ADVERSE DRUG REACTIONS Mary Teeling 27 April 2009

Did you know that In U.S. ADRs cause an estimated 100,000 deaths per year Up to 5% of all hospital admissions are due to ADRs 30% of hospital patients suffer an ADR This is huge cause of iatrogenic disease.

What is meant by the term “Adverse Drug Reaction (ADR)?

Adverse (Drug) Reaction (ADR) Defined as: a response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or the the restoration, correction or modification of physiological function. Not due to overdose or drug abuse Causal relationship between the drug and the response is suspected, but not necessarily proven

In plain english… An ADR is an unwanted, adverse occurrence (e.g. skin rash, GIT problems etc) in a patient which you suspect might be caused by a drug the patient has taken

Serious Adverse Drug Reaction Defined as: - Serious adverse reaction means an adverse reaction which results in death, is life- threatening, requires inpatient hospitalisation, or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly / birth defect.

Unexpected ADR This is a suspected ADR that is not listed in the prescribing information ( Summary of Product Characteristics) of a medicine. NOT ALL ADRS ARE KNOWN ABOUT A DRUG AT TIME IT IS LICENSED

Adverse Event (AE) Defined as: - An undesirable experience occurring following administration of a “medicinal Product” An adverse event does not necessarily have a “causal relationship” with a medicine

Why do ADRs occur? Most ADR’s are Predictable i.e. based on pharmacological action of the drug Dose-dependent May be preventable / avoidable (“Type A” or “pharmacological” ADR’s make up 80% of ADRs)

Examples of Type A reactions Warfarin orExcessive Aspirin bleeding Beta blockers cold hands and feet Cytotoxic Agents Myelosuppression (anti-cancer)

Type B Reactions These may be known as “idiosyncratic” / “bizarre” These are not predictable from pharmacological action of drug often –serious –dose-independent may be immune-mediated (e.g. IgE mediated hypersensitivity reactions)

[Type C Reactions] Includes Increased rate of disease being treated with drug –arrhythmias with use of anti-arrhythmic agents –suicide in depressed patients on anti-depressants Increased rate of “spontaneous” disease in specific populations –increased rate of vaginal cancers in daughters of women who received stilboestrol during pregnancy – 20 year time lapse **Not predictable, often hard to detect but pharmacovigilance may pick them up eventually**

Pharmacogenomics This is the study of how an individual’s genetic inheritance affects his / her response to drugs Genetic polymorphisms of several enzyme systems have already been elucidated Affecting Cytochrome p450 systems (e.g.CYP2D6) Functional Enzymes (e.g. ACE) This may impact on development of ADRs in future - ?how

Risk factors for ADR’s Extremes of age Health status (liver/renal disease) Concomitant drug use (“polypharmacy”) Female gender (?) But remember ADR’s can occur in the absence of any of these!

What drugs cause ADR’s All drugs can! Important areas for prescriber: Drugs with a narrow TI / therapeutic index (cytotoxics, anti-epileptic agents) Most commonly used drugs (NSAIDs, Cardiac drugs – greater exposure) Drugs in combination (e.g. diuretics and digoxin, warfarin and NSAIDs)

How to diagnose ADR’s (1) Should include ADR in differential diagnosis of disease state (e.g. liver disease, skin rash, G.I. bleeding) Check out Drugs that patient has been prescribed Drugs that patient is actually taking! Clarify dose, dosing interval Always ask for OTC / herbal medicine (remedy) usage

How to diagnose ADR’s (2) Check out Exact nature of disease state / reaction Possible temporal relationship with drug exposure Past history of similar events with other / similar drugs Perform relevant laboratory tests (LFT’s, FBC and Blood film) “Dechallenge” versus “rechallenge” -??

How to manage ADR’s Serious Need to treat symptoms urgently (e.g. anaphylaxis) Need to discontinue drug Warn patient for future Non – serious Treat symptoms as appropriate Decision to withdraw depends on ADR, underlying disease, availability of alternative therapy (cytotoxics)

Question A 70-year old is knocked down by a car, 4 days after starting a new drug treatment for hypertension ? Is this an ADR or AE?

Answer Well it could be ADR! Did she stumble in front of the car due to hypotension / altered consciousness / ataxia / other CNS effects from the drug? Or was the driver at fault?

What to do with this lady (1) History of event very important as is history of how she has been since starting the medicine –Symptoms of postural hypotension –Feelings of unsteadiness –Any new / unusual symptoms since starting the drug –Does she remember the event

What to do with this lady (2) Check for hypotension / postural hypotension, any signs of unsteadiness Check the prescribing information for similar reports of unsteadiness etc Remember Just because it is not listed doesn’t mean that the drug is not to blame If in doubt report to the regulatory authorities

Reporting ADRs All suspected reactions can be reported (i.e. don’t need absolute certainty that this is an ADR) to the Remember Irish Medicines Board (IMB)? Responsible for collecting information on ADRs in Ireland from healthcare professionals and acting on the information as appropriate

Why Report ADRs? Part of Pharmacovigilance (defined as the ongoing monitoring of safety of medicines in the marketplace i.e. real-life usage in the interest of public health) ADR reporting (“spontaneous reporting”) invaluable for picking up previously unknown ADR’s i.e. not identified in clinical trials

Why Report ADRs? Can identify problems with faulty batches of biological or biotechnological medicines (remember HIV and HCV with blood products) Can identify hitherto unknown ADRs in special populations (e.g. our 70-year lady) Can identify hitherto unknown problems with teratogenicity / longterm ADRs **Type B & C reactions usually only identified by pharmacovigilance**

Remember: - Majority of ADRs are predictable and due to the pharmacological action of the drug Certain patient characteristics may predispose to ADRs Prescribing information on each drug gives details of contraindications and special precautions for use Pharmacogenomics may help to further elucidate susceptibility to ADRs in future

Sources of Information on ADRs Irish Medicines Board Prescribing information (Summaries of Product Characteristics) at National Medicines Information Centre

Questions?