pharmacovigilance of drug resistant tuberculosis medicine presented by n. misra, pharmacy manager,...
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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 medicineSide 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 pain
Pyrazinamide, Moxifloxacin, Levofloxacin, Linezolid
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
• Number of spontaneous AME reports submitted – exclude
ARVs
INCOMPLETE, INACCURATE AND SPARSE - Spontaneous
RELATIVELY GOOD DATA - TSR
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 NATIONAL CASEPre-XDR(H +R , any injectable or a fluoroquinolone)
Where more than 3 months of pre-XDR or XDR treatment received
XDR (Rif, INH, injectable and Fluoroquinolone
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.MDR for drug substitution (A/E) Age < 18 years
MDR with both inhA and KatG mutations
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
Side Effect
CFZ, BDQ ,Moxi, Levo
Cardiac arrhythmias, QTC Prolongation
Linezolid Optic Neuritis, Anaemia, Thrombocytopenia, GI Disorders
BDQ 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.
QuestionWhich 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?
6.
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 OUTCOME1= RECOVERING
2 = MONITORING PATIENT
3 = DIED
Daily ADR Reporting Toolcardiac GIT Auto-
immunemusculo-skeletal Psych liver audio skin neuro respirator
y blood endocrine
electrolyte
abnormality
death
ADR Observed
(y/n) - wk1
List
Date of onset
Suspected drug
Grading
Action taken
NURSE TO COMPLETE
DOCTOR TO COMPLETE
NATIONAL PHARMACOVIGILANCE CENTRE (NPC)TEL: 012 395 9506/ 8099Fax2email: 086 241 2473Email: [email protected]
FACILITY NAME
SUB-DISTRICT
DISTRICT TEL
PROVINCE FAX
MEDICINES (AND CONCOMITANT MEDICINES, INCLUDING HERBAL PRODUCTS, IF KNOWN)
MedicineSuspect 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
PATIENT DETAILS:Patient Initials Age Date of Birth (dd/mm/yyyy) Reference No Gender M F Pregnant Yes No
Allergy Weight (kg) Height
(cm) Estimated Gestational Age
SUSPECTED ADVERSE DRUG REACTION REPORT HIV/AIDS AND TB TREATMENT PROGRAMME
ADVERSE DRUG REACTION
Date of onset of reaction (dd/mm/yyyy)
Date Reported (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 concentrationProblems with breathing
Vomiting
Anxiety Fat gain ImpotencePsychosis/hallucinations
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 lossPain/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)
K+ Creat eGFR ALT AST Hb Platelets CD4Viral Load
Lact
Other:
BL
CUR
ADVERSE REACTION OUTCOME
Intervention: Action Taken:Patient Outcome:
Patient Counseled Referred to expert Additional clinic visit Discontinued Suspected drug
Additional lab request
Discontinued suspected drug Replaced by Decreased dose Treated with Other
Recovering Died Other: Other:
Hospitalization Other:
RELEVANT CLINICAL HISTORY (ATTACH ADDITIONAL INFORMATION)
Date patient initiated ARVs (dd/mm/yyyy)
Initial regimen
How long has patient been diagnosed with HIV
Years Months
How long has patient been on ARV treatment
Years Months
CONCOMITANT MEDICAL CONDITION(S) (TICK ALL THAT APPLY):
HTN DM KS Hep B PCP Esophageal Candidiasis Oropharyngeal Candidiasis
Cryp Meningitis Other/s
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
ADR Report
Cluster
Information Patient
Information Flow
NPC
provinces
PV Nodes
PV Clusters
• Regulatory changes• Medicine alerts
MCC
• Request for cohort studies on specific problems (CEM)COHORT
• Rational use of drugs• Evaluate impact• Inform guidelines• Re-education / training of
staff
PROGRAMMATIC MANAGEMENT
ADR
info
from
TSR
Trends Feedback from Aggregate Data
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
Can We Rise to the Challenge?
Dying from a disease is sometimes unavoidable, but dying from a medicine is unacceptable.
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
References• World Health Organization. 2013. Multidrug-resistant tuberculosis (MDR-
TB). 2013 Update. World Health Organization Press.• World Health Organization. 2012. WHO Expert Committee on Leprosy.
World Health. Organ. Tech. Rep. Ser. 968:1-61.• Hastings, R. C., R. R. Jacobson, and J. R. Trautman. 1976. Long-term clinical
toxicity studies with clofazimine (B663) in leprosy. Int. J. Lepr. Other Mycobact. Dis. 44:287-293.
• Costa Queiroz, R. H., A. M. de Souza, S. V. Sampaio, and E. Melchior Jr. 2002. Biochemical and hematological side effects of clofazimine in leprosy patients. Pharmacol. Res. 46:191-194.
• Jopling, W. H. 1976. Complications of treatment with clofazimine (Lamprene: B663). Lepr. Rev. 47:1-3
• Jadhav, M. V., A. G. Sathe, S. S. Deore, P. G. Patil, and N. G. Joshi. 2004. Tissue concentration, systemic distribution and toxicity of clofazimine--an autopsy study. Indian J. Pathol. Microbiol. 47:281-283.
• Hudson, V., F. Cox, L. Taylor, M. Guill, B. Wray, and J. Steele. 1988. Pulmonary clofazimine crystals in a child with acquired immunodeficiency syndrome and disseminated Mycobacterium avium-intracellulare infection. Pediatr. Infect. Dis. J. 7:880-882.
ReferencesDepartment of Health of the Republic of South Africa. 2012. Management of Drug-Resistant Tuberculosis. Policy Guidelines. National Department of Health.Division of Clinical Pharmacology, Faculty of Health Sciences, University of Cape Town. 2012. South African Medicines Formulary. Health and Medical Publishing Group of the South African Medical Association.Novartis Drug Regulatory Affairs. 2005. LAMPRENE® (clofazimine) 50 or 100 mg capsules, soft. International Package Leaflet.Levy, L. 1974. Pharmacologic studies of clofazimine. Am. J. Trop. Med. Hyg. 23:1097-1109.Mansfield, R. E. 1974. Tissue concentrations of clofazimine (B663) in man. Am. J. Trop. Med. Hyg. 23:1116-1119Van Deun, A., A. K. Maug, M. A. Salim, P. K. Das, M. R. Sarker, P. Daru, and H. L. Rieder. 2010. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am. J. Respir. Crit. Care Med. 182:684-692. doi: 10.1164/rccm.201001-0077OC.
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