PV and Glossary.

8/9/2019 PV and Glossary.

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Pharmaco-vigilance

Nidhi


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Pharmaco-vigilanceWHO Definition

The science and activities relating to thedetection, assessment, understanding and

prevention of adverse effects or any other drug-related problem


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Need of PharmacovigilanceAt the time of approval, clinical trial data are available on limited

numbers of patients treated for relatively short periods

Once a product is marketed, large numbers of patients maybe exposed,including:

Patients with co-morbid illnesses

Patients using concomitant medications

Patients with chronic exposure

After marketing, new safety information may become available:

Through use of the product domestically or in other

countries Through use of other drugs in the same class

From preclinical studies,Pharmacological Studies andcontrolled clinical trials


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How Pharmacovigilance

Spontaneous ReportingIntensive monitoring (hospital)Prescription Event Monitoring

Case Control SurveillanceComprehensive population databases, data-miningPatient seriesObservational studies


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Definition:Adverse Event vs. Adverse Reaction

Adverse Drug ReactionA noxious and unintended response to a medicine whichoccurs at doses normally used in man for treatment,

prophylaxis, diagnosis or modification of physiologicalfunction .

Adverse Event:untoward medical occurrence which does not necessarilyhave to have a causal relationship with the treatment

Administration of the Drug may result in the developmentof:

Side effect

Untoward effects

Toxic effects

Allergic and idiosyncratic effects


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Serious Adverse Events

Any untoward medical occurrence that at any dose results in:DeathIs life-threatening

Requires or prolongs patient hospitalisationResults in permanent disability/incapacity or isA congenital anomaly/ birth defectOther medically significant event (e.g. blood dyscrasias,seizures)

Does not include NON-serious events that have thePOTENTIAL to be SERIOUS if allowed to progress further,nor SEVERE events


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Adverse Drug Reaction vs. Adverse Event

Adverse Drug Reaction(event attributed to drug)

Adverse Event

All Spontaneous

reports

Events not attributed to drug

Diseases

Other Drugs

Environment

Diet

Genetics

Compliance

Otherfactors


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Definitions

Side effects: Pharmacological effects produced with

therapeutic dose of the drug Side effect which are troublesome in a

particular condition may be useful under other circumstances.

Untoward effects:

Develop with therapeutic dose of a drug but areundesirable If severe may necessitate the cessation of

treatment


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Definition cont..... Toxic Effects:

With Repeated administration of the drug With large doses Dose dependent

eg. depression of respiration with morphine Hepatotoxicity due to paracetamol.


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Definition

Unexpected ADR:

Premarketing Drugs - ADR specificity or severity of which is not

consistent with the current investigator's brouchure Risk information described in general

investigational plan or elsewhere in thecurrent application .

Marketed Product

ADR not listed in the current labeling for the drug. Event having greater severity than listed in

labeling eg. hepatic necrosis- if the labeling only referred

to elevated hepatic enzyme


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Drug Intolerance Drug Intolerance

Quantitative Type A ADR

Qualitative

Type B ADR Idiosyncrasy

Genetic/ Unknown Mechanism Allergic

Immunological

Types I,II,III,IV


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Quantitative intolerance

Type A : Augmented/Attenuated Predictable Dose related

Hyper-response to the main action of a drug Hypoglycemia due to insulin

Effect due to an action of the drug at another site

Anti-cholinergic effect of phenothiazines.


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Qualitative Intolerance

Type B: (Bizarre) Unpredicatble Not dose related Mechanism is genetic or immunologic

Idiosyncrasy: genetically determined atypical /bizarre effect

Genetically determined total absence of

reduced activity of enzyme Barbiturate ---> excitement & mental confusion Quinine---->cramps , diarrhoea, purpura,

asthma, vascular collapse


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Drug Allergy

derived from Greek word: allos- altered and ergos -energy

Immunologically mediated

Independent of dose

Occurs in a small proportion;

Prior sensitization required

1-2 weeks required after first dose

Drug acts as an antigen or Hapten

Chemically related drugs may show cross sensitivity

Same drug can cause diff allergic reactions in diff individuals


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Immune System

Immune system consist of 2 divisions:

Innate immunity

(NK, macrophages, dendritic cells, neutrophils,

basophils, eosinophils, tissue mast cells, epithelialcells-recognizes & destroy foreign Ag &pathogens without prior exposure

Adaptive immunity

characterized by antigen-specific responses toforeign antigen or pathogens

Takes several days to develop


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Immunologic Reaction

Type I reaction (IgE-mediated)

Anaphylaxis from Lactam antibiotic Type II reaction (cytotoxic)

Hemolytic anemia from penicillin Type III reaction (immune complex)

Serum sickness from anti-thymocyte globulin Type IV reaction (delayed, cell-mediated)

Contact dermatitis from topic anti-histaminics Specific T-cell activation

Stevens-Johnson Syndrome


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Other types of ADRPhototoxic : Drug accumulates in skin --- absorbs light

--- photochemical reaction --- photobiologicalreaction --- tissue damage [Eg erythema, edema,blistering etc] Eg tetracyclines

Photoallergic : drug --- cell mediated immuneresponse --- contact dermatitis on exposure to light.Eg sulfonamides, griseofulvin etc.

Drug Dependence : Psychological: (Habituation) &Physical dependence: with withdrawal symptoms

Teratogenicity : Drug use in pregnancy affectsoffspring


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Adverse Reactions:Possible CausesIntrinsic factors of the drug Pharmacological

Idiosyncratic

Carcinogenicity, Mutagenicity

Teratogenicity

Extrinsic factors Adulterants

Contamination

Underlying medical conditionsInteractionsWrong usage


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Definition Cont....

Risk in a population of exposed persons; the probability of an eventaffecting members of a particular population (e.g. 1 in 1,000).Absolute risk can be measured over time ( incidence ) or at a giventime (prevalence).

Association

Events associated in time but not necessarily linked as cause andeffect.

Absolute risk


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Attributable risk Difference between the risk in an exposed population

(absolute risk ) and the risk in an unexposed population(reference risk ). Also referred to as excess risk.

Attributable risk is the result of an absolute comparison between outcome frequency measurements, such as incidence.

Examples : If the exposed persons with a particular outcome are A, the exposed persons without theoutcome are B, the unexposed persons with the outcomeare C and the unexposed persons without the outcome

are D, then the attributable risk is calculated as : [A / (A+B)] - [C / (C+D)].


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Glossary- Conti....

Benefit

An estimated gain for an individual or a population. See also Effectiveness/Risk.

Benefit - risk analysisExamination of the favourable (beneficial) and unfavourable results

of undertaking a specific course of action. (While this phrase isstill commonly used, the more logical pairings of benefit-harmand effectiveness-risk are slowly replacing it).

C li


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Causality assessment

The evaluation of the likelihood that a medicine was the causativeagent of an observed adverse reaction. Causality assessment is

usually made according established algorithms.De-challenge

The withdrawal of a drug from a patient; the point at which thecontinuity, reduction or disappearance of adverse effects may be

observed.Effectiveness/risk

The balance between the rate of effectiveness of a medicine versusthe risk of harm is a quantitative assessment of the merit of a

medicine used in routine clinical practice. Comparativeinformation between therapies is most useful. This is moreuseful than the efficacy and hazard predictions from pre-marketing information that is limited and based on selectedsubjects.


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Definition Cont....Incidence

The extent or rate of occurrence, especially the number of newcases of a disease in a population over a period of time.

Medical error

An unintended act (either of omission or commission) or one thatdoes not achieve its intended outcomes.

Rechallenge

The point at which a drug is again given to a patient after its previous withdrawal


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Definitions Cont.. Prescription event Monitoring (PEM)

System created to monitor AD events in apopulation.

Prescribers are requested to report all events,regardless of whether they are suspected adverse

events Also known as Cohort event monitoring.

Prescription only Monitoring

Medicinal product available to the public only onprescription

Prophylaxis Prevention or protection

D fi i i C


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Definition Cont... Signal

Reported information on a possible causalrelationship between as adverse event and adrug

Unknown relationship or incompletelydocumented information

Spontaneous Reporting

System whereby case reports of adverse drugevents are voluntarily submitted from healthprofessionals and pharmaceuticalmanufacturers to the national regulatoryauthority.


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Thank You

Next lecture: Signal Detection and Causality

Assessment

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