36-37: withdrawal Flashcards
what 6 safety studies are required before new drugs are used in humans
safety pharmacology
ADME
single dose in 2 mammalian species
repeated dose toxicity
genotoxicity
immuotoxicity
if a drug on the market is found to have major AEs but benefit > cost, a _______ will be done
black box warning
what are the 3 top types of toxicity associated with drug withdrawals
hepatic > CV > hematological
drugs tend to be withdrawn
1. earlier after launch
2. later after launch
3. if benefit > cost but the AE is fatal/ major
4. 1+3
1
______ is the primary cause of drug attrition
toxicity
T or F: drugs are less likely to fail today than in the 1970s
F- more likely to fail today
troglitazone is a _____ (class), ____ agonist
thiazolidinedione, PPARy agonist
troglitazone is used for
T2DM
troglitazone was removed from market due to
idiosyncratic liver toxicity (type B ADR) - dose v high + reactive metabolites
other glitazones are ______ hepatotoxic than troglitazone but _____ caused heart failure from water retention and was withdrawan
less
rosiglitazone
the structure of glitazones is similar to
antioxidant vit E
is dose important in predicting if a drug will be withdrawn?
yes- >100mg was 84% of drugs withdrawn from market due to IADRs and 81% of BBWs
select all that are true about lumiracoxib
1. it doesn’t have a reactive metabolite
2. it is not approved due to hepatotoxicity likely due to reactive metabolites
3. it has a high dose, potentially contributing to AEs
4. 2+3
4
why is ibuprofen used but ibufenac not
ibufenac has a more reactive acyl glucuronide which binds to proteins and increases hepatotoxicity compared to ibuprofen
not enough RA benefit to justify hepatotoxicity
T or F: reactive metabolites means a drug should not be used
F- ex- APAP, more R vs B comparison
black box warnings are imposed on
drugs we need to fulfill a certain tx but come at acceptable risk
clozapine BBW _________ due to _________
agranulocytosis due to many reactive metabolites
using clozapine requires (2)
special auth
monitoring registry specific to brand dispensed (blood tests for total WBCs and absolute neutrophil counts)
Eli Lilly tried to change the structure of clozapine to avoid agranulocytosis, what happened?
dose decreased which saw decrease in agranulocytosis compared to clozapine but still caused weight gain and lawsuits
isoniazid is an
antibacterial, antituberculosis
risk of isoniazid + reason
hepatotoxicity - Transient ↑ in ALT/AST obs in 25% pts, but most recover
1% of the 25% may experience hepatotoxicity (INH hepatitis)
If peripheral neuropathy = d/c tx
Reactive metabolites
lamotrigine BBW
cutaneous ADRs (other = blood dyscrasias and hepatotox (rare))
HLA associations can be used for screening for __________
lamotrigine
TKIs have ______ risks
liver injury
how to reduce BBW toxicity/ risk
combination tx
screening for HLA genotype
