSE - Spontaneous
Question 1
Have you ever reported an adverse drug reaction
related to ARVs.
1. Yes
2. No
Question 2
Have you ever reported an adverse drug reaction
related to other medicine?
1. Yes
2. No
New Drugs to Treat DR TB
• The field of drug-resistant TB treatment is
rapidly changing.
• The development of new drug to treat TB has
reached a critical phase.
• After nearly five decades, we have two new
agents registered by regulatory authorities
around the world
New Drugs to Treat DR TB
INTRODUCTION OF NEW DRUGS AND
DRUG REGIMENS FOR THE
MANAGEMENT OF DRUG-RESISTANT
TUBERCULOSIS IN SOUTH AFRICA:
POLICY FRAMEWORK
JUNE 2015
Objectives of the Framework
To ensure:
• appropriate selection of DR-TB patients
• appropriate monitoring and managing of
adverse events
• Programmatic pharmacovigilance - EDR
Other new and re-purposed drugs Group 5 medicine
• Clofazimine –
section 21
• Bedaquiline
• Linezolid
• Delaminid: awaiting
formal drug-drug
interaction study (to
start in 2016)
Limitations of Clinical Trials
• Pre-clinical studies done in animals.
• Sample sizes are small and confined due to
stringent inclusion and exclusion criteria.
• In practice, once registered the medicine goes
into untested populations such as children,
elderly, etc.
Bedaquiline (BDQ)
• Trial results: C208 and 209, Registration by FDA and MCC
for MDR TB in patients who are not on HAART.
• In 2014 rolled out in the BCAP programme – 69 patients
at KDHC.
• Lessons learnt – Target OF 1000 patients in KZN and 3000
PATIENTS in SA
• Pre-XDR, XDR, MDR with toxicties with or without HAART
INDICATIONS FOR BDQ
•
PROVINCIAL CASE
Pre-XDR
(H +R , any injectable or a
fluoroquinolone)
XDR (Rif, INH, injectable and
Fluoroquinolone
MDR for drug substitution (A/E)
MDR with both inhA and KatG
mutations
NATIONAL CASE
Where more than 3 months of pre-XDR or XDR
treatment received
Fewer than 2 of the following 4 core drugs (plus one other
drug) counted to be effective in regimen:
a) Injectable – only count if susceptible to injectable on
DST (within last 3 months);
b) Fluoroquinolone – only count if susceptible to
ofloxacin on DST (within last 3 months);
c) Bedaquiline – do not count if exposed to clofazimine
for more than 3 months previously;
d) Linezolid – do not count if exposed to linezolid
previously for DR-TB.
Age < 18 years
Pregnant
MDR failure (failure to convert at 4-6 months or
confirmed reconversion at any point)
Bedaquiline (BDQ)
- Drug side-effects linked to Bedaquiline include
an increased number of adverse events tied to
liver toxicity; QT prolongation, a potentially
serious disturbance in the heart’s electrical
rhythm; and an accumulation of phospholipids
in cells.
Bedaquiline (BDQ)
- BDQ - Long terminal half life of 4-5 months
- Side-effects could pose risk to patients
even after discontinuation of therapy
SIDE EFFECTS OF NOTE
•
Suspected Offending
Drug
CFZ, BDQ ,
Moxi, Levo
Linezolid
BDQ
Side Effect
Cardiac arrhythmias, QTC
Prolongation
Optic Neuritis, Anaemia,
Thrombocytopenia, GI Disorders
Hepatotoxicity
Types of Pharmacovigilance Activities
• Spontaneous Reporting
• Targeted Spontaneous Reporting
• Active Surveillance
1. Spontaneous reporting
• no active measures are taken to look for adverse
effects other than the encouragement of health
professionals and others to report safety concerns.
• Reporting is entirely dependent on the initiative
and motivation of the potential reporters.
Spontaneous Reporting
• Common form of Pharmacovigilance, sometimes
termed passive reporting.
• It is the easiest system to establish and the
cheapest to run.
• However, reporting is generally very low and
subject to strong biases.
2. Targeted spontaneous reporting (TSR)
• a variant of spontaneous reporting.
• It focuses on capturing ADRs in a well-defined group
of patients on treatment.
• Health professionals in charge of the patients are
sensitized to report specific safety concerns.
• intended to ensure that patients are monitored and
that ADRs are reported as a normal component of
routine patient monitoring and to achieve the
requisite standard of care.
3. Active surveillance
• Active measures are taken to detect adverse
events.
• Achieved by active follow-up after treatment and
the events may be detected by asking patients
directly or screening patient records.
• It is best done prospectively.
• “hot pursuit”.
Cohort Event Monitoring (CEM)
• the most comprehensive method of active
surveillance.
• It is an adaptable and powerful method of getting
good comprehensive data.
• Other methods of active monitoring include the use of
registers, record linkage and screening of laboratory
results in medical laboratories.
Recommendation
• Spontaneous reporting – POOR
• Targeted spontaneous reporting - BETTER
• Active pharmacovigilance techniques, such as ‘cohort
event monitoring’ (CEM) = BEST
• Guidelines have been published by WHO on CEM.
Translating Policy Into Practice
• Training – Ongoing.
• PCV is part of the Clinical Training
programme.
• Development of Daily Reporting Tools
• Weekly PCV Meetings to assess causality.
Which ADRs should be reported?
ADRs are graded according to severity
• Grade 1 Mild; asymptomatic or mild symptoms;
clinical or diagnostic observations only; intervention
not indicated.
• Grade 2 Moderate; minimal, local or non-invasive
intervention indicated; limiting age-appropriate
instrumental activities of daily living.
Grading of ADRs
• Grade 3 Severe or medically significant but not
immediately life-threatening; hospitalization
or prolongation of hospitalization indicated;
disabling; limiting self care activities of daily
living.
• Grade 4 Life-threatening consequences;
urgent intervention indicated.
• Grade 5 Death related to AE.
Question
Which type of ADR would require reporting on an
ADR Form to the MCC AND National PCV
Committee?
1 = All Grades
2 = Grade 1 and 2
3 = Grade 3, 4 and 5
Where would you report?
• As for any other drug the patient should be
encouraged to report to the attending health worker
any adverse event that occurs during the time the
drug is being taken.
• Such occurrences should also trigger a rapid response
to manage these untoward effects in the patient.
• Any grade 3, 4 or 5 adverse drug reaction should be
reported to the national pharmacovigilance centre
(NPC) via the hospital Pharmacy.
Who should report?
• Patients
• Doctors
• Nurses
• Pharmacists
CAUSALITY ASSESSMENT
• Difficult to definitively attribute causality to a specific
drug.
• Depends upon identification of a typical clinical
characteristic.
• Exclusion of all other contributing factors.
• Standardized assessments methods for attributing
causality for ADRs
Factors to consider
1. Describe the nature of reaction and an accurate
diagnosis.
2. Time of reaction relative to starting treatment.
3. Is it a known reaction?
4. Did the patient recover when the medicine was
stopped?
5. Did the reaction recur on rechallenge?
Factors to consider
6. Can this reaction be explained by other causes?
7. Did the event begin before the patient commenced the
medicine?
PCV MUST BE INCORPORATED IN ROUTINE
CLINICAL MANAGEMENT OF THE PATIENT.
Question 3
Do you agree that PCV must be integrated into
the routine clinical management of the patient?
1 = strongly agree
2= agree
3 = do not agree
Causality Assessment
Methodology
- The onset period of the adverse event in relation
to starting the medication (challenge).
- The timing of resolution in relation to stopping
the medication (de-challenge).
- Evidence of recurrence on re-exposure (re-
challenge)
Causality Assessment Tools
• WHO – UPSALA Monitoring Centre Causality
Assessment System – assesses the relationship
between the intake of a medicine and an ADR..
• Naranjo ADR Probability Scale – used to
determine whether an ADR is caused by a drug
or influenced by other factors.
WHO – UMC Model
• Scale is not determined by a scoring system.
• The causality assessment criteria are questions that are
answered as YES/NO answers in linear manner.
• If all questions in a specific category are answered as
YES then that category likely defines the causality.
• Certain / Uncertain / Probable or Likely
Naranjo ADR Probability Scale
• Questionnaire developed into the ADR Probability Scale.
• Consists of 10 questions that are answered as YES, NO or
DO NOT KNOW.
• Different point values (-1, 0, +1) are assigned to each
answer.
• Definitive (> 9); Probable (5-8); Possible (1-4);
Doubtful (< 0)
ACTION TAKEN:
A = DISCONTINUE SUSPECTED DRUG*
B = DECREASED DOSE*
C = ADJUVANT TREATMENT
*COMPLETE ADR FORM
PATIENT OUTCOME
1= RECOVERING
2 = MONITORING PATIENT
3 = DIED
Daily ADR Reporting Tool
cardiac
GIT
Auto- musculoimmune skeletal
Psych
liver
audio
skin
ADR
Observed
(y/n) - wk1
NURSE TO COMPLETE
List
Date of
onset
Suspected
drug
DOCTOR TO COMPLETE
Grading
Action taken
neuro
respirator
blood
y
electrolyt
endocrin
e
death
e
abnormal
ity
SUSPECTED ADVERSE DRUG REACTION REPORT
HIV/AIDS AND TB TREATMENT PROGRAMME
NATIONAL PHARMACOVIGILANCE CENTRE
(NPC)
TEL: 012 395 9506/ 8099
Fax2email: 086 241 2473
Email: npc@health.gov.za
FACILITY NAME
SUB-DISTRICT
DISTRICT
PROVINCE
PATIENT DETAILS:
Patient Initials
Reference No
Allergy
MEDICINES (AND
Medicine
TEL
FAX
Age
Gender
Height
(cm)
Weight (kg)
M
F
Date of Birth (dd/mm/yyyy)
Pregnant
Yes
No
Estimated Gestational Age
CONCOMITANT MEDICINES, INCLUDING HERBAL PRODUCTS, IF KNOWN)
Suspect drug/
Trade Name
Dose
Interval
Route
Date started
Date
stopped
Prescriber
(Dr/Pharm
/Nurse)
Key: 1. AZT 2. 3TC 3. TDF 4. FTC 5. D4T 6. ABC 7. DDI 8. NVP 9. EFV 10. ETR 11. ATV 12. DRV 13. RTV 14. LPV/r 15. ATV/r 15.R 16. RAL
17. TDF+FTC 18. TDF+FTC+EFV 19.R 20. 20. H 21. Z 22. E 23. RH 24. RHZE 25. Km 26. Am 27. Cm 28. Mfx29. Lvx30. Gfx31. Eto32.
Trd33. Pto34. Cs 35. PAS 36. Cfx37. AZI 38. Clr39. Amx/Clv40. MEROPENEM 41. Lzd42. Imipenem43. Bedaquiline44. Delamanid45.
PA 824 46. High Dose INH
ADVERSE DRUG REACTION
Date of onset of reaction
Date Reported
(dd/mm/yyyy)
(dd/mm/yyyy)
Description of reaction or problem (tick all that apply) – Attach additional information if
required
Abdominal pain
Dizziness
Hyper pigmentation
Persistent muscle
pain
Vision changes
Abnormal
behavior
Enlarged breast/s
Impaired concentration
Problems with
breathing
Vomiting
Anxiety
Fat gain
Impotence
Psychosis/hallucinatio
ns
Weight loss
Back pain
Fat loss
Insomnia/sleep issues
Rash
Other
Chills
Fat redistribution
Lactic acidosis
Ringing in the ears
Confusion
Fever
Loss of appetite
Unusual bleeding
Constipation
Headache
Nausea
Unusual bruising
Depression
Hearing loss
Pain/tingling/numbness in
extremities
Unusual fatigue
Diarrhoea
Heartburn
Pancreatitis
Violent behavior
LABORATORY RESULTS: SELECT ABNORMAL
ONE(S) AND WRITE THE VALUES
(BL=BASELINE; CUR=CURRENT)
Other:
K+
Creat
eGFR
ALT
AST
Hb
Platelets CD4
Viral
Lact
Load
BL
CUR
ADVERSE REACTION
OUTCOME
Intervention:
Patient Counseled
Referred to expert
Additional clinic visit
Discontinued
Suspected drug
Action Taken:
Additional lab
request
Hospitalization
Other:
Discontinued suspected drug
Replaced by
Decreased dose
Treated with
Other
Patient
Outcome:
Recovering
Died
Other:
Other:
RELEVANT CLINICAL HISTORY (ATTACH ADDITIONAL INFORMATION)
Initial
regim
en
Date patient initiated ARVs
(dd/mm/yyyy)
How long has patient been diagnosed
with HIV
How long has patient been on ARV
treatment
Years
Months
Years
Months
CONCOMITANT MEDICAL CONDITION(S) (TICK ALL THAT APPLY):
HTN
DM
Cryp Meningitis
KS
Hep B
PCP
Esophageal Candidiasis
Other/s
Oropharyngeal Candidiasis
Recommendation
• Daily monitoring tools be implemented.
• Multidisciplinary PCV Teams be established at
each facility.
• Weekly meetings be convened to assess
causality and reports sent to NPC.
• Grade 3/4/5 ADRs get reported.
• Ongoing training on tools
Decentralized PCV Feedback Loop
Clinical
Practice
Information
Patient
Cluster
ADR Report
Information Flow
NPC
• Regulatory changes
• Medicine alerts
MCC
provinces
COHORT
• Request for cohort
studies on specific
problems (CEM)
PV Nodes
PV Clusters
• Rational use of drugs
• Evaluate impact
PROGRAMMATIC • Inform guidelines
MANAGEMENT • Re-education / training of
staff
Steps in decentralized PCV
Cluster (Centralized Site/ Decentralized site/ clinics)
Collating and Trending of Reports by Pharmacists at the hospital
Classification of Safety Reports
(Causality, Probability, Severity and Outcomes)
Full PV Committee review of summary data.
Ratification of causality and probability of ADRs.
Recommendations made
Feedback on individual case management to clinicians and other HCP
at relevant Facilities / Clinics
Aggregate data forwarded to Provincial HAST
Programme and NPC
Take home message….
REPORT EVEN IF YOU ARE NOT
CERTAIN THE PRODUCT CAUSED
THE EVENT
Dying from a disease is sometimes unavoidable, but dying
from a medicine is unacceptable.
Can We
Rise to the
Challenge?
TOGETHER WE CAN…….we do not
have a choice
Acknowledgements
• Dr. I. Master, KDHC DR TB Clinical Head
• Dr. S. Maharaj – KDHC Medical Manager
• Dr. K. Naidu – KDHC CEO
• Clinicians, Pharmacists, Nurses at KDHC
•
•
•
•
•
•
•
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Cooke1,6 and Nathan Ford2,7*
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Approved: June 2015
nirupa.misra@kznhealth.gov.za
THANK YOU
NIRUPA MISRA.
B.Pharm, MMedSC