Pharmafrontiers

Naranjo Causality Scale (adapted)

1. Are there previous conclusive reports on this reaction?
Yes (+1) No (0) Do not know or not done (0)
2. Did the adverse event appear after the suspected drug was given?
Yes (+2) No (-1) Do not know or not done (0)
3. Did the adverse reaction improve when the drug was discontinued or a specific
antagonist was given?
Yes (+1) No (0) Do not know or not done (0)
4. Did the adverse reaction appear when the drug was readministered?
Yes (+2) No (-1) Do not know or not done (0)
5. Are there alternative causes that could have caused the reaction?
Yes (-1) No (+2) Do not know or not done (0)
6. Did the reaction reappear when a placebo was given?
Yes (-1) No (+1) Do not know or not done (0)
7. Was the drug detected in any body fluid in toxic concentrations?
Yes (+1) No (0) Do not know or not done (0)
8. Was the reaction more severe when the dose was increased, or less severe when the
dose was decreased?
Yes (+1) No (0) Do not know or not done (0)
9. Did the patient have a similar reaction to the same or similar drugs in any previous
exposure?
Yes (+1) No (0) Do not know or not done (0)
Scoring
· > 9 = definite ADR
· 5-8 = probable ADR
· 1-4 = possible ADR
· 0 = doubtful ADR

Naranjo et.al. Clin Pharmacol Ther. 1981 Aug;30(2):239-45

WHO Causality Assessment

Certain:
• Clinical event, lab test abnormality with plausible time relationship to drug intake
• Cannot be explained by concurrent disease or other drugs /chemicals
• Response to dechallenge- plausible
• Event must be definitive pharmacologically / immunologically
• Positive rechallenges (if performed).

Probable/ Likely:
• Clinical event, lab test abnormality with reasonable time relationship to drug intake
• Unlikely to be to concurrent disease, drugs / chemicals
• Clinically reasonable response to withdrawal (dechallenge)
• Rechallenge not required

Possible:
• Clinical event lab test abnormality with reasonable time relationship to drug intake
• Could also be explained by concurrent disease or other drugs or chemicals
• Information on drug withdrawal may be lacking or unclear

Unlikely:
• Clinical event , lab test with improbable time relationship to drug intake
• Other drugs , chemicals or underlying disease provide plausible explanations

Inaccessible /unclassifiable:
• Insufficient /contradictory evidence which cannot be supplemented or verified

Conditional / unclassified
• More data is essential for proper assessment or additional data are under examination

Column 1	Column 2
acetazolamide	aspirin^1E
allopurinol	azathioprine^2E captopril^E enalapril^E mercaptopurine^2E
aminophylline	carbamazepine^3B ciprofloxacin^1B clarithromycin^1B erythromycin^1Blithium^4Cmexiletine^1Bphenobarbital^3B phenytoin^3,4B primidone^3B propranolol^1Brifampin^3Britonavir^3Bzileuton
amiodarone	digoxin^2C,D fosphenytoin^2,3B phenytoin^2,3B procainamide^2B quinidine^2,3B warfarin^2B
amitriptyline	phenelzine^E selegiline^E tranylcypromine^E
amobarbital	warfarin^4B
aspirin	acetazolamide^2E methotrexate^2A,C
astemizole*	clarithromycin^1B,E erythromycin ^1B,E fluconazole^1B,E ketoconazole^1B,E itraconazole^1B,E nelfinavir^1B
azathioprine	allopurinol^1E captopril^1E
bromocriptine	midrin^E phenylpropanolamine^E
butabarbital	warfarin^4B
butalbital	warfarin^4B
captopril	allopurinol^Eazathioprine^2E mercaptopurine^2E
carvedilol	rifampin^3B
carbamazepine	aminophylline^4B clarithromycin^1Bcyclosporine^4B danazol^1B propoxyphene^1B tacrolimus^4B theophylline^4B topiramate^2B valproic acid^5B verapamil^1Bwarfarin^4B
chloramphenicol	fosphenytoin^2B phenytoin^2B warfarin^2B
chlorothiazide	lithium^2C
chlorpropamide	ethanol^E
choline salicylate	methotrexate^2A,C
ciprofloxacin	aminophylline^2B theophylline^2B
cisapride	clarithromycin^1B,E erythromycin^1B,E fluconazole^1B,E indinavir^1B itraconazole^1B,E ketoconazole^1B,E ritonavir^1B
cisplatin	ethacrynic acid^E
clarithromycin	aminophylline^2B astemizole ^2B,Ecarbamazepine^2B cisapride^2B,E cyclosporine^2B delavirdine^1,2B diazepam^2B disopyramide^2B midazolam ^2B ritonavir^1Btacrolimus^2B theophylline^2B warfarin^2B
clomipramine	phenelzine^E selegiline^E tranylcypromine^E
cyclosporine	carbamazepine^3B clarithromycin^1B digoxin^2C diltiazem^1B erythromycin^1B fluconazole^1B fosphenytoin^3B itraconazole^1B ketoconazole^1B pentobarbital^3B phenobarbital^3B phenytoin^3B primidone^3B rifampin^3B verapamil^1B
danazol	carbamazepine^2B warfarin^2F
delavirdine	clarithromycin^1,2B fluoxetine^1Bindinavir^2B ketoconazole^1B rifabutin^1,3B rifampin^3B
desipramine	phenelzine^E ritonavir^1B tranylcypromine^E
dextroamphetamine	phenelzine^E selegiline^E tranylcypromine^E
dextromethorphan	fluoxetine^E paroxetine^E phenelzine^E selegeline^E sertraline^E tranylcypromine^E
diazepam	clarithromycin^1B fluconazole^1B itraconazole^1B ketoconazole^1B
digoxin	amiodarone^1C,D cyclosporine^1C quinidine^1C,D rifampin^3B,D tacrolimus^1C
diltiazem	carbamazepine ^2Bcyclosporine^2B tacrolimus^2B
disopyramide	clarithromycin^1B erythromycin^1B
disulfiram	ethanol^E fosphenytoin^2B,C metronidazole^E phenytoin^2B warfarin^2B
enalapril	allopurinol^E
enoxaparin	ketorolac^E
erythromycin	aminophylline^2B astemizole^{2 B,E} carbamazepine^2B cisapride^2B,E cyclosporine^2B disopyramide^2B indinavir ^1,2Britonavir ^1Btacrolimus^2B theophylline^2Bwarfarin^2B
estrogens	nelfinavir^3B rifampin^3B ritonavir^3B topiramate^3B troglitazone^3B warfarin ^5B
ethacrynic acid	cisplatin^Egentamicin^E tobramycin^E
ethanol	chlorpropamide^E disulfiram^E methotrexate^B,Emetronidazole^E procarbazine^E tolbutamide^E
etretinate	methotrexate^B,E
felodipine	cabamazepine^3B
fluconazole	astemizole ^2B,Ecisapride^2B,E cyclosporine^2B diazepam^2B fosphenytoin^2B midazolam^2B phenytoin^2B rifampin ^{3 4B}tacrolimus^2B triazolam ^2B zidovudine ^1B
fluorouracil	metronidazole^1C
fluoxetine	carbamazepine^2B delavirdine^2B dextromethorphan^E phenelzine^E selegiline^E tranylcypromine^E
fluoxymesterone	warfarin^2F
fosphenytoin	aminophylline^3,4B amiodarone^1,4B chloramphenicol^1B cyclosporine^4B disulfiram^1B,C fluconazole^1B isoniazid^1B rifampin^3B tacrolimus^4B theophylline^3,4Bvalproic acid^5A,B warfarin^5A,B
ganciclovir	zidovudine^E
gemfibrozil	lovastatin^E simvastatin^E warfarin^2F
gentamicin	ethacrynic acid^E
heparin	ketorolac^E
hydrochlorothiazide	lithium^2C
imipramine	phenelzine^E selegiline^E tranylcypromine^E
indinavir	cisapride^2B clarithromycin^1,2B delavirdine^1B erythromycin^1,2B ketoconazole^1B rifabutin ^2,3B rifampin^2,3B
isoniazid	carbamazepine^2B fosphenytoin^2B phenytoin^2B
itraconazole	astemizole ^2B,Ecisapride^2B,E cyclosporine^2B diazepam^2Bfosphenytoin^3B lovastatin^2B midazolam ^2Bphenytoin^3B rifampin^3,4B simvastatin^2B tacrolimus^2Btriazolam^2B
ketoconazole	astemizole ^2B,Ecisapride^2B,E cyclosporine^2B delavirdine^2B diazepam^2B indinavir^2B midazolam^2B rifampin^3,4Btacrolimus^2Btriazolam^2B
ketorolac	enoxaparin^E heparin^E warfarin^E
lithium	aminophylline^3C carbamazepine^1F chlorothiazide^1C hydrochlorothiazide^1C phenelzine^E theophylline^3C thiazide diuretics^1C tranylcypromine^E
lovastatin	gemfibazil^E itraconazole^1B warfarin^2F
meperidine	phenelzine^E selegiline^E tranylcypromine^E
mercaptopurine	allopurinol^1E captopril^1E
mesna	warfarin^2F
methotrexate	aspirin^1A,C choline salicylate^1A,C ethanol^B,Eetretinate^B,ENSAIDs^1A,C probenecid^1C salicylates^1A,C trimethoprim/sulfamethoxazole ^1A,C
methylphenidate	phenelzine^E selegiline^E tranylcypromine^E
methyltestosterone	warfarin^2F
metronidazole	disulfiram^E ethanol^E fluorouracil^2Cwarfarin^2B
mexiletine	aminophylline^2B theophylline^2B
midazolam	clarithromycin^1B fluconazole^1B itraconazole^1B ketoconazole^1B
midrin	bromocriptine^E
mitomycin	vinblastine^E
nandrolone	warfarin^2F
nefazodone	phenelzine^E selegiline^E tranylcypromine^E
nelfinavir	astemizole^2B estrogens^4B oral contraceptives^4B rifabutin^2,3Brifampin^3B
NSAIDs	methotrexate^2A,C
oral contraceptives	nelfinavir^3B rifampin^3B ritonavir^3B topiramate^3B warfarin ^5B
paroxetine	dextromethorphan^E phenelzine^E selegiline^E tranylcypromine^E
pentobarbital	aminophylline^4B cyclosporine^4B tacrolimus^4B theophylline^4B valproic acid^1B warfarin^4B
phenelzine	amitriptyline^E clomipramine^E desipramine^E dextroamphetamine^Edextromethorphan^Efluoxetine^E imipramine^E lithium^E meperidine^E methylphenidate^Enefazodone^E paroxetine^E pseudoephedrine^E sertraline^E sumatriptan^E tramadol*^E
phenobarbital	aminophylline^4B cyclosporine^4B tacrolimus^4B theophylline^4B valproic acid^1B warfarin^4B
phenylpropanolamine	bromocriptine^E
phenytoin	aminophylline^3,4B amiodarone^1,4B chloramphenicol^1B cyclosporine^4B disulfiram^1B,C fluconazole^1B isoniazid^1B itraconazole^4B rifampin^3B tacrolimus^4Btheophylline^3,4B valproic acid^5A,B warfarin^5A,B
potassium	spironolactone^1C triamterene^1C
primidone	aminophylline^4B cyclosporine^4B tacrolimus^4B theophylline^4B valproic acid^1B warfarin^4B
probenecid	methotrexate^2C zidovudine^2C
procainamide	amiodarone^1B
procarbazine	ethanol^E
propoxyphene	carbamazepine^2B
propranolol	aminophylline^2B theophylline^2B
pseudoephedrine	phenelzine^E tranylcypromine^E
quinidine	amiodarone^1B digoxin^2C,D rifampin^3B
rifabutin	delavirdine^1,4Bindinavir^1,4B nelfinavir^1,4B ritonavir^1,4B saquinavir^4B
rifampin	aminophylline^4B carvedilol^4Bcyclosporine^4B delavirdine^4B digoxin^4B,D estrogens^4B fluconazole^3,4B fosphenytoin^4B ^4B itraconazole^3,4B ketoconazole^3,4Bnelfinavir^4B oral contraceptives^4B phenytoin^4B quinidine^4B ritonavir^4B saquinavir^4B tacrolimus^4B theophylline^4B warfarin^4B zidovudine^4B
ritonavir	aminophylline^4B cisapride^2B clarithromycin^2B desipramine^2B erythromycin ^2B estrogen^4B oral contraceptives^4B rifabutin^2,3B rifampin^3B theophylline^4B
salicylates	methotrexate^2C
saquinavir	rifabutin^3Brifampin^3B
selegiline	clomipramine^E dextroamphetamine^E dextromethorphan^E fluoxetine^E imipramine^E methylphenidate^E meperidine^E nefazodone^E paroxetine^E sertraline^E
sertraline	dextromethorphan^E phenelzine^E selegiline^E tranylcypromine^E
simvastatin	gemfibrazil^E itraconazole^1B warfarin ^2F
spironolactone	potassium^2C
sumatriptan	phenelzine^E tranylcypromine^E
tacrolimus	carbamazepine^3B clarithromycin^1Bdigoxin^2C diltiazem^1B erythromycin^1Bfluconazole^1B fosphenytoin^3Bitraconazole^1Bketoconazole^1B pentobarbital^3Bphenobarbital^3B phenytoin^3B primidone^3B rifampin^3B verapamil^1B
testosterone	warfarin^2F
theophylline	carbamazepine^3B ciprofloxacin^1B clarithromycin^1B erythromycin^1B fosphenytoin^3,4B lithium^4C mexiletine^1Bpentobarbital^3B phenobarbital^3B phenytoin^3,4Bprimidone^3B propranolol^1B rifampin^3B ritonavir^3Bzileuton^1B
thiazide diuretics	lithium^2C
tobramycin	ethacrynic acid^E
tolbutamide	ethanol^E
topiramate	carbamazepine^1B estrogen^4Boral contraceptives^4B
tranylcypromine	amitriptyline^E clomipramine^E desipramine^E dextroamphetamine^Edextromethorphan^E fluoxetine^E imipramine^E lithium^E meperidine^E methylphenidate^Enefazodone^E paroxetine^E pseudoephedrine^E sertraline^E sumatriptan^E tramadol*^E
triamterene	potassium^2C
triazolam	fluconazole^1B itraconazole^1Bketoconazole^1B
trimethoprim-sulfamethoxazole	methotrexate^2AC warfarin ^2B
troglitazone	estrogens^4B
valproic acid	carbamazepine^5Bfosphenytoin^5A,B pentobarbital^2B phenobarbital^2B phenytoin^5AB primidone^2B zidovudine^2B
verapamil	carbamazepine^2B cyclosporine^2B tacrolimus^2B
vinblastine	mitomycin^E
warfarin	amiodarone^1B amobarbital^3B butabarbital^3B butalbital^3B carbamazepine^3B chloramphenicol^1B clarithromycin^1B danazol^1F disulfiram^1B erythromycin^1Bestrogens^5B fluoxymesterone^1F fosphenytoin^5A,B gemfibrozil^1F ketorolac^E lovastatin^1F mesna^1F methyltestosterone^1F metronidazole^1B nandrolone^1Foral contraceptives^5B pentobarbital^3B phenobarbital^3B phenytoin^5A,B primidone^3B rifampin^3B simvastatin ^1Ftestosterone^1F trimethoprim-sulfamethoxazole^1Bzileuton^1B
zidovudine	ganciclovir^E probenecid^1C rifampin^3B valproic acid^1B
zileuton	aminophylline^2B theophylline^2Bwarfarin^2B

CLINICALLY SIGNIFICANT DRUG INTERACTIONS

LEGEND FOR SUPERSCRIPTS

Effect on Drug Concentrations Mechanism of Drug Interaction

1. increased level of drug in column 1 A. displacement from plasma proteins

2. increased level of drug in column 2 B. altered liver metabolism

3. decreased level of drug in column 1 C. altered renal elimination

4. decreased level of drug in column 2 D. altered absorption or altered metabolism in the gastrointestinal tract

5. variable effect on drug level E. toxicity or enhanced pharmacologic activity

F. unknown

*non formulary

References

1. Hansten PD, Horn JR. Hansten and Horn’s Drug Interactions Analysis and Management. Applied Therapeutic Inc., Vancouver, WA. 1997.

2. Zuccharo FJ, Hogan MJ. Evaluation of Drug Interactions. First Databank, St. Louis, MO. 1996.

3. Quinn DJ, Day RO. Drug interactions of clinical importance: an updated guide. Drug Safety. 1995; 12 (6): 393-452.

4. Hansten PD, Horn JR. Drug interactions with antiretroviral agents. Drug Interaction Newsletter: A Clinical Perspective and Analysis of Current Developments. Applied

Therapeutic Inc, Vancouver, WA. 1996: 961-968.

5. The University of Alabama at Birmingham/University Hospital Newsletter. Drug interactions of azole antifungals. Drug Information Bulletin . 1996; 30 (12): 1-4.

6. Package insert information for delavirdine, indinavir, lovastatin, nelfinavir, ritonavir, saquinavir, simvastatin and topiramate.

COURTASY: Carol Bonsignore, Pharm.D., Drug Information Service, Department of Pharmacy, 966-2373

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