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Pharmaco vigilance of ASU Drugs:an over view of Current Status

,Challenges and Solutions

Conference Paper · January 2011

DOI: 10.13140/RG.2.1.1003.1840

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 1

Pharmacovigilance for ASU

Drugs :An over view

N.SRIKANTH
Assistant Director
CENTRAL COUNCIL FOR RESEARCH
IN AYURVEDA AND SIDDHA
Department of AYUSH
Ministry of Health & Family Welfare
Govt. of India
 Outline
2

 What is Pharmacovigilance ?
 Core objective
 Aims and goals
 Historical perspective
 Need
 Benefits
 Relevance of Pharmacovigilance for ASU
 Need of hour
 Terminology
 Network
 Causality assessment
 What is Pharmacovigilance ?
3

Pharmacon (Greek): Drug

Vigilance :to keep awake or alert
:To watch
 Core Objective
4

• Detection
• Assessment
• Prevention
of adverse reactions to drugs
 Aims
5

• Early detection of hitherto unknown adverse reactions

and interactions
• Detection of increases in frequency of (known) adverse

reactions
• Identification of risk factors and possible mechanisms

underlying adverse reactions

• Estimation of quantitative aspects of benefit/ risk

analysis and dissemination of information needed to

improve drug prescribing and regulation.
 Goals
6

• The rational and safe use of medical drugs

• The assessment and communication of the

risks and benefits of drugs on the market

• Educating and informing of patients.

 Historical perspective
7

 1956 Thalidomide launched in market

 1959-61 Reports of foetal abnormalities (maximum in
Germany)
 1963 British Committee on Safety of drug monitoring
 1964 UK starts “yellow cards” system
 1964-65 National ADR reporting system UK, Australia,
New Zealand, Canada, West Germany, Sweden
 1978 WHO center moved from Geneva to Uppsala
 Why Pharmacovigilance ?
8

Safety data of Clinical trials (Phase I, II, III)……..

•May not identify infrequent or late-onset adverse

drug reactions
•Very limited information on safety in children,
elderly and other group of patients
•Safety of the drugs in co-morbid conditions
•Concomitant use of other drugs
 Benefits
9

• Consumer(end user)safety
• Industry keeps their reputation
• Helps in regulatory decisions
• Post Marketing surveillance
 Incidence (Allopathic medicine)
10

At least one ADR was reported in*

• 1.14% of the hospitalised patients

• 0.012% of the outpatients
In pediatric group$
• Reported incidence 9.5 %
• 2.1% required hospital admissions
• 39.3 of them are life threatening

e.g. Constipation, urticaria, palpitations, giddiness

* Ref: Jose J, Rao PG., Department of Pharmacy Practice, Manipal College of

Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal
$ Sandeep B. Bavdekar, Sunil Karande, National PharmacovigilanceProgram,
Indian Pediatrics, Volume 43, January 17, 2006
Relevance of Pharmacovigilance for ASU
11

Global market potential

 Herbals, account for largest share in the worldwide dietary

supplements market, with sales estimated at US$17,125
million for 2004.
 USA is the largest herbals market with sales estimated at
US$4,815 million for 2004, and is projected to retain its
dominance in herbals markets through 2010.
 Market for Herbal dietary supplements in US is projected to
reach US$23,122 million by 2010 registering a CAGR of
4.84% during 2000-2010
 Global situation of Use of Traditional medicine

12

CHINA 40%
CHILE 71%
COLUMBIA 40%
INDIA ( use of Ayurveda) 65%
AUSTRALIA 48%
BELGIUM 70%
CANADA 70%
FRANCE 49%
USA 42%
UK 70%
NORTH IRELAND 90%
SOURCE : WHO traditional medicine strategy 2002-2005. Document WHO/EDM/TRM/2002.
 Use of Plant Based therapies and CAM by
General Adult Population in USA
13

non-- CAM users -- 60 %

regular CAM users -- 40 %
 Country Scenario
14

 About 65% of population in India is reported to use

Ayurveda and medicinal plants to help meet their primary
health care needs (WHO traditional medicine Strategy
2002 – 2005, Document/ WHO/ EDM/ TRM/ 2002).
 Market comprising of Ayurvedic, Unani, Siddha &
Homoeopathic medicine is around US $ 1.5 billion ≅ Rs
8800 Crore.
 Approximate share of Ayurvedic formulations is 84%
(Homeopathy 14%, Unani 2% and Siddha less than 1%.)
 Need of the hour
15

 With the tremendous expansion in the use of Ayurveda

worldwide…………….
1
1. Safety
2. Efficacy
3. Quality Control 2 3

of ASU medicines and traditional procedure-based

therapies have become important concerns for both
 Health authorities and
 Public
 This has drawn the scientific presentation of facts in
universal language.
 Need of Hour
Stress on Q.C and safety of ASU drugs
16

 Changing eco-climatic conditions leading to……

 Change in Composition of active ingredients
 Chemical pollution
 Use of addictives and preservatives in drugs
and huge commercialization of herbal drugs ……are
hampering the quality of a drug which requires
regulatory mechanism for checking quality control
 The need of hour is focusing research on evolving

referral standards and safety parameters of these

drugs
 PIVOTAL FACTORS
17

 The issues may be discussed with the

following elucidations…..
 Non-observance of classical trends and
practices
 Drug Design
 Inherent phyto -constituents
 Export policy
 Lack of Awareness about Pharmacovigilance
 Concept of Pharmacovigilance in
18
Codified ASU literatures
 Toxicovigilance
 Information on possible ADR/ADE
 Systems approach
 Recommendations for rational use
 Causal relation
 Poisonous Drugs
 Reverse pharmacology (Re-challenge /
De-challenge)
 Food toxicology and Immuno- pharmacology
 Safety issues of ASU drugs
19
 Dosage
20

Dose also distinguishes a poison from a

remedy
PHARMACOVIGILANCE FOR ASU DRUGS
2004 2008
Adulteration and contamination of
Ayurvedic Herbal Medications
(page : 20) Krishna Prasad et al
Drug Interactions of Guggulu
With Hypolipidemic drugs:
Potentiates cholesterol - and triglyceride-lowering effects

Lowers the dose Reduces likelihood of side-effects.

*Satyavati GV, et al. Experimental studies on the hypocholesterolemic effect of commiphora

mukul. Indian J Med Res 1969;57(10):1950-62.

*Nityanand S, et al. Clinical trials with gugulipid. A new hypolipidaemic agent. J Assoc
Physicians India 1989;37(5):323-8.

*Satyavati GV, et al. Guggulipid: a promising hypolipidemic agent from gum guggul
(commiphora wightii). Econ Med Plant Res 1991;5:48-82.
Drug Interactions of Guggulu

Guggulu With Anticoagulant drugs

Aspirin; warfarin; coumadin; or plavix
•Potentiates the effects
•Monitoring of Prothrombin time

Guggulu With Thyroid medications

Stimulates the thyroid gland
•May alter the dosing requirement of thyroid medications
*Tripathi YB, et al. Thyroid stimulatory action of (Z)-guggulsterone: mechanism of
action. Planta Med 1988;54(4):271-7.

*Panda S, Kar A. Gugulu (commiphora mukul) induces triiodothyronine production:

possible involvement of lipid peroxidation. Life Sci 1999;65(12):PL137-41.
 Strategic plan: A broad Outlook
26

• A strategic plan need to be developed as part of overall

planning considering of problems and benefits in the
following three major areas……

 Standardization and Quality Control of traditional drugs

 Creation of scientific evidences on Safety and Efficacy

 Mainstreaming of through integration

 Suggested approaches for sustainability of
quality and safety
27

 Observance of classical methods/SOPs

 Limited preclinical Safety studies
 Pharmacovigilance mechanism
 Export policy for ASU drug.
 Developing consumer guidelines on appropriate use
of ASU drugs
 Pharmacovigilance Mechanism
28

 Putting the Pharmaco- vigilance

mechanisms of classical and propriety
pharmaceutical products in to force by ASU
Pharmaceutical industry.

 Reporting of unusual episodes SAE,AE,ADR

 Rechecking the quality based on reported

episodes of product oriented SAE,AE,ADR.
Terminology

• Adverse Event (AE)

• Adverse Drug Reaction (ADR)
• Serious Adverse Event (SAE)
• Unexpected adverse drug reactions
• Serious unexpected suspected adverse
reaction (SUSAR)
Terminology

ADVERSE DRUG REACTION

Any noxious, unintended and undesired effect of a
drug, which occurs at a dose used in humans for
prophylaxis, diagnosis, therapy or modification of
physiological functions
ADVERSE EVENT
Any untoward medical occurrence that may present
during treatment with a drug but which does not
necessarily have a causal relationship with its use
Terminology

SERIOUS ADVERSE EVENT (SAE)

• Death
• Life-threatening
• Requires hospitalization or its prolongation
• Persistent or significant disability or incapacity
• Congenital anomaly
 Terminology

UNEXPECTED ADVERSE REACTIONS

• Any AE occurring in subjects participating in a
research protocol, the nature, severity, or frequency
of which is not reported in the protocol, Investigator’s
brochure or product summary
SIGNAL
• Reported information on a possible causal relationship
between an adverse event and a drug, the relationship
being unknown or incompletely documented previously
Usually more than a single report is required to
generate a signal depending upon the seriousness of
the event and the quality of the information
Classification of ADR

A. Type A-Augmented
• extension of pharmacologic effect
• often predictable and dose dependent
• responsible for at least two-thirds of ADRs
B. Type B – Bizarre (odd/peculiar)
• idiosyncratic or immunologic reactions
• rare and unpredictable

C. Type C-Chronic
• associated with long-term use
• involves dose accumulation

D. Type D- Delayed
• delayed effects (dose independent)
• Carcinogenicity
• Teratogenicity
Classification based on Severity
 Mild
 no changes in therapy are needed

 Moderate
 change of therapy is desired but the events are not
life-threatening or causing disability
 Serious
 is either life-threatening, fatal, cause of prolong
hospital admission, cause persistent disability
Initiatives

29th & 30th of August 08

WHO, India Office
Protocol was finalized
 National Pharmacovigilance
Net work Program for ASU drugs

•National Pharmacovigilance Resourse Center (NPRC), IPGTRA-

GAU, Jamnagar

•8 Regional Pharmacovigilance Centers (RPC)

(East, West, North, South, Central, CCRAS, NIUM, NIS)

27 (53) Peripheral Pharmacovigilance Centers (PPC)

East – 3 West – 4

North – 7 South – 4

Central – 4 CCRAS – 1 (27)

NIUM – 3 NIS – 1
Reporting of Adverse Drug Reactions
Pharmacovigilance case report
A notification relating to a patient with an adverse medical event (or laboratory test
abnormality) suspected to be induced by a medicine.
Reporting form for suspected adverse reactions to ASU drugs
Contents
1. Patient details:
• Name, Ethnicity, Address,
• Age, Sex and Prakriti
• Brief medical history (when relevant)

2. Description of Suspected Adverse Reaction:

• Date and time of initial observation
• Description (nature, localization, severity, characteristics, etc.)
• Results of investigations and tests
Reporting of Adverse Drug Reactions
3. List ASU and Other drugs used by the patient during reported period
• Name
• Manufacturer
• Dose and dosage schedule
• Route
• Start/ stop dates
• Indication for use (with particular drugs, a batch number is important)

4. Brief details of suspected ASU medicine (including self-medication):

• Name, composition, expiry date
• Dietary restrictions if any,
• Whether the drug consumed under medical supervision or self medication

5. Treatment provided for suspected adverse reaction

6. Outcome
- Recovered/ not recovered/ unknown/ fatal
- Hospitalized, if yes details……
- Severe: Yes/ No
- Re-challenge
- De-challenge
Reporting of Adverse Drug Reactions
7. Laboratory investigations which provide suspicion of drug involvement

8. Any other associated chronic disorders

•Hepatic/ Renal/ Cardiac/ Diabetes/ Malnutrition/ Others

9. History of previous allergies

10. Identification of the reporter

- Nurse/ Doctor/ Pharmacist/ Health worker/ Patient/ Attendant/ Manufacturer
Distributor/ Supplier/ Others
- Name
- Address
- Telephone, email id:

Duly signed and dated

PPC RPC NPRC

Serious Suspected Adverse reactions

Reporting of Adverse Drug Reactions
What to report ?
All suspected adverse reactions
• known or not
• serious or not
Adverse reactions to cosmetics
Problems related to medical devices and equipment

Reporting of lack of efficacy and suspected pharmaceutical defects

Drug interactions
Dependence and abuse
Poisoning (?)
Medical error (?)
Reporting of Adverse Drug Reactions
Who can report ?

•Physicians

• Nurses

• Pharmacists

• Medical students
Reporting of Adverse Drug Reactions
Who can report ?

Whether treatment with

• Only herbal preparations
• Herbal preparations with poisonous plants (E1)
• Metallic/ Mineral preparations
• Herbomineral preparations
• Others

Need to be added in the form ,

A comprehensive systems approach suitable to ASU
 Constrains &Challenges for implementation
of ADR Monitoring
43

 Standardization and QC of traditional Drugs

 Dosage Forms/Delivery System
 Diverse concepts and Theories of application are different
 Interaction between Drugs of different Systems(Herb – drug
interactions)
 Huge number of products to monitor
 Multiple ingredient based formulations
 Similar name of formulation with different ingredients
Causality assessment (Adverse Events)

• An assessment of whether the adverse event is related to the

drug or not
• 5 categories
not related
 unlikely
 possibly
 probably
definitely)
• Best done by clinicians closest to patient
Causality assessment (Adverse Events)

Assessment criteria

• The association in time between drug administration and event

• Pharmacology (features, previous knowledge of side effects)

• Medical plausibility (characteristic signs and symptoms,

laboratory tests, pathological findings) Tools used

• WHO ADR Probability
• Likelihood or exclusion of other causes Scales
• Naranjo’s Scale
Causality assessment (Adverse Events)

Factors considered in causality assessment

•Temporal relationship
• Pharmacological plausibility
• Recognised association with product/class
• Underlying illness/concurrent condition
• Dechallenge
• Rechallenge
• Dose relationship
• Quality of information
Causality assessment (Adverse Events)

TOOLS USED

• WHO ADR Probability Scales

• Naranjo’s Scale
 Naranjo score
Y N Don’t know
1. Are there previous conclusive reports on this reaction? +1 0 0

2. Did the adverse event appear after the suspected drug was +2 -1 0
given?
3. Did the adverse reaction improve when the drug was +1 0 0
discontinued or a specific antagonist was given?
4. Did the adverse reaction appear when the drug was re +2 -1 0
administered?
5. Are there alternative causes that could have caused the -1 +2 0
reaction?
6. Did the reaction reappear when a placebo was given? -1 +1 0
7. Was the drug detected in any body fluid in toxic +1 0 0
concentrations?
8. Was the reaction more severe when the dose was +1 0 0
increased, or less severe when the dose was decreased?
9. Did the patient have a similar reaction to the same or +1 0 0
similar drugs in any previous exposure?
10. Was the adverse event confirmed by any objective +1 0 0
evidence?

Scoring: 0 = Doubtful 1-4 = Possible 5-8 = Probable 9 = Definite

 WHO-UMC Causality Categories
CAUSALITY TERM ASSESSMENT CRITERIA*

Certain • Event or laboratory test abnormality, with plausible time relationship to drug
intake
• Cannot be explained by disease or other drugs
• Response to withdrawal plausible (pharmacologically, pathologically)
• Event definitive pharmacologically or phenomenologically (i.e. an objective
and specific medical disorder or a recognised pharmacological phenomenon)
• Rechallenge satisfactory, if necessary
Probable / • Event or laboratory test abnormality, with reasonable time relationship to
Likely drug intake
• Unlikely to be attributed to disease or other drugs
• Response to withdrawal clinically reasonable
• Rechallenge not required

Possible • Event or laboratory test abnormality, with reasonable time relationship to drug
intake
• Could also be explained by disease or other drugs
• Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that
makes a relationship improbable (but not impossible)
• Disease or other drugs provide plausible explanations

Conditional / • Event or laboratory test abnormality

Unclassified • More data for proper assessment needed, or
• Additional data under examination

Unassessable/ • Report suggesting an adverse reaction

Unclassifiable • Cannot be judged because information is insufficient or contradictory
• Data cannot be supplemented or verified
Information

• The information in the form shall be handled in confidentiality.

• Peripheral Pharmacovigilance Centres shall forward the form to the respective

Regional Pharmacovigilance Centres who will carry out the causality analysis.

• This information shall be forwarded to the National Pharmacovigilance

Resource Centre.

• The data will be statistically analysed and forwarded to the Dept. of AYUSH,

Govt. of India
Suggested Reading

Protocol for National Pharmacovigilance Programme for Ayurveda, Siddha and

Unani drugs
National Pharmacovigilance Resource Centre, IPGTRA, GAU, Jamnagar
WHO guidelines on safety monitoring of herbal medicines in
pharmacovigilance systems
http://whqlibdoc.who.int/publications/2004/9241592214_eng.pdf

Pharmacovigilancae
http://www.cdsco.nic.in/html/pharmaco.html

Pharmacovigilance Protocol
http://www.cdsco.nic.in/html/Pharmacovigilance%20Protocol%20.pdf

Download ADR Reporting Form

http://www.cdsco.nic.in/html/ADR_form_PDF_file.pdf
 PV - A TOOL FOR DEVELOPING CONSUMER
GUIDELINES
52

 Developing consumer guidelines on

appropriate use of ASU drugs for the
benefit of end-user.
 It is the need of hour to create awareness
among scientific community on suitable use
of Ayurvedic medicines for better clarity on
their rational uses.
 Awareness creation among consumer for
rational use of ASU medicines and providing
clarifications on wrong notions prevailing on
the safety of these medications.
 PV - A TOOL FOR DEVELOPING CONSUMER
GUIDELINES
53

 The ideal component of guidelines comprise …………

 Method of preparation
 Quality control mechanism and regulations
 Selection of prescription by a physician
 Diet and practices
 Co-medications
 Purchase of product
 Possible adverse effects on improper use
 Reporting mechanism of side effects, etc.
is pivotal for a user for promotion of Ayurveda and Siddha
practices.
 54

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