Pharmacovigilance Flashcards
How do you classify ADRs by onset?
acute (<60 min)
sub-acute (1-24 hours)
latent (>2 days)
How do you classify ADRs by type?
Type A/1 (augmented/exaggerated) - based on the pharmacological properties of the drug so can be predicted, prevented and reversible, e.g. bronchospasm from beta-blockers (pharmacodynamic), or deafness from aminoglycoside overdose (toxic). About 75% of ADRs
Type B/2 (bizarre) - have no direct relationship to dose or mechanism of drug. Often allergic response (e.g. anaphylaxis), medicine-induced diseases (e.g. antibiotic-associated colitis), or idiosyncratic reactions (due to genetic predisposition). Often need to immediately withdraw drug
Type C/3 (continuous) - mostly associated with cumulative-long term exposure. E.g. osteoporosis with oral steroids
Type D/4 (delayed) - manifest with significant delay e.g. teratogenic, mutagenetic or carcinogenic effects
Type E/5 (ending use) - withdrawal syndromes and rebound phenomenon, e.g. withdrawal from beta-blocker long-term use can cause tachycardia and hypertension
How do you classify ADRs by severity?
mild (no treatment required)
moderate (need a change in treatment)
severe (need to discontinue drug)
lethal (death of patient)
What are predictable reactions?
Dose dependent
Related to drug’s actions
Occur in normal patients
80% of adverse effects
Overdosage or toxicity
Side effects
Secondary/Indirect effects
Drug interactions
What are unpredictable reactions?
Dose-independent
Not related to drug’s actions
Related to immune response (allergy)
What is DoTs?
a different classification system
Dose, Time and Susceptibility (age, sex, ethnicity, genetic, disease)
What are the types of adverse drug reaction mechanisms?
Increased therapeutic response at the target site, e.g. hemorrhaging with anticoagulants
Expected pharmacological response at another site, e.g. vasodilation-induced headache with GTN
Additional secondary pharmacological actions, e.g. drug induced prolongation of the QT interval
Immunological responses, e.g. antibiotic induced anaphylaxis
Most ADRs mimic naturally occurring syndromes or diseases such as some drug-induced hepatic conditions, however some syndromes are only caused by drugs
What are some predisposing factors for adverse drug reactions
Age, polypharmacy, co-morbidity, inappropriate medication prescribing/use, pregnancy, malnourishment, prior history of ADRs, drug abuse, genetic predisposition
What is a safe drug?
Safety is a relative absence of harm
A safe drug has a low probability of harm that, in the context of the disease being treated and the expected benefits, can be considered acceptable
Patients with more serious diseases are more likely to accept a potentially harmful treatment than a patient with a minor disease
Acceptability – a subjective judgement made when comparing both the positive and negative aspects of a course of action versus another
What are the different categories of amount of safety knowledge?
Well-established – drug used widely for prolonged period of time, unlikely that unidentified issues will emerge
Established – drug with a substantial body of knowledge available
Provisional – all new drugs until they’ve ben used extensively for at least 2 years
Limited – investigational drugs, or only authorized for a small population for treatment, or drugs with a great clinical need where large risks may be acceptable
What is causality?
A suspected Adverse Effect could have other contributory factors that are not the drug, e.g. differential diagnosis, other medications, food, environmental factors etc.
Need to evaluate the degree to which the AE could be linked to one or more suspected causes
Categorized as – probable, possible, unlikely or unassessable
What are the steps of ADR management?
Step 1 evaluate nature of the event –
obtain detailed history of patient.
identify and document clinical reaction, look up suspected medications and known ADRs in the literature that match the reaction described by the patient.
Classify severity of the reaction.
Step 2 establishing the cause -
Use Naranjo algorithm or other system to assess the patient reaction.
Evaluate quality of medicine.
Check for medication error.
Step 3 take corrective and follow-up actions -
Severe ADRs – educate and monitor prescribers, change formulary or standard treatment guidelines is necessary, modify patient monitoring procedures, notify drug regulatory authorities and manufacturers.
All ADRs – educate and warn patients.
What are the safety evaluations throughout pre-clinical trials/animal studies?
Establish toxic dose levels, identify organs adversely affected at high dose
Some identified ADRs may be acceptable depending on use of the drug
ADRs may or may not be specific to particular species
If major toxicity is identified usually further studies are precluded
What are the safety evaluations throughout phase I/healthy volunteer studies?
Closely monitored volunteers, establish possible dosage regimen
Cytotoxic drugs are an exception
Generally, no issues seen in healthy volunteers
What are the safety evaluations throughout phase II and III clinical trials?
Study safety and efficacy, reduced bias by randomization into treatment groups and blind trials. Measures surrogate markers rather than exact endpoints, and patients are in artificial clinical setting may not be representative of real use
Not large enough to identify rarer but serious ADRs, those more at risk of ADRs are often excluded
Duration of follow up is usually short (weeks)
What are the safety evaluations throughout phase IV/post-marketing surveillance?
Signal detection/hypothesis generation – characterize possible ADRs that arise spontaneously. The relationship is unknown and previously incompletely documented. Usually more than one report is required to generate a signal
What is spontaneous ADR reporting?
Aims to collate individual case reports of clinical suspicions, identify unknown and potentially serious harmful effects of drugs, and examine causation with each case
Reports are voluntarily submitted and entered into a database which is regularly screened for signals
To be successful schemes need health professionalss who are willing to take part, submitting reports must be simple, entry of reports into database should be prompt, follow-up systems exist for serious reports, analytical tools and processes are available to detect signals, feedback systems exist for reporters
Issues with underreporting and bias
What are pharmacoepidemiological studies?
Discipline of studying drug effects in populations
Cohort studies -
All users identified and followed to identify what AEs occur, will measure absolute and relative risk, lower chance of bias
Case-control studies -
All cases of the disease (i.e. the ADR) are identified and their use of the drug is compared to controls without the disease, may be nested in a cohort study, measures relative risk
PE studies are often conducted using data collected in databases for other purposes, e.g. prescribing data, event data, other health data sources
What is the process of signal detection?
Identified from spontaneous AR reports -
Calculating reporting rates based on usage denominator data, e.g. prescriptions dispensed. Can be used to identify a signal of a particular ADR by comparing with alternative treatments, however underreporting can lead to crude comparisons prone to bias
Profiling, looking at the proportions of all ADRs for a particular drug that are of a particular type e.g. GI or skin reactions. Independent of level of drug usage, graphical ADR profile can be developed, no external data is required and can be based on a single database
