36-37: withdrawal

Question 1

what 6 safety studies are required before new drugs are used in humans

Answer 1

safety pharmacology
ADME
single dose in 2 mammalian species
repeated dose toxicity
genotoxicity
immuotoxicity

Question 2

if a drug on the market is found to have major AEs but benefit > cost, a _______ will be done

Answer 2

black box warning

Question 3

what are the 3 top types of toxicity associated with drug withdrawals

Answer 3

hepatic > CV > hematological

Question 4

drugs tend to be withdrawn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

Answer 4

1

Question 5

______ is the primary cause of drug attrition

Answer 5

toxicity

Question 6

T or F: drugs are less likely to fail today than in the 1970s

Answer 6

F- more likely to fail today

Question 7

troglitazone is a _____ (class), ____ agonist

Answer 7

thiazolidinedione, PPARy agonist

Question 8

troglitazone is used for

Answer 8

T2DM

Question 9

troglitazone was removed from market due to

Answer 9

idiosyncratic liver toxicity (type B ADR) - dose v high + reactive metabolites

Question 10

other glitazones are ______ hepatotoxic than troglitazone but _____ caused heart failure from water retention and was withdrawan

Answer 10

less
rosiglitazone

Question 11

the structure of glitazones is similar to

Answer 11

antioxidant vit E

Question 12

is dose important in predicting if a drug will be withdrawn?

Answer 12

yes- >100mg was 84% of drugs withdrawn from market due to IADRs and 81% of BBWs

Question 13

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

Answer 13

4

Question 14

why is ibuprofen used but ibufenac not

Answer 14

ibufenac has a more reactive acyl glucuronide which binds to proteins and increases hepatotoxicity compared to ibuprofen
not enough RA benefit to justify hepatotoxicity

Question 15

T or F: reactive metabolites means a drug should not be used

Answer 15

F- ex- APAP, more R vs B comparison

Question 16

black box warnings are imposed on

Answer 16

drugs we need to fulfill a certain tx but come at acceptable risk

Question 17

clozapine BBW _________ due to _________

Answer 17

agranulocytosis due to many reactive metabolites

Question 18

using clozapine requires (2)

Answer 18

special auth
monitoring registry specific to brand dispensed (blood tests for total WBCs and absolute neutrophil counts)

Question 19

Eli Lilly tried to change the structure of clozapine to avoid agranulocytosis, what happened?

Answer 19

dose decreased which saw decrease in agranulocytosis compared to clozapine but still caused weight gain and lawsuits

Question 20

isoniazid is an

Answer 20

antibacterial, antituberculosis

Question 21

risk of isoniazid + reason

Answer 21

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

Question 22

lamotrigine BBW

Answer 22

cutaneous ADRs (other = blood dyscrasias and hepatotox (rare))

Question 23

HLA associations can be used for screening for __________

Answer 23

lamotrigine

Question 24

TKIs have ______ risks

Answer 24

liver injury

Question 25

how to reduce BBW toxicity/ risk

Answer 25

combination tx
screening for HLA genotype