ADR Flashcards
Definition of adverse events
Medical occurrence temporally associated with use of a medicinal product
NOT necessarily causally related
Definition of side effects
Unintended effect occurring at normal doses, due to pharmacological properties of medicinal product
May be positive/negative
Definition of adverse drug reactions
Response to drug that is noxious/harmful & unintended
Causal relationship
Occurs at doses normally used in prophylaxis, treatment, diagnosis of disease / for modification of physiological function
Excludes medication errors, overdose, drug abuse
Definition of serious adverse reaction
Adverse effect that is unintended, occurs at normal doses & causes any of the following outcomes:
1) Death
2) Life-threatening
3) Hospitalization / Prolonged hospital stay
4) Persistent/Significant disability/incapacity
5) Congenital abnormalities / Birth defects
6) Judged to be medically important, even though effect might not be immediately life-threatening / result in death/hospitalization
- Jeopardize patient health OR
- Requires intervention to prevent any one of the outcomes mentioned above
Definition of labelled / Expected / Listed ADR
ADR that is adequately described, in terms of kind, intensity, specificity
Listed in package insert / summary of product characteristics
Definition of unexpected ADR
ADR not consistent with product information / characteristics of drug
Definition of spontaneous reporting
Voluntary submissions of reports on AEs/ADRs by HCPs to national regulatory authority, outside of systematically planned studies
Definition of mandatory reporting of ADRs
Legal obligation
Pharmaceutical companies mandated by law to report suspected ADRs
Definition of prevalence
No. of cases of an event in a given population within a given period of time
Includes old & new cases
Definition of incidence
No. of NEW cases of an event in a given population within a given period of time
Definition of frequency
Prevalence OR Incidence OR Both
What is the frequency of:
1) Very common
2) Common (frequent)
3) Uncommon (infrequent)
4) Rare
5) Very rare
1) ≥ 1/10
2) ≥ 1/100 & < 1/10
3) ≥ 1/1,000 & < 1/100
4) ≥ 1/10,000 & < 1/1,000
5) < 1/10,000
Definition of pharmacoepidemiology
Study of utilizations & effects of drug in large no. of people
Types of studies used in pharmacoepidemiology
1) Cohort studies
2) Case studies
3) Nested case studies
4) Case-cohort studies
5) Cross sectional studies
Definition of predictive values
1) Positive predictive values
2) Negative predictive values
1) Probability that, if patient tests positive, patient actually has disease
2) Probability that, if patient tests negative, patient truly does not have disease
Definition of pharmacogenetics
Study of how different individuals respond differently to therapy/treatment due to differences in genes/genetic makeup
Detecting ADRs - Rule of three
If a given ADR is not detected in a clinical trial with population size of ___, can say with 95% confidence that frequency of that ADR is < 3/population size
Limitations of clinical trials in terms of detecting ADRs
1) Small sample size
- ~ 1,500-3,000 patients exposed to drug prior to approval
- Clinical trials generally only able to detect common ADRs (frequency = 1/100 - 1/1,000)
2) Short duration
- Unable to detect ADRs that occur after long-term treatment
Overall: 50% of approved drugs have serious adverse effects not detected prior to approval
ICH E1 guidelines
Purpose: Establish guidelines for extent of population exposure needed to assess clinical safety of drugs intended for long-term treatment (chronic / repeated intermittent use for > 6 months) in non-life-threatening conditions
Guidelines:
1) Expose 300-600 patients to drug for 6 months
- Most ADRs will occur within first few months of treatment
2) Expose 100 patients to drug for min 1 year
- Concerns over ADRs that may occur after treatment lasting > 6 months
- 100 patients sufficient –> reasonable assurance that true accumulative 1 year incidence ≤ 3%
Causes of ADR
1) Inherent drug characteristics
2) Quality issues
- Toxic heavy metal contaminants
- Counterfeits/Substandard products
3) Long term use/High doses
4) Adulterants
5) Substitution of ingredients
6) Individual susceptibility
- Genetic variation
7) In-use problems
8) Drug interactions
- Drug-drug / Drug-food
Toxic heavy metal limits
Arsenic - 5 ppm
Cadmium - 0.3 ppm
Lead - 10 ppm
Mercury - 0.5 ppm
Adverse events commonly associated with drug use
1) SJS
2) TEN
3) Agranulocytosis
4) Acute dystonia
5) Drug-induced liver injury (DILI)
6) Cushing’s syndrome
SJS / TEN
1) Non-drug induced causes
2) Mortality rate
3) Incidence
4) Clinical presentation
1) Viral / Bacterial / fungal
2) SJS: 5%
TEN: 40%
3) 1-6/million/year
4) Widespread erythematous macules Severe mucosal erosion (at eyes, oropharynx, genitalia, anus) Epidermal detachment - SJS: < 10% - TEN: > 30% - Transitional SJS-TEN: 10-30%
Drug-induced liver toxicity (DILI)
1) Non-drug induced causes of acute liver failure
2) Mortality rate
3) Incidence
4) Diagnosis
1) Viral infection
2) Up to 12%
3) 7-13/100,00 (European studies)
4) CIOMS-RUCAM Scale
