PHARMACOVIGILANCE

Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems. Recently, its concerns have been widened to include herbals traditional and complementary medicines blood products biologicals medical devices vaccines. IMPORTANCE OF PHARMACOVIGILANCE IN EVERY COUNTRY There are differences among countries (and even regions within countries) in the occurrence of ADRs and other drug-related problems. This may be due to differences in diseases and prescribing practices, genetics, diet, traditions of the people, drug manufacturing processes used which influence pharmaceutical quality and composition, drug distribution and use including indications, dose and availability. The use of traditional and complementary drugs (e.g. herbal remedies) may also pose specific toxicological problems, when used alone or in combination with other drugs.Therefore, Pharmacovigilance is needed for detecting ADRs and specifically to combat counterfeit and substandard quality products. ADR monitoring ensures that patients obtain safe and efficacious products. The Specific Aims of Pharmacovigilance are to improve patient care and safety in relation to the use of medicines and all medical and paramedical interventions. improve public health and safety in relation to the use of medicines. contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost-effective) use. promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public.

Pharmacovigilance Programme of India (PvPI) The Central Drugs Standard Control Organization (CDSCO), Directorate General of Health Services under the aegis of Ministry of Health & Family Welfare, Government of India in collaboration with Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi has launched the nation-wide Pharmacovigilance programme for protecting the health of the patients by assuring drug safety. The programme is coordinated by the Department of Pharmacology at AIIMS as a National Coordinating Centre (NCC). The centre will operate under the supervision of a Steering Committee. Steering Committee Pharmacovigilance Programme of India Chairman Director, All India Institute of Medical Sciences, New Delhi, ex officio Members Drugs Controller General (India), ex officio Head of Department, Pharmacology, AIIMS, ex officio Scientific Director, India Pharmacopeia Commission, Ghaziabad, ex officio Nominee of Director General, ICMR, ex officio Nominee of Vice Chancellor of Medical/Pharmacy University, ex officio Member Secretary Mr. AK Pradhan, Assistant Drugs Controller, New Drugs (India)

Goal and Objectives Goal To ensure that the benefits of use of medicine outweighs the risks and thus safeguard the health of the Indian population. Objectives y  To monitor Adverse Drug Reactions (ADRs) in Indian population

y To create awareness amongst health care professionals about the importance of ADR reporting in India

y y y y y

To monitor benefit-risk profile of medicines Generate independent, evidence based recommendations on the safety of medicines Support the CDSCO for formulating safety related regulatory decisions for medicines Communicate findings with all key stakeholders Create a national centre of excellence at par with global drug safety monitoring standards

Programme governance and reporting structures The Pharmacovigilance Programme of India will be administered and monitored by the following two committees. I. Steering Committee

II.

Strategic Advisory Committee

Technical support will be provided by the following committees: I. Signal Review Panel

II. Core Training Panel III. Quality Review Panel

Collaboration with World Health Organization-Uppsala Monitoring Centre (UMC) WHO-UMC work with and/or provide technical support to more than 94 countries worldwide. The long term objective of the PvPI is to establish a Centre of Excellence for Pharmacovigilance in India. To achieve this objective, the PvPI National Coordinating Centre will collaborate with the WHO - UMC Collaborating Centre based in Sweden.
y y y y y

Training of the staff at the PvPI national coordinating centre at AIIMS, the ADR Monitoring centers in medical colleges across the country Usage of UMCs Vigiflow software (for medicines) and Paniflow (for vaccines) at no cost to PvPI. Access to Vigibase, which contains worldwide medicines safety data Access to early information about potential safety hazards of medicines (worldwide data) Technical collaboration for Pharmacovigilance Programme of India

Technical collaboration for a regular publication that will be issued by the PvPI National Coordinating Centre for distribution to the ADR Monitoring centers and other stakeholders.

CDSCO Headquarters has held several meetings with UMC over the past few years to discuss the potential role and approach for technical collaboration. Functions of the stakeholders in the Programme
Functions of the Stakeholders in Medical Collection of ADR reports Perform follow up with the complainant to check completeness as per SOPs Data entry into Vigiflow Reporting to PvPI National Coordinating Centre (PvPI NCC) through Vigiflow Training/ sensitization/ feedback to physicians through newsletters circulated by the PvPI NCC Collection of ADR reports Perform follow up with the complainant to check completeness as per SOPs Report the data to CDSCO HQ

PvPI ADR Monitoring Centre College

(PvPI AMCs)

PvPI ADR Monitoring Centre other than medical colleges [Corporate hospitals, autonomous institutes, public health programmes]

PvPI National Coordinating Centre

Preparation of SOPs, guidance documents & training manuals Data collation, Cross-check completeness, Causality Assessment etc as per SOPs Conduct Training workshops of all enrolled centers Publication of Medicines Safety Newsletter Reporting to CDSCO Headquarters Analysis of the PMS, PSUR, AEFI data received from CDSCO HQ

(PvPI NCC, AIIMS, New Delhi)

ZONAL/Subzonal CDSCO Offices

Provide procurement, financial and administrative support to ADR monitoring centers Report to CDSCO HQ

CDSCO, HQ, New Delhi

Take appropriate regulatory decision & actions on the basis of recommendations of PvPI NCC Propagation of medicine safety related decisions to stakeholders Collaboration with WHO-Uppsala Monitoring Center - Sweden Provide for budgetary provisions & administrative support to run National PvPI

ADVERSE DRUG REACTION (ADR) AND ADR REPORTING

DEFINITION of ADR "A response which is noxious and unintended and which occurs at doses normally used in humans for the prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function." (WHO, 1972) Karch and Lasagna defined ADR as Any response to a drug that is noxious and unintended, and that occurs at doses used in humans for prophylaxis, diagnosis, or therapy, excluding failure to accomplish the intended purpose. ADVERSE EVENT "Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment."(WHO)

Side effect: Any unintended effect of a pharmaceutical product occurring at normal dosage which is related to the pharmacological properties of the drug. Unexpected adverse reaction: An adverse reaction, the nature or severity of which is not consistent with domestic labelling or market authorization, or expected from characteristics of the drug. 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. The publication of a signal usually implies the need for some kind of review or action. Serious unexpected adverse drug reaction(SUADR): A serious adverse drug reaction that is not identified in nature, severity or frequency by the risk information provided in the clinical investigator's brochure (CIB) or on the drug label.

TYPE A ADVERSE EVENT(A- augmented) It is due to an extension of the active pharmacologic properties of the drug.They are also called predictable or anticipated events. There are two subclasses:Exaggerated Desired Effect: The undesirable exaggeration of a desired pharmacologic effect after a normal dose in a susceptible subject or after a higher than normal dose. Undesired Effect: The appearance of an undesired pharmacologic effect, known as lateral or parallel stimulation, can be seen after a normal dose or a higher than normal dose in a susceptible subject; it is due to the stimulation of untargeted receptors by the therapeutic agent. ____________________________________________________________________________________ ___________________________________________ TYPE B ADVERSE EVENT(B - bizarre) These are called pharmacologically unexpected, unpredictable, or idiosyncratic adverse reactions. There are two subclasses:Immunologic An allergic or hypersensitivity reaction occurs as a result of an immunologic mechanism. A pseudoallergy or anaphylactoid reaction is the result of a mechanism involving the release of the same mediators released during an immunologic reaction due to immunoglobobulin E (IgE). Idiosyncratic These reactions are qualitatively abnormal adverse reactions that occur in a given individual and whose mechanism is not yet understood.They are usually quite rare and in some cases may be due to a genetic or acquired enzyme abnormality with the formation of toxic metabolites. This is also known as primary toxicity.

Adverse Drug Reactions Classifcations

Rawlins and Thompson, 1977

Type A(Augmented) Pharmacologically predictable Dose dependent Frequency Incidence Mortality Treatment Yes Yes Common High Low Adjust Dose

Type B(Bizzare) No No Rarer Low High Stop the Drug

Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, ed. Textbook of adverse drug reactions . Oxford : Oxford University Press, 1977: 10.

Type of reaction A: dose related B: non-dose related C: dose and time related D: delayed effect E: Withdrawal

Mnemonics Augmented Bizarre Continuous or chronic Delayed Delayed

Features Related to pharmacology (toxic effect or side effect--for example, digoxin toxicity) Unrelated to pharmacology (idiosyncratic for example, malignant hyperthermia, or immunological--for example, penicillin rash) Related to cumulative drug use--for or chronic example, NSAID induced renal failure Apparent only some time after use of drug--for example, thalidomide in first trimester and phocomelia limb defects Apparent only some time after use of drug--for example, thalidomide in first trimester and phocomelia limb defects Results from the ineffective treatment (previously excluded from analysis according to WHO definition) e.g: accelerated hypertension because of inefficient control

F: Failure of therapy

Failure

Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis and management. Lancet 2000; 356:1255-9. Aronson JK. Drug therapy. In: Haslett C, Chilvers ER, Boon NA, Colledge NR, Hunter JAA, eds.Davidson's principles and practice of medicine 19th ed. Edinburgh: Elsevier Science, 2002:147-63. Time related classification of adverse drug reactions 1. Time Independent

Type of reaction Due to change in dose or concentration

Examples Toxicity due to increased systemic availability

Implications Beware of changing formulations of some drugs (e.g. modified-release formulations of lithium) Forewarn the patient.

(pharmaceutical effect)

Due to change in dose or concentration (pharmacokinetic effects)

Digitalis toxicity due to renal insufficiency

Monitor carefully throughout treatment. Alter dosage when pharmacokinetics change (e.g. renal

insufficiency). Avoid interacting drugs. Forewarn patient. Occurs without change in dose (pharmacodynamic effects) Digitalis toxicity due to hypokalaemia Monitor carefully throughout treatment. Avoid precipitating (pharmacodynamic) factors. Avoid interacting drugs

2. Time dependant

Type of reaction Rapid (due to rapid administration) First dose reactions

Examples Red man syndrome (vancomycin) Hypotension (a 1 adrenoceptor antagonists and angiotensin converting enzyme inhibitors)

Implications Administer slowly Take special precautions for the first dose Monitor during early stages.

Early (abates with repeated exposure)

Adverse reactions that involve tolerance (e.g. nitrate induced headache)

Give appropriate reassurance. Expect adverse effects if strategies to avoid tolerance are adopted. Monitoring not needed after the high risk period unless susceptibility changes.

Intermediate (risk increases at first, then diminishes)

Venous thromboembolism (antipsychotic drugs) Withdraw drug if a reaction develops. Assess baseline function. Forewarn the patient. Monitor periodically during prolonged treatment. Avoid or screen.

Late (risk increases with time)

Osteoporosis (corticosteroids)

Delayed

Carcinogenesis (cyclosporine, diethylstilbestrol) Counsel or forewarn the patient.

Joining the DoTS: new approach to classifying adverse drug reactions. Aronson JK , Ferner RE . BMJ. 2003 Nov 22;327(7425):1222-5 Classification based on frequency

Very common Common (frequent) Uncommon (infrequent) Rare Very rare

> 1/10 > 1/100 and < 1/10 > 1/1,000 and < 1/100 > 1/10,000 and < 1,000 < 1/10,000

( > 10%) ( > 1% and < 10%) ( > 0.1% and < 1 %) ( > 0.01% and < 0.1%) (< 0.01%)

Based on avoidability of the ADR s

Definitely avoidable Possibly avoidable

The ADR was due to a drug treatment procedure inconsistent with present day knowledge of good medical practice The ADR could have been avoided by an effort exceeding the obligatory demands of present day knowledge of good medical practice

Unavoidable

The ADR could not have been avoided by any reasonable means

Hallas J, Harvald B, Gram LF, Grodum E, Prosen K, Haghfelt T, et al. Drug related hospital admissions: the role of definitions and intensity of data collection, and the possibility of prevention. J Intern Med1990;228: 83-90 Based on severity

Severity Mild Moderate

Description No antidote or treatment is required; hospitalization is not prolonged A change in treatment (e.g., modified dosage, addition of a drug), but not necessarily discontinuation of the drug, is required; hospitalization may be prolonged, or specific treatment may be required An ADR is potentially life threatening and requires discontinuation of the drug and specific treatment of the ADR An ADR directly or indirectly contributes to a patient's death

Severe Lethal

Common Terminology for Adverse Events (CTCAE) Grading adverse events By this grading scale, all adverse events are classified as follows: 0=No adverse event or within normal limits 1=Mild adverse event 2=Moderate adverse event 3=Severe and undesirable adverse event 4=Life-threatening or disabling adverse event 5=Death related to adverse event Common Terminology for Adverse Events (CTCAE)

Causality assessment
Causality assessment is the method by which the extent of relationship between a drug and a suspected reaction is established

Currently wide variety of causality assessment scales exist, to attribute clinical events to drugs in individual patients or in case reports, each with their own advantages and limitations. These scales include

Karch & Lasagna scale Naranjo's scale WHO probability scale Spanish quantitative imputation scale Kramer's scale Jones scale European ABO system Bayesian system. The Naranjo's scale and the WHO scale of assessment are the most commonly used scales.

NARANJO's ALGORITHM

question Are there previous conclusion reports on this reaction?

Yes +1

No 0

Don't know 0

Did the adverse event appear after the suspect drug was administered?

+2

-1

Did the AR improve when the drug was discontinued or a specific antagonist was administered?

+1

Did the AR reappear when drug was readministered?

+2

-1

Are there alternate causes [other than the drug] that could solely have caused the reaction?

-1

+2

Did the reaction reappear when a placebo was given?

-1

+1

Was the drug detected in the blood [or other fluids] in a concentration known to be toxic?

+1

Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?

+1

Did the patient have a similar reaction to the same or similar drugs in any previous exposure?

+1

Was the adverse event confirmed by objective evidence?

+1

SCORING FOR NARANJO's ALGORITHM > 9 = definite ADR 5-8 = probable ADR 1-4 = possible ADR 0 = doubtful ADR _______________________________________________________________________________________________________________________________ WHO SCALE OF ASSESSMENT

1.CERTAIN

2.PROBABLE/ LIKELY

3.POSSIBLE

4.UNLIKELY

5.CONDITIONAL/ UNCLASSIFIED

A clinical event, including laboratory test abnormality, occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary. A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfil this definition.ical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfil this definition. A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear. A clinical event, including laboratory test abnormality, with a temporal relationship to drug administration which makes a causal relationship improbable, and in which other drugs, chemicals or underlying disease provide plausible explanations. A clinical event, including laboratory test abnormality, reported as an adverse reaction, about which more data is essential for a proper assessment or the additional data are under examination. A report suggesting an adverse reaction which cannot be judged because information is insufficient or contradictory, and which cannot be supplemented or verified.

6.UNASSESSIBLE/ UNCLASSIFIABLE