CPIC recommendations Flashcards
abacavir HSR what are the symptoms (and onset)
fever, rash, GI (n/v/d), fatigue, malaise, respiratory sx (cough, dyspnea)
within 6 weeks of therapy
median time 8 days
what genotype affects abacavir
HLA-B*57:01
what happens when HLAB 5701 positive (abacavir)
significant risk of HSR
DO NOT RECOMMEND
what happens when HLAB 5701 NEGATIVE (abacavir)
LOW OR reduced risk of HSR
use per standard dosing guidelines
when to test for abacavir (locally)
screen only for Malay and Indian patients with late stage HIV
(CD4 < 200 cells/mm3)
what is the positive and negative predictive value for abacavir HSR.
what are the implications
ppv = around 50%
npv = >99%
= only 99/100 people will test negative, but 1 will still test positive,
therefore even a negative test result ≠ zero risk of HSR.
allopurinol scar reactions s/sx + onset
SJSTEN = fever, mucotaneous lesions (necrosis and sloughing of epidermis)
DRESS = fever, rash, multi organ failure (liver, heart , kidney, lungs)
ONSET weeks to months
what genotype affects allopurinol
HLA B 5801
what happens when HLAB 5801 positive (ALLOPURINOL)
stabilised?
significantly increased SCAR risk
CONTRAINDICATED
UNLESS patient has been stabilised and on target dose - continue taking despite being a carrier
what happens when HLAB 5801 NEGATIVE (ALLOPURINOL)
LOW OR REDUCED risk of SCAR
use standard dosing
when to test for allopurinol (locally)
locally only if patient has risk factors
- renal impairment
- old age
high prevalence among Chinese population
what other factors increase risk of allopurinol scar
antibiotics e.g. penicillin, ampicillin, cephalosporin; cyclophosphamide; thiazide diuretics; thiopurines e.g. azathioprine, mercaptopurine).
CBZ hypersx reactions s/sx + onset
SJS TENS (1502)
DRESS (hla3101)
MPE (hla3101)
MPE = mild HYPERSX reaction with only rash without mucosal or organ involvement, or systemic features
ONSET 4-28 days
what genotype affects CBZ
HLAB3101
HLAB1502
when to test for CBZ locally
STANDARD OF CARE TO TEST ALL patients for HLAB 1502
- 1502 common in asian ancestry, HLAB3101 more common in EU and JAP only
what happens when HLAB1502 negative AND 3101negative (CBZ)
normal risk = standard dosing
what happens when HLAB1502 negative AND 3101 positive (CBZ)
greater risk = if naive = do not use
if no alt agents = increase freq of monitoring and discontinue at first sign of cutaneous reaction
caution with other aromatic anticonvulsants unless severe hypersx
what happens when HLAB1502 positive AND 3101negative/positive (CBZ)
greater risk = if naive = do not use
caution with other aromatic anticonvulsants
if long term CBZ? but still carrier?
if >3 months
= continue taking
because onset is short at 4-28 days
phenytoin toxicity reactions s/sx + onset
dose related side effects: sedation, ataxia, dizziness, nystagmus, nausea, cognitive impairment
phenytoin induced SJS/TEN
usually 4-28 day onset
may also cause hematologic and hepatic toxicity
what genotype affects phenytoin
cyp2c9 polymorphism
hlab1502
when to test for phenytoin locally
no indication
what happens when HLAB1502 positive (phenytoin)
regardless of phenotype for 2c9
there is increased risk of phenytoin induced SJS TEN
DO NOT START IS PHENYTOIN NAIVE
IF already using for 3 months without incidence for cutaneous reactions, may consider continuing (with caution)
what happens when HLAB1502 negative + cyp2c9 NM (phenytoin)
NO CHANGE
what happens when HLAB1502 negative + cyp2c9 IM (AS 1.5) (phenytoin)
SLIGHLTY REDUCED phenytoin metabolism
may increase side effect risk but no evidence for dosing change need
what happens when HLAB1502 negative + cyp2c9 IM (as 1.0) (phenytoin)
reduced phenytoin metabolism
- increased risk of toxicity
first dose: initial loading dose
subsequent doses: 25% less than typical maintenance dose
adjust to TDM
what happens when HLAB1502 negative + cyp2c9 pm (phenytoin)
reduced phenytoin metabolism
- increased risk of toxicity
first dose: initial loading dose
subsequent doses: 50% less than typical maintenance dose
adjust to TDM
what genotype affects clopidogrel
2c19
what happens with 2c19 and clopidogrel
it affects the conversion of clopidogrel to the active metabolite
= increases risk of MACE due to decreased action (reduced platelet inhibition)
local recommendations for testing pgx clopidogrel?
no indication/?
what happens when cyp2c19 UM(clopidogrel)
increased metabolite formation
no change
use standard dose 75mg OD
what happens when cyp2c19 RM (clopidogrel)
increased metabolite formation
no change
use standard dose 75mg OD
what happens when cyp2c19 NM (clopidogrel)
increased metabolite formation
no change
use standard dose 75mg OD
what happens when cyp2c19 IM (clopidogrel)
avoid standard dose
use prasugrel or tica
reduce active metabolite formation = increased MACE risk.
what happens when cyp2c19 PM (clopidogrel)
avoid standard dose
use prasugrel or tica
reduce active metabolite formation = increased MACE risk.
what genotypes affect nsaids (and which main ones affected)
2c9
with ibuprofen, celecoxib
what happens when 2c9 polymorphism with nsaids
ibuprofen, celecoxib
increased irsk of serious GI renal and cardio ADR
2C9 main route of clearance = REDUCED FUNCTION = prolonged half life.
what happens when 2c9 NM for ibuprofen./ celecoxib
initiate recommended starting dose
lowest effecrtive dose, shortest duration
what happens when 2c9 IM AS1.5 for ibuprofen./ celecoxib
initiate recommended starting dose
lowest effecrtive dose, shortest duration
(MILDLY reduced metabolism)
what happens when 2c9 IM AS1.0 for ibuprofen./ celecoxib
initiate with lowest recommended starting dose and titrate upward with caution
lowest effective dose for shortest duration
what happens when 2c9 PM for ibuprofen./ celecoxib
25 - 50 % of starting dose
titrate to 25-50% of max dose (do not dose titrate until steady state is reached = 5 and 8 days respectively)
OR
CHOOSE ALTERNATIVE not metabolised by 2c9
relevant cyp genotypes for opioids in cpic and their mechanism
codeine and tramadol
metabolised by 2D6
to more active metahbolites
reduced function = risk of diminished response
increased function = risk of toxicity
what other genotypes affect opioids
OPRM1
COMT
also associated with opioid clinical effec.t
what happens if UM 2D6 for tramadol and codeine
avoid use
increased active metabolite = increased toxicity
what happens if IM 2D6 for tramadol and codeine
reduced morphine formation
can continue using age specific or weight specific dosing
what happens if PM 2D6 for tramadol and codeine
avoid
possible diminished anlageisa
relevant cyp genotypes for ppi in cpic and their mechanism
2c19
reduced function = more plasma concentration = more toxicity
what happens if UM 2C19 for ppi
Increase starting dose by 100 percent
decreased plasma conc = risk of therapeutic failure
what happens if RM 2C19 for ppi
decreased plasma conc
but same dosing as normal
monitor
what happens if IM 2C19 for ppi
increase plasma conc = increased toxicity
initiate at starting dose
for chronic therapy >12 weeks and efficacy achieved, consider 50% reduction in daily dose
what happens if PM 2C19 for ppi
increase plasma conc = increased toxicity
initiate at starting dose
for chronic therapy >12 weeks and efficacy achieved, consider 50% reduction in daily dose
if 2d6 UM and fluvoxamine
no data
paroxetine metabolised by what enzyme and mechanism
2d6
less active
if 2d6 im and paroxetine
reduced metabolism = higher plasma conc = more side effects
lOWER STARTING DOSE
slower titration
if 2d6 UM and paroxetine
increased metabolism = less active compounds
CHOOSE ALTERNATIVE AGENT
if 2d6 pM and paroxetine
reduced metabolism = higher plasma conc = more side effects
50% starting dose
slower titration
50% maintenance dose
fluvoxamine metabolised by what enzyme and mechanism
2d6
if 2d6 PM and fluvoxamine
reduced metabolism = more conc = more side effects
25-50% starting
slow titration
OR
CHOOSE ALTERNATIVE
if 2d6 IM and fluvoxamine
reduced metabolism = more conc = more side effects
NO CHANGE
venlafaxine metabolised by what enzyme and mechanism
2d6
active metabolite
if 2d6 UM and venlafaxine
increased metabolism
NO CHANGE?
if 2d6 IM and VENLAFAXINE
decreased metabolism to active
NO CHANGE
vortioxetine metabolised by what enzyme and mechanism
2d6
iless active
if 2d6 PM and VENLAFAXINE
DECREASEd metbaolism
CHOOSE ALTENRATIVE
if 2d6 UM and vortioxetine
increased metabolism to inactive = less clinical benefit
CHOOSE ALTERNATIVE
or start at normal starting dose but maintenance dose increase by 50%
if 2d6 IM and vortioxetine
reudced metbaolism = more side effects
NO CHANGE
if 2d6 PM and vortioxetine
reduced metabolism = more side effects
50% OF STARTING DOSE
or
ALTENRATIVE
citalopram/escitalopram metabolised by what enzyme and mechanism
2c19
metabolise to less active
2c19 um and citalopram
incraease metabolism = less clinical benefit
ALTERNATIVE
or
normal starting dose, higher maintenance dose
2c19 im and citalopram
reduced metabolism = more SE
recommended starting dose
slower titration
lower maintenance dose
2c19 PM and citalopram
reduced metabolism = more SE
ALTERNATIVE
OR
lower starting dose
slower titration
50% maintenance dose
sertraline is metabolised by what enzyme and mechanism
2c19
2b6
less active metabolite
2c19 more relevant, if IM or PM
lower starting dose, 50% maintenance dose
OR
choose alternative
2b6 = just 25% if IM or PM
what genotypes for statins
SLCO1B1 = metabolises ALL statins
ABCG2 = rosuva
2c9 = fluvastatin
recommendations for statins prescribing
if slcob1 decreased or poor function,
if mod sams risk + stable statin dose ≥4 weeks = continue long term
if high sams risk + stable statin dose ≥1 year = continue long term
OTHERWISE = CHANGE
slco1b1 phenotypes
transporter
increased
normal
decreased
poor function
rosuva + slco1b1 decreased function
increased exposure
starting dose
but monitor for SAMS
rosuva + slco1b1 poor function
<20 mg starting dose
if >20 consider combination therapy
atorva + slco1b1 decreased function
<40mg starting dose
if >40 consider combination therapy
atorva + slco1b1 poor function
<40mg starting dose
if >40 consider combination therapy
simva + slco1b1 decreased function
<20mg starting dose
OR CHOOSE ALT
simva + slco1b1 poor function
<20mg starting dose
OR CHOOSE ALT
rosuva + abcg2 decreased function
increased exposure
<20 mg starting dose
if >20 consider combination therapy or alternative
rosuva + abcg2 POOR function
increased exposure
<20 mg starting dose
if >20 consider combination therapy or alternative
fluva 2c9 IM
<40mg starting dose
if >40 = alternative
fluva 2c9 PM
<20mg starting dose
if >20 = alternativ
