20
–1
________________________________________________________________________________
2559
20
–1
________________________________________________________________________________
Analgesics
Diclofenac
1
Ibuprofen
3
Mefenamic acid
5
Meloxicam
7
Naproxen
9
Celecoxib
11
Etoricoxib
14
Tramadol
16
Codeine
18
/
Probenecid
19 21
Benzbromarone
22
Allopurinol
Dexamethasone
24
Prednisolone
26
Disease-modifying antirheumatic drugs
Sulfasalazine
28
Alendronate (Fosamax®)
30
Menatetrenone, Vitamin K2 (Glakay®)
31
Antibacterial agents
Penicillin V
33
Penicillin G
35
Amoxicillin, Amoxicillin/clavulanate
37
Ampicillin
40
Cloxacillin
41
Dicloxacillin
44
Cephalexin
46
Cefazolin
48
Cefuroxime
50
Cefotaxime
51
Cefoxitin
53
2559
20
–1
________________________________________________________________________________
Ceftriaxone
55
Ceftazidime
58
Cefoperazone/sulbactam
60
Cefixime
63
Imipenem/cilastatin
65
Meropenem
67
Ertapenem
69
Azithromycin
71
Erythromycin
73
Clarithromycin
77
Roxithromycin
79
Norfloxacin
81
Ofloxacin
83
Ciprofloxacin
85
Levofloxacin
88
Trimethoprim/ Sulfamethoxazole
91
Metronidazole
95
Vancomycin
Antifungal
97
Fluconazole
100
Ketoconazole
102
Itraconazole
104
Voriconazole
106
Amphotericin B
108
Nystatin
110
Griseofulvin
112
Terbinafine
113
Antiviral drugs
Acyclovir
115
Valacyclovir Ganciclovir
116 118
Oseltamivir
Abacavir
119
Antiretroviral 121
Emtricitabine
123
Tenofovir
125
2559
20
–1
________________________________________________________________________________
Zidovudine
127
Didanosine
129
Lamivudine
130
Stavudine
131
Efavirenz
132
Nevirapine
134
Etravirine
136
Rilpivirine
137
Ritonavir
138
Lopinavir
140
Saquinavir
142
Darunavir
143
Atazanavir
144
Indinavir
145
Raltegravir
146
Maraviroc
148
Rifampicin Isoniazid
149 152
Streptomycin
154
Ethionamide
155
Amikacin
157
antiarrhythmic agents
Digoxin
157
Propafenone
161
Amiodarone Hydrochloride
163
Flecainaide Acetate
166
(antiplatelet)
Aspirin
167
Clopidogrel Bisulfate (Plavix®, Apolets®, Plavix GPO®) Ticlopidine
170 173
Ticagrelor
175
Prasugrel
177
Dipyridamole
179
Eptifibatide
181
Cilostazol
182
2559
20
–1
________________________________________________________________________________
Lipid-lowering agents
Simvastatin
183
Atorvastatin
185
Pravastatin
186
Rosuvastatin
187
Fluvastatin
189
Lovastatin
191
Pitavastatiin
192
Gemfibrozil
193
Fenofibrate
195
Nicotinic acid
197
Ezetimide
199
Cholestyramine
201
Furosemide
203
Indaparmide
206
Amiloride Hydrochloride/Hydrochlorothiazide (Moduretic®)
207
Spironolactone
208
antianginal agents
Glyceryl Trinitrate
210
Isosorbide Dinitrate
211
Isosorbide mononitrate
212
Beta-blockers
Propranolol
213
Atenolol
215
Carvedilol (Dilatrend®)
218
Timolol
220
Nebivolol
221
Esmolol hydrochloride inj. (Brevibloc®)
222
Nadolol
223
alpha-1 blockers
Doxazosin
224
Prazosin
225
angiotensin-converting enzyme inhibitors (ACEIs)
Fosinopril
226
Lisinopril
227
2559
20
–1
________________________________________________________________________________
Perindopril
228
Ramipril
229
Quinapril
230
Angiotensin receptor antagonists (ARB)
Olmesartan
231
Irbesartan
232
Telmisatan
233
Valsartan
235
Azilsartan
236
Candesartan
237
Calcium Channel blockers
Felodipine
238
Lercanidipine
239
Manidipine
240
Nitrendipine
241
(Asthma/COPD)
Theophylline
242
Salbutamol (Albuterol Sulfate) Terbutaline Sulfate
244 245
Montelukast
246
antihistamine
Chlorpheniramine
248
Diphenhydramine
249
Loratadine
250
Fexofenadine
251
Hydroxyzine Hydrochloride
252
Brompheniramine Maleate
253
Cetirizine Hydrochloride
254
/
Estrogen(Conjugated Estrogen, Estradiol) Medroxyprogesterone
255 257
Testosterone
259
Cyproterone Acetate
261
Acarbose
262
Pioglitazone
264
2559
20
–1
________________________________________________________________________________
Repaglinide
266
Sitagliptin
267
Methimazole
269
Propylthiouracil
271
Levothyroxin
274
SSKI (saturated solution of potassium iodide)
276
Esomeprazole
277
Omeprazole
279
Lansoprazole
281
Pantoprazole
283
Rabeprazole
284
Cimetidine
287
Famotidine
290
Ranitidine
292
Lactulose
294
Milk of Magnesia (MOM) Psyllium seed (mucillin)
296 297
Senna
298
Dicyclomine
299
Hyoscine N-butylbromide
230
Mebeverine
301
Cisapride
302
Domperidone
304
Metoclopramide hydrochloride
305
Mosapride citrate
306
Activated charcoal
307
Aluminum Hydroxide
308
Alum milk Bismuth subsalicylate
309 310
Itopride
312
Loperamide
313
Polidocanol
314
Smecta® (dioctahedral smectite)
315
Sucralfate
316
2559
20
–1
________________________________________________________________________________
Ursodiol (Ursodeoxycholic acid)
318
Immunosuppressant
Tacrolimus
319
Mycophenolatemotetil
320
Basiliximab
321
Azathioprine
322
Sirolimus
324
Immune globulin (human) intravenous ( IGIV, –IVIG ) Live BCG for intravesicle use ( TICE BCG )
325 326
antineoplastic drugs
Busulfan
327
Chlorambucil
328
Cyclophosphamide
329
Melphalan
331
Ifosfamide
332
Bleomycin
334
Dactinomycin
335
Doxorubicin Hydrochloride Idarubicin
336 337
Mitomycin
338
Mitoxantrone hydrochloride
339
Cytarabine
340
Fluorouracil
341
Mercaptopurine
344
Methotrexate
346
Capecitabine
348
Gemcitabine
350
Oxaliplatin
352
Tegafur+Uracil
353
Thioguanine Etoposide
354 355
Vinblastine sulfate
356
Vincristine sulfate
357
Asparaginase (Crisantapase)
358
Cisplatin
359
Carboplatin
361
2559
20
–1
________________________________________________________________________________
Hydroxyurea (Hydroxycarbamine)
363
Dacarbazine
364
tretinoin
365
Paclitaxel
366
Docetaxel
367
Imatinib
368
Nilotinib
369
Dasatinib
371
Trastuzumab
372
2559
20
–1
2559
________________________________________________________________________________
Diclofenac
:
Prostaglandins
Cyclooxygenase I , II (COX I , II )
:
: __x__
____
100%
:
50-60 Peak plasma concentration 1-1.5 mcg/ml 99-99.8, Vd1.3-1.4 L/kg
: /
Hydroxylation Conjugation Glucuronic acid, taurine amide, sulfuric acid Diclofenac Substrate CYP 2C9, 3A4 50-70 30-35 : 1.2 – 2 Diclofenac warfarin Drug Interaction Facts: Diclofenac warfarin Diclofenac Anticoagulant Significant ( 1, Onset Delayed, Severity Major, Documentation Probable) Leaflet / package insert: Diclofenac
Clinical trials: 1
warfarin
/
1975
Michot F, et al,doubleblind
J Int Med Res. 1975;3(3):153-7.
Dicofenac 25
Anticoagulant
Acenocoumarol
mg qid
(stable INR 2-3)
crossover trial
Diclofenac
PT
(N=32) Retrospective cohort study :
warfarin NSAIDs NSAIDs warfarin
13 Med. 1993;153:1665-1670 Observational study : 738 warfarin NSAIDs relative risk (95% CI 2.3 to 13.6). warfarin NSAIDs . Knijff-Dutmer EAJ, Ann Pharmacother 2003;37:12-6
NSAIDs
ShorrRI,et al,Arch Intern
warfarin 681
12.2
5.8
warfarin
1
20
–1
2559
________________________________________________________________________________
Retrospective cohort study 35,548 warfarin GI bleed 3.58 warfarin TC et al, Ann Pharmacother. 2009 Nov;43(11):1765-73. Diclofenac warfarin
Diclofenac
warfarin
NSAIDs
warfarin Cheetham
2
20
–1
2559
________________________________________________________________________________
Ibuprofen
:
prostaglandins ___X__ : ____
:
T max 1-2
cyclooxygenase I
II
bioavailability
80
: Protein binding / 99 :% substrate 2C9 45-79% : 1% 1.5-1.8 : ibuprofen warfarin Drug Interaction Facts : Significant rating: 1 Onset: Delayed Severity: Major Documentation: Probable Mechanism: NSAIDS gastric irritation platelet function pharmacokinetics substrate CYP 2C9 warfarin albumin free drug warfarin Leaflet / package insert: NSAIDs warfarin serious GI bleeding
Clinical trials:
2
/
1973
1989
Penner JA, Abbrecht PH/RCT
CURRTHERR ESVolume 18, 1975: 862
ibuprofen
warfarin
1200 mg 2400 mg/day 14 day
7.5 mg/day
Schulman S,et al. Br J 600 mg tid experimental study Rheumatol. 1 wk (N=20) 1989 Feb;28(1):46
-9 Case report : INR start
37 SLE INR 2 .87 PT 17.8 ibuprofen 400 mg 3 tab skin necrosis INR 2.2 PT 15.8 14
VTEs stable INR 2-3
warfarin ibuprofen total plasma warfarin, PT PTT Bleeding time prolong 90 1 4 INR normal range ,
vein thrombosis warfarin 5 mg/day deep prednisolone 100 mg/day 15 1 16 ( ) w arfarin heparin
3
20
–1
2559
________________________________________________________________________________
74 INR 5.3 Ibuprofen 400 mg tid 1 w arfarin Ibuprofen ibuprofen
AF warfarin 5 INR in target tramadol tramadol INR 3 4.4,3 .9 5.7 INR 2 warfarin ibuprofen warfarin drug interaction
ibuprofen skin drug interaction warfarin 1800 mg/day INR prolong necrosis ibuprofen warfarin INR,PT bleeding risk drug interaction INR 1 dose dependent INR 2-3
9
warfarin
4
20
–1
2559
________________________________________________________________________________
Mefenamic acid
:
COX-2
prostaglandins cytokine
:
:
COX-1
__X __
_____
: /
COX-1
bioavailability
cyclooxygenase (COX) neutrophil
:
-2520
100
90
CYP2C9
66
: 2 – 3
Mefenamic acid warfarin Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Probable, Mechanism: Gastric irritation and decreased platelet function contribute Leaflet / package insert: mefenamic acid warfarin
2 /
Clinical trials:
1989
Diana FJ, et al.
1995
Chan TY. / Review article
J Pharm Sci. 1989 Mar;78(3):195-9.
-
-
Ann Pharmacother. 1995 Dec;29(12): 1274-83.
-
-
Mefenamic acid warfarin secondary binding site albumin molecule free warfarin 5-11.5%
Mefenamic acid anticoagulant effect
bleeding
warfarin induce GI
warfarin
Observational studies / case reports: Mefenamic acid warfarin Mefenamic acid warfarin Mefenamic acid acid molecule 90) Mefenamic secondary binding site albumin free warfarin 5-11.5% CYP2C9 Enzyme substrate warfarin Mefenamic acid warfarin COX-1 NSAIDs induced GI bleeding warfarin Bleeding Mefenamic acid warfarin
5
20
–1
2559
________________________________________________________________________________
Non-NSAIDs analgesic PT, INR
6
20
–1
2559
________________________________________________________________________________
Meloxicam
: COX 2
2
:
prostaglandins COX 1 : __X__ _____
: / 60) 5’-hydroxymethyl meloxicam ( In vitro CYP2C9 : 15 – 20 meloxicam warfarin Drug Interaction Facts: Leaflet / package insert: meloxicam INR meloxicam 1.8 meloxicam prothrombin time (PT)
8
9
(
cyclooxygenase (COX) isoenzymes 1
bioavailability 99.4
:
CYP450
5’-carboxymeloxicam
9)
meloxicam
warfarin warfarin
warfarin
INR
1.2 -
1.5
2.1
warfarin 1
CYP3A4
INR
(Mobic Product information, 2008) Micromedex: severity= moderate, documentation=good, summary= meloxicam warfarin , possible mechanism= inhibition of platelet aggregation, gastric erosion 2 /
Clinical trials:
1997
Turck D, et al (Abstract)
J Clin Pharmacol 1997;51(5):421-5.
15
/
1
7
INR
(N=13) 2010
Choi KH, et al Retrospective case control study (N=98)
J Korean Med Sci 2010;25:337-41.
Observational studies / case reports: meloxicam
INR 3.0 NSAIDs
2.0warfarin
3
meloxicam ) INR
warfarin
7
20
–1
2559
________________________________________________________________________________
warfarin meloxicam retrospective NSAIDs
meloxicam 1 INR warfarin INR meloxicam INR
meloxicam
warfarin
warfarin
meloxicam
warfarin /
meloxicam
INR
2-3
8
20
–1
2559
________________________________________________________________________________
Naproxen
:
(COX)I
II
prostaglandins anti-inflammatory, analgesic ( inhibit COX I)
: ___X__
____
2 isoenzymes c yclooxygenase inhibit COX II) GI erosion,
antipyretics (
: bioavailability : Vd=0.16 L/kg albumin 99% / : Naproxen substrate CYP 2C9 1A2 metabolized 6-desmethylnaproxen conjugate 66-92% 6-desmethylnaproxen (<1%) 5% plasma T1/2 10-20 : naproxen warfarin
95
CYP 1A2 2C9 95% glucuronide unchanged naproxen (<1%)
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Probable pharmacodynamics anticoagulant Mechanism: activity platelet function gastric irritation naproxen hypoprothrombinemic warfarin pharmacokinetics substrate CYP 2C9 warfarin Leaflet / package insert: NSAIDs warfarin Observational studies / case reports:
Clinical trials:
albumin
free drug warfarin severe bleeding
1979 Slattery JT, observational
ClinPharmacolTher. 1979
375 mg bid
50 mg
single
Jan;25(1):51-60 17
Naproxen
serum (
dose
free
fraction warfarin
oral
( 10
naproxen
study,N= 10 healthy adults
/
1979
albumin) total clearance, Vd, Hf
anticoagulant warfarin)
2. 11-20 Naproxen
adults 26 Naproxen 375 mg bid healthy warfarin Naproxen warfarin PT Jain (A et al, ClinPharmacolTher. 1979 Jan;25(1):61-6)
activity
warfarin
9
20
–1
2559
________________________________________________________________________________
3.
retrospective cohort study 2203 warfarin 1371 peptic ulcer disease 661 (48%) hemorrhagic peptic ulcer disease warfarin NSAIDs hemorrhagic peptic ulcer disease12.7 ( RR 12.7 ; 95% confidence interval, 6.3 to 25.7). Arch InternMed.1993 Jul 26;153(14):1665-70. 4. retrospective cohort study Diclofenac Naproxen Ibuprofen I NR 112
INR stable ( level ( INR INR (46%) therapeutic therapeutic level 3.5 12INR 4)> 6 ) 60NSAIDs INR (54%) INR -41 CYP2C9 genotype drug interaction (van DijkKN,ThrombHaemost. 2004 Jan;91(1):95-101) 5. case control analysis 98,821 warfarin 361 (0.3%) upper GI hemorrhage warfarin NSAIDs upper GI hemorrhage 1.9 warfarin OR, 1.9 ( ; 95% confidence interval [CI], 1.4-3.7), Arch Intern Med. 2005 Jan 24;165(2):189-92. 6. retrospective cohort study 35,548 warfarin NSAIDs warfarin GI bleed warfarin hazard ( ratio 3.58, (95% CI 2.31 to5.55; p <0.01) Cheetham TC et al, Ann Pharmacother. 2009 Nov;43(11):1765-73. naproxen warfarin naproxen anticoagulant observational study activity warfarin free fraction warfarin serum healthy adults
52 warfarin stable
NSAIDs ulcer disease
retrospective cohort study bleeding hemorrhagic peptic naproxen warfarin alternative analgesic benefit > risk monitor PT, INR warfarin
10
20
–1
2559
________________________________________________________________________________
Celecoxib
:
:
prostaglandin _____ __X__
:
bioavailability)
(AUC
: 400 :
:
11
cyclooxygenase II (COX-II)
Tmax 3
97
100 Cmax (peak plasma level) 705 ng/mL 10-20% (volume of distribution, Vd)
/ m etabolized cytochrome P 450 2C9
inactive metabolites <3%
celecoxib warfarin Significant rating: 2 Onset: Delayed, Severity: Major, Documentation: Probable, Effects: Increased anticoagulant effects off warfarin, Mechanism: Unknown. Leaflet / package insert: celecoxib warfarin Drug Interaction Facts:
Clinical trials:
2006
4
/ Dentali F, et al n=15
L. Chung MD, et al. Retrospective analysis
Ann Pharmacother . 2006 JulAug;40(7-8):1241-7. Epub 2006 Jun 27
200
/
Journal of Clinical Pharmacy and Therapeutics Volume 30, Issue 5, pages 471– 477, October 2005
5
2005
codeine (controlled) 100-200 mg 1-2
INR stable 2-3
INR celecoxib codeine
stable INR celecoxib
warfarin UGIH Major bleeding
(RR=1.34
(95% CI:0.7-2.57) RR=1.04 (95% CI:0.14-7.85)
11
20
–1
2559
________________________________________________________________________________
/
2005
Battistella M, et al. case-control analysis of multiple linked health care
Jama international medicine January 24, 2005, Vol 165, No. 2
on warfarin 66 admit UGIH
databases
nonselective NSAIDs UGIH 1.9
Schaefer MG, et al. prospective, openlabel, randomized, crossover study n=16
American Jurnal of HealthSystem Pharmcy. 2003;60(13)
200 7
/
(OR, 1.9; 95% confidence interval [CI], 1.43.7), celecoxib 1.7 (OR, 1.7; 95% CI, 1.2-3.6) rofecoxib 2.4 (OR, 2.4; 95% CI, 1.7-3.6)
2003
celecoxib stable INR INR 2-3 1, 2.5-3.5 2 3 13%, 6%
Observational studies / case reports: 64 bipolar disorder ,DM type 2, hypercholesterolemia, DVT bowel and colon obstruction, osteoarthritis, anemia, chlorpromazine 500 mg prostatic hypertrophy and status post-hemicolectomy with colostomy per day, risperidone 2 mg, pioglitazone 30 mg once a day, gemfibrozil 600 mg once a day , ranitidine 150 mg twice a day, tamsulosin 0.4 mg once a day, 15 unit neural protamine Hegadorn insulin injected at bed time, vitamin E 400 mg three time a day warfarin 4 mg once a day celecoxib INR PT 1 celecoxib 2 .8 30 19 celecoxib 2 3.6 INR PT 38.2 celecoxib 7 INR PT 3.8 40.2 celecoxib 16 INR PT 6.7 30 warfarin vitamin E K 2 INR PT 3.31 22.1 warfarin TWD 21 mg INR (Jurnal of American geriatrics society. May 2003.vol 51,No.5 ) intarget celecoxib warfarin case report celecoxib warfarin INR UGIH) celecoxib albumin albumin warfarin free drug warfarin celecoxib warfarin substate CYP2C9 warfarin celecoxib warfarin 12
5%
20
–1
2559
________________________________________________________________________________
INR INR
warfarin
.
13
20
–1
2559
________________________________________________________________________________
Etoricoxib
:
Prostaglandin (PGE2) : __X__ _____
area under the curve (AUC0-24hr)
:
6 ’–hydroxymethyl
120 mg 1 1
(
3 7.8 μg*hr/ml
( steady state) T max)
etoricoxib
92% Etoricoxib / CYP3A4
0.05-5 μg/ml
(
Mechanism: Leaflet / package insert: INR 13% Clinical trials: 1
Etoricoxib
1%
etoricoxib metabolite metabolite
120 mg/day INR
:
CYP1A2,CYP2C19 hydroxymethyl oxidation 6’-carboxylic acid cyclooxygenase-1(COX1) : etoricoxib 22 : Etoricoxib warfarin Drug Interaction Facts:
5
50 ml/min
warfarin 2-3
etoricoxib
J Clin
Etoricoxib 120
double-blind,
Pharmacol.
mg/day
randomized,
2007;47:620627
portion of the study
warfarin
INR 1.4-1.7 4
INR
13%
etoricoxib pharmacokinetic S-warfarin AUC 24 hr R-warfain
10%
(N=14) Observational studies / case reports: etoricoxib warfarin 14
Jules IS et al
crossover
CYP2D6, CYP2C9, 6’metabolite
/
2007
cyclooxygenase-2 (COX-2)
bioavailability 100% : plasma peak levels)
20
–1
2559
________________________________________________________________________________
hr
etoricoxib INR 13% pharmacokinetic R-warfarin R-warfain 10% Jules ( IS et al, J ClinPharmacol. 2007;47:620-627) etoricoxib warfarin Etoricoxib mg/day 120 warfarin INR etoricoxib INR
AUC 24
15
13%
20
–1
2559
________________________________________________________________________________
Tramadol
:
2 reuptake
:
mu receptor norepinephrine
serotonin _____ : __X__
75
/
bioavailability :
weak agonist
20
:
tramadol metabolized N– O –demethylation glucuronidation sulfation CYPP450 2 D6 CYPP450 3 A4 active metabolites O -desmethyltramadol (M1) CYPP 450 2D6 m etabolite 60 % unchanged 30 % Tramadol : 5–7 tramadol warfarin Drug Interaction Facts: Significant rating: 2, Onset: Delayed, Severity: Moderate, Documentation: Suspected, Mechanism: Unknown prothrombin Micromedex Drug Interactions: warfarin tramadol times bleeding Leaflet / package insert:
warfarin
Clinical trials: Observational studies / case reports:
61
mg/wk
tramadol times prothrombin
tramadol
INR
warfarin
mitral (S/P MVR ) warfarin 45 tramadol 50 mg 6 2 ecchymosis PT 39.6 INR 10.6 tramadol warfarin 3 INR warfarin Sabbe et al,( 1998) 76 aortic (S/P AVR ) warfarin 35 mg/wk tramadol 50 mg 3 1 INR 3.5 7.31 tramadol INR Scher et ( al, 1997) 60 mg/wk 65 warfarin tramadol 50 mg 2 6 INR 2.5 6.14 warfarin tramadol warfarin 30% (42 mg/wk) I NR warfarin tramadol warfarin 25-30 % INR 1 warfarin INR ( et al, 2006) 3 Dumo Tramadol warfarin
tramadol
3
16
20
–1
2559
________________________________________________________________________________
tramadol
Target INR
warfarin
1-4
INR RCT tramadol tramadol INR
case reports dose
warfarin warfarin
warfarin 2006 control
30 %
INR
3-7
I NR
INR
with mutations inHedenmalm the cytochrome K. etPal450 2D6 Increased gene liability 2004 oftramadol–warfarin interaction in individuals tramadol warfarin CYP2D6 tramadol CYP3A4 metabolized CYP2D6 (Hedenmalm K. et al , 2004) metabolized Tramadol warfarin warfarin tramadol tramadol INR tramadol warfarin
17
20
–1
2559
________________________________________________________________________________
Codeine
:
:
:
mu receptor medullary cough reflex _____ __X__
:
: / UDP-glucuronosyltransferase
: codeine 3 Codeine Drug Interaction Facts:
severity
90
metabolite warfarin
10
codeine
60
codeine
INR
INR
3
codeine
-25, Vd 3-6 7 L/Kg Morphine CYP2C6, CYP3A4
warfarin onset codeine warfarin Codeine warfarin
Leaflet / package insert: warfarin codeine Clinical trials: Observational studies / case reports: codeine warfarin
warfarin
18
20
–1
2559
________________________________________________________________________________
Allopurinol
1 allopurinol
xantine oxidase hypoxanthine de novo purine
2 allopurinol xanthine
oxypurinol xanthine
metabolite xanthine uric acid
de novo purine nucleotide
_____
, ___X__
uric nucleic acid
feedback
Bioavailability 80% - 90% T max 1.5 allopurinol, 4.5 oxipurinol 1.6 L/kg 70% Oxipurinol active form 80% 20% 1-2 , oxipurinol 12-30 15 Allopurinol Warfarin Drug interaction fact Significance rating : 4 Onset : delayed
Leaflet/packet insert
Severity : moderate Documentation : possible Mechanism : inhibition of hepatic metabolism by allopurinol is suspected Allopurinol Warfarin Warfarin Allopurinol INR
Clinical trials
4
/ Rawlins MD & Smith SE /cohort
Br J pharmacol . 1973;48(4):693
100 mg thrice daily (21 days)
3,5 mg once daily
1 eliminate ( rate constant) 1
1981
McInnes GT, et al/ cohort study
1973
Annals of the Rheumatic Diseases, 1981,40,245 -249
300 mg 2 day
-
intrapulmonary hemorrhage PT 71 s . Hb drop 10 g/dl renal failure BUN 6.8 mmol/l
19
20
–1
2559
________________________________________________________________________________
/
2004
Wittkowsky, Ann K., et al/cohort study
-
The Journal of Human Pharmacology and Drug Therapy 24.12 (2004): 16681674. APA
-
warfarin allopurinol 180
5 148.7 patient year at risk 100 patient year at risk 3 .4 drug interaction 1 ( amiodarone, aspirin)
4 2007
Kotirum S, et al. /case control
-
Pharmacoepide miol Drug Saf. 2007;16(2):216222.
Observation study/case study Allopurinol Warfarin Drug interaction allopurinol INR warfarin polypharmacy
/wk
20 mg
warfarin low-potential 15.3% Allopurinol low-potential warfarin 36 4% INR
Allopurinol
warfarin
allopurinol
RCT
Warfarin
warfarin
drug interaction
Allopurinol
Warfarin
Warfarin drug interaction INR dose allopurinol
INR 1 INR, PT
low potential
2 Allopurinol 300 mg/day
20
20
–1
2559
________________________________________________________________________________
Probenecid
:
:
urate
urate
tophi
:
pemicillins
Cephalosporins
:
:
_____
__X__
90
:/ glucuronide conjugation oxidation Probenecidmonoacylglucuronide, a carboxylated metabolite hydroxylated compounds
: 4-12
Probenecid
dose dependent warfarin
Drug Interaction Facts: Leaflet / package insert: Clinical trials: Observational studies / case reports: Probenecid H, et al. Eur J clin Pharmacol. 1990; 39:261-265. Probenecid warfarin Probenecid INR INR onset Probenecid warfarin Probenecid Probenecid warfarin INR
INR
(Moning
INR
21
:
20
–1
2559
________________________________________________________________________________
Benzbromarone
:
proximal : ________ ___X____
: Bioavailability : : /
activity
50
non-micronized 99
18
hydroxylated
hydroxylation
: 2-4
benzbromarone warfarin Drug interaction facts : Leaflet/package insert: anticoagulant Micromedex: Benzbromarone CYP2C9, Severity moderate, Onset delay Substantiation probable Clinical trials: Pubmed 2 Google scholar 1 /
1995
benzbromarone
Tatsuhiko
血 栓止 血 誌
K, et al
6(2):119-124,
8
50-100 mg/d
1995 (Clinical
warfarin 1-3 mg/d
62.5 mg
PT
PT
mg/d
58-70
1.94
20.7%
benzbromarone
trial) 7
1996
Shimodaira
J CIIn
H, et al
Pharmacol
7
50-100 mg/d
1996;36:168(Clinical
174
trial)
PT
58-70
PT
1-3 mg/d
22.6%
benzbromarone 7
1999
Takahashi
Clin
H, et al
Pharmacol Ther
(Randomiz ed control
1999;66:56981
31
50 mg/d
benzbromarone 1 3
Target
1
benzbromarone 36%
INR
2 22
20
–1
2559
________________________________________________________________________________
/
benzbromarone
trial)
49-79
warfarin
(S)-warfarin serum
benzbromarone
(S)-warfarin
26%
CYP2C9
Benzbromarone
Benzbromarone
potent competitive inhibitor CYP 2C9
benzbromarone warfarin benzbromarone warfarin clotting factor benzbromarone potent competitive inhibitor CYP 2C9 (S)-warfarin warfarin benzbromarone 7
benzbromarone warfarin
warfarin 30 %
benzbromarone
INR
23
20
–1
2559
________________________________________________________________________________
Dexamethasone
:
capillary permeability, _____ : __X__
1.8-2.23
Tmax : 1- 2 : 2 L/kg Vd: 6β-hydroxylation
inflammatory mediators,
neutrophill migration,
/
, Bioavailability 86.1%
Substrate :
CYP3A4
CYP3A4,
P-glycoprotein
10%,
:
dexamethasone warfarin Cytochrome P450 Effect : Substrate of CYP3A4 (minor), 2C9 (weak), 3A4 (weak) Drug Interaction Facts : Significance rating 2 Onset : Delayed Severity : Moderate Documentation : Suspected Mechanism : Unknown effects : Corticosteroids may reduce Anticoagulant dose requirements and occasionally induce hypercoagulation that could oppose Anticoagulant action Leaflet / package insert : corticosteroids warfarin warfarin INR anticoagulant effect Clinical trials : .... 1....
/
2006
Jérémie Sellam, et al. /prospective study
Joint Bone Spine Volume 74, Issue 5, October 2007, Pages 446–452
DXM (40 mg/day for 4 days every 28 days
All patients received oral anticoagulants in the evening: fluindione (n = 8) or warfarin 4 mg (n = 1)
warfarin cycle
DXM
1 1.99 (day 3.09 (day 4) warfarin 2.5 mg/l (day 0) 3.2 mg/l (day 4), cycle 2 INR 2.89(day 0) 4.40(Day 3) minor bleeding INR 0)
24
20
–1
2559
________________________________________________________________________________
Observational studies / case reports:
dexamethasone warfarin warfarin high dose dexamethasone minor bleeding 1 day 0 day4) drug interaction warfarin dexamethasone drug interaction warfarin INR warfarin dexamethasone
Dexamethasone
INR
dose, bleeding warfarin
warfarin 2
major
warfarin 2 cycle(1 cycle = 28 days : RCT , dexamethasone INR 4
25
20
–1
2559
________________________________________________________________________________
Prednisolone
:
Polymorphonuclear leukocytes (PMNs)
:
Fibroblasts Lymphatic system
: ____ __X__
capillary permeability
:
bioavailability 65-91
80, Duration 18-36 hr
: /
Prednisolone Substrate CYP 3A4 (Minor) metabolite Glucuronides, Sulfates metabolite : 3.6 , 3-5 Prednisolone warfarin Drug Interaction Facts: Significant 4, Onset Delayed, Severity Moderate, Documentation Possible) Effect : corticosteroids anticoagulant , corticosteroids Leaflet / package insert: Prednisolone
warfarin
inactive unconjugated
anticoagulant
Clinical trials:
Corticosteroids Retrospective study:
RCT
Prednisolone
warfarin
warfarin
INR warfarin longterm oral corticosteroid (5-30 oral prednisone )( 50% methylprednisolone 50%) oral corticosteroid 9 29 90.6%)( INR , 1 INR 2 INR , INR corticosteroid 1.24 (95% CI 0.86 - 1.62, p < 0.001), INR 6.7 ± 3.3 corticosteroid, INR 5 INR 62.5% , 12 37.5%)( 50%) ( 1 dose, 16 INR minor epistaxis1 (Hazlewood KA, et al.Ann Pharmacother 2006;40:2101-6.) Case report : 49 malignant lymphoma rituximab Etoposide , Cispatin , Cytarabine methylprednisolone( R-ESHAP) warfarin secondary prevention Pulmonary embolism with deep venous thrombosis
26
20
–1
2559
________________________________________________________________________________
INR
4.71
INR
1 5 R-ESHAP 5 warfarin INR
INR Prednisolone warfarin warfarin Corticosteroid Prednisolone warfarin
Prednisolone PT/INR
INR
2.44 R-ESHAP
hypercoagulation prothrombin time/INR
warfarin
prednisolone warfarin
warfarin Prednisolone
27
20
–1
2559
________________________________________________________________________________
Sulfasalazine
: The mechanism of action of the sulfasalazine and the metabolites in rheumatoid arthritis
is unknown
Sulfasalazine : ; Sulfapyridine ;
_____ :
__X__
Bioavailability Bioavailability
5-aminosalicylic acid ; Bioavailability
:
10 - 30 99.3
15
60
Sulfapyridine (active form) 5aminosalicylic acid(active form) N4-acetylation, ring hydroxylation glucuronic acid conjugation Sulfasalazine :(7.6 ), Sulfapyridine (0.4 - 14.8 ) sulfasalazine warfarin Drug Interaction Facts: Significant rating: 1, Onset: Delayed, Severity: Major, Documentation: Established, Mechanism: Unclear Leaflet / package insert: Clinical trials: 2
2000
/
:
/
Teefy AM, Martin
Ann Pharmacother.
JE, Kovacs MJ.
2000 Nov;34(11):
(Case report)
1265-8.
1000 mg four times daily
INR
30 mg/wk (Stable
INR)
)
30
75 mg/wk
( 75
6 wk
)
mg/wk (2.5
warfarin
45
mg/wk
2011
Hall S, Rindone JP. (Case Report)
J Clin Pharm Ther. 2011 Apr;36(2):2468.
500 mg twice daily for 7days , then 500 mg 4 times daily
INR Sulfasalazine2.23
40 mg/wk (Stable INR)
42.5 mg/wk
42.5 mg/wk (
(
INR 3
6.1
Sulfasalazine
28
20
–1
2559
________________________________________________________________________________
3 )
Sulfasalazine 3 wk) S ulfasalazine
hold
3
(42.5 mg/wk)
INR
1.9
3.3
1 wk
3 wk
Sulfasalazine
sulfasalazine
warfarin
Sulfasalazine
Rindone JP. J Clin Pharm Ther. 2011 Apr;36(2):246-8.) warfarin resistance Sulfasalazine 2.5 MJ. Ann Pharmacother. 2000 Nov;34(11):1265-8.) warfarin sulfasalazine case report INR INR warfarin Sulfasalazine
INR
Hall S1, Sulfasalazine Teefy AM1, ( Martin JE, Kovacs
Sulfasalazine
warfarin INR
(
29
20
–1
2559
________________________________________________________________________________
Alendronate (Fosamax®)
:
bisphosphonate osteoclast
(resorption)
:
: 60 Protein binding : :
_____
__X__
bioavailability
78%
Drug Interaction Facts : Micromedex : Leaflet / package insert: Clinical trial :
: / Alendronate alendronate
Alendronate
Alendronate warfarin
warfarin
warfarin
Alendronate
warfarin
warfarin Alendronate warfarin
30
20
–1
2559
________________________________________________________________________________
Menatetrenone, Vitamin K2 (Glakay®)
:
bone resorption differentiation mature osteoclast osteoclast (osteoclast apoptosis)
menatetrenone mineralization 1,25(OH)2D3 menatetrenone
:
__X __
____
-
:
: 1.5-3
: metabolites /
Menatetrenone (Vitamin K2)
Drug Interaction Facts:
Singnificant 2 , Onset Delayed , Severity Modurate , Documentation Established
Leaflet / package insert: Clinical trials:
Gla-osteocalcin osteocalcin menatetrenone mineralization osteocalcin
:
Menatetrenone 1
warfarin
/
1995
Sakamoto N, Kimura M, Hiraike H, Itokawa Y.
Int J Vitam Nutr Res. 1995;65(2):105-10
95 micrograms
INR
1.7
2.0
INR 2.0
Observational studies / case reports: -
Menatetrenone
warfarin
Menatetrenone vitamin K
INR anticoagulant warfarin Menatetrenone clotting factor ( II , VII , IX , X ) prothrombin warfarin antagonist cyclic interconversion vitamin K epoxide reductase vitamin K warfarin vitamin K-dependent carboxylation carboxy protein C protein S 31
20
–1
2559
________________________________________________________________________________
(Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E: The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126(3 Suppl):204S-233S. ) Menatetrenone
Warfarin resistance
warfarin Menatetranone
warfarin
INR
32
20
–1
2559
________________________________________________________________________________
Penicillin V (Phenoxymethylpenicillin potassium)
:
:
:
:
transpeptidation _____ __X__
Bioavailability 60% - 73% , , 80% : /
penicillin-binding proteins (PBPs) peptidoglycan
,
,
,
:
30
(
V penicillin
)
warfarin
Drug Interaction Facts: Significant rating: 2, Onset: Delayed, Severity: Moderate, Documentation: suspected, Mechanism: induced inhibition of adenosine diphosphonate-mediated platelet aggregation Micromedex: Onset: Delayed, Severity: Major, Documentation: Good, Mechanism:
Clinical trials: Observational studies:
Leaflet / package insert:
drug interaction
warfarin (Penicillin-VK® )
drug interaction
warfarin
/
2012
Baillargeon, et al Nested casecontrol study
Am J Med Feb. 2012 Feb; 125(2):183-89.
penicillin 1
15
penicillin V
( ( 65 ) penicillin ) (aOR, 1.92; 95% CI, 1.212.07)
Case report:
65
penicillin V
) warfarin
drug interaction
warfarin
warfarin
case-control nested study penicillin penicillin V penicillin
(
33
20
–1
2559
________________________________________________________________________________
penicillin V
warfarin
INR
warfarin
warfarin
penicillin
penicillin v
penicillin V warfarin penicillin v
34
20
–1
2559
________________________________________________________________________________
Penicillin G (Benzylpenicillin)
:
:
3.3 – 5.1
:
transpeptidation _____ __X__
:
penicillin-binding proteins (PBPs) peptidoglycan
65%
: / Penicilloic 30% acid 30 – 50 end-stage renal disease penicillin G
Drug Interaction Facts:
warfarin
Significant rating: 2, Onset: Delayed, Severity: Moderate, Documentation: suspected, Mechanism: induced inhibition of adenosine diphosphonate-mediated platelet aggregation Onset: Delayed, Severity: Major, Documentation: Good, Mechanism:
Micromedex:
Leaflet / package insert: Clinical trials:
interaction drug
warfarin drug interaction
warfarin
Observational studies:
/
2012
Baillargeon, et al Nested casecontrol study
Am J Med Feb. 2012 Feb; 125(2):183-89.
penicillin 1
15
penicillin V
( ( 65 ) penicillin ) (aOR, 1.92; 95% CI, 1.212.07)
Case reports: warfarin 2.5 mg hypoprothrombinaemia penicillin G 24 base line (Brown M A, et al. Can J Hosp Pharm. 1979;32:18-9.)
65 )
penicillin G
warfarin
PT
warfarin
nested case-control study penicillin
(
35
20
–1
2559
________________________________________________________________________________
penicillin G
24
warfarin
hypoprothrombinaemia
penicillin warfarin hypoprothrombinaemia
penicillin G
INR
warfarin
penicillin penicillin G
penicillin G
warfarin warfarin
36
20
–1
2559
________________________________________________________________________________
Amoxicillin, Amoxicillin/clavulanate
: Transpeptidation
:
Amoxicillin; Peptidoglycan
Clavulanate; beta-lactamase : _____
autolysis
Penicillin-binding-protein
beta-lactamase (broad spectrum) __X__ body fluid 74-92%), ( 17-20% 17-20% 50-70%(amoxicillin), 25-40%
: Amoxicillin; Clavulanate; : / (clavulanate) unchanged :Amoxicillin; 1-2 hr (infants and children) , 0.7-1.4 hr (adults) Clavulanate; 0.8-1.4 hr
chlordiazepoxide
warfarin
Drug Interaction Facts: Significant rating: 2, Onset: Delayed, Severity: Moderate, Documentation: Probable, Mechanism: Warfarin hypoprothombinemia Peniciilins adenosine diphosphonate-mediated platelet aggregation Medscape drug interaction checker: Significant ;monitor closely ; Amoxicillin may enhance anticoagulant effect of vitamiv K antagonists Leaflet/package insert: Warfarin Clinical trials: 2
2010
/
Zhang Q, et al double-blind, cross-over, placebo-controlled study(N=12)
Br J ClinPharmacol. 2010 Sep;71(2):232-6.
Amoxicillin/Clavulanate (500/62.5 mg) 2 2 7
stable INR (2.39±0.24) 6.13 ±1.67 mg/day
INR 0.22±0.3
day 6
day 10 2015
Hahmoud I.et al prospective crosssectional observational study (N=46)
The Journal of Clinical Pharmacology 2016; 56(1):39-46
Amoxicillin/Clavulanate Hight dose (10-20g/day)
stable
INR
Hight dose INR > 4 87.5%
37
20
–1
2559
________________________________________________________________________________
normal dose (3.6g/day) INR >4 28.9%
Amoxicillin, Amoxicillin/clavulanate 1. 66 atrial fibrillation , INR=2.8 A moxicillin (500mg) 1 INR=5.8 12
case reports:
3
INR
warfarin (7.5 mg/day) 7 5 INR=2.0
warfarin (Jason H. et al. General densitry 2003July:50-6) 2. 58 atrial fibrillation warfarin (7.5 mg/day) 1 , Amoxicillin/Clavulanate(500/125 mg) 1 3 7 3 INR=3.2 4 INR = 2.55 2 INR = 6.5 INR INR=8.7 FFP 2 Unit vitamin K 10 mg SC INR = 3.43 Vitamin K 2 .5 mg 2 warfarin 2 I NR = 1.9 5 mg/day 7.5 mg/day warfarin (INR 2-3) 6.5 mg/day (Davydov L, et al. Ann Pharmacother 2003;37:367-70) 3. 53 DVT, PE warfarin INR stable Amoxicillin/Clavulanate (500/125 mg)1 2 5 5 FFP 2 unit vitamin K 10 mg IV 1 Enoxaparin INR=20.4 INR=1.3 1 100 mg SC OD 5 day + Warfarin INR=2.3 (Timothy R. et al. Am J Case Rep,2014;15:45-8)
Amoxicillin, Amoxicillin/clavulanate
warfarin
Amoxicillin, Amoxicillin/clavulanate INR (0.22±3 INR 10-20g/day) ( case reports
INR ) INR INR Amoxicillin/clavulanate Amoxicillin 1-2 INR 1-2 INR INR vitamin K Vitamin K Amoxicillin, Amoxicillin/clavulanate warfarin
38
20
–1
2559
________________________________________________________________________________
INR
warfarin
39
20
–1
2559
________________________________________________________________________________
Ampicillin
:
:
peptidoglycan : _____
__X__
/ :
50
:
penicillin-binding proteins (PBPs)
:
( 1-1.8
15– 25
90) ESRD 7-20
24
Ampicillin
Drug Interaction Facts: Significant rating: 2, Onset: Delayed, Severity: Moderate, Documentation: Probable, Mechanism: Warfarin hypoprothombinemia Peniciilins adenosine diphosphonate-mediated platelet aggregation 1 /
Clinical trials:
2012
Baillargeon J, et al case-control study nested within a cohort (N=38,762)
Am J Med. 2012 Feb; 125(2):183-9
warfarin
warfarin penicillins
2 P enicillins
Penicillins ; Amoxicillin, Ampicillin, Bacampicillin, Carbenicillin, Cloxacillin, Dicloxacillin Sodium, Methicillin Sodium, Mezlocillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, PiperacillinSodium, Ticarcillin Observational studies / case reports:
Ampicillin
warfarin
Drug Interaction Facts Ampicillin warfarin INR
Ampicillin
warfarin
warfarin
40
20
–1
2559
________________________________________________________________________________
Cloxacillin sodium
:
transpeptidation _____ :
:
penicillin-binding proteins peptidoglycan
__X__
:
13.7 mL/min :
: / 0.5-1
30 - 60
50 - 75
94
– 95
40 – 70
cloxacillin
warfarin
Drug Interaction Facts: Micromedex: Onset: Delayed, Severity: Major, Documentation: Excellent, Probable mechanism: vitamin K synthesis, Summary: INR bleeding cloxacillin flora warfarin intestinal vitamin K cloxacillin PT 50-60% antibiotic low-risk bleeding monitor INR Leaflet / package insert: cloxacillin INR (Orbenil®) Clinical trials: Observational studies / case reports: warfarin
2012
warfarin
cloxacillin
2
warfarin
bleeding INR
cloxacillin
Marusic S, et al
Int J Clin
Cloxacillin
10
Khalili H, Nikvarz N, Najmeddin F, Khavidaki SD.
Eur J Clin Pharmacol. 2013 ; 69:721–4
Cace 1 Cloxacillin 2 g
ampicillin 2 g
2 INR 4.6 INR baseline 1.9 warfarin 3 cloxacillin INR 1.8
3 mg 4.5 mg on alternate days
Pharmacol
Ther. Mar 2012.
2013
4
(
5 mg OD INR 2.5)
( 6
5
1.2 warfarin 21
INR
10 mg/day
41
20
–1
2559
________________________________________________________________________________
gentamicin 80 mg/8 h)
INR
Cloxacillin 2.4
5 mg/day
warfarin Cace 2
5 mg OD
cloxacillin 2g 4 ( ampicillin 2 g 6 gentamicin 60 mg 8
(2.2) INR
3
2
9
INR
INR
1.5
)
cloxacillin
(4 week) warfarin 6.25 mg/day INR 1.4 24 Cloxacillin INR 5.3 warfarin 3 INR 3.2
warfarin 3.75 mg/day Cace 3 cloxacillin intravenous 2g 4
cloxacillin
warfarin
Micromedex
bleeding
5 mg/day 4 INR heparin 1.3 subcutaneous 5,000 units 8 cloxacillin ( INR 2.3) (12 ) warfarin 6.25 mg/day INR 1.1 25 Cloxacillin INR 2.75 warfarin 7.5 mg/day
cloxacillin
warfarin
vitamin K
interaction
vitamin K
cloxacillin
intestinal flora warfarin case reports 42
20
–1
2559
________________________________________________________________________________
INR
INR
INR cloxacillin 2-9
INR
21
therapeutic
casewarfarin reports INR cloxacillin 3
cloxacillin
cloxacillin
3
INR
1
cloxacillin INR
3
warfarin
4-5 therapeutic range
warfarin
43
20
–1
2559
________________________________________________________________________________
Dicloxacillin sodium
:
:
_____
:
__X__
bioavailability
:
60-80
88-98
synovial
fluid
:
: / 0.7
35-90
dicloxacillin sodium
Drug Interaction Facts:
100 mL/min
warfarin
Significant rating: 2 Onset: Delayed, Severity: Moderate, Documentation: suspected, Mechanism: Possible hepatic enzyme induction for
dicloxacillin induced warfarin resistance. Onset: Delayed, Severity: Major, Documentation: Excellent, Probable mechanism:
Micromedex: Unknown, Summary:
PT/INR warfarin dicloxacillin monitor INR dicloxacillin 3 low-risk interaction warfarin warfarin Leaflet / package insert: dicloxacillin enzymes inducer PT, INR (Dicloxsig®) Clinical trials: Observational studies / case reports: dicloxacillin warfarin 4
1996
2004
warfarin
hepatic microsomal anticoagulant INR
PT
Mailloux AT, Gidal BE, Sorkness CA.
Lacey CS,
Ann Pharmacother Dec 1996; 30:1402-1407. Ann Pharmacother
500 mg 10
mg
1,2 6
4
500 10
22 mg/wk PT baseline 20.7 seconds
35-40 mg/wk
5 dicloxacillin PT 16.9 seconds PT baseline 17% INR
44
20
–1
2559
________________________________________________________________________________
May 2004; 38(5):898.
3 6
dicloxacillin (target INR 23)
500 mg 30
dicloxacillin
2 INR
Pottegard A, et
JAMA. July 21,
al
2015;314 (3)
dicloxacillin
warfarin 1998-2012
1998 2012
50-60 71.4%
warfarin mg/wk 2015
INR 2.59 2-4 INR 1.97 ( 23%) 0.62 61% INR <2 ) 2-4
dicloxacillin
(
17%( 2-4
23%
warfarin
dicloxacillin
Micromedex
warfarin
case reports ) 71.4%
INR
warfarin warfarin
dicloxacillin Drug Interaction Facts dicloxacillin 2-4 warfarin
INR 4-5
PT
dicloxacillin warfarin
INR
INR
INR
45
20
–1
2559
________________________________________________________________________________
Cephalexin
:
Penicillin-binding protein (PBP)
Peptidoglycan
_____ __X__ : : 90% bioavailability liver, kidneys, : gallbladder, bone, sputum, bile, pleural synovial fluids 6 -15 : / -100 80 8 : 0.5-1.2 cephalexin warfarin
80
Drug Interaction Facts: Onset: Not Specified, Severity: Major, Documentation: goods, ( microdedex) Mechanism: disruption of vitamin K synthesis Leaflet / package insert: 2 Clinical trials:
2006
2008
2012
2014
/ Zhang K, et al Cohort study (N=17,895)
JMCP. 2006;12(8): 640648
stable INR 2-3
Schelleman et al A nested case-control and casecrossover study Baillargeon et al Nest-case control study (N=38,762)
Clin Pharmacol Ther. 2008 Nov;
-
Am J Med. 2012 Feb; 125(2): 183– 189.
-
Lane M, et al Retrospective cohort
Am J Med July, 2014; 127(7): 657-663
-
-
hemorrhage oral warfarin cepharosporin ( 17.2) warfarin ( 14.2) OR = 1.157, p<0.05 s hort-term cephalexin warfarin
84(5): 581–588.
GI bleeding OR = 1.53 [95% CI: 1.09 to 2.15 ]
5
-
cephalosporin cephalexin
stable INR 2-3
6,595 bleeding event 34 95%CI = 0.48-1.04)
( HR =0.07, 46
20
–1
2559
________________________________________________________________________________
study (N=22,272)
INR > 6
2.9 INR
3-14 Observational studies / case reports:
cephalexin
cephalexin cephalexin warfarin cephalexin INR malnutrition -5 1
cephalexin
warfarin
47
20
–1
2559
________________________________________________________________________________
Cefazolin
:
Penicillin-binding protein (PBP)
:
: bone, sputum, bile, pleural 86 : : 2
__X__ synovial fluids
Peptidoglycan
_____
/
cefazolin
gallbladder, liver, kidneys, 74-
-100 80
warfarin
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: suspected, Mechanism: unknown Leaflet / package insert: cefazolin prothombin malnutrition cefazolin Prothrombin time Clinical trials: 3
/
1987
DAVID M. et al
Ann Surg. 1987 Aug;206(2):155-61.
Cefazolin 1 g IV q 6 hr
10
mg 67%
Shearer MJ et al
J Clin Pharmacol. 1988 Jan;28(1):88-
-
-
1988
95.
cefazolin prothombin bleeding
cefazolin induced hypoprothrombinemia methyl thiadiazole side chain
vitamin K 2012
Baillargeon et al Nest-case control study (N=38,762)
case reports: case reports
Am J Med. 2012 Feb; 125(2): 183– 189.
cefazolin
-
-
cephalosporin cefazolin INR
48
20
–1
2559
________________________________________________________________________________
50 acute renal failure cefazolin 1 g 24 INR INR 4 7 cefazolin vitamin K INR 1.1 (Chung AH&Watson K. Am J Health Syst Pharm. 2008 May 1;65(9):823-6) 2: 53 septicemia femur osteomyelitis 24 13 15 cefazolin 2 g coffee ground necrotizing esophagitis INR 8.11 PT 89.2 4 vitamin K FFP 1:
1.3
et al. Ann Pharmacother September 2014 vol. 48 no. 9 1214-1218) (Kaakeh warfarin 1.55 PT 17 cefazolin cefazolin INR major bleeding G I bleeding prothrombin 7 -15 cefazolin prothombin vitamin K vitamin K cefazolin warfarin major bleeding cefazolin cefazolin INR PT/ malnutrition INR
49
20
–1
2559
________________________________________________________________________________
Cefuroxime
:
Penicillin-binding protein (PBP)
:
:
:
: / 1-2
Cefuroxime
Drug Interaction Facts: Leaflet / package insert: Clinical trials: 1
Peptidoglycan
bioavailability -50 33
:
_____ __X__
37
52
blood brain barrier
-100 66
warfarin
/
2012
Baillargeon et al Nest-case control study (N=38,762)
Am J Med. 2012 Feb; 125(2): 183– 189.
-
-
cephalosporin cefuroxime
cefuroxime PT aPTT 29 cefuroxime metronidazole 4 PT 28 (10-14s) aPTT 38.3 (25.0-35.0s) prothrombin (Van den Berg SAA, et al. BMJ Case Rep 2014) complex concentrate PT aPTT cefuroxime warfarin warfarin cefuroxime cefuroxime metronidazole PT aPTT 4 factor V cephalosporin warfarin cefuroxime cefuroxime INR PT malnutrition
Observational studies / case reports:
50
20
–1
2559
________________________________________________________________________________
Cefotaxime
:
:
inhibit cell wall synthesis __×__
to peak serum: 30 time
IM
aqueous humor ascetic
: / inactive metabolite : 1-1.5
20-36, active metabolite
Cefotaxime
Drug Interaction Facts: Drug information: Martindale: Micromedex:
15-25
warfarin
Drug interaction warfarin Drug interaction warfarin Drug interaction warfarin warfarin cefotaxime INR cefotaxime intestinal flora
cefotaxime warfarin Cefotaxime Leaflet / package insert: (Product Info Claforan® , 2014) Clinical trials: ……1……
: prostatic fluid
bactericidal _____ :
/
vitamin K INR PT/INR
warfarin
2012
Baillargeon J.,et al
Am J Med
-
-
≥ 65 (n = 38,762 warfarin
)
warfarin
2 Nested casecontrol
(adjusted odds ratio (aOR), 2.01; 95% CI, 1.62 to 2.5) A zole antifungals (aOR, 4.57; 95% CI, 1.9 to 11.03), cotrimoxazole (aOR, 2.7; 95% CI, 1.46 to 5.05) , cephalosporins (aOR, 2.45; 95% CI, 1.52 to 3.95), penicillins (aOR, 1.92; 95% CI, 1.21 to 2.07), macrolides (aOR, 1.86; 95% CI, 1.08 to 3.21) quinolones (aOR, 1.69; 95% CI, 1.09 to 2.62) * Cephalosporins = cefotaxime , cefixime, 51
20
–1
2559
________________________________________________________________________________
cefoperazone, cefdinir, cefazolin, ceftazidime, ceftriaxone, cefuroxime, cephalexin) case reports:
bleeding
INR
cefotaxime
pubmed
micromedex
Cefotaxime
intestinal flora
cefotaxime warfarin
INR
bleeding
cefotaxime
INR
bleeding cephalosporins
vitamin K cephalosporins warfarin warfarin
warfarin
case-report
cephalosporins warfarin
cefotaxime cefotaxime
warfarin
cefotaxime warfarin PT/INR onset, offset of INR increase/decrease ) ceftriaxone (sig 1)
(
cephalosporins
52
20
–1
2559
________________________________________________________________________________
Cefoxitin
:
_____
Cephalosporins, Second-Generation
__ X __
:
:
IM, IV well absorbed , Rectal 7 – 17 % : Protein Binding 41% - 75% Volume of Distribution 0.2 L/kg : / Liver < 2 % Descarbamyl metabolite inactive 85% - 90% : 0.8 - 1 hour
Cefoxitin sodium
warfarin
Drug Interaction Facts: Significant rating: 2 Onset: Delayed, Severity: Moderate, Documentation: Suspected, Mechanism: Unknown Leaflet / package insert: May enhance the anticoagulant effect of warfarin. (Mefoxin ®) Clinical trials:
1988
/
M. J. Shearer Et al,
The Journal of Clinical Pharmacology (1988) 28, 88– 95
hypoprothrombinem ia
Cefoxitin
warfarin
Cephalosporins Cefoxitin
2012
Baillargeon et al, case-control cohort study
The American Journal of Medicine (2012) 125, 183-189
warfarin 65 65
Cephalosporins Cefoxitin
15
Observational studies / case reports:
Cefoxitin
bleeding
warfarin
53
20
–1
2559
________________________________________________________________________________
Cefoxitin
65
cohort study
Cefoxitin
bleeding
Cefoxitin
warfarin
Cefoxitin
warfarin 65 Cephalosporin
65
bleeding
INR warfarin 65
54
20
–1
2559
________________________________________________________________________________
Ceftriaxone
:
:
:
mucopolysaccharide __×__ _____
IM
:
: /
: 5-9
bioavailability 95
40-65
case-report
Mechanism: unknown Leaflet / package insert:
warfarin
INR
drug interaction
Clinical trials:
/
N-
INR
( Product Info
warfarin
ceftriaxone warfarin ( Product Info Rocephin®, 2015) 3
ceftriaxone
Drug Interaction Facts: Significant rating: 1 Onset: delayed Severity: major Documentation: suspected Package insert: ceftriaxone warfarin Rocephin® , 2015) ) Martindale: drug interaction warfarin ceftriaxone methylthiotriazine side chain warfarin Micromedex:
warfarin
2016
Saum LM Balmat RP
J pharm pract
-
-
Retrospective Chart review
1992
Tawara S. Matsumoto S.
J Antibiot
warfarin
-
-
4 Ceftriaxone
INR 1st gen Cephalosporin, Penicillin Ciprofloxacin (3.56, 2.66, 2.98 2.3 ) Ceftriaxone INR : P=0.04 Ciprofloxacin (Ceftriaxone INR 54.4% Ciprofloxacin INR 12.7%: P=0.037) Cephalosporin high affinity Human serum albumin (HAS)
55
20
–1
2559
________________________________________________________________________________
2012
Matsumoto Y. Kamimura T. Goto S.
(Tokyo)
Baillargeon J. Holmes HM
Am J Med
-
warfarin binding site c eftriaxone ceftazidime, cefotaxime cefoperazone binding site wafarin ≥ 65 (n = 38,762 warfarin
-
Lin YL Raji MA Sharma G Kuo YF
2
)
warfarin
(adjusted odds ratio (aOR), 2.01; 95% CI, 1.62 to 2.5) Azole antifungals (aOR, 4.57; 95% CI, 1.9 to 11.03), cotrimoxazole (aOR, 2.7; 95% CI, 1.46 to 5.05) , cephalosporins (aOR, 2.45; 95% CI, 1.52 to 3.95), penicillins (aOR, 1.92; 95% CI, 1.21 to 2.07), macrolides (aOR, 1.86; 95% CI, 1.08 to 3.21) quinolones (aOR, 1.69; 95% CI, 1.09 to 2.62) * Cephalosporins = cefotaxime , cefixime, cefoperazone, cefdinir, cefazolin, ceftazidime,
Nested casecontrol
ceftriaxone, cefuroxime, cephalexin) Case reports
Ceftriaxone American-Indian 67 INR 2 16.99 68 (17): 1603-5.)
INR warfarin warfarin INR stable (TWD = 52.5-54.5 mg) 10.74 2 Ceftriaxone 1 g IM OD UTI INR Vit K 5 mg (Clark TR, Burns S. Am J Health Syst Pharm. 2011 Sep 1;
ceftriaxone
warfarin
case-report
ceftriaxone
ceftriaxone
INR 3.56 ceftriaxone 3 interaction Cephalosporin ceftriaxone high affinity warfarin binding site
INR
Saum LM, case-report INR 10.74 INR Tawara S. Human serum albumin (HAS)
Balmat RP 16.99
ceftriaxone
warfarin
Ceftriaxone
warfarin
warfarin
INR
56
20
–1
2559
________________________________________________________________________________
ceftriaxone 2011. ( Am J Health Syst Pharm. Clark Burns S.) onset of ( INR increase: 3 ) INR 3.56 report: INR = 10.74)
INR ceftriaxone INR
(case
57
20
–1
2559
________________________________________________________________________________
Ceftazidime
:
bactericidal _____ :
: bioavailability :
:2
: /
80-90
ceftazidime
Drug Interaction Facts: Drug Interaction Facts: Drug information: Martindale: Micromedex:
10
2012
warfarin
Onset: not specified Severity: major, Drug interaction warfarin Drug interaction warfarin Drug interaction warfarin ceftazidime warfarin INR ceftazidime intestinal flora vitamin K
ceftazidime warfarin (Onset: not specified, Severity: major, Documentation: good) Documentation: good Mechanism: vitamin K Leaflet / package insert: ceftazidime prothrombin activity / , malnutrition. PT/INR gsk, 2007) Clinical trials: 2
1992
Significant rating: ….-...
-
__×__
91 (IM route)
Tawara S
Baillargeon J. Nested casecontrol
( Info FORTAZ® Product
/
INR
warfarin
J Antibiot (Tokyo) Am J Med /
-
-
-
-
binding site warfarin human serum albumin
Ceftazidime
≥ 65 (n = 38,762 ) warfarin 2
warfarin (adjusted odds
ratio (aOR), 2.01; 95% CI, 1.62 to 2.5)
58
20
–1
2559
________________________________________________________________________________
A zole antifungals (aOR, 4.57; 95% CI, 1.9 to 11.03), cotrimoxazole (aOR, 2.7; 95% CI, 1.46 to 5.05) , cephalosporins (aOR, 2.45; 95% CI, 1.52 to 3.95), penicillins (aOR, 1.92; 95% CI, 1.21 to 2.07), macrolides (aOR, 1.86; 95% CI, 1.08 to 3.21) quinolones (aOR, 1.69; 95% CI, 1.09 to 2.62) * Cephalosporins = cefotaxime , cefixime, cefoperazone, cefdinir, cefazolin, ceftazidime, ceftriaxone, cefuroxime, cephalexin) Case-reports
bleeding INR micromedex ceftazidime PT ceftazidime warfarin Antimicrob Chemother.1984 Sep; 14 Suppl B: 325-30)
ceftazidime
ceftazidime
warfarin
ceftazidime
warfarin
vitamin K deficiency cephalosporin 13 1 ( Shimada K, et al. J
warfarin
cephalosporin Ceftazidime binding site human serum albumin (HSA) INR ceftriaxone warfarin ceftazidime INR HAS intestinal flora vitamin K ceftazidime warfarin warfarin 2 warfarin ceftazidime
ceftazidime
warfarin high affinity ceftazidime
)
pubmed
warfarin
/ , ceftazidime PT/INR ( onset, offset of INR increase/decrease ceftriaxone (sig 1) cephalosporins
59
20
–1
2559
________________________________________________________________________________
Cefoperazone + Sulbactam
:
sp. Generation –
nosocomial infection Cefoperazone
:
:
:
:
Acinetobacter Cephalosporins, Third sulbactam
_____ __ X __
Cefoperazone + Sulbactam
warfarin
Significant rating: 2 Onset: Delayed, Severity: Moderate,
1988
M. J. Shearer Et al,
The Journal of Clinical Pharmacology Volume 28, Issue 1, pages 88– 95, January 1988
/
Documentation: Suspected, Mechanism: Unknown N-methylthiotetrazole Leaflet / package insert: Cefoperazone (NMTT) Activation prothrombin Hypoprothrombinemia Vitamin K Vitamin K poor prolonged hyperalimentation regimens nutritional status, malabsorption states, alcoholism (CEFOBID®) Micromedex: Severity: Moderate, Documentation: Fair, Concurrent use of warfarin and Cefoperazone may result in an increased risk of bleeding.
Intramuscular (cefoperazone): 50% - 75% 90 – 95% : / : cefoperazone 14% - 36%, sulbactam 75% cefoperazone 19 – 36 %, sulbactam < 1% cefoperazone 2 , sulbactam 1 - 1.3
Drug Interaction Facts:
Clinical trials:
hypoprothrombinemia
Cefoperazone
N- methylthiotetrazole
warfarin
Cephalosporins Cefoperazone
60
20
–1
2559
________________________________________________________________________________
2006
Alagozlu et al. Case report
Clin Drug Invest 2006; 26 (8):
79
hypoprothrombinemia INR 5
2.46, 3.34 4.99 5, 6 7 Vitamin K FFP
I. O. Ozen et al. Case report
Acta Chir Belg, 2008, 108, 777778
9
cefoperazone 50 mg/kg/day
2012
Baillargeon et al, case-control cohort study
The American Journal of Medicine (2012) 125, 183-189
15
2
PT
cefoperazone
(Fresh frozen plasma ; FFP)
5
PT 12.2 s (1014s), PTT 22.5 s (20-36s)
3
cefoperazone 2 2 g( 1g ) 7 2008
INR
jaundice) 1.1 (cholestatic (sphincterotomy)
481-484
Vitamin K
Cephalosporins Cefoperazone bleeding 65 65
FFP
Case reports:
79 (sphincterotomy) c efoperazone INR 1.1 INR 5 Vitamin K FFP
cholestatic ( jaundice) 1g 2 2 g( ) 7 2.46, 3.34 4.99 5, 6 7 3 (Alagozlu et al., Clin Drug Invest 2006; 26 (8):
481-484)
9 14s), PTT 22.5 s (20-36s)
5
cefoperazone 50 mg/kg/day
s (10PT 12.2 2 61
20
–1
2559
________________________________________________________________________________
PT cefoperazone Acta Chir Belg, 2008, 108, 777-8) Cefoperazone
Vitamin K INR , PT
Cefoperazone + Sulbactam
(I. O. Ozen et al.,
warfarin
Cefoperazone + Sulbactam
FFP
INR , PT
+ Sulbactam 65 65 Cefoperazone bleeding INR , PT case report Warfarin Cefoperazone + Sulbactam cefoperazone N-methylthiotetrazole (NMTT) cefoperazone 4.5 / 2
cohort study
Cefoperazone + Sulbactam
Warfarin Warfarin
INR PT INR Vitamin K poor nutritional status, malabsorption states ( ), alcoholism prolonged hyperalimentation regimens ( ) Cefoperazone + Sulbactam Warfarin Cefoperazone + Sulbactam Warfarin INR Warfarin Cefoperazone + Sulbactam warfarin Cefoperazone + Sulbactam warfarin Heparin/LMWH Cefoperazone Sulbactam +
warfarin
Cefoperazone + Sulbactam
62
20
–1
2559
________________________________________________________________________________
Cefixime
:
bactericidal _____ :
: 3-4
: / 60
11.5 cefixime
65
20
40-50
__×__
Bioavailability: :
renal failure
warfarin
Drug Interaction Facts: Significant rating: - Onset: not specified, Severity: major, Documentation: good Drug Interaction Facts: Drug interaction warfarin Prothrombin time Drug information: Drug interaction warfarin Martindale: Drug interaction warfarin cefixime
methylthiotetrazole side chain Micromedex:
hypoprothrombinemia warfarin cefixime INR cefixime intestinal flora
cefixime warfarin Mechanism: vitamin K prothrombin time Leaflet / package insert: cefixime (Product Info SUPRAX® Oral capsule, suspention, 2012) Clinical trials: 1 2012
Baillargeon J. /Nested case-control
INR
Am J Med
N-
vitamin K
/
-
-
≥ 65 (n = 38,762 ) warfarin
2
warfarin (adjusted odds ratio
(aOR), 2.01; 95% CI, 1.62 to 2.5)
Azole antifungals (aOR, 4.57; 95% CI, 1.9 to 11.03), cotrimoxazole (aOR, 2.7;
63
20
–1
2559
________________________________________________________________________________
95% CI, 1.46 to 5.05) , cephalosporins (aOR, 2.45; 95% CI, 1.52 to 3.95), penicillins (aOR, 1.92; 95% CI, 1.21 to 2.07), macrolides (aOR, 1.86; 95% CI, 1.08 to 3.21) quinolones (aOR, 1.69; 95% CI, 1.09 to 2.62) * Cephalosporins = cefotaxime , cefixime, cefoperazone, cefdinir, cefazolin, ceftazidime, ceftriaxone, cefuroxime, cephalexin) Observational studies / case reports
cephalosporin N-methyl-thio-tetrazole methyl hypoprothrombinemia metabolism vitamin K1 400 mg metabolism vitamin K1 metabolism vitamin K1 (Trenk D, et al. J Clin Pharmacol. 1990 Aug; 30(8): 737-42
thiadiazole cefixime 200 cefixime
cefixime case-report cephalosporins warfarin warfarin INR bleeding
cefixime
cefixime cefixime
warfarin
cefixime warfarin cefixime cephalosporins warfarin cefixime
warfarin
warfarin
PT/INR INR cefixime ( onset, offset of INR increase/decrease ) ceftriaxone (sig 1) cephalosporins
64
20
–1
2559
________________________________________________________________________________
Imipenem/cilastatin
:
broad spectrum synthetic carbapenem Beta-lactam Imipenem penicillin binding protein (PBP) covalent PBP
PBP
Cilastatin sodium inhibition enzyme dehydropeptidase I imipenem
:
_____
lysozyme renal metabolism imipenem brush border renal tubules
__X__
bone
2-3
: 95-100 (cilastatin) : 20 % (imipenem)
competitive synergistic effect
IM
60- 75 (imipenem)
3.5 (IM) 40 (cilastatin)
sputum, pleural fluid, peritoneal fluid, interstitial fluid, bile, aqueous humor
pleural fluid, interstitial fluid peritoneal fluid L/kg Vd, : 0.14-0.23 : 60 (IV : both drug, prolonged with renal impairment) (IM : imipenem) :
proximal renal tubular cells imipenem; cilastatin :
fluid
metabolism
dehydropeptidase I (
CSF
brush border
open lactam metabolite); cilastatin metabolism metabolism 70 unchanged drug (
imipenem
)
warfarin
Drug Interaction Facts : Martindle the complete drug reference www.drugs.com (interactions checker) http://reference.medscape.com/drug-interactionchecker http://www.webmd.com/interaction-checker/ http://www.rxlist.com/drug-interaction-checker.htm Micromedex drug interaction Leaflet / package insert : Clinical trials : Observational studies / case reports :
none found : none found : No results found : No interactions found : No interactions found : No interactions found : none found ® (PRIMAXIN I.V.)
65
20
–1
2559
________________________________________________________________________________
imipenem
warfarin
INR
imipenem
bleeding
warfarin warfarin
imipenem
PT
warfarin INR
malabsorption warfarin
warfarin
warfarin
hypermetabolic
66
20
–1
2559
________________________________________________________________________________
Meropenem
: Meropenem broad spectrum synthetic carbapenem Beta (PBP) penicillin binding protein transpeptidation transpeptidase
lactam
:
: :
_____
-
0.3 L/kg (
: -
__X__
2%
: 1 – 1.5 hr : 1.9 – 3.3 hr : 3.82 – 5.7 hr 70 (
meropenem
:
www.drugs.com (interactions checker) http://reference.medscape.com/drug-interactionchecker http://www.webmd.com/interaction-checker/ http://www.rxlist.com/drug-interaction-checker.htm Micromedex drug interaction Leaflet / package insert : Clinical trials : Observational studies / case reports : meropenem
)
warfarin
Drug Interaction Facts Martindle the complete drug reference
)
Normal renal function Clcr 3080 – ml/min Clcr 2 30 – ml/min : /
1 0.4-0.5 L/kg (
),
none found : none found : : : : :
No results found No interactions found No interactions found No interactions found none found ® (MERREM I.V.)
warfarin
meropenem
warfarin
(D trivedi, JD newton, A Mitra, et al. A serious drug interaction leading to spontaneous total hyphema.JPGM 2010;56(1):46-7)
warfarin warfarin PT INR warfarin hypermetabolic
meropenem
malabsorption
67
20
–1
2559
________________________________________________________________________________
warfarin
68
20
–1
2559
________________________________________________________________________________
Ertapenem
:
broad spectrum synthetic carbapenem Beta-lactam Ertapenem penicillin binding protein (PBP) cytoplasmic membrane B-lactamases (ESBL) extended spectrum : _____ __X__
– 12
:
0.12 L/kg ( 4 : /
(
)
ertapenem
ertapenem
ertapenem ertapenem
)
, 2.5
(
3
hydrolysis 10 (
B-lactamases
90
85 – 95% 0.2 L/kg ( 3
), – 12
)
)
none found : none found : No results found : No interactions found : No interactions found : No interactions found : none found ® (INVANZ )
warfarin
INR
warfarin PT INR
ertapenem warfarin bleeding
ertapenem warfarin
warfarin
warfarin
warfarin
Drug Interaction Facts : Martindle the complete drug reference www.drugs.com (interactions checker) http://reference.medscape.com/drug-interactionchecker http://www.webmd.com/interaction-checker/ http://www.rxlist.com/drug-interaction-checker.htm Micromedex drug interaction Leaflet / package insert : Clinical trials : Observational studies / case reports :
IM a 2.3 0.16 L/kg ( 13-17
),
13
80 (
: :
)
69
20
–1
2559
________________________________________________________________________________
malabsorption warfarin
hypermetabolic
70
20
–1
2559
________________________________________________________________________________
Azithromycin
:
(translocation)
:
peptide :
_____
:
7
6( 6.7
Azithromycin
) ( 11 -14
68
38
-51
: /
50 s
-
__X__
bioavailability
:
)
Warfarin
Drug Interaction Facts:
Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Good, Mechanism: disruption of vitamin K synthesis 22 warfarin Leaflet / package insert: azithromycin 5 prothrombin times azithromycin times prothrombine Clinical trials: 6
2000
2004
anticoagulant
Nick P, et al Retrospective case-control study (N=52)
Pharmacot herapy. 2000;20(9): 1055–1059
McCall KL, et al Retrospective cohort review study (N=37)
Pharmacot herapy 2004;24(2): 188–194
Jeffrey J, et al
/
J GEN
stable
control (trazocin) case (azithromycin) control case >65 INR 1-14 p=0.60) ( 15 -30 p=0.22) ( 1- 30 p=0.18) ( stable 13.1 INR INR control (felodopine) 15.2 control (azithromycin) 0.19 0.14 5 case control INR (therapeutic INR±0.2) 2 visit
500 mg/day
250 mg/day
2005
oral anticoagulant
stable
> 65
INR
3- 71
20
–1
2559
________________________________________________________________________________
2013
2013
2014
retrospective cohort study (N=95, N azitromycin = 32) Kari A, et al
INTERN MED 2005; 20:653– 656
retrospective review (N=100)
Therapeuti cs. 2013;35:42 5–430
Yuji Kusafuka, et al ( N=18)
Michael A, et al Retrospective cohort study (N=22,272 , N azitromycin = 9,331 )
warfarin doses INRs
Clinical
Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:1 48-151 Am J Med. 2014 July ; 127(7): 657–663
5 ) -(17
singledose 2.0-g extended release azithromy cin 1
>3
15 7( ) INR 0.51 (p<0.05) terazocin 31 % therapeutics dose (p<0.05)
stable INR (therapeutic INR±0.2) 2 visit
-
3 30
-
> 65
INR
(p<0.01) INR INR1 INR3 INR2 INR3 0.3 (p<0.01) mg/wk 30 29.2 mg/wk long-term 72.5 stable warfarin therapy INR INR< 3 azithromycin 1 7 2 1.76 , 1.75, ( INR , 1.80 mg 2.5 2.00 ) daily dose
warfarin ≥ 30 stable warfarin regimen
azithromycin serious bleeding HR( 1.93, 95% CI 1.13-3.30) low risk antibiotics INR < 4 = 91.4% INR < 4 - ≤6 = 7%
INR > 6 = 1.6%
72
20
–1
2559
________________________________________________________________________________
Observational studies/ case reports:
Mitral valve INR -2.8 2 2.8 11 azithromycin 5 -2 1 INR PT=106 FFP Phytonadione 2.93 4 INR multiorgan failure (Woldtvedt et al, 1998)
ER warfarin
53
12
71 warfarin ER INR INR 11.15 1 INR 15.6 hematoma (Foster & Milan, 1999) 80 mg 4.5 gentamicin ampicillin IV azithromycin 500 mg 3 azithromycin INR 7.2 10 2 INR 2.0(Wiese & Cosh, 1999).
Phytonadione
scan CT
INR=3.6
8
5 azithromycin
warfarin
1
INR
2 vitamin K
Azithromycin
Warfarin
azithromycin INR INR -0.5 0.2 bleeding serious azithromycin single dose INR case INR reports INR 5 azithromycin INR azithromycin vitamin K (Nick P et al, 2000)
warfarin
Azithromycin
azithromycin
INR azithromycin
INR
Warfarin
5-7 INR
azithromycin
30
warfarin
azithromycin
73
20
–1
2559
________________________________________________________________________________
Erythromycin
:
ribosome peptidyl transferase
aminoacyl translocation complex
P site
rRNA complex : _____
Erythromycin base Erythromycin Stearate Erythromycin Estolate Erythromycin Ethyl succinate
Distribution
Bioavailability (%) 25 45-60 70-80 50-60
tRNA
food effect
Metabolism
Vd (L/kg) 0.6
A site
rRNA
elimination
Protein Bound (%) 74-90
bioavailability
) 4) ester ethylsuccinate esterase ester bond ester ester bond
0.5-1
esterase erythromycin base :
2
74 –base 90
73-81
estolate
: / CYP3A4
5
: 1 – 1.5
90
96
demethylation
CYP450 system
gastric emptying time
stearate stearate
reversible
base
- erythromycin base pH - estolate
s50
:
__X__
ESRD 5-6
74
20
–1
2559
________________________________________________________________________________
Erythromycin
Drug Interaction Facts:
warfarin
Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Excellent, Mechanism: disruption of vitamin K synthesis ;inhibition of
CYP3A4mediated warfarin metabolism Leaflet / package insert: Erythromycin
2
Clinical trials:
1984
2012
/
warfarin
Schwartz JI, Bachmann KA. (N=12)
Baillargeon J, et al. Case-control study nested within a cohort of 38,762 patients
Arch Intern Med. 1984 Oct; 144(10):2094. Am J Med. 2012 Feb; 125(2):183-9
250 mg 6
1 mg/kg
Creatinine clearance Warfarin %
8 Warfarin
15
2
65
14
Macrolides
1.86 95 % Erythromycin
Observational studies / case reports:
1.
2.
INR
77 atrial fibrillation hyperlipidemia, osteoarthritis, hypothyroidism, coronary artery disease, myocardial infarction, congestive heart failure breast cancer alprazolam, carvedilol, furosemide, levothyroxine sodium, lisinopril, nitroglycerin, potassium chloride, propoxyphene hydrochlorideacetaminophen, simvastatin trazodone warfarin INR 4 Erythromycin eye ointment -2.51.8 3 INR 8.5 warfarin 2 INR 4.7 2 warfarin 12 5 1.5 Erythromycin INR INR eyeointment Warfarin INR 5 16 5 -3.42.9 Erythromycin eye ointment INR 5 INR 4.2 Warfarin 13 INR 1.8-2.4 (Paker DL, et al. Am J Health Syst Pharm January 1, 2010 67:38-41.) 77 Warfarin 7.5 P T 22-27.5 erythromycin stearate 500 mg 4 right lower lobe infiltrate PT 64 fresh 75
14
20
–1
2559
________________________________________________________________________________
2
frozen plasma
p, hytonadione 10 mg 2
22 (Bartle R, Arch Intern Med. 1980;140(7) :985-987) 59 Warfarin 4 peripheral embolization PT 24 4 erythromycin ethylsuccinate
phytonadione 15 mg Warfarin 5
PT
3.
erythromycin ethylsuccinate phytonadione 10 mg (Schwartz et al, Arch Intern Med. 1984;144(12):2413-2414.).
Erythromycin
INR
INR
PT 120
PT
INR
1.86 INR ) INR 4-5 2 vitamin K
(
APTT of 72 parotitis
22
warfarin
Erythromycin
cohort
INR
CYP3A4 mediated warfarin metabolism (Accessed: http://www.micromedexsolutions.com/ available at 23 Jun 2016) Erythromycin
INR
warfarin
warfarin
erythromycin
76
20
–1
2559
________________________________________________________________________________
Clarithromycin
:
:
:
:
50 s
:
55 ( Vd) 243-266 L : / - Systemic: Hepatic: Active metabolite: 14-hydroxyclarithromycin , 4 -40 20 14-Hydroxyclarithromycin -15 10 - CYP3A4 P-glycoprotein CYP3A4 - substrate 250 mg 12 ; 3-4 , 0 mg 12 ; 5-750 14-Hydroxyclarithromycin 250 mg 12 ; 7
Clarithromycin
Warfarin
Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Good, Mechanism: disruption of vitamin K synthesis, inhibition of
CYP3A4Leaflet / package insert:
mediated warfarin metabolism warfarin serious hemorrhage INR
1
Clinical trials:
2014
__X___
bioavailability
Drug Interaction Facts:
_____
CYP3A4 prothrombin time
Michael A, et al Retrospective cohort study (N=22,272 , N clarithromycin = 584 )
/
Am J Med. 2014 July ; 127(7): 657–663
>3
warfarin ≥ 30 stable warfarin regimen
claritromycin serious bleeding HR( 1.71, 95% CI 0.45-6.57 ) low risk antibiotics INR < 4 = 89.2 % INR < 4 - ≤6 = 46.0% INR > 6 = 17%
77
20
–1
2559
________________________________________________________________________________
Observational studies/ case reports:
digoxin 0.25 mg
INR=7.3
warfarin
72 INR 2.6-3.1 clarithromycin 7 warfarin 22.5 mg clarithromycin 500 mg 3 2 Helicobacter pylori 12 clarithromycin concentration= 4.6 ng/L, digoxin digoxin 11
digoxin 0.125 mg warfarin 2.5 mg therapeutic range (Gooderham et al, 1999)
digoxin level
1 2 warfarin 3 INR
61 INR warfarin 2.5 mg 500 mg 2 clarithromycin 2 serum digoxin=2.2 mcg/L, INR=90.3 PT=98.4 clarithromycin phytonadione INR 2.6 anticoagulant antibiotics ofloxacin (Oberg, 1998) 70 INR 2- 3 warfarin 3 mg 1 1 presumed pneumonia clarithromycin 500 mg 52 dehydration, mild digoxin toxicity pneumonia digoxin concentration=2.4 mcg/L, INR=5.6, prothrombin time=26.8 warfarin clarithromycin 2 INR 2.7(Oberg, 1998).
Clarithromycin
CYP3A4 substrate serious bleeding > 65 INR
Warfarin
warfarin
Warfarin
CYP3A 4 case report
Clarithromycin
clarithromycin clarithromycin INR azithromycin 3
INR
78
20
–1
2559
________________________________________________________________________________
Roxithromycin
:
( translocation)
ribosome s50 reversible aminoacyl transfer-RNA
_____ __X__ : bioavailability 3 – 96 7
:
:
72-85
alpha-1-acid glycoprotein
: /
1988
macrophage
53
demethylation
10
CYP450 system
Erythromycin : 12
Drug Interaction Facts: Medscape Roxithromycin Leaflet / package insert: Clinical trials:
Roxithromycin
:
warfarin
interaction drug Roxithromycin Serious - Use Alternative Warfarin Roxithromycin warfarin
1
Warfarin
/
1.
Paulsen O, et al. a double-blind, randomized control trial (N=21)
Pharmacology & Toxicology. 1988 Oct;63(4): 215-20.
150
2
Warfarin INR stable 2-3
14 28
AUC
Warfarin
Roxithromycin Roxithromycin
Observational studies / case reports: Roxithromycin Warfarin
report case
R
S
isomer warfarin drug interaction
79
20
–1
2559
________________________________________________________________________________
for Adverse Reactions Monitoring; CARM) ADRAC) CARM ADRAC erythromycin) warfarin ( Drug Invest. 1995;10(5): 302-9.)
( Roxithromycin
RCT
) warfarin
Roxithromycin
Roxithromycin Roxithromycin 9 ethyl-oxime
Roxithromycin
Warfarin
AUC
INR
warfarin
warfarin
CYP450 system erythromycin A CYP450 (Ghose K,
warfarin
Roxithromycin
carbonyl Asht on J, Rohan A. Clin. Drug Invest. 1995;10(5): 302-9.)
warfarin
Roxithromycin
) The Centre )The Adverse Drug Reactions Advisory Committee; roxithromycin warfarin 7 9 1992-1995 roxithromycin (Ghose K, Ashton J, Rohan A. Clin.
Macrolides
Warfarin INR
80
20
–1
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________________________________________________________________________________
Norfloxacin
:
topoisomerase type II (DNA gyrase)
: _____ __X__ : / m etabolism
:
:
DNA
bioavailability 15 10 –
metabolite 6
30 - 40
40
39
CYP450 system
CYP1A2 (strong)
CYP3A4
(moderate)
:
3-4
norfloxacin
warfarin
Drug Interaction Fact : Significance = 1 Onset: Delayed, Severity: Major, Documentation: Probable, Mechanism: may alterations in intestinal flora that synthesize vitamin K Leaflet / package insert: norfloxacin Observational studies / case reports:
warfarin warfarin norfloxacin PT 95 warfarin norfloxacin 5 brain hemorrhage PT 36.4 21.6 (Linville & Matanin, 1989) warfarin 30 mg single interaction norfloxacin warfarin norfloxacin 400 mg ( et al, 1990) dose 2 Rocci case control studies continuous warfarin 65 quinolone 15 bleeding aOR, [ 1.69; 95% CI, 1.09-2.62] (Baillargeon et al, 2012)
Norfloxacin
15
5
)
Bleeding
normal flora (Baillargeon et al, 2012)
Norfloxacin
Norfloxacin 65
95
PT (21.6 quinolone
quinolone
vitamin k (moderate)
warfarin
case report
36.4
CYP1A2 (strong)
CYP3A4
warfarin
INR drug interaction warfarin
81
20
–1
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2
(65
INR
INR
)
Drug interaction warfarin Ciprofloxacin > Levofloxacin > Ofloxacin > Norfloxacin
5 2
quinolone
82
20
–1
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Ofloxacin
:
DNA gyrase (Topoisomerse II)
Topoisomerase IV
:
______ :
__X__
bioavailability
90 - 98
Steady Stage 20 – 25 hr
:
: /
65-80 4-8
20
– 32
5
m etabolite
48 desmethyl and N-
oxide substrate
:
5 – 7.5
CYP3A4
CYP1A2 (strong)
ofloxacin
warfarin
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Moderate, Documentation: Probable, Mechanism: may alterations in intestinal flora that synthesize vitamin K Leaflet / package insert: Ofloxacin Warfarin 1–2 ( 2508 ) Clinical trials: Case reports: hypoprothrombinemia seconds)
ofloxacin warfarin pubmed Ofloxacin Warfarin Warfarin 1 Prothrombin Time (77.7 Ofloxacin Warfarin (Baciewicz et al, 1993)
Observational studies : cohort study n = 38,762 bleeding 1.69 al, 2012)
ofloxacin
Ofloxacin
Quinolone Warfarin 15 Warfarin (aOR, 1. 69; 95% CI, 1.09-2.62) (Baillargeon et
warfarin
ofloxacin warfarin
hypoprothrombinemic response hypoprothrombinemic
83
20
–1
2559
________________________________________________________________________________
quinolone
Ofloxacin
2
K
CYP1A2
R-Wafarin
warfarin
interaction drug (65 )
Drug interaction warfarin Ciprofloxacin > Levofloxacin > Ofloxacin > Norfloxacin
77
PT
warfarin INR INR
2 – 3 2
quinolone
84
20
–1
2559
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Ciprofloxacin
:
topoisomerase type II (DNA gyrase) DNA _____ __ X __
:
:
:
CYP1A2 (strong) : 3-6
bioavailability – 40
60 -
80
4 desethyleneciprofloxacin (M1), formylciprofloxacin (M4) 50% oxociprofloxacin (M3) CYP450 system
CYP3A4 (moderate)
Ciprofloxacin
Drug Interaction Facts:
warfarin
Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Probable, Mechanism: may alterations in intestinal flora that synthesize vitamin K
Leaflet / package insert: Clinical trials:
: /
sulphociprofloxacin (M2), oxociprofloxacin (M3) 15%
20
topoisomerase IV
2
warfarin
/
1992 1996
Bianco et al
Israel DS et al
Pharmacotherapy 1992;12(6):435439) Clin Infect Dis. 1996;22(2):251.
500 mg 10
2 n=16 ( )
750 mg 12
2 n=34 ( )
stable INR 23
stable INR 23
INR
R-warfarin level 1.15 PT (p=0.57)
85
20
–1
2559
________________________________________________________________________________
Observational studies
2014
3
/
Lane, et al a retrospective cohort study
>= 30
Am J Medicine. 2014; 127:657-663.
Ciprofloxacin
>= 30
serious bleeding; HR 1.87; 95% Cl, 1.42-2.50 INR <= 4 90.5%
7.5% 2.0% UGI hemorrhage (aOR, 1.94; 95% CI, 1.28-2.95) INR >4-<=6 INR > 6
2010
Hadas D, et al nested case-control study
Arch Intern Med. 2010;170(7):617621
N/A
N/A
2012
Baillargeon et al /case-control study n = 38,762 ( 65 )
The American Journal of Medicine, Vol 125, No 2, February 2012
N/A
N/A
Case reports:
/
Warfarin 1.69
Quinolone bleeding
Warfarin (aOR, 1.69; 95% CI, 1.09-2.62)
Kamada AK. DICP. 1990 Jan;24(1):27-8.
Renzi R et al.Am J Emerg Med. 1991 Nov;9(6):551-2. Rindone et al, 1991 Ellis et al, Am J Hematol 2000; 63:28-
31.
72-year-old man pulmonary embolus recurrent DVT stable PT warfarin 5 9 Warfarin 50-year-old woman rheumatoid arthritis history of stroke
500 mg bid 7 days
2.5 mg/d
PT
N/A
N/A
500 mg bid 7 days 500 mg bid 5 days
N/A
PT
N/A
INR
15.5
PT
22
3.0
8.8
86
20
–1
2559
________________________________________________________________________________
ciprofloxacin
INR 750 mg case report 5-7
warfarin
RCT
ciprofloxacin 500 mg
2 2 1 ciprofloxacin 500 mg
2 10 (Bianco et al. 1992.) R-warfarin (Israel DS et al. 1996) PT ( 15.5 22) INR 2 Kamada ( AK. DICP. 1990 Jan;24(1):27-8.)
INR
-
; 63:28 31.) 3 8.8 5 (Ellis 2000vitamin et al, Am J Hematol k normal flora CYP1A2 (strong) CYP3A4 (moderate) warfarin ciprofloxacin quinolone INR 8.8 5 drug interaction warfarin INR 2 2 INR 2 (65 ) Drug interaction warfarin quinolone
Ciprofloxacin > Levofloxacin > Ofloxacin > Norfloxacin
87
20
–1
2559
________________________________________________________________________________
Levofloxacin
:
levofloxacin
topoisomerase IV
DNA gyrase
(bacterial topoisomerase II)
:
:
__X__
14% )
:
levofloxacin
Peak plasma 1 -2 hrs Oral form; Bioavailability 99 IV form; Peak plasma 60 mins (500 mg), 90 mins (750 mg) Steady Stage: IV, Oral 48 hrs 1 2 ( prolong time to
: /
oxide
_____
peak, peak concentrate :
6–8
87
4 5
24 - 38
metabolite
48
72
desmethyl and N
-
levofloxacin
warfarin
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Moderate, Documentation: Probable, Mechanism: may alterations in intestinal flora that synthesize vitamin K Clinical trials: 2
/
1996
Liao S, et al / RCT (n =16)
J Clin Pharmacol
500 mg twice daily
2008
Douglas NC et al / Review literature (n =22)
The Annals of N/A Pharmacotherapy 2008 May, Volume 42
healthy male 30 mg single dose N/A
PKPD 6 INR
3 – 4 .5
31 – 37 warfarin 14
Observational studies
/
5
88
20
–1
2559
________________________________________________________________________________
2005
2009
2012
2013
2014
Levofloxacin
Kenneth L . et al./ Retrospective cohort study
PHARMACOTHE RAPY Volume 25, Number 1,
n = 43 Orfila MG et al /Retrospective Analysis n = 21
2005 Pharm World Sci (2009) 31:224–229
Baillargeon et al /case-control study n = 38,762 ( 65 ) Brady S. Moffett. et al./ retrospectivecohor
The American Journal of Medicine, Vol 125, No 2, February 2012 Pediatr Blood Cancer 2013;60:1503–
t study n = 4,883
1506
Michael A. et al/ retrospective cohort study n = 22,272 ( )
The American Journal of Medicine, Vol 127, No 7, July 2014
500 mg/day (16) 250 mg/day (6) 500 mg OD (1case 250 mg; glomerular filtration rate < 50 ml /min)
-
INR Warfarin Levofloxacin ( 15
-
-
-
< 19
INR
)
28
Levofloxacin
-
INR +/ - 0.82 (p = 0.65) 0.31 Levofloxacin warfarin 2 – 8 Levofloxacin INR 1.85 2.64P (= 0.001 ) Quinolone Warfarin bleeding 1.69 Warfarin (aOR, 1.69; 95% CI, 1.09-2.62)
-
-
8.3 Levofloxacin (OR 8.3, P <
Levofloxacin Serious bleeding 1.77 low risk ATB (Clindamycin, Cephalexin) INR 3 – 14 Serious bleeding 39 INR High risk ATB 7.8% INR > 4 - ≤6 Levofloxacin Azitromycin ( 15 Ciprofloxacin 37.13 29.40 )
/
Nemoto C, et al. J
30
900 mg/day
4 mg/day
0.01)
-
ATB
Case reports:
nasal
89
20
–1
2559
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Anesth. 2012.
idiopathic dilated cardiomyopathy 70 MVR,
Susan L, at el.
75
For 6 days
hemorrhage hypovolemic shock
500 mg/day for 10 days 500 mg/day
5 mg/day levofloxacin 5 5.7
levofloxacin
levofloxacin
Warfarin INR Levofloxacin (Orfila MG et al, 2009 ) Levofloxacin (Douglas N Carroll and Dana G
Levofloxacin
INR 0.79 2 – 8 INR 3 – 4.5 Carroll, 2008) Bleeding Placebo DI 28 8.3 INR 3 – 14 reports INR Case INR –2
levofloxacin 1 3.6 7.9INR
warfarin
7 mg TWD
for 5 days
INR
Levofloxacin Warfarin Warfarin (1.69 1.77 ) Levofloxacin (OR 8.3, P < 0.01) Serious bleeding 39 2
K
Serious bleeding
levofloxacin 1
warfarin
INR 0.79 2 drug interaction warfarin INR 2 2 INR 2 (65 ) Drug interaction warfarin quinolone quinolone
Ciprofloxacin > Levofloxacin > Ofloxacin > Norfloxacin
90
20
–1
2559
________________________________________________________________________________
Sulfamethoxazole+Trimethroprim
:
sulfamethoxazole trimethoprim
Metabolism:
nucleoside _____
__X__
thymidine
uridine
Sulfamethoxazole
dihydropteroate sythetase dihydrofolate reductase
:
Trimethroprim
90-100, Time to peak serum: 1-4 68 45 1. N-acetylate N4-Acetyl Metabolized to oxide and hydroxylated sulfonamide metamolites ( substrate 2. CYP P450 N-Oxidation reactive CYP2C9 (major), metabolites glucuronidated Non CYP3A4 (major), P-glycoprotein, OCT1 toxic metabolites ( substrate CYP3A4 CYP2C9(major) CYP2C9 inhibitor)
9
(hemodialysis
OCT2 metabolic transporter systems, CYP2C8inhibitor (moderate), CYP2C9 inhibitor (moderate) OCT2 inhibitor) metabolites 6-17 failure (20-30 renal ) Dialyzable: peritoneal )
Sulfamethoxazole+Trimethroprim
warfarin
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Established, Mechanism: 1.increases effects of warfarin by decreasing metabolism 2.increases effects of warfarin by plasma protein binding competition 3.increase the level or effect of warfarin by affecting hepatic enzyme CYP2C9/10 metabolism Leaflet / package insert: Sulfamethoxazole+Trimethroprim warfarin Clinical trials: 6
2005
/
Jeffrey J
J Gen Intern
-
stable
TMP/SMX
warfarin,
91
20
–1
2559
________________________________________________________________________________
2008
2008
Glasheen, et al /Retrospective cohort study (N=869)
Med. 2005 Jul; 20(7): 653–656.
Hedi Schelleman,
Clin Pharmacol
et al/ (N=308,100)
Ther. 2008 Nov; 84(5): 581–588. J Thromb Thrombolysis Aug 1, 2008; 26(1):44-48.
Abrar Ahmed, et al/ placebo controlled, prospective cohort study (N=40)
INR (+0.5) 30
6-10
median F/U INR 6 3-15 ( ) mean INR 1.76, INR 69%, INR ≥1 (56%), INR≥2 (38%), INR≥4 (44%), INR≥5 (31%) 13% GI bleeding
-
2012
2014
cotrimoxazole [95% CI:1.21 ORs for–2.33]) (OR:1.68 -
stable INR 2.53±0.12
warfarin 10-20% (Mean 16.3±2.8%) TMP/SMX INR prolongation
INR ≥4
Fischer HD, et al /population-
Arch Intern Med. 2010 Apr
based, nested case-control study (N=134,637) Jacques Baillargeon, et al/case-control study nested within a cohort (N=38,762)
12;170(7):61721.
Michael A. Lane et, al/
Am J Med.
Am J Med. 2012 Feb; 125(2): 183– 189.
2014 July ;
-
-
2151
tract hemorrhage cotrimoxazole (aOR, 3.84; 95% confidence interval [CI], 2.33-6.33). warfarin
15
warfarin
(AF, VTE, prosthetic heart valve, stroke)
>3
88.9 (p<0.02) INR 7.1-17.4 (44%,P=0.08) 134,637 UGI
25
0
INR ≥6
2010
warfarin
(adjusted odds ratio (aOR), 2.01; 95% CI, 1.62 to 2.5) Azole antifungals (aOR, 4.57; 95% CI, 1.9 to 11.03), cotrimoxazole (aOR, 2.7; 95% CI, 1.46 to 5.05) , cephalosporins (aOR, 2.45; 95% CI, 1.52 to 3.95), penicillins (aOR, 1.92; 95% CI, 1.21 to 2.07), macrolides (aOR, 1.86; 95% CI, 1.08 to 3.21) quinolones (aOR, 1.69; 95% CI, 1.09 to 2.62) . TMP/SMX
2
92
20
–1
2559
________________________________________________________________________________
Retrospective cohort study (N=22,272)
127(7): 657– 663.
30
(HR 2.09, 95%
CI 1.45-3.02),
stable INR >2
Observational studies / case reports: + Trimethroprim Sulfamethoxazole INR 1. 39 rheumatic heart disease, atrial fibrillation pulmonary (thrombotest readings 9-15%) 4 embolism warfarin 6 mg upper respiratory tract infection associated with general malaise, myalgia and dyspnea ampicillin 7 7 right-sided pleuritic chest signs of consolidation Pneumonia cotrimoxazole 2 2 2 massive haematemesis warfarin. repeat thrombotest spontaneous bleeding haematuria haematemesis one-stage prothrombin time 90 sec (control 14 sec) cephalin-kaolin clotting time 180 sec (control 46 sec), haemoglobin 11 g/dl, total plasma albumin 35 g/l : infusion of prothrombin concentrate, vitamin K 1 10 mg IV, transfused 3 u. of whole blood, Barium meal, intravenous pyelography et al. Interaction between 4 (W. J. TILSTONE, warfarin and sulphamethoxazole Postgraduate Medical Journal (July 1977) 53, 388-390. ) 2. 71 CVA warfarin 5 mg 1 cotrimoxazole 2 2 3 (Urine culture sensitivity pending) cotrimoxazole prothrombin time (PT) 23 32 33 37 2 (Greenlaw CW. ampicillin warfarin prothrombin time 21 Am J Hosp Pharm 1979; 36:1155-1156.) 3. 55 long term 2 Sulfamethoxazole + Trimethroprim bronchitis CT scan massive bleeding liver parenchyma 8 Erichsen (C, et al. Hepatogastroenterology 1993 Dec;40(6):604. ) 4. 90 atrial fibrillation warfarin 3 mg cotrimoxazole urinary tract infection 3 INR 10 admit . Cotrimoxazole frozen INR plasma phytomenadione 2.6 1.4 12 24 3 mg discharge admit 3 Warfarin INR of 1.8 (Cotrimoxazole/warfarin interaction. Reactions Weekly. 2014 Nov; 1526 (1): 54 –54.) 5. 80 warfarin 7.5 mg atrial fibrillation admit cotrimoxazole 5 INR 9 SC + oral vitamin K 3 discharge Warfarin 5 mg 7.5 mg (Cotrimoxazole/warfarin interaction. Reactions Weekly. 2014 Nov; 1526 (1): 54 –54.)
93
20
–1
2559
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3
Sulfamethoxazole+Trimethroprim
Sulfamethoxazole + Trimethroprim (Baglin T, 2002)
warfarin
onset INR prolong case report 3 8 Sulfamethoxazole warfarin + Trimethroprim
INR
6
warfarin by decreasing 1.increases effects of metabolism 2.increases effects of warfarin by plasma protein binding competition 3.increase the level or effect of warfarin by affecting hepatic enzyme CYP2C9/10 metabolism Sulfamethoxazole+Trimethroprim
warfarin
Sulfamethoxazole + Trimethroprim (Baillargeon et al, 2012) Sulfamethoxazole + Trimethroprim LMWH warfarin Sulfamethoxazole + Trimethroprim warfarin LMWH INR therapeutic level LMWH Sulfamethoxazole + Trimethroprim warfarin INR warfarin 1-3 Sulfamethoxazole + Trimethroprim (Todd R. Mary. Warfarin and cotrimoxazole. ASHP’s Clinical PEARLS. Bruce Canaday. American Soceity of Health-System Pharmacist. 2008; 71-75) INR 2-5 Hale ( SF, et al. Interaction of vitamin K antagonists and trimethoprimsulfamethoxazole: ignore at your patient's risk. Drug Metabol Drug Interact. 2014;29(1):53-60 )
94
20
–1
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Metronidazole
:
metronidazole DNA
:
-2 :
-
: - 1
__X ___
: /
-
metronidazole cytoplasm anaerobic bacteria nitroso free radical electron ferredoxin DNA bacteria
____ Vd)
-80
nitro group
bioavailability 80 : 0.55 L/kg; neonate) ( ( : 0.54-0.81 L/kg
20
60 oxidation side-chain conjugation parent compound (20%) hydroxyl metabolite in vitro antimicrobial activity - -15 6 - hemodialysis : 8 ( 6-12 ) Metronidazole Warfarin -
glucuronide peritoneal
Drug Interaction Facts:
Significant rating: 1Onset:Delayed, Severity:Major, Documentation: Good, Mechanism:decreased warfarin metabolism Leaflet / package insert: Metronidazole warfarin prolongation prothrombin time 1 Clinical trials:
/
2014
Michael A, et al Retrospective cohort study (N=22,272 , N metronidazole = 1,003 )
Am J Med. 2014 July ; 127(7): 657–663
>3
warfarin ≥ 30 stable warfarin regimen
metronidazole serious bleeding HR( 1.63, 95% CI 0.61-4.39 ) INR low risk antibiotics < 4 = 85.0 % INR < 4 - ≤6 = 10.1% INR > 6 = 4.9%
95
20
–1
2559
________________________________________________________________________________
Observational studies/ case reports:
8
52
potassium 40 mEq
1 bleeding 2 metronidazole 500 mg 3 warfarin 5 mg
2
1 PT=75, aPTT=120, Hb=8.5 g/100ml, Hct=27.6%, BP=104/56 mmHg etronidazole PRC FFP 24 warfarin m PT aPTT 34.9 93.5 S-warfarin metronidazole (Dean & Talbert, 1980) 78 warfarin mg/day 7 INR 2.5 metronidazole 250 mg 8 hours levofloxacin 5 500 mg 1 96 intraparenchymal hemorrhage INR=8 Naranjo adverse drug reaction metronidazole 7 (probable) levofloxacin (possible)4 1 S-warfarin metronidazole
digoxin 0.125 mg , furosemide 40 mg CHF; quinidine 200 mg 6 AF clotting mitral valve warfarin INR PT 4 4
(Howard-Thompson et al, 2008)
Metronidazole
time metronidazole metronidazole INR, PTT aPTT
metronidazole prothrombin S-warfarin CYP450 2C9 (major) 3A4 (minor) serious bleeding case report 3 metronidazole PT
Metronidazole
Warfarin
warfarin
Warfarin
INR
30-35%
96
20
–1
2559
________________________________________________________________________________
Vancomycin
:
linking
:
:
:
inflammation)
peptidoglycan
bactericidal ( activity) D-alanyl-D-alanine peptide-glycan precursor cross
Vancomycin
:
_____ __X__ – – bioavailability 50 : / IV : Oral : -
19-29 80-90 (urine : unchanged drug)
Children > 3 years Infant and children (3 month-4 years) Newborns
: 2.2 – 3 hrs : 4 hrs : 6 – 10 hrs
-
CSF
-
Leaflet / package insert : -
(bowel
warfarin
none found : none found : No results found : No interactions found : No interactions found : No interactions found : Interaction - Severity - Onset - Documentation - Mechanism
: moderate : delayed : good : unknown
warfarin : severity moderate (DATA FACT SHEET Vancomycin 500 mg injection (Vancin-S ®)) (sterile vancomycin hydrochloride, USP ® : Pfizer)
-
vancomycin
38
: 200 – 250 hrs : 5 – 11 hrs
2
End-stage renal disease Adult
Drug Interaction Facts : Martindle the complete drug reference www.drugs.com (interactions checker) http://reference.medscape.com/drug-interactionchecker http://www.webmd.com/interaction-checker/ http://www.rxlist.com/drug-interaction-checker.htm Micromedex drug interaction
Clinical trials :
97
20
–1
2559
________________________________________________________________________________
/
1983
1987
David M, et al
Ann.surg.1984 Jan;199(1):107-
Cefamandole 2 gm
Retrospective study Angaran DM, et al Prospective randomized trial
11
Vancomycin 500 mg Cefamandole 2 gm Cefazoline 1 gm Vancomycin 500 mg
Ann.Surg.1987 Aug;206(2):15561
15 – 20 mg
cefamandole prothrombine time
vancomycin
PT warfarin 1 vancomycin = 51 (p<0.005) cefamandole = 29 cefazolin = 38 PT 1-3 cefamandole = 64 (p<0.0001) cefazolin = 51.1 vancomycin = 44.6 PT 3 30 ( )
≥ 10
mg
cefamandole = 6 cefazolin = 1 vancomycin =1
warfarin
(Prophylactic
antibiotic) prothrombin time (PT) cefamandole 64 , cefazolin 51 vancomycin 45 Observational studies / case reports
vancomycin
vancomycin
vancomycin
warfarin
clinical trial
2–3
:
Prothrombin time (PT) INR
warfarin
98
20
–1
2559
________________________________________________________________________________
PT
INR
malabsorption warfarin
vancomycin P rothrombin time (PT) vancomycin warfarin warfarin hypermetabolic
99
20
–1
2559
________________________________________________________________________________
Fluconazole
:
highly selective inhibitor lanosterol cellular content
Fluconazole lanosterol C-14 demethylase
:
_____ :
:
:
: / 30
70
__X__ bioavailability
– 90
80
10
Fluconazole
cytochrome P450 ergosterol
warfarin
Drug Interaction Facts:
Significant rating: 1 Onset: Delayed, Severity:major, Documentation: Established, Mechanism: disruption of vitamin K synthesis; inhibition of CYP3A4-mediated warfarin metabolism warfarin Leaflet / package insert: Fluconazole Clinical trials: 2 Fluconazole
Micromedex :
2014
1993
warfarin
bleeding
/ Michael A. Lane, et al Retrospective cohort study Crussell P., et al
The American Journal of Medicine. 2014 July;127(7):658662. Achives of internal Medicine. 1993 Jan;153(1):102104.
3 warfarin
100 mg OD 7
30
bleeding 2.3% INR 6 9.7 %
PTs 15.8 18.9 5 15.8 21.9 8 bleeding Gastrointrstinal bleeding
PTs
Observational studies / case reports: drug interaction 1 fluconazole warfarin (Harry D. Kerr.The American journal. 1993 Mar;305(3):164-165.) 39 warfarin fluconazole 50 fungal urinary tract infection 2.0 – 2.7 mg/day INR 4 INR 5.2 warfarin fluconazole INR 1.5 (Gericke KR. Pharmacotherapy. 1993 Sep-Oct;13(5):508-509.)
100
20
–1
2559
________________________________________________________________________________
fluconazole
warfarin
fluconazole
Fluconazole
INR
INR warfarin INR
INR
CYP3A4 bleeding INR
INR CYP2C9
warfarin floconazole warfarin INR 3 4 INR fluconazole warfarin INR bleeding
case report 3-4
fluconazole
Metobolism warfarin 2-3 GI bleeding
INR
INR
INR
101
20
–1
2559
________________________________________________________________________________
Ketoconazole
:
imidazole broad spectrum lanosterol cellular content _____ __X__
lanosterol C-14 demethylase
:
:
Bioavalability
:
13% :
: /
Albumin
95-99 (
metabolism
cytochrome P450 ergosterol
)
in active metabolites 85 – 90%
2
Dose
8-10
Ketoconazole
warfarin
Drug Interaction Facts:
Significant rating: 1 Onset: Delayed, Severity:major, Documentation: Established, Mechanism: disruption of vitamin K synthesis; inhibition of CYP3A4-mediated warfarin metabolism Leaflet / package insert: ketoconazole Clinical trials: 2 Micromedex :
ketoconazole
warfarin
bleeding
/
1981
Corstiaan B., et al
Antimicrob agente and chemother. 1981 Jan;21(1):151158.
200 mg OD 3
7.5 – 15 mg/week
PT serum ketoconazole ketoconazole comcentration 3
Observational studies / case reports: 59 warfarin indication AVR ketoconazole 400 mg TID INR 3.03 4.27 warfarin 35% (Cynthia A. Case report in Medicine. 2009) indication MI ketoconazole 75 warfarin vaginal thrush infection 200 mg BID I NR 5.4 3 warfarin INR 3 (British medical journal. 1984. Jan;288:188189)
Ketoconazole
warfarin
102
20
–1
2559
________________________________________________________________________________
Metobolism INR 2 -3
warfarin
Ketoconazole
Ketonazole INR Ketoconazole CYP3A4 ketonazole case report
ketoconazole 2-3 warfarin ketoconazole
warfarin INR
warfarin
INR
Ketoconazole reportwarfarin case
INR
INR INR INR
4-6
INR
103
20
–1
2559
________________________________________________________________________________
Itraconazole
:
(
:
Itraconazole cell membrane : _____
cytochrome P450 ) cell membrane
__X__
ergosterol
Bioavailability 149%±68% : : / Metabolite CYP3A4 metabolite itraconazole 3-18% drug 40% metabolites : 64 steady state
itraconazole
99.9
active metabolite 0.03% parent
hydroxyl
warfarin
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Good, Mechanism: inhibition of warfarin metabolism Leaflet / package insert: itraconazole warfarin Clinical trials: 2
/
2004
Ann K. Wittkowsky, et al. Retrospective, longitudinal cohort study.
Pharmacotherapy 2004;24(12):1668 –1674
No data
No data
2011
Miura M et al. Case study (N=1)
ClinicaChimicaActa412.2011;2002 – 2006
200 mg/day
2.0 mg/day
INR
INR 0.98 INR 2.43 s-warfarin
216 ng/ml
104
20
–1
2559
________________________________________________________________________________
763
ng/ml 2014
Hiroki Yamamoto, et al. Retrospective
Biol. Pharm. Bull. 2014;37(12):1990 –1993
200 mg/day
1.0-3.5 mg/day
INR
cohort study
itraconazole INR pulmonary embolism warfarin itraconazole 200 mg 2 4 INR >8 itraconazole warfarin FFP INR 2.4 (Yeh J, et al. BMJ. 1990 Sep;301:669) 65 65 warfarin 4. 5 warfarin bleeding
Observational studies / case reports:
1.
2.
2
azole
antifungals : itraconazole (Baillargeon et al, 2012).
study
itraconazole
itraconazole case study 200 mg/day)
INR retrospective, longitudinal cohort INR ( 2.43 itraconazole case reports INR ( ) INR itraconazole metabolism warfarin
itraconazole
Itraconazole INR
warfarin
Warfarin
warfarin
INR
Bleeding warfarin
105
20
–1
2559
________________________________________________________________________________
Voriconazole
:
(
:
voriconazole cell membrane : _____
cytochrome P450 ) cell membrane
__X__
ergosterol
Bioavailability 96%
:
58
: /
Metabolite CYP2C19 (major) CYP2C9,CYP3A4 (less significant) (inactive metabolite) : variable (dose dependent) : non-linear pharmacokinetic
voriconazole
warfarin
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Good, Mechanism: inhibition of warfarin metabolism warfarin Leaflet / package insert: voriconazole Clinical trials: 2
2003
2014
/
Purkins L, et al. doubleblind, placebocontrolled, two-way crossover study (N=14) Yamamoto H, et al. Retrospective cohort study
Br J Clin Pharmacol. 2003;56:24 –29
300 mg/day
Biol. Pharm. Bull. 2014;37(12):1990 – 1993
100-400 mg/day
30 mg/day
PT
36 - 48 healthy male ( volunteer)
voriconazolel
Observational studies / case reports:
0.5-2.5 mg/day
INR 1.7
(
)
71
INR
1.
74
voriconazole 300 INR 3.0
4.1-5.8
atrial fibrillation 1 600 FFP vitamin K
warfarin
2 warfarin
8
106
3
20
–1
2559
________________________________________________________________________________
2.
3.
INR 1.9 (A. Scott Mathis and Daryl S. Schiller. The Open Transplantation Journal. 2008 Jul;2:29-34.) ( ) warfarin ( dose INR ) 172% 167% voriconazole (Yamamoto H, et al. 1990-3, No. 12 - Japan) 65 65 warfarin bleeding 4.5 et al, 2012). antifungals : Voriconazole (Baillargeon
voriconazole
PTT baseline INR 1.7 INR INR
azole
RCT PTT 2 // Retrospective cohort study baseline // case reports FFP vitamin K ( ) INR 3
INR
voriconazole
metaobolism
CYP2C9
voriconazole
INR
warfarin
warfarin
voriconazole
warfarin
warfarin
voriconazole warfarin
warfarin
107
20
–1
2559
________________________________________________________________________________
Amphotericin B
:
ergosterol permeability
Amphotericin B
autooxidation free radicals mycoplasma host( cell) sterol Amphotericin B fungistatic fungicidal : _____ __X__ : : 90 : / 2-5% ( ) 40% 7 7 : Biphasic : Initial 15-48 , Terminal 15
amphotericin B
Drug Interaction Facts : no data Leaflet / package insert : no data Micromedex® : no data Clinical trial : Drug interaction Warfarin Observational studies / case reports: 1. 71 admit INR 2 (
Pubmed, Sciencedirect, Drugline
amphotericin B nephritic syndrome warfarin 2-2.5 mg/day)
1 amphotericin B
warfarin
2. bladder 3.5-4.5 case report
62
INR
thrombosis
miconazole oral gel amphotericin B
2 (ReikoTajima-Okubo, et al. CENCaseRep.2012 Apr;28(1):55–57.)
irritable bowel syndrome warfarin 5-5.5 mg/day INR haematuria discussion
warfarin miconazole oral gel INR=7.25 vitamin K INR
7
warfarin
(400 mg/day)
bowel cancer INR=11.9
large
108
20
–1
2559
________________________________________________________________________________
nystatin 531)
bleeding risk (M. N. Pemberton, et al. BRITISH DENTAL JOURNAL.2004;MAY;196(9):529-
Pubmed, Sciencedirect, Drugline Warfarin 3mg 1.5 2-3 Warfarin
3.
75
1 Amphotericin B 4
drugline
1mg/kg
[Internet]. Sweden: Swedish Institute for Drug c2012 [updated 2000 Jun (drugline.se Sep 12]. Informatics (SIDI); 7; cited 2014 Available from: http://www.drugline.se/questions/en/16655/?print=True&query=atc:%22J02AA01%22% 20AND%20language:english%20AND%20mesh:%22drug%20interactions%22)
amphtericin B
amphotericin B
warfarin
amphotericin B INR case reports 2 case candidiasis warfarin 1 case report warfarin
amphotericin B
warfarin amphotericin B
warfarin
INR
109
20
–1
2559
________________________________________________________________________________
Nystatin
:
ergosterol
polyene antifungal agents Amphotericin B cellular content
_____ __X__ : : : Distribution : / : Nystatin warfarin Drug Interaction Facts: Leaflet / package insert: Clinical trials: 1 Micromedex :
2012
/
Kovac M., et al Retrospective study (N=43)
J clin Pharm Ther. 2012 Feb;37(1):458.
nystatin Miconazole oral gell miconazole vaginal suppositories
INR stable
44.2 bleeding 15 32 Miconazole 4 bleeding nystatin nystatin
14.5 mg/week 9 mg/week INR
2.5
10.6
110
20
–1
2559
________________________________________________________________________________
Observational studies / case reports:
Nystatin
4
nystatin warfarin INR stable minor bleeding 2 major bleeding 2 nystatin
9 mg/week INR
warfarin
Nystatin
2.5
pharmacokinetic nystatin
warfarin
bleeding
warfarin
nystatin
bleeding
mg/week
case report
INR
14.5
warfarin Miconazole nyststin warfarin
10.6
Miconazole
bleeding
111
20
–1
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________________________________________________________________________________
Griseofulvin
:
:
:
:
10-50%
:
9-21
microtubules
: /
_____
(fungal mitosis) __X__
metabolize
Griseofulvin
1994
warfarin
warfarin
Philip S., et al
Ann intern
INR stable
warfarin
Med. 1994 griseofulvin, ;121(9):676-683. rifampin, and nafcillin Observational studies / case reports: 61 warfarin indication MVR 12 INR griseofulvin INR 41% (Okino K. Drug intell clin Pharm. 1986 Apr;20(4):291-3) 45 griseofulvin warfarin indication MI 16 INR 65 warfarin indication MVR griseofulvin 250 mg QID warfarin (Stanley I.,JAMA. 1976 Feb;199(8):582-583)
INR
/
Drug Interaction Facts: Significant rating: Leaflet / package insert: Griseofulvin INR Clinical trials: 1 Micromedex : Onset: Delayed, Severity: Moderate, Documentation: Good, Mechanism:
Griseofulvin
warfarin
Griseofulvin INR INR Griseofulvin warfarin Griseofulvin warfarin INR
warfarin
INR warfarin
INR
INR
112
20
–1
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________________________________________________________________________________
Terbinafine
:
epoxidase
:
Terbinafine ergosterol : _____
(
:
70%
:
: / 36
allylamine ergosterol __X__
70%) bioavailability 99
squalene2,3
40
CYP2C9, CYP1A2, CYP3A4, CYP2C8 20%
CYP2C19
Terbinafine
warfarin
Drug Interaction Facts:
Significant rating: 4 Onset: Delayed, Severity:major, Documentation: Possible, Mechanism: induction of hepatic metabolism Leaflet / package insert: Terbinafine warfarin Clinical trials: 3 Micromedex : warfarin bleeding
/
1999
1998
Aditya K., et al Clinical review
J MA ACAD dermatol. 1999 Aug;41 (2):239-244.
J A warwick., et al (n=20)
BMJ. 1998 Feb;361:440.
interaction report 250 mg OD 6-7
INR stable
drug case terbenafine PTs
1997
warfarin
Pharmacotherpy. 250 mg/day 30 mg Plasma concentration 1997; 17(4): 76714 time 773 8 profile Observational studies / case reports: 71 Gastrointrstinal bleeding warfarin terbinafine 250 mg OD 32 terbinafine INR 2.3 warfarin 45 mg/week INR 4.5 35 mg/week INR 3.1 INR 6 11 17.5 mg/week (A.K. gupta.Dermatology. 1998 Aug;196:266-267.) 68 warfarin 5.5 mg/day indication MVR INR 2-3 terbinafine 250 Guerret M, et al
113
20
–1
2559
________________________________________________________________________________
mg OD 3 INR mg/day terbinafine 4 al. BMJ.1998;317(7152):205)
Terbinafine
CYP2C9
terbinafine
warfarin 7.5 (Gantmacher J. et
INR 4
substate
Terbinafine
warfarin
INR
warfarin
INR
potencial INR GI bleed
Terbinafine
bleeding warfarin
warfarin
28 5.5 mg/day
warfarin
Terbinafine substate substate warfarin
1.1
Terbinafine
warfarin
4
INR
INR
1
INR
1
terbinafine
114
20
–1
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Acyclovir
(1,2): Acyclovir synthetic purine nucleoside analog (acyclic deoxyguanosine ) HSV-1, HSV-2 VZV Thymidine kinase (TK) acyclovir monophosphate, diphosphate triphosphate acyclovir triphosphate
:
:
____
__ X __
(1,2)
:
DNA
% 9 – 33 : metabolism / 9-(carboxymethoxy)methylguanine (inactive) , % 2 2.5 – 3.3 Acyclovir warfarin
case reports
Observational studies / case reports: warfarin acyclovir
acyclovir
acyclovir
observational studies
interactions
warfarin
acyclovir
acyclovir
INR
warfarin
INR
- 20 10
Drug Interaction Facts: no drug interaction (3) Leaflet / package insert: Clinical trials: warfarin
oral, bioavailability
:
DNA polymerase
DNA replications
DNA
1.
McLean W & Ariano R: Acyclovir - Therapy of Polyunsaturated Fat Deficiency (Drug Consult). In: Klasco RK (Ed): DRUGDEX® System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com (cited: 06/24/2016). 2. Kastrup EK, Johnson PB, Williams AL, Moore LL, Bush AJ, Horenkamp JR, et al. Drug facts and comparisons. USA: Wolters Klumer Health; 2012 3. Tatro DS. Horm JR, Waler SE, Ganeral JA, Johnson PB, Maives CA. et al. Drug interactions Facts. USA: Wolters Klumer Health; 2015
115
20
–1
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________________________________________________________________________________
Valacyclovir
(1,2,3): Valacyclovir prodrug (L-valylester) Acyclovir ( ) hydrolyzed acyclovir acyclovir -53 analog (acyclic deoxyguanosine) HSV-1, HSV-2 VZV
Thymidine kinase (TK) monophosphate, diphosphate acyclovir acyclovir triphosphate DNA replications polymerase DNA DNA ____ __ X __ :
:
(2,3)
triphosphate DNA
Acyclovir (active drug) bioavailability 54.5% : Valacyclovir (prodrug), Protein binding: 13.5% to 17.9% : Valcyclovir / pass intestinal and/or hepatic metabolism acyclovir valcyclovir enzyme Valacyclovir (prodrug), Fecal: 47% Renal: 46% Acyclovir (active drug), Renal clearance: 255 mL/min [9] : 2.5 – 3.3 (14 ESRD)
purine nucleoside synthetic
valacyclovir
warfarin
Drug Interaction Facts: no drug interaction(4) Leaflet / package insert: no drug interaction(5) Clinical trials: Observational studies / case reports:
Valacyclovir
Valacyclovir
acyclovir first m etabolism P-450
warfarin
Valacyclovir warfarin
valacyclovir
warfarin
valacyclovir
INR
warfarin
INR
( agents). [Internet] Antiviral [cited on 2016/06/24] 2. McLean W & Ariano R: Valacyclovir - Therapy of Polyunsaturated Fat Deficiency (Drug Consult). In: Klasco RK (Ed): DRUGDEX® System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com (cited: 06/24/2016). 3. Kastrup EK, Johnson PB, Williams AL, Moore LL, Bush AJ, Horenkamp JR, et al. Drug facts and comparisons. USA: Wolters Klumer Health; 2012 1.
116
20
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________________________________________________________________________________
4.
Tatro DS. Horm JR, Waler SE, Ganeral JA, Johnson PB, Maives CA. et al. Drug interactions Facts. USA: Wolters Klumer Health; 2015 5. Valacyclovir. [Internet]. New York: [update 2006 Jan 31; cited on 2016 Jun 25]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019661 s030lbl.pdf
117
20
–1
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Ganciclovir
Ganciclovir
(1,2,3):
Thymidine kinase (TK) polymerase
:
synthetic purine nucleoside analog (acyclic deoxyguanine) acyclovir CMV acyclovir monophosphate, diphosphate triphosphate
acyclovir triphosphate
Ganciclovir
____
:
DNA __ X __
:
oral bioavailability 5%
protein binding 1 – 2 % : 91.3% / + 5% 1.7 – 5.8 5 – 28
Ganciclovir
(
ganciclovir
warfarin
ganciclovir warfarin
ganciclovir
warfarin
gancilovir
ESRD)
Drug Interaction Facts: no drug interaction (4) Leaflet / package insert: warfarin Clinical trials: Observational studies / case reports:
DNA
:
DNA replications DNA
gancilovir
INR
warfarin
INR
Antiviral ( agents). [Internet] [cited on 2016/06/24] 2. McLean W & Ariano R: ganciclovir - Therapy of Polyunsaturated Fat Deficiency (Drug Consult). In: Klasco RK (Ed): DRUGDEX® System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com (cited: 06/24/2016). 3. Kastrup EK, Johnson PB, Williams AL, Moore LL, Bush AJ, Horenkamp JR, et al. Drug facts and comparisons. USA: Wolters Klumer Health; 2012 4. Tatro DS. Horm JR, Waler SE, Ganeral JA, Johnson PB, Maives CA. et al. Drug interactions Facts. USA: Wolters Klumer Health; 2015 1.
118
20
–1
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________________________________________________________________________________
Oseltamivir
:
carboxylate
Hemagglutinin
prodrug hydrolyzed active form Oseltamivir neuraminidase Oseltamivir carboxylate inhibitor sialic acid
Oseltamivir influenza virus neuraminidase
:
_____
budding
__X__
: carboxylate)
bioavailability
: Oseltamivir Oseltamivir carboxylate : /
: Oseltamivir 1– 3 Oseltamivircarboxylate 6 – 10
2012
42
3
90CYP450 system
Oseltamivir
warfarin
/
Lee SH, Kang HR, Jung JW et al retrospective review (N = 15)
Onset: Delayed Severity:Major Documentation:Good
Probable Mechanism:unknown Leaflet / package insert: Clinical trials: 1
% (Oseltamivir 75
>90
Drug Interaction Facts:
infected cells
Clin Drug Investig 2012; 32(2):131137.
150 mg/
INR 5 stable INR 2.08 +/- 0.46 - 2.00.5.15 +/ 2-3 46.7 % (7 15) 3 bleeding warfarin 2-5 INR oseltamivir INR influenza A H1N1 azithromycin, levofloxacin, prednisolone paracetamol INR
oseltamivir INR (Lee et al, 2012).
Oseltamivir
warfarin
warfarin
119
20
–1
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________________________________________________________________________________
warfarin
Oeltamivir
INR
warfarin
INR INR
-3 2
Reference(s): Lee SH, Kang HR, Jung JW et al: Effect of oseltamivir on bleeding risk associated with warfarin therapy: a retrospective review. Clin Drug Investig Feb 1, 2012; 32(2):131 -137.
120
20
–1
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________________________________________________________________________________
Abacavir
:
dGTP
:
Guanosine analog HIV-1 reverse transcriptase replication Nucleoside reverse transcriptase inhibitors : NRTIs viral : _____ __X__
:
bioavailability
: /
99 alcohol dehydrogenase Glucuronyltransferase 5’-glucoronide (inactive) 16 1 (unchanged Abacavir) : 1.5
Abacavir
2004
/
80
Bocedi A, et al In vivo (Binding of anti-HIV drugs to human serum albumin)
5’- carboxylic acid
warfarin
Drug Interaction Facts: no drug interaction Leaflet / package insert: no drug interaction Clinical trials: 6
83
50
(inactive)
IUBMB Life. 2004 Oct;56(10):609-14.
-
-
Anti-HIV drug(PIs, NNRTIs, NRTIs) human serum albumin 0.63-0.91% in vivo plasma protein
α1-acid glycoprotein
2007 2009
Matthew Foy, et al Review literature (85 articles Michelled D liedtke, R.ChrisRathbun Review primary literature ; MEDLINE (1950-July 2008) and International Pharmaceutical Abstracts (1970-July
HIV/AIDS Rep. 2014 Sep; 11(3): 212-222 Annals of Pharmacotherapy. 2009 Mar;43(2):3228J ClinPharmacol.
-
-
-
-
INR
INR
NRTIs
NRTIs
121
20
–1
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________________________________________________________________________________
2010
2012
2013
2008) Michelle D LiedtkePharmD BCPS & R Chris RathbunPharmD BCPS Albert M.Anderson, et al Retrospective study (N = 73) Lauren J Gleason, et al Review literature (135 articles)
Expert Opinion. Drug Safty (2010) 9(2):215-223
-
NRTIs
drug interactions warfarin NRTIs
AIDS patient care and STDs. 2012 Jun;26(8):454-62.
-
Polypharmacy in the HIV-infected older adult population Clinical Interventions in Aging. 2013Jun;8:749-763.
-
Abacavir
Abacavir
-
50
CYP450
metabolized
Observational studies / case reports:
-
NRTIs
INR
INR
NRTIs
INR
warfarin
Abacavir
INR Cohort, case control study PIs NNRTIs I NR CYP450 HAART Retrospective study PIs, NNRTIs (Albert INR M.Anderson, et al AIDS patient care and STDs. 2012 Jun;26(8):454-62. ) in vivo 91 α 1-acid Abacavir 50 NRTIs 10-40 case report Abacavir INR warfarin Abacavir warfarin Abacavir Lopinavir/Ritonavir, Atazanavir/Ritonavir, Efavirenz INR warfarin
NRTIs (Abacavir) glycoprotein
122
20
–1
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________________________________________________________________________________
Emtricitabine
:
phosphorylation RNA DNA
_____ :
:
Cytosine analog Emtricitabine phosphate Emtricitabine5’ -triphosphate DNA polymerase Nucleoside reverse transcriptase inhibitors : NRTIs
__X__
conjugated
: /
glucoronic acid 14 : 10 (
2004
/
), 5-18
) (
IUBMB Life. 2004 Oct;56(10):609-14.
-
-
Anti-HIV drug(PIs, NNRTIs, NRTIs) human serum albumin 0.63-0.91% in vivo plasma protein
2009
Matthew Foy, et al Review literature (85 articles Michelled D liedtke, R.ChrisRathbun Review primary literature ; MEDLINE (1950-
α1-acid glycoprotein
2007
86
30
warfarin
Bocedi A, et al In vivo (Binding of anti-HIV drugs to human serum albumin)
3’ -sulfoxide diastereomers
Oxidation hemodialysis
Drug Interaction Facts: no drug interaction Leaflet / package insert: no drug interaction Clinical trials: 6
93
4
2’ -O-glucoronidealcohol
Emtricitabine
bioavailability
:
HIV/AIDS Rep. 2014 Sep; 11(3): 212-222 Annals of Pharmacotherapy. 2009 Mar;43(2):322-8J ClinPharmacol.
-
INR
INR
-
-
NRTIs
NRTIs
123
20
–1
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________________________________________________________________________________
2010
July 2008) and International Pharmaceutical Abstracts (1970July 2008) Michelle D
-
Expert Opinion.
LiedtkePharmD BCPS & R Chris RathbunPharmD BCPS
-
Drug Safty (2010) 9(2):215-223
interactions warfarin
2013
Albert M.Anderson, et al Retrospective study (N = 73) Lauren J Gleason, et al Review literature (135 articles)
NRTIs NRTIs
AIDS patient care and STDs. 2012 Jun;26(8):454-62.
-
Polypharmacy in the HIV-infected older adult population
-
-
Emtricitabine
NRTIs
INR
warfarin
Emtricitabine
Emtricitabine
Cohort, case control study Retrospective study INR PIs, NNRTIs Jun;26(8):454-62. )
INR
NRTIs
Observational studies / case reports:
Emtricitabine
50
CYP450
INR
Clinical Interventions in Aging. 2013Jun;8:749763.
metabolized 2012
drug
INR
NNRTIs HAART
PIs
I NR
CYP450
M.Anderson, et al AIDS patient care and STDs. 2012 (Albert
warfarin
Emtricitabine
warfarin
124
20
–1
2559
________________________________________________________________________________
Tenofovir
:Tenofovir nucleotide analogues aliphatic sidechain tenofovir-diphosphate phosphate group kinase 2 tenofovir reverse transcriptase
primer
reverse transcription DNA reverse transcriptase DNA nucleic acid nucleotide triphosphate (active site)tenofovir-diphosphate reverse transcriptase DNA
:
_____
__X__
: oral bioavailability 25% oral bioavailability 40% : : / (Tenofovirdiphosphate)
1
:
17
7%, Vd = 1.2-1.3 L/kg prodrug (Tenofovirdisproxilfumarate ) hydrolysis 70% - 80%
Tenofovirdisproxilfumarate
Drug Interaction Facts: no drug interaction Micromedex :no drug interaction Leaflet / package insert: Clinical trials: 6
2004
active drug
/
warfarin
Bocedi A, et al In vivo (Binding of anti-HIV drugs to human serum albumin)
IUBMB Life. 2004 Oct;56(10):609-14.
-
-
Anti-HIV drug(PIs, NNRTIs, NRTIs) human serum albumin 0.63-0.91% in vivo plasma protein glycoprotein
2007
Matthew Foy, et al Review literature (85 articles
HIV/AIDS Rep. 2014 Sep; 11(3): 212-222
-
INR
α1-acid
NRTIs
125
20
–1
2559
________________________________________________________________________________
2009
Michelled D liedtke, R.ChrisRathbun Review primary literature ; MEDLINE (1950-July 2008) and
Annals of Pharmacotherapy. 2009 Mar;43(2):322-8J ClinPharmacol.
International Pharmaceutical Abstracts (1970-July 2008) Michelle D LiedtkePharmD BCPS & R Chris RathbunPharmD BCPS
2010
Expert Opinion. Drug Safty (2010) 9(2):215-223
-
-
-
INR
-
drug
interactions warfarin
NRTIs NRTIs
metabolized 2012
2013
Albert M.Anderson, et al Retrospective study (N = 73)
AIDS patient care and STDs. 2012 Jun;26(8):454-62.
-
Lauren J Gleason1 Amneris E Luque2 Krupa Shah Review literature (135 articles)
Polypharmacy in the HIV-infected older adult population Clinical Interventions in Aging. 2013Jun;8:749763.
-
drug interactions Tenofovirdisproxilfumarate
50
INR
CYP450
INR
Tenofovir disproxil fumarate
-
NRTIs
NRTIs
warfarin
warfarin Tenofovir disproxil fumarate 70%-80%
NRTIs
126
20
–1
2559
________________________________________________________________________________
Zidovudine
:
transcription)
thymidine analog AZT reverse trancriptase AZT
DNA (reverse AZT thymidine kinase,thymidylate
RNA
nucleotide phosphate
_____ __X__ AZT-triphosphate diphosphatekines : Bioavailability : 65 : 38 : AZT/ substarte CYP2A6(minor), CYP2C19(minor), CYP2C9(minor), CYP3A4(minor) first pass effect inactive glucoronidation 72-74% inactive metabolite 14-18% unchanged drug 14-18% 14( 12 – ) 30% : 1 2 ( -13 ) 1-1.8 14 3 zidovudine13 kinase
zidovudine
warfarin
Drug Interaction Facts: no drug interaction Leaflet / package insert: no drug interaction Clinical trials: 6
2004
/
Bocedi A, et al In vivo (Binding of antiHIV drugs to human serum albumin)
IUBMB Life. 2004 Oct;56(10):60914.
-
-
Anti-HIV drug(PIs, NNRTIs, NRTIs) human serum albumin 0.63-0.91% in vivo plasma protein
α1-acid glycoprotein
2007 2009
Matthew Foy, et al Review literature (85 articles Michelled D liedtke, R.ChrisRathbun
HIV/AIDS Rep. 2014 Sep; 11(3): 212-222 Annals of Pharmacotherap
-
-
INR
-
INR
NRTIs
NRTIs
127
20
–1
2559
________________________________________________________________________________
Review primary literature ; MEDLINE (1950-July 2008) and International Pharmaceutical Abstracts (1970-July
y. 2009 Mar;43(2):322-8J ClinPharmacol.
2008) Michelle D LiedtkePharmD BCPS & R Chris RathbunPharmD BCPS
2010
Expert Opinion. Drug Safty (2010) 9(2):215-223
-
-
drug
interactions warfarin
NRTIs NRTIs
2012
2013
Albert M.Anderson, et al Retrospective study (N = 73) Lauren J Gleason1 Amneris E Luque2 Krupa Shah
AIDS patient care and STDs. 2012 Jun;26(8):454-62.
-
Polypharmacy in the HIV-infected older adult
-
Review literature (135 articles)
population Clinical Interventions in Aging. 2013Jun;8:749763.
Zidovudine
drug interactions 2C9, 2C19 3A4
zidovudine
zidovudine
INR
50
INR
NRTIs
NRTIs
warfarin
warfarin warfarin warfarin
-
Zidovudine (minor)
zidovudine
CYP substrate CYP metabolism
warfarin
warfarin
CYP450
metabolized
128
20
–1
2559
________________________________________________________________________________
Didanosine
:
:
: / 0.9-1.6
<5%
42
HIV-1 reversetranscriptase
:
: bioavailability :
HIV _____ __X__
dideoxyadenosine 5-triphosphate
didanosine warfarin
Drug Interaction Facts: no drug interaction Leaflet / package insert: no drug interaction
Didanosine
warfarin
129
20
–1
2559
________________________________________________________________________________
Lamivudine
:
:
HIV-1 reverse transcriptase
:
:
:
HIV _____ __X__
: /
bioavailability
36
warfarin lamivudine
447
Lamivudine
1997 2012
warfarin
(26 may 2016)
warfarin
5-7
86
trans-sulfoxide metabolite
Drug Interaction Facts: no drug interaction EhealthMe
lamivudine
130
20
–1
2559
________________________________________________________________________________
Stavudine
:
:
HIV _____ __X__
:
44
bioavailability
86
phosphorylation 40 :
:
HIV-1 reverse transcriptase
: / deoxynucleoside reverse transcriptase inhibitor stavudine triphosphase
thymidine kinase
2 .3
warfarin stavudine
Drug Interaction Facts: no drug interaction
Stavudine
warfarin
131
20
–1
2559
________________________________________________________________________________
Efavirenz (EFV)
: (NNRTIs)
DNA
Non-Nucleoside Analog Reverse Transcriptase Inhibitors Reverse Transcriptase ( enzyme) DNA RNA DNA Reverse Transcriptase ( enzyme)
:
:
DNA
__ X__
___
:
99.5 – 99.75
: / M etabolite CYP3A4 CYP2B6, Efavirenz induce CYP3A4 CYP2B6 Metabolite Efavirenz enzyme inhibitor CYP2C9,CYP2C19 CYP3A4 16-61 Unchanged drug 14-34 inactive metabolite 1 unchanged drug : Single dose : 52-76 , Multiple doses : 40-55
Drug Interaction Facts: :CYP2C9 CYP3A4 inhibitor) Leaflet / package insert: Clinical trials:
Efavirenz
warfarin
Significant rating: 4 Onset: Delayed, Severity: Moderate, Documentation: Possible, Mechanism: inhibition of warfarin metabolism(Efavirenz
Efavirenz
-
warfarin
Efavirenz INR 34 Antiretrovral therapy Didanosine, Lamivudine Efavirenz Deep vein thrombosis (DVT) Anticoagulant warfarin Antiretrovral therapy Didanosine, Lamivudine Efavirenz warfarin INR 2-3 Platelet count 432,000 Platelet /mcL Didanosine, Lamivudine Efavirenz warfarin(5 mg) 1 35( mg/ ) D/C 22 Macrohematuria INR=7, Platelet count 58,000 Platelet /mcL INR 3( INR=2.7) Admit warfarin Antiretrovral therapy Vitamin K Didanosine, Lamivudine Efavirenz INR ( efavirenz plasma 12 3125 ng/mL.) D/C platelet count Observational studies / case reports:
132
20
–1
2559
________________________________________________________________________________
Didanosine, Lamivudine Efavirenz 1 4 Dis. 2008;46(1):146.)
Efavirenz
warfarin 5mg/
35 mg/
)
1.25 mg 1 ( (Bonora S. et al. Clin Infect
warfarin
Efavirenz
INR
Enzyme A4 ( S-Warfarin substrate inhibitor( CYP 2C9 drug metabolism) CYP 2C9 CYP 3CYP 3A4 ) R-Warfarin Clinical trials case report 1.25 mg 1 ( 1 4 ) Antiretrovral therapy 5mg/ 35 mg/ Didanosine, Lamivudine Efavirenz Warfarin INR (Bonora S. et al. Clin Infect Dis. 2008;46(1):146.)
Efavirenz
Efavirenz
warfarin
INR
warfarin
Efavirenz
133
20
–1
2559
________________________________________________________________________________
Nevirapine
:
HIV transcriptase
Non-nucleoside reverse transcriptase inhibitor (NNRTI) RNA single strand DNA
Retrovirus
: (Nevirapine
reverse
Warfarin )
:
91±8 %)
90% ( F= 93±9 % (Mean ±SD
50mg single dose
12 F =
Oral solution
:
highly lipophilic Vd = 1.21±0.09 L/kg ( : Precaution
Nevirapine circulation
: /
90
Nevirapine induce Glucuronide conjugation T1/2 (in plasma) dose) 200-400 mg/day
Nonionized
60 %)
)
CYP3A4
Blood Protein 60 ( bind
Oxidation CYP2B6
45 dose () Single
CYP2B6
CYP3A4
-25 %
-30
20
multi
25(
:
Nevirapine
Warfarin
Drug Interaction Facts : Significant rating : 2 Onset : Delayed Severity : Moderate to Severe (Tammy J. Bungard, BSP, PharmD; Erin Yakiwchuk, BSP, ACPR; Michelle Foisy, BScPharm, PharmD, FCSHP; Cynthia Brocklebank, PharmD, ACPR) Documentation : Excellent Mechanism : Increase warfarin metabolism warfarin Leaflet / package insert : Nevirapine Clinical trials : 4
134
20
–1
2559
________________________________________________________________________________
/
2007
2010
Patricia Pecora Fulco, Michelle M. Zingone and Robert T. Higginson
PHARMACOTHERAP Y Volume 28, Number 7, 2008
200
Michelle D
Expert Opin. Drug Saf. (2010) 9(2):215-223
200 2
Liedtke† & R Chris
Rathbun(N=12) (N nevirapine = 4)
2011
Tammy J. Bungard, et al
2015
2
53-12 mg/day = 12-20 mg/day = 1 2
2
5 0%
)
50% Target
INR (2-3)
Drug Interaction Warfarin
target INR (2-3)
200
BMJ Case Rep 2015. doi:10.1136/bcr2015-211651
INR = 0.9 (
200 2
CPJ/RPC JANUARY/FEBRUAR Y 2011 VOL 144, NO 1
Perram J, et al.
5 mg/day
INR target INR (2-3)
Observational studies / case reports :
Warfarin
INR 39 Admit dyspnea and right leg swelling 150 mg twice/day , zidovudine 300 mg lamivudine
Caucasian 11 twice/day , and nevirapine 200 mg twice/day Admit CD 4+ count = 528 cells/mm3 HIV viral load = 593 copies/ml. lower extremity revealed a pulmonary embolism and deep venous thrombosis subcutaneous enoxaparin 80 mg (1 mg/kg) twice/day and oral warfarin 5 mg/day = 0.9 12.5 mg/day target INR (2-3)
Nevirapine
right
baseline INR
Warfarin Warfarin
Nevirapine
Nevirapine
HIV
Warfarin
CYP3A4
Warfarin (
Moderate to Severe) ( ) 1
2-4( fold)
135
20
–1
2559
________________________________________________________________________________
Etravirine(ETR)
:
Etravirine
HIV
non-nucleoside reverse transcriptase inhibitor (NNRTI)
HIV
highly flexible diarylpyrimidine
HIV ( NNRTI receptor) HIV Reverse Transcriptase ( enzyme ) DNA RNA DNA DNA Reverse Transcriptase ( enzyme ) DNA Etravirine CYP3A4 CYP2C9, CYP2C18, CYP2C19 drug metabolism) ( methylhydroxylation glucuronidation Etravirine CYP 3A4 2C9, 2C19 P-glycoprotein : __ X__ ___ unknown) ( : ,bioavailability : : 99.9 : / etabolite CYP450 system M CYP3A4 , CYP2C9 CYP2C19 93.7 changed drug 81.2 - 86.4 unchanged drug 1.2 changed drug : 9.05 – 41
Etravirine(ETR)
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
warfarin
warfarin
Etravirine(ETR)
warfarin
CYP2C9 CYP3A4 inhibitor CYP2C9 CYP3A4 bleeding (Prod Info INTELENCE(TM) oral tablets, 2008). Etravirine(ETR)
Etravirine
warfarin CYP3A4 )
warfarin
warfarin
Etravirine CYP2C9 warfarin bleeding (Prod Info INTELENCE(TM) oral tablets, 2008). Etravirine warfarin INR bleeding
Etravirine
warfarin
warfarin(
warfarin
warfarin
136
20
–1
2559
________________________________________________________________________________
Rilpivirine
:
HIV transcriptase
Non-nucleoside reverse transcriptase inhibitor (NNRTI) RNA single strand DNA
:
:
reverse
Retrovirus
Cmax
absolute bioavailability
4-5
:
Relpivirine
T1/2 (in plasma) :
50
Relpivirine
Warfarin
Protein bind
99.7 %)
CYP3A system
Feces 85%6.1% Urine
case report Warfarin
free form Warfarin
Oxidation () Single dose
Warfarin
Rilpivirine
Drug Interaction Facts : Mechanism : Plama Leaflet / package insert : Clinical trials : Observational studies / case reports :
99.7 (
: /
Rilpivirine blood circulation
Protein binding Warfarin
Rilpivirine
Warfarin
137
20
–1
2559
________________________________________________________________________________
Ritonavir (RTV)
:
:
%
HIV-2 protease
HIV-1
:
_____ __X__
gag-polpolyprotein
: /
60
bioavailability
:
CYP 3A4 (Strong inhibitor)
15
98–99
2C19 (Inducer) % 11
86
% :
3–5
Ritonavir
warfarin
Significant rating: 4Onset: Delayed, Severity: Moderate, Documentation: Possible , Mechanism: Unknown , Effect : The anticoagulant effect of warfarin may be decrease. Leaflet / package insert: Ritonavir warfarin Drug Interaction Facts:
2
Clinical trials:
/
2013
2012
John S. Esterly, et al Case control study Albert M. Anderson et al
J AntimicrobChemother. 2013 Jun;68(6):1360-3.
200 mg OD
AIDS PATIENT CARE and STDs Volume 26, Number 8, 2012
lopinavir/riton avir 800/200 mg azatanavir/rit onavir 300/100 mg
Observational studies / case reports:
42
stable INR 2-3
Ritonavir aortic valve
stable INR 2-3
warfarin maintain dose 3.7mg (95% CI: 0.53–6.89, P= 0.03) EFV base ragimen warfarin 46mg INR
lopinavir/RTV AZA/RTV base ragimen 68mg warfarin mg 71
INR warfarin
mg/d 5.5 138
20
–1
2559
________________________________________________________________________________
INR -3 2 Ritonavir 400 mg 1.1-1.3 warfarin 13mg/d (Christine A., et al. CMAJ August 14, 2007 vol. 177 no. 4 357-359.)
2
Ritonavir
Ritonavir
warfarin warfarin% 50INR reports warfarin Ritonavir active 5 R-form CYP 2C9 S-form warfarin
-3 2
1
warfarin
Ritonavir
INR
INR
INR
INR warfarin
S-form
2
Ritonavir case warfarin S-form warfarin CYP 2C9 Ritonavir induced
warfarin
Ritonavir
INR monitor INR
warfarin
139
20
–1
2559
________________________________________________________________________________
Lopinavir (LPV)
: noninfectious virus
:
:
:
:
cleavage
Gag-pol
peak plasma time / CYP450 system
:
HIV-1 protease replication _____ __X__
4
98-99
CYP3A4
5-6
paracetamol
warfarin
Drug Interaction Facts: Significant rating: 4, Onset: Delayed, Severity: Moderate, Documentation: Possible, Mechanism: Unknown, Effect : Anticoagulant effect of warfarin may be decrease Leaflet / package insert: Lopinavir/ritronavir CYP3A4 in-vivo auto-inducer metabolized CYP2C9 , CYP2C19 (CYP2C9 CYP2C19 inducer) glucuronidation Clinical trials: Observational studies / case reports:
lopinavir/ritronavir
warfarin
warfarin 40-140%
/
2008
2007
Fulco PP, et al.
Pharmacotherapy 2008;28: 945-9.
Hughe CA, et al.
CMAJ 2007;177:357-9
17.5
12.5
warfarin 12.5 17.5 mg/day TDF,ddi,Nelfinavir TDF,ddi FTC,LPV/r INR warfarin LPV/r , Fluconazole cotrimoxazole fluconazole cotrimoxazole INR
mg/day
5.5 mg/day 13 mg/day
warfarin
Lopinavir
warfarin
Lopinavir(LPV) (Ritronavir;r) LPV report case ritronavir warfarin INR
auto-inducer
LPV/r
LPV
LPV/r
Boosted PIs warfarin enzyme inducer
140
20
–1
2559
________________________________________________________________________________
CYP2C9 LPV/r
metabolized
Lopinavir
warfarin
INR
warfarin
Package insert
warfarin
LPV(
LPV/r)
Warfarin
warfarin
141
20
–1
2559
________________________________________________________________________________
Saquinavir (SQV)
:
:
_____ __X__
:
HIV-2 protease
HIV-1
:
/
13
:
Saquinavir
gag-polpolyprotein
:
98 CYP 3A4 (Inhibitor) -3%
-88% 81
1
warfarin
Significant rating: 4 Onset: Delayed, Severity: Moderate, Documentation: Possible , Mechanism: Unknown , Effect : The anticoagulant effect of warfarin may be decrease. Leaflet / package insert: Saquinavir warfarin Clinical trials: Observational studies / case reports: Drug Interaction Facts:
stavudine Saquinavir 600
lamivudine mg TID INR
(Darlington
Saquinavir
INR Saquinavir inhibit
4 %20
5 mg/d
INR
82.46
warfarin
Saquinavir Saquinavir
INR warfarin 5
Saquinavir warfarin MR. Ann Pharmacother 1997;31:647.)
4.84
Saquinavir Atrial fibrillation
Saquinavir
CYP 3A4
Saquinavir Warfarin
Warfarin
warfarin R-form R-form warfarin
warfarin INR Saquinavir monitor INR
INR
-4 2
CYP 3A4
Saquinavir
20 %
warfarin
142
20
–1
2559
________________________________________________________________________________
Darunavir (DRV)
:
noninfectious virus
HIV-1 protease replication _____ __X__
:
: ritronavir low dose (100 mg BID) : acid glycoprotein : / :
15
cleavage
Gag-pol
Gag
bioavailability 37
13.9% 75.9%
95%
CYP3A4
82%
protein plasma
alpha-1
Darunavir
warfarin
Drug Interaction Facts: Significant rating: 4, Onset: Delayed, Severity: Moderate, Documentation: Possible, Mechanism: Unknown, Effect : Anticoagulant effect of warfarin may be decrease warfarin ( s-warfarin Leaflet / package insert: Darunavir AUC 21%) Clinical trials: Observational studies / case reports: warfarin TRIO regimen 50 DVT recurrent Emtricitabine monotherapy warafarin 13.3 mg/wk TRIO regimen (Darunavir/ritronavir, Etravirine, Raltegravir) Warfarin 19.3 mg/wk INR 2 2 4 3) warfarin 45% TRIO regimen D arunavir CYP2C9 Warfarin Ritronavir warfarin (Liedtke MD,Vanguri A, Rathbun RC. Ann Pharmacother. 2012 Nov;46(11):e34. Doi:10.1345/aph.1R290.Epub 2012 Oct 31.)
Darunavir
warfarin
warfarin
warfarin
warfarin
case report Darunavir ritronavir warfarin warfarin INR darunavir ritronavir INR warfarin darunavir ritronavir CYP 2c9 s-warfarin (potent enantiomer) control trial warfarin HIV darunavir auto-inducer PIs Booster(ritronavir)
Darunavir
(
INR
Darunavir
143
20
–1
2559
________________________________________________________________________________
Atazanavir (ATV)
: atazanavir :
polyproteins
protease inhibitor (PIs) (HIV-1) _____ __X__
viral Gag
Gag-Pol
: 2.5 , bioavailability 86, 1 : 89, cerebrospinal fluid (CSF) : / monooxygenation dioxygenation CYP3A glucuronidation, N-dealkylation, hydrolysis oxygenation (inactive) 79 13 : 7 HIV, 12 CYP450: strong CYP 3A inhibitor, weak CYP 2C9 & 1A2 inhibitor UGT1A1 inhibitor
atazanavir
warfarin
Drug Interaction Facts: Significant rating: 4, Onset: Delayed, Severity: Moderate, Documentation: Possible, Mechanism: Unknown, Effect : Anticoagulant effect of warfarin may be decrease Leaflet / package insert: atazanavir Clinical trials: Observational studies / case reports:
atazanavir
CYP450 3A, 1A2
atazanavir
atazanavir
INR
warfarin
(REYATAZ ®)
warfarin
Atazanavir
-
INR 2C9 case report warfarin warfarin
warfarin
warfarin
Atazanavir S-form R-form
atazanvir
warfarin
144
20
–1
2559
________________________________________________________________________________
Indinavir (IDV)
:
:
: bioavailability :
CYP450:
65
Indinavir (IDV)
(HIV-1)
60 glucoronide conjugate 83
strong CYP 3A4 inhibitor
: / CYP450 3A4 : 1.8
viral Gag Gag-Pol polyproteins __X__ _____
0.8
oxidative metabolites 19
weak CYP 2C9, 2C19, 2D6 inhibitor
warfarin
Drug Interaction Facts: Significant rating: 4, Onset: Delayed, Severity: Moderate, Documentation: Possible, Mechanism: Unknown, Effect : Anticoagulant effect of warfarin may be decrease Leaflet / package insert: indinavir warfarin warfarin R-warfarin indinavir/ritonavir ritonavir CYP1A2 CPY2C9 inducer (CRIXIVAN®)
Clinical trials: indinavir 50 Observational studies / case reports: warfarin prosthetic aortic valve (PCA; prothrombin complex activity; target range 25-35%) warfarin 5 mg/day 17 indinavir 800 mg 8 10 PCA 53% warfarin 6.25 mg/day 25 PCA 43% 20 62% 8.75 mg/day ritonavir PCA warfarin PCA 33% 24 (Gatti G, et al. Influence of indinavir and ritonavir on warfarin anticoagulant activity.AIDS 1998;12:825-6.)
Indinavir (IDV)
warfarin
indinavir INR CYP3A4 inhibitor warfarin 1-4
indinavir case report indinavir 50 INR Indinavir (IDV)
warfarin 1-2
50-75
warfarin ritonavir warfarin
INR INR
indinavir 25
warfarin ritonavir
145
20
–1
2559
________________________________________________________________________________
Raltegravir
replication
:Raltegravir
:
:
_____
glucuronidation
:
bioavailability :
HIV-1 integrase
HIV __X__
32
83
(Tmax)
3
: / uridinediphosphateglucuronosyltransferase-mediated raltegravirglucoronide (major inactive metabolite) 51 32 9 paracetamol
Drug Interaction Facts: Leaflet / package insert: Clinical trials: -
warfarin
Observational studies / case reports : patients treated with warfarin
case reports
can be used safely in HIV-1-infected Raltegravir
HIV-1- infected 5 warfarin stable dose warfarin 3-4 mg/ INR (1.5-2.5 -case1-3 2.0-3.0) antiretroviral agents antiretroviral agents INR warfarin abacavir/lamivudine/fosamprenavir -case4 62 HIV abacavir/lamivudine/raltegravir warfarin INR (1.5-2.5) warfarin -case5 52 abacavir/lamivudine/lopinavir+ritronavir chronic atrial flutter warfarin 1 mg/day INR (1.5-2.5) 4 (0.7-0.91) warfarin 4 mg/day w arfarin warfarin raltegravir (9 warfarin ) ARV abacavir/lamivudine/raltegravir/etravirine warfarin 1 mg/day 3 INR(1.5-2.5) INR= 1.46-2.49 INR(1.5-2.5) warfarin 3.5 mg/day
Raltegravir warfarin CYP isoenzymes / warfarin (Honda H ,et al.Raltegravir can be used safely in HIV-1-infected patients treated with warfarin. International journal of STD&AIDS.2012; 23: 903-904.)
Raltegravir
warfarin
146
20
–1
2559
________________________________________________________________________________
Raltegravir Cytochrome P450 Clinical trial Raltegravir warfarin warfarin Raltegravir
Raltegravir warfarin Cytochrome P450 Drug Interaction Facts ,Leaflet / package insert warfarin case reports Raltegravir warfarin
warfarin
Raltegravir
warfarin
147
20
–1
2559
________________________________________________________________________________
Maraviroc
:Maraviroc CD4
receptor CCR5 glycoprotein120
chemokine receptor antagonist membrane fusion HIV
_____ :
: 23
CCR5
__X__
bioavailability maraviroc 300 mg
33 : glycoprotein
Viral envelope
33
bioavailability single dose 300 mg Cmax AUC
single dose 100 mg
human chemokine
76
albumin
alpha-1 acid
: /
Cytochrome P450
CYP3A
CYP2C9,CYP2D6, CYP2C19
:
14-18
76
20
Maraviroc
warfarin
Drug Interaction Facts: Leaflet / package insert: Clinical trials: Observational studies / case reports: -
Maraviroc warfarin Maraviroc warfarin Maraviroc substrate Cytochrome P450 CYP 3A4 Cytochrome P450 D rug Interaction Facts ,Leaflet / package insert ,Clinical trial Observational studies / case reports warfarin
Maraviroc
warfarin
Maraviroc
warfarin
148
20
–1
2559
________________________________________________________________________________
Rifampicin
Mycobacterium tuberculosis RNA polymerase DNA-dependent RNA : _____ __X__ :
:
30 :
beta
84-91 liver, lungs, bile, pleural fluid, prostate, seminal fluid, CSF, saliva, tear bone CSF inflamed meninges 10-20 : / deacetylation active metabolite enterohepatic circulation active metabolite 24 600 mg/day 3-30 unchanged drug active metabolite 60
:
3–4
Drug Interaction Facts:
Rifampicin
warfarin
Significant rating: 2 Onset: Delayed, Severity: Moderate, Documentation: Established, Mechanism: hepatic enzyme inducer causing increased
warfarin metabolism (Induced CYP2C9, 2C19, 3A4) warfarin Leaflet / package insert: Rifampicin Observational studies / case reports: 5 case report
1975
/
John A. R, et al
()
Annals of Int Med
2010
Lee CR, et al
Pharmacot herapy.20 01 Oct;21(10) 1240-6
600
Rifampicin warfarin warfarin Rifampicin warfarin 50%.
1-2
/ 4
%
warfarin 200 %
Rifampicin 1-2
100-200 INR
50
149
20
–1
2559
________________________________________________________________________________
4
2010
Krajewski KC, et al
J Chin Pharmacol .2010 Jun;50(6):7 10-13.
300
2
6
Martins MA, et al
BMC Pharmacol Toxical 2013 May; 14(27):3-5.
35-40
/
45
J Clin Pharmacol . 2016 Jan;39(1):2 -5.
/
45
80
6
INR INR
MVR
2
105
, 155 5-30
210
52.5
)
50 %
1-2
(
INR
INR
7.5
Rifampicin
hematuria
)
5
Rifampicin inducer
3 INR 3
600
3-4
Fahmi AM et al, Case report
175
enzyme
AF 2016
INR
Rifampicin warfarin (
2 Rifampicin
600
AF
2013
(50-300 %)
Rifampicin 11 10.2
INR
52.5
80
INR
INR
5
29 45 . cerebrospinal fluid (CSF) examination polymerase chain reaction (PCR) 300 isoniazid rifampicin 450 ./ pyrazinamide 1,250 ./ streptomycin 750 ./ mitral warfarin INR 2.0 – 2.5 (INR 2.5 – 3.5) digoxin 125 ./ amiloride 2.5 ./ hydrochlorothiazide 25 ./ 3.18 INR baseline INR 1.56 1.35 7 15 INR
./
150
20
–1
2559
________________________________________________________________________________
INR warfarin 85 ./ cerebrospinal fluid INR hepatic microsomal enzyme Rifampicin
Rifampicin
(
rifampicin 3.7 )
rifampicin
(
INR PCR for M.tuberculosis rifampicin
rifampicin INR
warfarin
)
warfarin
potent enzyme inducer CYP 450 warfarin warfarin warfarin 1-2 Rifampicin 1 enzyme CYP 450 case report Rifampicin INR 1-2 INR warfarin 50 %– 200 % ( Lee CR, et al. Pharmacotherapy.2001 Oct;21(10)1240-6.) INR Rifampicin warfarin Rifampicin 50 % INR warfarin 4 INR Rifampicin
warfarin
warfarin 100-200%
2
warfarin R ifampicin induction
50%
warfarin rifampicin INR
INR 4-5 warfarin
INR warfarin
INR
1-3 1-2
1-2 enzyme
151
20
–1
2559
________________________________________________________________________________
Isoniazid (INH)
:
Mycoloic acid
(cell wall )
Mycobacterium tuberculosis
:
_____ :
_×__
:
/
10 – 15
:
acetylation
dehydrazination
acetylation
Rapid inactivator
50%
slow inactivator acetylation slow acetylation adverse effects 50-70 : 1-4 hr Metabolism Fast acetylator 0.5-1.6 hr Adults (including elderly patiants) Genetic
Slow acetylator 2-5 hr Adults (including elderly patiants) Isoniazid
warfarin
Drug Interaction Facts : Significant rating: 4 Onset: Delayed, Severity: Moderate, Documentation:Possible Mechanism: CYP2C9 Leaflet / package insert: Isoniazid warfarin Clinical trials : No data Observational studies/Case Reports:
/
1977
JAMA. 1977 Nov 14 ; 238(20):2177.
Rosenthal, et al
Isoniazid
600
/
10
/ Prothrombin time, hematuria and bleeding gums
warfarin
Isoniazid 600 / warfarin 10 / Prothrombin Bleeding gums ( Rosenthal, et al. JAMA. 1977 Nov 14 ; 238 (20):2177 .) metabolism warfarin CYP2C9 (www.remedysrxsp.ca/pdf/Warfarin-INRAntibx_Interaction.pdf) Isoniazid 300 / case report time , Hematuria
Isoniazid
warfarin
152
20
–1
2559
________________________________________________________________________________
Isoniazid
Isoniazid
300 Isoniazid 600
/ / warfarin
case report
10-15%
INR Isoniazid
153
20
–1
2559
________________________________________________________________________________
Streptomycin
:
aminoglycosides bactericidal drugs 30 S subunit Brucella, Calymmatobacterium, E. coli, Haemophilus and Mycobacterium
: _____ __X__ : IM : 1 : / : 90 1 2-4.7 : streptomycin warfarin Drug Interaction Facts : Micromedex : Leaflet / package insert: streptomycin warfarin http://( www.rxlist .:com/drug-interactions/streptomycin-im-and-warfarinoral-interaction.htm) significant interaction possible , monitor closely platelet warfarin warfarin report Case Report : Case 1. streptomycin platelet Adverse ( Reaction : Sec2:155) warfarin warfarin (rare case) warfarin 2. streptomycin thrombocytopenia warfarin ( https://www.drugs.com/pro/streptomycin.html) streptomycin warfarin streptomycin INR case reports streptomycin warfarin platelet
streptomycin
warfarin
warfarin
monitor INR streptomycin
platelet streptomycin 2 ) ( 6 ) MDR -TB ( streptomycin
154
20
–1
2559
________________________________________________________________________________
Ethionamide (Protionamide)
:
bacteriostatic against : _____
: :
ethionamide Mycobacterium tuberculosis. __X__
Hypothyroid
:
bioavailability 100%
Vd: 2.8 L/Kg
/ : active metabolite CYP450 1 5 active metabolite 2-3 : ethionamide warfarin Drug Interaction Facts : Micromedex : Leaflet / package insert: ethionamide platelet warfarin warfarin hypothyroid Case Report : Case report 1. ethiomamide Adverse( Reaction : Sec2:155) warfarin warfarin 2. ethionamide thrombocytopenia (rare case) warfarin warfarin ( Micromedex) (rare case) warfarin warfarin ( 3. ethionamide Hypothyroid hypothyroid Micromedex) case report ethionamide Case 1 : 48 on ethionamide 1 g/day 8 hypothyroid ethionamide 2 thyroid function ( Thomas M and Robert F. Amer Rew Resp Dis. 1970; 101: 90-94 .) Case 2 : 42 on ethionamide 1 g/day hypothyroid ethionamide 5 thyroid function ( Druker DE et, al. Ann Intern Med. 1984;100(6):837-839.)
ethionamide
ethionamide warfarin platelet
ethionamide
warfarin
ethionamide rare (case )
INR case reports thrombocytopenia, hypothyroidism
hypothyroid
warfarin
155
20
–1
2559
________________________________________________________________________________
platelet hypothyroidism ethionamide warfarin monitor INR level
ethionamide
monitor CBC, thyroid function
156
20
–1
2559
________________________________________________________________________________
Amikacin
:
bactericidal drugs
glomerulus
Drug Interaction Facts : Micromedex Leaflet / package insert Case Report
: : Amikacin
monitor INR
5 2-3
99
warfarin significant interaction platelet warfarin
warfarin
www .rxlist.com
warfarin
amikacin
28-86
amikacin INR warfarin platelet
amikacin
,
amikacin
warfarin
Case report
amikacin
amikacin http://(www.rxlist.com/drug-interaction-checker.htm) possible , monitor closely warfarin
30s
0–
11
/
: : :
:
__X__
: _____ 1
:
ribosome
platelet amikacin
warfarin
157
20
–1
2559
________________________________________________________________________________
CYP450 drug
warfarin Micromedex
interaction
Pyrazinamide Ethambutol Cycloserine PAS Kanamycin Streptomycin Amikacin
Ethionamide
Drug fact and
Rxlist.com
Medscape
comparison
warfarin
monitor INR
158
20
–1
2559
________________________________________________________________________________
Digoxin
: Digoxin
Na+-K+-ATPase digoxin
(positive inotropic effect)
+
digoxin
sympathetic
2+
protein) Na -Ca exchanger) contractile (( AV node
sympathetic
:
:
_____
__X __
) ( - 80% : 60% ( : 70% )- 85%
:
Vd: 6-7 L/kg Vd, hyperthyroid:
Vd, renal impairment:
; hypothyroid:
: 13% : 50-70% : 3-5% : 6-8%
25%
: /
CYP450
: 1.5
2
Leaflet / package insert: Clinical trials:
:
digoxin
digoxin
warfarin
warfarin
digoxin digoxin mg/day 2 INR insulin10 25 unit/day 60 0.25 warfarin 2 mg/day (14 mg/wk) 6 digoxin 9.1 nmol/L( 6 ( therapeutic ) level =1.2–2.4 nmol/L) INR 10 digoxin warfarin 5 digoxin specific antibody fragments digoxin INR
case reports:
159
20
–1
2559
________________________________________________________________________________
digoxin
0.065 mg/day warfarin 2 mg/day (Bhattacharyya A, et al. Br J Cardiol. 2002 Jun;9:356-7.)
digoxin
digoxin digoxin
warfarin
warfarin
warfarin
digoxin albumin
albumin INR
(Bhattacharyya A, et al. Br J Cardiol. 2002 Jun;9:356-7.)
INR digoxin
warfarin
( report) case digoxin
160
20
–1
2559
________________________________________________________________________________
Propafenone
:
atrium
ventricle : onset
:
:
3.5
_____
__X __
refractory period
3 8
(extended release capsule):
:
Vd: 252 L
95%
: / 10
:
2
CYP2D6, CYP3A4 P450
CYP1A2
metabolites
50 %
propafenone
warfarin
Facts: Significant rating: 4, Onset: Delayed, Severity: Moderate, Documentation: Drug Interaction Probable, Mechanism: decreased warfarin clearance Leaflet / package insert: propafenone warfarin Clinical trials:
1
/
1987
Robert E.et al
Clin Pharmacol Ther 1987;42:305-11.
Phase I:propafenone 225 mg t.i.d. 7 (
) Phase III: 7
propafenone
propafenone INR warfarin INR warfain 1 Jan/Feb : 4 4 (1): 25.e5)
warfarin
warfarin 2 t1/2 ( =2-10 propafenone (Bungard TJ,et al. C P J / R P C . 2 0 1
2-5
PT (P < 0.01) mg/day 7 ( ) warfarin Phase
II:warfarin 5
161
20
–1
2559
________________________________________________________________________________
propafenone
warfarin
Propafenone phannacokinetics Pharmacol Ther. 1987 Seb;42:305-11.) propafenone
pharmacologic warfarin INR
warfarin (Robert E.et al. Clin warfarin warfain
162
20
–1
2559
________________________________________________________________________________
Amiodarone Hydrochloride
antiarrhythmic ( drugs) Vaughan-Williams benzofuran 2-butyl-3benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride Amiodarone
class III
:
Amiodarone
2 prolongation of the myocardial cell-action potential duration and refractory period 2. Non-competitive α - and β -adrenergic inhibition : __X__ ____ 1.
:
bioavailability Amiodarone
30-80% (
)
Amiodarone
CYP3 A4
C9,3A4,2 2 D6
96
A2 (moderate 1
warfarin
Drug Interaction Facts: Significant rating: 1 Onset: Delayed Severity: Moderate to severe Documentation: Excellent Mechanism: Inhibit Warfarin metabolism and may also increase or reduce INR by inducing hyperthyroidism or hypothyroidism,respectively Leaflet / package insert: Amiodarone warfarin Clinical trials:
6
loading dose
Vd18-148L/kg : / CYP3A4 CYP 2C8 CYP inhibitor CYP3A4 inhibitor,weakly CYP1A2,2C9,2D6 inhibitor) : Amiodarone 20( -100 )
50%) (2-3
1
:
3-7
2
163
20
–1
2559
________________________________________________________________________________
/
1988
Nicholas Z, et al Retrospective study (N=8)
Arch InternMed 1988;1 48:1779-1781
Amiodarone
Amiodarone therapeutic prothrombin time stable
PT
stable
% 25 Amiodarone PT 1
warfarin
therapy amiodarone PT 22% to 108% Warfarin 2
2 2002
Sanoski CA, Bauman JL. Clinical observations (N=43)
Chest.2002;121(1):
19-23.
100,200,300, 400 mg/day
stable INR 2-3
amiodarone maintenance doses of 400, 300, 200 100 mg/d warfarin 40%, 35%, 30%, or 25%
2012
2013
1. G McDonald, et al Retrospective study (N=73)
Clinical Pharmacology & Therapeutics. 2012; 91(4), 709717
Jason Lam, et al Retrospective cohort study (N=14,248)
Am J Cardiol 2013;112:420-423
INR 5 (12%) minor bleeding Amiodarone
stable anticoagulatio n therapy INR 2-3
warfarin dose
Amiodarone+ Warfarin
Warfarin
1.
requirement 6-60 % ,1247 Amiodarone Warfarin 50 (0.8%) hemorrhage
Amiodarone
stable anticoagulation therapy
warfarin 2.
30 Risk Hemorrhage Amiodarone+warfarin Warfarin adjusted hazard ratio 2.45; 95% confidence interval, 1.49 to 4.02
164
20
–1
2559
________________________________________________________________________________
2014
Greg Flaker, et al Randomized, double-blind, placebocontrolled trial (N=18,201)
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2014,VOL. 64, NO. 15:1541-50
Warfarin
Amiodarone
1.
Warfarin + Amiodarone therapeutic range 5 Amiodarone(56.5% vs. 63.0%; p <0.0001)
Amiodarone Apixaban (2.5 mg
bid)
+ apixaban warfarin+ amiodarone 3. Apixaban + amiodarone Major no amiodarone bleeding major bleeding of 4. Warfarin + no 1.86%/year 3.06%/year amiodarone (HR: 0.61, 95% CI: 0.39 to 0.96) Case report: Case report case 10 Amiodarone anticoagulant Warfarin Amiodarone vitamin K-dependent coagulation factors Amiodarone Warfarin A ( Hamer, et al.American Heart Association 1982:1025-29 ) 2.
Amiodarone
Amiodarone
Warfarin
Amiodarone
Warfarin
Amiodarone
INR
PT Adverse
event Minor Major bleeding inhibitor bleeding CYP1A2,2C9,2D6 3A4 block biotransformation warfarin Active form(-)S-enantiomer inactive metabolites anticoagulant Warfarin INR PT Sanoski CA, ( Bauman JL.Chest.2002;121(1):19-23. ) Amiodarone
warfarin
warfarin Adverse Event Warfarin -25 50% Amiodarone monitor INR PT INR PT Amiodarone IV loading dose clinical Amiodarone trial Warfarin dose-dependent Loading dose Amiodarone dose loading half-life elimination half-life elimination Amiodarone -100 )(20 bleeding
warfarin
Amiodarone
165
20
–1
2559
________________________________________________________________________________
Flecainaide Acetate
: PR interval
class Icantiarrhymic QRS complex ventricle His-Purkinje
stimulation threshold
pointes
:____
:
Vd
5-13.4 L/kg
40-50 % : / unchanged drug metabolites) : Flecainide , 7-22 19 -26 Flecainide
electrical negative inotropic
EADs
torsade de
alpha1 acid glycoprotein
(80-90%
renal dysfunction
CHF
- 50%10
-12 ,11
8
warfarin
No drug interaction report
Flecainide
warfarin
Flecainide Substance CYP2D6 CYP1A2,2C9,3A4 Warfarin ( http://medicine.iupui.edu/clinpharm/ddis/main-table) Flecainide
:
K+ channel __x__
Drug Interaction Facts:
cardiac conduction QT interval local anesthetic
warfarin
Flecainide
warfarin
166
20
–1
2559
________________________________________________________________________________
Aspirin (acetylsalicylic acid)
cyclooxygenase (COX) Thromboxane A2 10 :
aspirin
PGI 2
prostaglandins(PG) (Cytoprotection)
__X__
____
:
PGE2
:
:
80-100%
90%
75%
: /
Aspirin 68%
Salicylic acid conjugation
irreversible inhibition) ( aspirin
Vd 150-170 ml/kg
32%
Hydrolysis Salicylic acid
hepatic
: parent drug 15-20 Renal: 10% (salicylic acid), 75% (salicyluric acid), 10% (phenolic glucuronide), 5% (acyl glucuronide) aspirin
warfarin
Drug Interaction Facts:
Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Established, Mechanism: warfarin may be enhanced. The adverse reactions of aspirin on gastric mucosa and platelet function also may enhance the possibility of hemorrhage. Leaflet / package insert: aspirin warfarin Clinical trials: 6
2002
/ Matte H, et al
Randomized controlled study (N=3630)
N Engl J Med 2002 Sep;347:969-74
-ASA alone
-Warfarin alone keep INR
160 mg/day
2.8-4.2
-ASA 75
-Warfarin+ASAkeep INR 2.02.5
/
+warfarin
warfarin alone warfarin+ASA
Major,non fatal bleeding (
GI bleeding)
alone
ASA
(0.62% vs 0.17% patient per treatmet167
20
–1
2559
________________________________________________________________________________
year,P<0.001)
acute MI 60 70 4 2005
Michael B, et al
Ann Intern Med 2005 Aug;143:241-250.
80-325
Meta-analysis
Keep INR 2.0-2.5
/
Major bleeding (
)
9
(10 Randomized
3
Controlled Study (N=5938)) 2006
Greg C, et al
Am Heart J 2006 Nov;152:967-73
<100
Randomized
keep INR 2.0-3.0 /
Major bleeding
(3.9% per
year vs 2.3% per
Controlled
y,P<0.01) Study (N=7304)
*Base line characteristic
warfarin
warfarin+ASA
2010
Morten LH, et al
Arch Intern Med. 2010;170(16):1433-1441
Cohort study
75-100
/
nonfatal
(N=118606)
fatal
bleeding
2
warfarin alone (6.8 vs 3.9 % per Patient-
year)
70
2011
Ming-Feng D, et al. Prospective randomized study (N=1496)
Thrombosis research. 2011 Aug;128:e91-4
75-100
3
/
mg/day
3
undergoing
mechanical heart valvular
Keep INR 1.8-2.5 Replacement
168
35±8.5
20
–1
2559
________________________________________________________________________________
major
bleeding
mortality ofbleeding (
2
Skin
ecchymosis) 2014
Jian-tang WANG,
J HuazhongUnivSciTechnol(Med Sci).2014
et al.
Oct;34(6):902-905
75-100
2.9 mg/day
/
keep INR 1.8-2.5
atrial fibrillation after mechanical heart
Randomized
valve replacement
Controlled
major bleeding mortality
Study (N=1016)
36.8±7.7
ofbleeding
5
-2
aspirin
aspirin gastric mucosa GI bleeding
INR INR INR 1.8-2.5
aspirin
INR
platelet
INR
warfarin
aspirin
3
warfarin
warfarin
169
20
–1
2559
________________________________________________________________________________
1.
2. 3.
4.
Micromedex® Solution. Aspirin [Internet].Truven Health Analytics Inc.© 2016[cited 2016 Jun25].Available from:http://www.micromedexsolutions.com/micromedex2/librarian/CS/90DF38/ND_PR/evidencex pert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/1A3B90/ND_PG/evidencexpert/ND_B/evidenc expert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.DoIntegrate dSearch?SearchTerm=aspirin&UserSearchTerm=aspirin&SearchFilter=filterNone&navitem=searchAL L# Kastrup EK, et al., Drug facts and comparisons 2012, St. Louis,Missouri,USA. Facts and comparisons Drug Interaction Fact 2014, Fact and Comparison St. Louis,Missouri,USA. MetteHurlen, Michel Bdelnoor, Pal Smith, JanErikssen, HaraldArnesen. Warfarin, aspirin, or both aftermyocardial infarction. N Engl J Med 2002 ;347(13):969-74. Michael B. Rothberg, Carmel Celestin, Louis D. Fiore, Elizabeth Lawler, James R. Cook. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: Meta-analysis with estimates of risk and benenefit. Ann Intern Med 2005;143:241-250.
5.
Greg C. Flaker, Michael Gruber,Stuart J. Connolly, Steven Goldman, Sandra Chaparro,Alec Vahanian, et al. Risks and benefits of combining aspirin withanticoagulant therapy in patients with atrialfibrillation: An exploratory analysis of strokeprevention using an oral thrombin inhibitor inatrial fibrillation (SPORTIF) trials. Am Heart J 2006;152:967-73.
6.
Morten L. Hansen, RikkeSørensen, Mette T. Clausen, Marie Louise Fog-Petersen, JakobRaunsø, NielsGadsbøll, et al. Risk of Bleeding With Single, Dual, or Triple Therapy With Warfarin, Aspirin, and clopidogrel in patients with atrial fibrillation.Arch Intern Med 2010;170(16):1433-1441.
7.
Ming-Feng Dong, Zeng-Shan Ma, Sheng-Jun Ma, Shou-Dong Chai, Pei-Zhe Tang, Dao-Kuo Yao. Anticoagulation therapy with combined low dose aspirin and warfarin followingmechanical heart valve replacement. Thrombosis research. 2011;128:e91-4. Jian-tang WANG, Ming-feng DONG,Guang-min SONG, Zeng-shan MA, Sheng-jun MA. Combined lowdose aspirin and warfarin anticoagulant therapy of postoperative atrial fibrillation following mechanical heart valve replacement. J HuazhongUnivSciTechnol(Med Sci).2014;34(6):902-905 .
8.
170
20
–1
2559
________________________________________________________________________________
Clopidogrel Bisulfate (Plavix®, Apolets®, Plavix GPO®)
:
(ADP)
P2Y12 receptor
ADP
1
2011)2
:
Prodrug
Clopidogrel Bisulfate
:
glycoprotein GP IIb/IIIa complex
-10
_____
1
:
(Hall,
bioavailability 30 , - 60
(dose-limited) 50
90
85 : clopidogrel hydrolysis carboxylic acid carboxylic acid 15 2-oxo-clopidogrel ( intermediate metabolite) cytochrome P450 CYP2C19(major), CYP3A4/A5(minor) enzyme inhibitor C YP2C8 (strong), CYP2B6(moderate) 2-oxo-clopidogrel :
paraoxonase-1 (PON1)
7
__X__
adenosine diphosphate (selectively and irreversibly)
:
50 ,
thiol metabolite
46
6
171
20
–1
2559
________________________________________________________________________________
2
clopidogrel
(Yin and Miyata, 2011) 3
clopidogrel
warfarin
Drug Interaction Facts:
Significant rating: 2 , Onset: Delayed , Severity: Major, Documentation: Suspected Mechanism: Pharmacodynamic synergism/Additive effects Leaflet / package insert: clopidogrel warfarin
2
Clinical trials:
/
Clopidogrel
2003
Christer Lindell, et al
Thrombosis and
75
8
Haemostasis. 2003:89/5(May)
randomized
adverse events
Atrial fibrillation
stable INR 2-3
pp.771-950.
-
non-valvular
-
controlled trial,
Clopidogrel
(N=43)
-
stable INR
warfarin
Clopidogrel75 mg/
2007
DeEugenio, et al
Pharmacotherapy. 2007 May;27(5):691-6
retrospective ,
active :
matched cohort clopidogrel + aspirin+
active :
-
major bleeding 14 (
active bleeding 3
1
)
major
172
20
–1
2559
________________________________________________________________________________
study, (N=194)
warfarin(long- term) PCI
control :
Warfarin
control
(long- term)
- Hazard ratio for major
%
59
Atrial fibrillation
active
-
PCI
bleeding = 5
clopidogrel + aspirin
warfarin
clopidogrel + aspirin major PCI
bleeding
clopidogrel
warfarin
I NR
warfarin antiplatelet
clopidogrel
clopidogrel
warfarin
clopidogrel
RCT,Cohort study clopidogrel clopidogrel hemodynamic
INR
warfarin warfarin major bleeding
warfarin anticoagulant
2. 3.
clopidogrel 1 INR
warfarin
warfarin
1.
Product Information: PLAVIX(R) oral tablets, clopidogrel bisulfate oral tablets. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Bridgewater, NJ, 2010 . Hall R, Mazer CD. Antiplatelet drugs: a review of their pharmacology and management in the perioperative period. Anesth Analg 2011; 112:292-318. Yin T, Miyata T. Pharmacogenomics of clopidogrel: evidence and perspectives. Thromb Res 2011; 128:307-16.
173
20
–1
2559
________________________________________________________________________________
Ticlopidine
:
ADP
:
:
:
:
bioavailability
bioavailability
ADP receptor platelet ( aggregation) __X__ _____
- 90
80
20
98 : / metabolized N-dealkylation N-oxidation 60 30 250 mg 12.5 2 4 – 5
Ticlopidine
repeat dose 250 mg
warfarin
Drug Interaction Facts: ticlopidine warfarin Leaflet / package insert: ticlopidine warfarin Medscape: Coadministration of warfarin and antiplatelet agents may increase the risk of bleeding. Monitor patients closely for signs or symptoms of bleeding and evaluate promptly. Clinical trials: ticlopidine warfarin
1 Observational studies / case reports: Observation study ticlopidine pharmacodynamics pharmacokinetics 9 warfarin ticlopidine 250 mg 2 2 steady-state warfarin enantiomer INR 14 Baseline S-warfarin concentration INR warfarin concentration baseline (Gidal BE, et al. Ther Drug Monit. 1995 Feb;17(1):33-8.)
warfarin
Ticlopidine warfarin ticlopidine INR Ticlopidine
warfarin
ticlopidine ticlopidine
R-
R-
warfarin
174
20
–1
2559
________________________________________________________________________________
Ticagrelor
:
P2Y(12) ADP-receptor
:
:
__x___
: 7
: / CYP 3A4
36
58
ticagrelor
26
ticagrelor 2
warfarin
ticagrelor ticagrelor ticagrelor ticagrelor ticagrelor
warfarin warfarin warfarin warfarin warfarin
ref.) (
/
2014
Drug Interaction Facts: Leaflet / package insert: AHFS drug: Martindale: Micromedex: Medscape: Clinical trials:
bioavailability 99
____
:
Lu W, et al
Contemp Clin Trials.
/
180
2015 Jan;40:166-71.
A multicenter,
1
6
ASA
active-
81
+/ Clopidogrel
controlled,
75
/
Dual therapy beeding
triple therapy
beeding
19.4
44.4
open-label, randomized trial (N=296) 2015
Braun OÖ, et al
Thromb Res. 2015
Dual therapy
Jan;135(1):26-30.
(ticagrelor 180
Retrospective, medical recordbased analysis (N=363)
stable )/
INR 2-3
triple therapy (ASA 75
+/ Clopidogrel
75
/)
3
HAS-BLED
bleeding risk score
(ticagrelor+warfarin)
Dual therapy
triple
therapy(HAS-BLED 2.2+/-
0.8 vs 2.2+/-1.0 units,
175
20
–1
2559
________________________________________________________________________________
p=NS; duration 2.7+/-0.8 vs 2.5+/-0.9months, p=NS; DT vs TT)
(bleeding 8/106 (7.5%) vs 11/157 (7.0%), p=NS; thrombosis 5/106 (4.7%) vs 5/157 (3.2%), p=NS;
DT vs TT).
Observational studies / case reports:
ticagrelor
ticagrelor of platelet Inhibition aggregation
P2Y(12) adenosine diphosphate
ticagrelor
triple therapy
ticagrelor warfarin
triple therapy
warfarin
ticagrelor
warfarin
ticagrelor
warfarin
warfarin INR
176
20
–1
2559
________________________________________________________________________________
Prasugrel
Acute coronary syndrome - Percutaneous coronary intervention - Thrombosis; Prophylaxis : thienopyridine prodrug active metabolite P2Y12 adenosine diphosphate (ADP) receptor irreversible aggregation __√__ ____ :
:
:
98
hydrolysis CYP2B6
68-70 active metabolite 25-27 non-active metabolite : active metabolite 7-8 ( prasugrel
albumin
platelet
metabolite CYP3A (major) CYP2C9 CYP2C19
activation
active metabolite : /
platelet
active
active metabolite
2-15
)
warfarin
Drug Interaction Facts: Micromedex: Significant rating: - , Onset: Not Specified, Severity: Major (micromedex) serious (medscape), Documentation: Fair Mechanism:warfarin, prasugrel. Either increases effects of the other by pharmacodynamic synergism. Enhanced risk of hemorrhage. Leaflet / package insert: warfarin Clinical trials: US FDA prasugrel warfarin 15 mg bleeding time
Observational studies / case reports: prasugrel INR 1 58 85 elevation myocardial infarction, severe leftventricular dysfunction, hypertensive c reatinine, hemoglobin platelet count
anterior STdyslipidemic Dual
antiplatelet therapy aspirin prasugrel thrombus stent 9 echocardiography warfarin 4 left temporoparietalintraparenchymal hemorrhage INR 3.4 (previous values were a maximum of 2.5-3.0) Hemoglobin platelet count (Savonitto S, et al. Rev EspCardiol. 2014;67:225-6.) 2 68 96 anterior ST-elevation I NR 1.15 myocardial infarction severe left ventricular dysfunction 177
20
–1
2559
________________________________________________________________________________
stent atrialfibrillation enoxaparin fresh frozen plasma 1 unit
prasugrel
warfarin
Clinical trials bleeding)
Dual antiplatelet therapy (aspirin prasugrel) warfarin 13 rectal bleeding hemoglobin 8.3 g/dL prasugrel warfarin (Savonitto S, et al. Rev EspCardiol. 2014;67:225-6.)
(
prasugrel
warfarin
prasugrel warfarin Acute coronary syndrome Percutaneous coronary intervention Triple therapy INR PT prasugrel transient ischemic attack stroke 75 intracranial bleeding prior MI
1. MICROMEDEX® [Database on the internet]. Colorado: Thomson Reuters (Healthcare).DRUGDEX® System, Prasugrel;[cited 23 Jun 16]. Available from:http://www.thomsonhc.com 2. Approved draft labeling of EFFIENT®Eli Lilly & CO., Inc.Drug@FDA; [cited 23 Jun 16]. Available from: http://www.USFDA.com. 3. Savonitto S, et al. Fatal bleedings with prasugrel as part of triple antithrombotic therapy. Rev EspCardiol. 2014;67:225-6.
178
20
–1
2559
________________________________________________________________________________
Dipyridamole
:
:
:
A2
_____
: / glucuronides
: 10 – 12
Drug Interaction Facts: Micromedex:
__X__
:
cyclic GMP phosphodiesterase activity (coronary vasodilator)
adenosine uptake
thromboxan
bioavailability 99
91
66
27
conjugation
dipyridamole
warfarin
dipyridamole warfarin Onset: not specific , Severity: Major, Documentation: Fair, Mechanism: Additive effect prothrombin time (1. Kalowski S, Kincaid-Smith P. Interaction of dipyridamole with anticoagulants in the treatment
of glomerulonephritis. Med J Aust 1973; 2: 164-6. (PubMed id:4741342 2. Levine MN, et al. Hemorrhagic complications of long-term anticoagulant therapy. Chest 1989; 95 (suppl): 26S-36S. (PubMed id:2644101)) Leaflet / package insert: dipyridamole warfarin INR ( )
1
Clinical trials:
/
1983
Sylven C, Anderson P. Observational
BMJ. 1983; 286:1181.
[IDIS 169731] [PubMed 6404381]
3
1.85-2mg/day
warfarin
bleeding dose
thrombosis
study (N=7 patient )
58 9 coronary care unit cardiac infraction LV failure atrial tachycardia IV bolus disopyramide phosphate (1-5 mg/kg body weight) reversion sinus rhythm maintenance dose 100 mg 6 heparin 48 Case report: . 1997
200mg
179
20
–1
2559
________________________________________________________________________________
warfarin
warfarin 3 mg/day
digoxin 0-25 mg/day, frusemide 80 mg/day, potassium supplements, 1 00 mg
disopyramide
INR
in vivo
vitro
6
4
disopyramide
hypotensive (80/60 mm Hg)
malaise
disopyramide
warfarin
in
disopyramide
protein
(personal communication, Searle Laboratories)
plasma protein binding site
admit
potential negative inotropic effect
27%
E Haworth, A K Burroughs.
Disopyramide and warfarin interaction.Br Med J. 1977 October 1; 2(6091): 866 –867.
dipyridamole
dipyridamole
INR warfarin
dipyridamole
dipyridamole INR ( )
warfarin
warfarin
warfarin
warfarin
warfarin
180
20
–1
2559
________________________________________________________________________________
Eptifibatide
:
glycoprotein IIb/IIIa receptor vonWillebrand factor adhesiveligands platelet aggregation
:
:
__X__ 25 50-71.4 Eptifibatide
fibrinogen,
_____
:
reversible glycoprotein IIb/IIIa receptor
: / : 2.5 eptifibatide
metabolites
warfarin
Significant rating: , Onset: Not Specified, Severity: Major, Documentation: Fair, Mechanism: additive effects (MICROMEDEX® [Database on the internet]. Colorado: Thomson Reuters (Healthcare); c2016. DRUGDEX® System, eptifibatide; [cited 2016 Jun 24]. Available from:http://www.thomsonhc.com) Leaflet / package insert: eptifibatide anticoagulants Drug Interaction Facts:
Clinical trials:
eptifibatide
warfarin
Observational studies / case reports:
eptifibatide
UFH eptifibatide
enoxaparin warfarin
eptifibatide
eptifibatide
eptifibatide
warfarin
warfarin
parenteral
anticoagulants
eptifibatide
warfarin warfarin INR
181
20
–1
2559
________________________________________________________________________________
Cilostazol
:
type 3 (PDE3) platelet aggregation
:
:
Antiplatelet ( drug) cAMP cAMP vasodilation
__ X __
____
phosphodiesterase
bioavailability
90
95 -98 : / CYP3A4 and CYP2C19 : 20; 74 : 11 – 13 Cilostazol warfarin Cilostazol warfarin Drug Interaction Facts: Leaflet / package insert: Cilostazol warfarin Clinical trials: 1 Cilostazol :
1999
/
warfarin
randomised doubleblind 2-
healthy
Clinical
-
1 cilostazol100 mg
pharmacokinetic
13
2
-
volunteers
2 placebo
warfarin cilostazol 100 mg 2
warfarin 25 mg
14
2
7
13
pharmacokinetics (R)- and (S)-
15 Mallikaarjun S, Bramer SL.
warfarin,prothrombin
cilostazol
time, partial
placebo
thromboplastin time,
Ivy bleeding times,
cilostazol
Cilastazol
warfarin
Cilostazol
INR
182
20
–1
2559
________________________________________________________________________________
Simvastatin
HMG-CoA reductase HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) Mevalonic acid Mevalonic acid Cholesterol rate -limiting enzyme endogenous cholesterol
:
Cholesterol LDL receptor
Cholesterol LDL -C : _____ __X__ : bioavailability 5%, Tmax : 1.73 - 4 : 95 / : prodrug hydrolysis active beta-hydroxyacid metabolite extensive first pass metabolism Substrate CYP3A4(major) 13 60 2 – 3 : active metabolite ( ) 4.42 - 4.88
simvastatin
Drug Interaction Facts :
warfarin
Significant rating: 1 Onset: Delayed, Severity: Major, Documentation:
Probable, Decreased S- and R-warfarin clearance by inhibition of CYP2C9 and CYP3A4 metabolism, respectively Leaflet / package insert: INR warfarin Product Information Merck & Co 2clinical studies cholesterol simvastatin /day INR 1.7 -1.8 -40 mg20 -3.4 2.6 baseline Mechanism:
Clinical trials: Observational studies / case reports: rhabdomyolysis 7 Observational studies
-
-
simvastatin
Retrospective, open-label, cohort study (N=46)
± 0.76 pravastatin ) 20 mg simvastatin (p=0.002 INR > 3.020 mg 2 .74 K., et al. J ClinPharmacol 1999;39 :86-90)
Cohort study (N=29) INR 2.5 3.15) INR 9 (p<0.001) ( 2003; 89: 949 –50)
3 visits
INR
INR 6
warfarin
± 0.59 p = 20.42 16 026( ) (Lin
warfarin INR 2-3 27 (p<0.003) ( warfarin 4.2 mg/day ) (3.8 Kamali F., et al. ThrombHaemost
simvastatin
183
20
–1
2559
________________________________________________________________________________
-
case -control study nested (n=353,489) warfarin ≥ 18 simvastatin (n=15186) odds ratio gastrointestinal bleeding 1 .46 [95% CI, 1.03-2.07] for the first prescription 1.60 [95% CI, 1.07-2.39] for the second prescription (Schelleman H., et al.Am J Med. 2010 Feb; 123(2): 151) case reports -
-
82
Deep vein thrombosis
warfarin 2.5 mg
10 mg INR 26 atorvastatin simvastatin10mg 4 INR 8 . vitamin K (Westergren T, et al . Ann Pharmacother 2007;41:1292-5.)
2
5 61 warfarin subdural haematoma 4 simvastatin ( warfarin) (Rise IR. ActaNeurologicaScandinavica 96: 339, Nov 1997)
simvastatin
CYP3A4 simvastatin
3 hematoma
off-set
bilateral SDH
INR
9
warfarin warfarin
2-3
INR
INR
CYP2C9(weak)
warfarin
metabolism
30
INR case report onset 4
184
warfarin
warfarin simvastatin INR observational study INR < case reports INR observational study ( )
warfarin
substrate
70 arterial thrombosis warfarin 2mg/ 6 2-3.5 atherosclerosis, ischemic heart disease hypercholesterolaemia diltiazem, ISMN simvastatin 3 simvastatin INR simvastatin warfarin INR 2-3 G (Enric, et al. The Lancet 437:405, Feb 1996 )
20
–1
2559
________________________________________________________________________________
Atorvastatin
HMG-CoA reductase HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) Mevalonic acid Mevalonic acid Cholesterol rate -limiting enzyme endogenous cholesterol
:
Cholesterol LDL receptor
Cholesterol LDL -C : _____ __X__ : bioavailability 14%, Tmax: 1-2 : 98 / : CYP450 system CYP3A4 2 14 active : metabolite ( 4.42 - 4.88 ) Atorvastatin warfarin Drug Interaction Facts : Leaflet / package insert: Atorvastatin prothrombin time warfarin Clinical trials: Observational studies / case reports: 2
Observational studies
-
-
case -control study nested (n=353,489) warfarin ≥ 18 atorvastatin ( n=32,588) odds ratio gastrointestinal bleeding 1.39; [95% CI, 1.07-1.81] for the first prescription; 1.05 [95% CI, 0.73-1.52] for the second prescription). (Schelleman H., et al.Am J Med. 2010 Feb; 123(2): 151)
I NR
p=0.016
Case control (N=12) warfarin 1 Atorvastatin 80mg Prothrombin time 3-5 p=0.0002, ( p=0.0001 )S (Ralph, et al. J ClinPharmacol1997;37:1062-1064) Atorvastatin warfarin metabolism
atorvastatin
CYP 3A4(weak) warfarin
substrate
CYP3A4(major)
warfarin
INR
INR
185
20
–1
2559
________________________________________________________________________________
Pravastatin
:
HMG-CoA reductase HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) Mevalonic acid Mevalonic acid Cholesterol rate-limiting enzyme endogenous cholesterol Cholesterol LDL receptor
:
:
bioavailability
:
: / extensive hydroxylation 71
Cholesterol LDL-C _____ __X__ 17%, Tmax : 1–1.5 43-55 (Vd 0.46 l/kg) first pass metabolism inactive metabolite
isomerization 20
: 2.6– 3.2 pravastatin warfarin Drug Interaction Facts: Mechanism: Leaflet / package insert: Pharmacokineticsdrug interaction pravastatin mg BID 20 for 6 days warfarin 5 mg OD for 6 days AUC Cmax warfarin 17 15 mean prothrombin time 0.4 AUC pravastatin 13Cmax 6.7 Clinical trials: Observational studies / case reports: 1 Observational studies pravastatin INR case-control study nested(n=353,489) warfarin ≥ 18 pravastatin (n=8765) gastrointestinal bleeding 0.75; [95% CI,
0.39-1.46] for the first prescription; 0.90 [95% CI, 0.43-1.91] prescription(Schelleman H., et al.Am J Med. 2010 Feb; 123(2): 151)
pravastatin
pravastatin pravastatin
warfarin warfarin
the
second
warfarin
Pravastatin
for
AUC
Cmax
INR
warfarin
186
20
–1
2559
________________________________________________________________________________
Rosuvastatin
:
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) rate-limiting enzyme cholesterol synthesis lipoprotein (VLDL) low density lipoprotein (LDL)
:
:
_____
bioavailability
:
: 19
: /
10
__X__ 20 88 CYP450 system
selective inhibitor very low density
CYP2C9
rosuvastatin
warfarin
Drug Interaction Facts:
Significant rating: 1 Onset: Delayed, Severity: Moderate, Documentation: Good, Mechanism: Concurrent use of rosuvastatin and warfarin may result in increase in international normalized ratio (INR) and increased risk of bleeding Leaflet / package insert: rosuvastatin warfarin Clinical trials: 2
2005
/
J Daisy, et al
Eur J ClinPharmacol
open labeled,
(2005) 61: 621–625
Rosuvastatin40mg
Warfarin 5mg
Clotting
OD
placebo
placebo- controlled,
- Bleeding time ,
time,INR
PT
2
randomized, twoperiod, crossover trial (N=12) 2005
SG Steven. et al
J ClinPharmacol. 2005
Trial A:
Trial A:
Trial A (a
Aug;45(8):927-34.
rosuvastatin 40
warfarin 25 mg
randomized, doubleblind, 2- period crossover study (N=18)
mg OD 10
placebo
7
rosuvastatin warfarin placebo
AU-INR0-t
10 (p<0.001)
INRmax
(p<0.001)
187
19
20
–1
2559
________________________________________________________________________________
Trial B (an
Trial B:
open-label, 2-
2
Trial B:
rosuvastatin 10
stable INR 2-3
INR>4 (
period
study)(N=7)
rosuvastatin 10mg
mg OD 14
period
period 1)
4
rosuvastatin80mg
2
INR >4( period 2)
INR <3
rosuvastatin
80 mg
INR
2-5
rosuvastatin warfarin
Observational studies / case reports: rosuvastatin 76 warfarin 4 rosuvastatin INR 8.0 INR stable K 10
rosuvastatin
80 mg
hematuria
)
fresh frozen plasma 2 units
vitamin
placebo rosuvastatin rosuvastatin rosuvastatin 40 mg
international normalized ratio (INR)
INR
warfarin
rosuvastatin (
rosuvastatin 10 mg placebo rosuvastatin
warfarin
rosuvastatin
INR
rosuvastatin
warfarin
188
20
–1
2559
________________________________________________________________________________
Fluvastatin
:
reversible competitive inhibitor HMG–CoA reductase (3– hydroxy–3–methylglutaryl coenzyme A reductase) HMG-CoA mevalonate Rate limiting enzyme cholesterol enzyme
cholesterol expression LDL – C
LDL LDL receptor gene – C hepatocyte LDL LDL receptor –C : _____ __X__ : capsule: Time to peak 1 , Bioavailability 24 ( 9 - 50) 29 extended-release tablet: Time to peak 3 , Bioavailability ( 9-66) : 98 , Vd 0.35 L/kg : / hydroxylation, N-dealkylation beta-oxidation 75 P450 20 P450 CYP3A4 feces CYP2C9, 5 P450 CYP2C8 90 metabolite, unchanged 2 5
:
capsules
3
fluvastatin
extended-release tablet
9
warfarin
Drug Interaction Facts:
Significant rating: 2, Onset: Delayed, Severity: Moderate, Documentation: good, Mechanism: increased warfarin serum concentrations due to inhibition of CYP2C9-mediated S-warfarin metabolism Leaflet / package insert: fluvastatin warfarin bleeding Clinical trials: No Data Observational studies / case reports: fluvastatin INR
-
-
67 warfarin 4 mg/day atorvastatin 20 mg/day INR 6.6
recurrent INR
deep vein thrombosis hypierlipidemia 2-3 5 fluvastatin 80 mg/day 9 w arfarin 4
4 MR: INR (Andrus Oral anticoagulant drug interactions with statins: case report of fluvastatin and review of the literature. Pharmacotherapy 02/2004; 24:285-290.) 3 68 warfarin 42.50 mg/week I NR fluvastatin 20 mg/day 2 INR 4.17 warfarin INR (2.5-3.5) 83 warfarin 22 mg/week INR 1.84-2.73 fluvastatin 20 mg/day 1 INR 3.47 189
20
–1
2559
________________________________________________________________________________
warfarin 14 mg/week fluvastatin warfarin I NR warfarin 60 mg/week 1 20 mg/day mg/week 4
I NR
therapeutic range 51 INR 1.95-3.4 fluvastatin INR 4.2 warfarin 52.50 INR Therapeutic range (Kline
1.67
fluvastatin
SS & Harrell CC: Potential warfarin-fluvastatin interaction (letter). Ann Pharmacother 1997; 31:790. ) 81 warfarin 2.5 mg/day INR 2.0–3.0 warfarin (2009-2011) fluvastatin 80 mg/day 2 INR hematoma 5 (Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin pharmaco Ther 1981;30:239 –45.)
-
fluvastatin f luvastatin
9
warfarin warfarin fluvastatin
warfarin
CYP2C9 Mediated S-warfarin metabolism
INR case reports INR therapeutic range fluvastatin INR 3 .47 6.6 bleeding 1 INR increased warfarin serum concentrations due to inhibition of
warfarin
fluvastatin
INR
lovastatin
190
20
–1
2559
________________________________________________________________________________
Lovastatin
:
reversible competitive inhibitor HMG–CoA reductase (3– hydroxy–3–methylglutaryl coenzyme A reductase) HMG-CoA mevalonate Rate limiting enzyme cholesterol enzyme cholesterol expression LDL – C
LDL – C hepatocyte LDL LDL receptor –C : _____ __X__ : time to peak 2 , bioavailability : 95 : / effect first-pass hydroxyacid (active) feces 83 : 1.1 - 1.7 lovastatin warfarin
LDL
receptor
gene
5 hydrolysis 10
beta-
Drug Interaction Facts: Significant rating: 2, Onset: Delayed, Severity: Moderate, Documentation: Fair, Mechanism: unknown
lovastatin
Leaflet / package insert:
warfarin
bleeding
Clinical trials: lovastatin trial lovastatin prothrombin time (Ahmad S: Lovastatin:warfarin interaction. Arch Intern Med 1990; 150:2407.) small clinical trial prothrombin time lovastatin warfarin lovastatin prothrombin time (Product Information: Mevacor(R), lovastatin. Merck & Co., Inc., Whitehouse Station, NJ, 06/2002.) ( ) Observational studies / case reports: No data
lovastatin
warfarin
)
warfarin
lovastatin
prothrombin time
warfarin
lovastatin
INR
lovastatin
warfarin
warfarin
lovastatn fair (
191
20
–1
2559
________________________________________________________________________________
Pitavastatiin
:
reversible competitive inhibitor HMG–CoA reductase (3– hydroxy–3–methylglutaryl coenzyme A reductase) HMG-CoA mevalonate Rate limiting enzyme cholesterol enzyme cholesterol expression LDL – C
LDL LDL receptor gene – C hepatocyte LDL LDL receptor –C : _____ __X__ : Tmax 1 , bioavailability 51 : (albumin alpha 1-acid glycoproteins) 99 : / conjugation UDP-glucuronosyltransferase subtype 1A3 (UGT1A3) UDP-glucuronosyltransferase subtype 2B7 (UGT2B7) CYP450 system feces 79 CYP2C9 CYP2C8 15 : 11 – 12
pitavastatin
Drug Interaction Facts: Leaflet / package insert: Clinical trials: Observational studies / case reports:
warfarin
pitavastatin warfarin pitavastatin warfarin pitavastatin warfarin pitavastatin warfarin
192
20
–1
2559
________________________________________________________________________________
Gemfibrozil
peroxisome proliferators activated receptor -α (PPAR-α) nuclear transcription factor fatty acid transporter protein fatty acid oxidation lipoprotein lipase lipoprotein :
HDL
VLDL, remnant lipoproteins
: ______
___ X___
:
:
/ : oxidation ring methyl group carboxyl metabolite (inactive) enterohepatic recycling 70 glucoronide conjugate , 2 6 CYP450 Substrate of CYP3A4 (minor) Inhibits CYP1A2 (moderate), 2C8 (strong), 2C9 (strong), 2C19 (strong) 1.3 : gemfibrozil warfarin
Observational studies
/
hydroxyl methyl
Drug Interaction Facts : Onset: Severity: Documentation: Probable Mechanism: Leaflet / package insert:
%
Protein Binding99
VLDL
Significant rating1 Delayed Major (Drug Interaction Fact ),Moderate (Micromedex) Established (Drug Interaction Fact ),Good (Micromedex) metabolism warfarin ; Protein warfarin warfarin case reports:
gemfibrozil
INR
62 paroxysmal atrial fibrillation warfarin 45 mg / 9 INR stable 2-3 1 gemfibrozil 600 mg 2 3 I NR 5.8 warfarin 22 % 35-37 mg/ I NR 4 gemfibrozil Myalgia ( ) I NR 1.7-1 .8 warfarin 4.5 mg/ INR Dixon (& Williams, Pharmacotherapy Jun, 2009; 29(6):744-748.) 5 gemfibrozil 38 warfarin 5 mg 1200 mg ( dose ) 2 PT warfarin 2.5 mg 2 (Ahmad S,Chest 1990; 98:1041-1042.) warfarin INR 2 .6 73 5 mg 7.5 mg 3 (1.8-3.8) gemfibrozil 1200 mg 1 5 INR 2.6 43 193
20
–1
2559
________________________________________________________________________________
warfarin INR 3 7.5 mg) 8 (Rindone&Keng, Chest 1998; 114:641-642.1998) gemfibrozil warfarin case report warfarin
vitamin K 10 mg
( INR
INR 3
5 mg
1 .9-3 .0
gemfibrozil
vitamin K gemfibrozil parahydroxylation warfarin warfarin gemfibrozil protein binding warfarin free fraction warfarin metabolim CYP2C9 (strong) substrate CYP3A4 (minor) coagulation factor receptor PT
INR
gemfibrozil
warfarin warfarin INR onset ~2-3 PT INR ΔINR ~3 20 50 gemfibrozil warfarin offset ~ 2
gemfibrozil
INR
warfarin
-
20 25
INR
194
20
–1
2559
________________________________________________________________________________
Fenofibrate
:
peroxisome proliferators activated receptor- α (PPAR- α) fatty acid transporter protein fatty lipoprotein lipase lipoprotein
transcription factor acid oxidation triglyceride
HDL
triglyceride
VLDL
nuclear
: __X__
_____
:
bioavailability 81 99 / : Fenofibrate m etabolite enzyme esterases active form fenofibric acid inactive glucuronidation glucoronide conjugate 60 25 20 : Substrate of CYP 3A4 (minor) Inhibits CYP2A6 (weak), 2C8 (weak), 2C9 (weak), 2C19 (weak) :
Fenofibrate warfarin Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Established Mechanism: Coagulation factor synthesis may be affected. Leaflet / package insert: Fenofibrate warfarin warfarin
Clinical trials:
fenofibrate
Observational studies / case reports:
-
79
6
furosemide fenofibrate
-
atrial fibrillation
/ INR gemfibrozil
1
INR
coronary heart disease
warfarin digoxin fosinopril TG gemfibrozil
INRINR (
; grossly)
(MA Aldridge, et al.Pharmacotherapy 21:886, 2001 886-9) 2 71 80 atrial fibrillation warfarin warfarin/ (TWD) 23 I NR 20 fenofibrate INR 3 2 warfarin 30 – 40 (Karissa Y Kim,Michael A Mancano. Ann Pharmacother. 2003 Feb; 1, 37:212-215)
TWD
195
20
–1
2559
________________________________________________________________________________
-
atrial 47 septal defect warfarin -15mg/ 12.5 INR 2-2.5 fenofibrate 200mg/ 1 flank ( pain) tea-coloured) ( INR 8.5 vitamin K warfarin fenofibrate INR INR warfarin fenofibrate warfarin 10 mg/ fenofibrate / 56 aortic warfarin -
INR 5 mg/ f enofibrate 3.5 2.8 fenofibrate INR (KJ Ascah, et al., Annals of Pharmacotherapy 32: 765-768, Jul-Aug 1998)
fenofibrate
case report INR
5.6
INR
warfarin
warfarin
INR
fenofibrate
vitamin K
fenofibrate clofibrate free fraction warfarin pharmacokinetic interaction coagulation factors fenofibrate parahydroxylation warfarin warfarin fenofibrate p rotein binding warfarin free fraction metabolim warfarin CYP2C9 (weak) substrate CYP3A4(minor) coagulation factor II VII receptor fenofibrate 16 baseline fibrinogen plasma 4 ( ) ( p<0.01) fibrinogen Fenofibrate
warfarin
-35
onset ~1
20
warfarin
INR
1
INR
INR
INR
INR ∆ ~2-6
warfarin
196
20
–1
2559
________________________________________________________________________________
Nicotinic acid
:
lipoprotein lipase
: ______
:
/
conjugation
metabolism metabolite
LDL
HDL
Bioavailability 60% - 76%
extensive
first-pass,
n icotinamide adenine dinucleotide (NAD)
Nicotinic acid
warfarin
Drug Interaction Facts : Onset:
( micromedex) Not Specified
Severity:
Moderate (micromedex)
Documentation:
Good (micromedex)
Probable Mechanism:
60 % - 88%, 12% (Nicotinic acid)
20 - :45
, extended release : 4 -5
:
, immediate release 30 - 60
:
chylomicron triglyceride VLDL
___X___
adipose tissue ,
Nicotinic acid
metabolism warfarin CYP 450 metabolite Nicotinic acid(micromedex) Leaflet / package insert: Prothrombin time ~ 4 warfarin Observational studies / case reports: nicotinic acid INR 69 17.5 warfarin extended -releasenicotinic acid500 mg mg/ I NR 1 acid
4.8
3 1000 mg
K 2 .5 mg
Day 2
warfarin 17 mg/
INR 2 .2 ,2 .9,2 .4 nicotinic 12.3 warfarin Nicotinic acid INR INR 10 .43 Day 1 INR I NR 2 .2 warfarin INR 2 .3(Christopher A. Ann Pharmacother Nov, 2011; 45(11):e58.) nicotinic acid warfarin 1
INR
11
INR
197
20
–1
2559
________________________________________________________________________________
case
warfarin
INR
INR
1
1000 ( mg
nicotinic acid
500( mg
) 3
)
nicotinic acid
1
1
metabolism
n icotinic acid
report
warfarin
CYP 450
warfarin INR warfarin
metabolite
nicotinic acid
acid
nicotinic
198
20
–1
2559
________________________________________________________________________________
Ezetimide
cholesterol C1-Like1 (NPC1L1) sterol
: Niemann Pick
:
:
_____
:
: / metabolize active metabolite ezetimibe enterohepatic recirculation
phytosterol transporter
__X__
brush border
bioavailability 90
35 - 65
Ezetimide
Drug Interaction Facts:
ezetimibeglucuronide
69% Micromedex, ( Zetia® leaflet;Issued 2012) : 22
Glucuronidation metabolite
ezetimibeglucuronide
9%
warfarin
Drug Interaction from Micromedex: Significant rating: _ Onset: Delayed, Severity:Moderate, Documentation:Fair, Mechanism:may result in risk of increased prothrombin time or INR. Leaflet / package insert: warfarin INR 2
Clinical trials:
/
ezetimbe
2001
Bauer KS, et al. Two-way crossstudy (N=12)
J ClinPharmacol. (2001) 69, P5
10
11
25
7
AUC R-warfarin Swarfarin
2%
4% Ezetimibe placebo
Cmax R-warfarin Swarfarin 3%
1%
warfarin prothrombin time 199
20
–1
2559
________________________________________________________________________________
2016
10
Hashikata T, et Heart Vessels. al 2016 Apr 6. retrospective single-center study (N=101)
Ezetimide
baseline 0.06± 0.36, p =
INR
Pubmed,Sciencedirect
ezetimibe
statin
stabilize
ezetimide
statin
INR
warfarin
warfarin
warfarin warfarin
1.4
±
0.03
Ezetimide warfarin ( 2016)
anticoagulant anticoagulant effect
3.1
Observational studies / case reports: New England Journal of Medicine
200
20
–1
2559
________________________________________________________________________________
Cholestyramine
:
:
:
:
-
:
_____
__X__
: /
100
%
cholestyramine
warfarin
Drug Interaction Facts:
Significant rating: 2, Onset: Delayed, Severity: Moderate, Documentation: Probable, Mechanism: w arfarin warfarin Micromedex: Severity: Moderate, Onset: Delayed, Documentation: Good, arfarin enterohepatic recirculation Mechanism: w Leaflet / package insert: cholestyramine warfarin Clinical trials:
2
/
Jahnchen E, Meinertz
Br J Clin Pharmacol
T, Gilfrich HJ et al
1978; 5:437-440.
4g
3
8
Clin Pharmacol Ther
Benjamin DM &
1971; 12:491-495
4g
IV single dose
37.4±8.4
warfarin
25%
3
40
PTT
McCormick JJ
17.3 ± 1.0
13.7 ± 0.8
controlled, crossover study (N=6)
AUC
Robinson DS,
warfarin
52.5±17.9 ml/kg/day
warfarin
total body clearance
controlled, crossover study (N=5)
1.0-1.2 mg/kg 2
1971
1978
10
201
20
–1
2559
________________________________________________________________________________
Observational studies/ Case reports: cholestyramine 25 warfarin warfarin
warfarin INR pulmonary embolism 2 , dextropropoxyphene 10 vitamin K 10 mg/d ( Fresh frozen
plasma ) INR 1.3 8.8 3( INR vitamin 9.2 k ) 6 INR cholestyramine 4 g QID 7 INR 2.0 4 cholestyramine (S Renowden, D Westmoreland, J P White, and P A Routledge, Oral cholestyramine increases elimination of warfarin after overdose. Br Med J (Clin Res Ed). Aug 24, 1985; 291(6494): 513–514.)
cholestyramine
admission 5 cholestyramine 1
Anticoagulant Phenprocoumon (Prostheric bileaflet aotic valve) INR 2.5-3.5 3.0) Hypercholesterolemia admission Cholestyramine
65
5 INR
(
202
20
–1
2559
________________________________________________________________________________
1 admission admission “ ” admit 2 pulmonary congestion INR 1.1 EKG anterior leaflet aortic Thrombosis rt-PA heparin (Nicola Balmelli, Frederic
Phenprocoumon
compliance
Domine, Matthias Pfisterer, Stephan Krahenbuhl, Stephan Marsch, European Journal of Internal Medicine;13 (2002):210–211)
cholestyramine
cholestyramine cholestyramine warfarin reabsorption warfarin
Warfarin
Warfarin warfarin enterohapatic circulation cholestyramine
Warfarin
warfarin
cholestyramine
warfarin
warfarin
cholestyramine
3
Harvengt C & Desager JP: Effect of colestipol, a new bile acid sequestrant, on the absorption of phenprocoumon in man. Eur J Clin Pharmacol 1973; 6:19-21.
Jahnchen E, Meinertz T, Gilfrich HJ et al: Enhanced elimination of warfarin during treatment with cholestyramine. Br J Clin Pharmacol 1978; 5:437-440.
Koch-Weser J & Koch-Weser J: Drug interactions in cardiovascular therapy. Am Heart J 1975; 90:93116.
Koch-Weser J & Sellers EM: Drug interactions with coumarin anticoagulants (part 2). N Engl J Med 1971; 285:547-558.
Meinertz T, Gilfrich MJ, Bork R et al: Treatment of phenprocoumon intoxication with cholestyramine. Br Med J 1977; 2:439.
Robinson DS, Benjamin DM & McCormick JJ: Interaction of warfarin and nonsystemic gastrointestinal drugs. Clin Pharmacol Ther 1971; 12:491-495.
Renowden S, Westmoreland D, White JP, and Routledge PA , Oral cholestyramine increases elimination of warfarin after overdose. Br Med J (Clin Res Ed). Aug 24, 1985; 291(6494): 513 –514.
Drug interaction analysis and management 2013 Drug Interaction Facts 2012 Micromedex solution 2016
203
20
–1
2559
________________________________________________________________________________
Furosemide
:
CI-
Na+/K+/2CI- symport thick ascending limb K+, Ca2 +, Mg2+ aldosterone carbonic andrase
:
_____
:
/
60
:
bioavailability 95
:
__X__
Na+, distal tubule
loop of Henle K+
:
: 0.5 – 2
,
ESRD : 9
Furoseminde warfarin Significant rating: 4 Onset: Delayed, Severity: Moderate, Documentation: Possible, Mechanism: displacement warfarin from albumin-binding sites Leaflet / package insert: F urosemide warfarin Drug Interaction Facts:
1
Clinical trials:
/
Furosemide
1978
Nilsson CM,
J ClinPharmacol. 1978
/
80
50
Horton ES, Robinson DS.
PT Feb-Mar;18(2-3):91-4.
(N=11)
Observational studies / case reports: warfarin 1.2
-
furosemide / furosemide
5 – 10
/
warfarin
anticoagulant effects. (Ogiso T, et al. J Pharmacobiodyn. 1982;5(10):829) warfarin stable Furosemide INR 28 hypoprothrombinemic effect of warfarin. acute diuresiseffect (Laizure SC1, Madlock L, Cyr M, Self T. Ther Drug Monit. 1997 Jun;19(3):361-3.)
80
/
204
20
–1
2559
________________________________________________________________________________
furosemide
diuresis furosemide
warfarin
furosemide warfarin warfarin clotting factors PT
case reports
Hypoprothrombinemic responses, furosemide
INR
Prothrombin time
warfarin
INR
warfarin
warfarin a cute
warfarin
warfarin
furosemide
warfarin
PT INR 28 furosemide warfarin
Furosemide
Warfarin
Monitor
205
20
–1
2559
________________________________________________________________________________
Indaparmide
:
Ca2+
NaCl distal convoluted tubule +-Ca2+exchanger 2+ Na Ca
: __X__ _____ : bioavailability 93-100%, Tmax : 0.5–2 : 71-79 (Vd 24-25 l/kg) : / 70 (unchanged 7%) : 14– 25 indapamide warfarin
Drug Interaction Facts:
Leaflet / package insert:
indapramide
23
warfarin
indapamide warfarin chlorthalidone hypoprothrombinemic response 3 hypoprothrombinemic response indapramide warfarin indapamide warfarin
NaCl
Significant rating: 4 Onset: Delayed, Severity: Moderate, Documentation: Possible, Mechanism: higher plasma concentrations of clotting factors as a of diureticinduce volume contraction has been proposed
Clinical trials: Observational studies / case reports:
-
Na+
case report
1
206
20
–1
2559
________________________________________________________________________________
Amiloride Hydrochloride/Hydrochlorothiazide (Moduretic®)
:
Amiloride hydrochloride
distal renal tubular : _____
k idney tubules
sodium
chloride
reabsorption electrolyte
__X__
bioavailability bioavailability
30% - 90% 60% - 80%
40%
(not metabolized by the liver)
:
warfarin
® (Moduretic )
Drug Interaction Facts: Leaflet / package insert: Clinical trials: Observational studies / case reports:
® (Moduretic )
warfarin
Amiloride
Hydrochloride/Hydrochlorothiazide
warfarin (Moduretic®)
warfarin
Amiloride Hydrochloride/Hydrochlorothiazide (Moduretic®)
(not metabolized)
Amiloridehydrochloride: 6 - 9 Hydrochlorothiazide: 5.6 - 14.8
(Moduretic®)
Hydrochlorothiazide:
: Amiloride hydrochloride: Hydrochlorothiazide: : Amiloride hydrochloride: Hydrochlorothiazide: : / Amiloride hydrochloride:
sodium reabsorption potassium hydrogen
Hydrochlorothiazide
AmilorideHydrochloride/Hydrochlorothiazide
(Moduretic®)
warfarin
warfarin
207
20
–1
2559
________________________________________________________________________________
Spironolactone
:
tubule ATPase(
K+
aldosterone receptors collecting duct basolateral) Na+ Channels (
:
_____
:
:
91-98%
Cytosol
apical
principal cells
lumen)
distalconvoluted +/K+ Na + Na
__ X __ 80-100%
: / Spironolactone m etabolite active metabolite c anrenone 7-alpha-spirolactone : Spironolactone 78-84 , canrenone 10-23 7-alpha-spirolactone , 7-20
Spironolactone
Drug Interaction Facts:
Significant rating: 5 Onset: Delayed, Severity: Minor, Documentation: Possible , Mechanism: Diuretic-induced hemoconcentration of clotting factors may be
responsible Leaflet / package insert:
1
Clinical trials:
warfarin
/
1980
R. A. O'Reilly, J ClinPharmacol. M.D. San 1980feb;27(2):198201. Jose, Calif.
50 mg tablet 4 times/day
1.5 mg/kg bodyweight (single dose)
Spironolactone
Spironolactone clotting factor warfarin
warfarin
(
warfarin
Spironolactone warfarin INR
Spectrophotometric assay
warfarin
Hematocrit
9
PT
Plasma water spironolactone INR
warfarin 7 warfarin warfarin
208
20
–1
2559
________________________________________________________________________________
1.
Micromedex® Solution. Aspirin [Internet].Truven Health Analytics Inc. © 2016[cited 2016 Jun 25].Available from:http://www.micromedexsolutions.com/micromedex2/librarian/CS/B085EC/ND_PR/evidencex pert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/BB3841/ND_PG/evidencexpert/ND_B/evidenc expert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.DoIntegrate dSearch?SearchTerm=spironolactone&UserSearchTerm=spironolactone&SearchFilter=filterNone&n
avitem=searchGlobal# 2. Kastrup EK, et al., Drug facts and comparisons 2012, St. Louis,Missouri,USA. Facts and comparisons 3. Drug Interaction Fact 2014, Fact and Comparison St. Louis,Missouri,USA. 4. R. A. O'Reilly. Spironolactone and warfarin interaction. J ClinPharmacol. 1980;27(2):198-201.
209
20
–1
2559
________________________________________________________________________________
Glyceryl Trinitrate
:
:
:
_____
__X__
Bioavailability, intra-anal: 50% Tmax, lingual: 7.5 minutes
:
guanosine 3'5' monophosphate (cyclic GMP) guanylatecyclase d ephosphorylation
60
: /
: Extrahepatic: RBCs vascular walls :Total body clearance: 13.6 L/min Hepatic (first pass) : 3 GlycerylTrinitrate warfarin Drug Interaction Facts: Leaflet / package insert: Clinical trials: Observational studies / case reports: GlycerylTrinitrate warfarin Glyceryl Trinitrate Glyceryl Trinitrate
GlycerylTrinitrate
warfarin
warfarin
warfarin GlycerylTrinitrate
warfarin
210
20
–1
2559
________________________________________________________________________________
Isosorbide Dinitrate
:
cytoplasm
:
_____
NO
bioavailability 10% - 90% Vd: 2 L/kg - 4 L/kg : Hepatic / (first pass) : 5
Isosorbide Dinitrate
Isosorbide Dinitrate
warfarin
Isosorbide Dinitrate
warfarin
Isosorbide Dinitrate
nitric oxide (NO) g uanylylcyclase cGMP
Drug Interaction Facts: Leaflet / package insert: Clinical trials: Observational studies / case reports:
__X__
:
:
intracellular cGMP
nitrosothiols
Isosorbide Dinitrate
warfarin
warfarin
warfarin Dinitrate Isosorbide
warfarin
211
20
–1
2559
________________________________________________________________________________
Isosorbide mononitrate
:
nitrosothiols intracellularcGMP
:
cGMP :
nitric oxide (NO) cytoplasm
guanylylcyclase _____
__ X __
NO
relase 93-100% immediate : Vd0.6L/kg , 5% : / Isosorbidemononitrate metabolite inactive metabolite Isorsobide, 5isosorbide mononitrateglucuronide, sorbitol :Parent drug 6.2-6.6 , glucuronide metabolite 6 sorbital metabolite , 9 Drug Interaction Facts: Leaflet / package insert: Clinical trials:
Isosorbide mononitrate
warfarin
Isosorbide mononitrate Isosorbide mononitrate
warfarin warfarin
P
212
20
–1
2559
________________________________________________________________________________
Propranolol
β1-receptors , renin β2-receptors
:
,
(Vasoconstriction)
:
β, 1-receptors
_____
__ X __
30-70% Vd 4L/kg , : / etabolite m 4-hydroxylpropanolol :
aqueous humor
Tmax
90%
:
CYP2D6
CYP1A2
96-99% : Immediate-release formulation 3-6
Propranolol
activemetabolite
warfarin
Drug Interaction Facts: Significant rating: 4 Onset: Delayed, Severity: Moderate, Documentation: Possible ,Mechanism: unknown Leaflet / package insert: Clinical trials: 2
/
1984
Scott AK, et al
Br. J. clin. Pharmac.
80 mg 2 times/day
3.2 mg/day
1984, 17, 559-64 Controlled
Prothrombin time
study (n=6)
1984
BAX NDS, et al
Br. J. clin. Pharmac.
80 mg 2 times/day
15 mg single dose
Propranolol
1984, 17, 553-7
Randomized Controlled
warfarin 3
Warfarin AUC
Prothrombin time
study (n=6)
propranolol
warfarin
213
20
–1
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________________________________________________________________________________
β 1-receptorsantagonist
Propranolol
AUC
warfarin
Propranolol
warfarin
INR
1.
2. 3. 4.
5.
propranolol
warfarin
pharmacokinetic
prothrombin time (Scott et al, 1984;Bax et al, 1984)
INR
Micromedex® Solution. Aspirin [Internet].Truven Health Analytics Inc. © 2016[cited 2016 Jun 25].Available from:http://www.micromedexsolutions.com/micromedex2/librarian/CS/CC6006/ND_PR/evidencex pert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/76785F/ND_PG/evidencexpert/ND_B/evidenc expert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.DoIntegrate dSearch?SearchTerm=propranolol&UserSearchTerm=propranolol&SearchFilter=filterNone&navite m=searchALL# Kastrup EK, et al., Drug facts and comparisons 2012, St. Louis,Missouri,USA. Facts and comparisons Drug Interaction Fact 2014, Fact and Comparison St. Louis,Missouri,USA. A. K. Scolt, B. K. Park, A. M. Breckenridge. Interaction between warfarin and propranolol. Br Jclin Pharmac1984;17:559-64. N. D. S. Bax, M. S. Lennard, G. T. Tucker, H. F. Woods, N. R. Porter, R. G. Malia,F. E. Preston. The effect of f3-adrenoceptor antagonists on thepharmacokinetics and pharmacodynamics of warfarin after asingle dose.Br JclinPharmac. 1984;17: 553-7.
214
20
–1
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________________________________________________________________________________
Atenolol
:
adrenoreceptors
:
beta(1)-selective adrenoreceptor bronchial vascular musculature _____ __X__
:
: /
: 6–7
bioavailability
:
–
50
50
atenolol
50
warfarin
atenolol atenolol atenolol
warfarin warfarin warfarin
Observational studies / case reports: atenolol atenolol
6 warfarin serum warfarin concentration
warfarin(N D Bax, et al. Br J ClinPharmacol. 1984 May; 17(5): 553 –557.) warfarin 6 26-65 prothombin time (PT) 3 atenolol 100 / , metoprolol 200 / placebo 3 PT et al.Br J ClinPharmacol. 1984;17Suppl 1:94S-96S.)
25 10
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
beta( 2)-
atenolol warfarin atenolol atenolol
atenolol
/
AUC
PT (Mantero F,
warfarin
INR
warfarin
INR 100
15
atenolol
100
/
warfarin
Metoprolol
: Metoprolol selective beta-2 adrenoreceptors : _____ __X__
beta-1-adrenoreceptors
215
20
–1
2559
________________________________________________________________________________
:
bioavailability 2
:
: /
CYP 2D6
77
1
unchanged 5
: 3–7
metoprolol
Facts: Drug Interaction Leaflet / package insert: Clinical trials:
warfarin metoprolol metoprolol metoprolol
warfarin warfarin warfarin
Observational studies / case reports: 6 warfarin 15 metoprolol metoprolol serum warfarin concentration AUC warfarin (N D Bax, et al. Br J ClinPharmacol. 1984 May; 17(5): 553 –557.) warfarin 6 26-65 prothombin time (PT) 3 atenolol 100 / , metoprolol 200 / placebo 3 PT PT (Mantero F,et al. Br J ClinPharmacol. 1984;17Suppl 1:94S-96S.)
metoprolol
INR 200
/
warfarin
INR
warfarin
warfarin
metoprolol metoprolol
metoprolol
atenolol
200
/
warfarin
Bisoprolol Fumarate (Concor®)
:
Selective beta-1-adrenergic receptors blocker catecholamine receptor catecholamine beta-1-adrenergic receptors cardiac output Bisoprolol membrane stabilizing effect intrinsic sympathomimetic effect (partial agonist) : _____ __X__
:
, bioavailability
20
) ,
(
first-pass 80 effect
216
20
–1
2559
________________________________________________________________________________
:
:
30 , blood-brain barrier
:
9 –hepatic 12
-
cirrhosis
,
50
,
2
, 27 36
mg/ bisoprolol
Drug Interaction Facts: Leaflet / package insert: Bisoprolol Clinical trials: 1
cytochrome P450 CYP3A 4(major), CYP2D6(minor) 95 uncharged drug (50%) , inactive metabolized(50%)
inactive metabolized
:
CrCl , 8-22 < 40 mL/minute 10m g/
2.5
warfarin
prothrombin time
warfarin
Bisoprolol: studies of potential interactions with theophylline and warfarin in healthy volunteers Warrington SJ, Johnston A, Lewis Y, Murphy M. 1990 J Cardiovasc Pharmacol. 1990;16 Suppl 5:S164-8. In a balanced, two-way, crossover study , healthy volunteers (N=12) Bisoprolol 10 mg 10 warfarin times 1.5 prothrombin control bisoprolol 10 warfarin 5 warfarin 10 mg bisoprolol prothrombin times bisoprolol bisoprolol warfarin times bisoprolol prothrombin warfarin bisoprolol warfarin bisoprolol warfarin bisoprolol warfarin INR warfarin
217
20
–1
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Carvedilol (Dilatrend®)
:
non-selective beta-adrenergic receptors blocker catecholamine receptor beta-1 , beta-2 alpha-1 adrenergic receptor
:
catecholamine carvedilol
effect
:
:
bioavailability cirrhosis b ioavailability peak serum level 98 Albumin
:
:
7 – 10
carvedilol
Drug Interaction Facts: Leaflet / package insert:
-35 ( 25
)
cytochrome P450 enzyme
warfarin
carvedilol
prothrombin time
warfarin
1
Clinical trials:
Lack of a pharmacokinetic interaction between carvedilol and digitoxin or phenprocoumon Harder S, Brei R, Caspary S, Merz PG. 1993 Eur J Clin Pharmacol. 1993;44(6):583-6. two-way, experimental study ,non-randomised , healthy volunteers (N=12) (
carvedilol 25 mg phenprocoumon( phenprocoumon
phenprocoumon
coumarin)
warfarin)
6
carvedilol
first-pass
83
,
CYP2D6(major), CYP3A4(minor), CYP2C9(minor), CYP1A2(minor) inhibitor P -glycoprotein
sympathomimetic
cardiac output alpha-1 adrenergic receptor vascular resistant Carvedilol membrane stabilizing effect effect (partial agonist) : _____ __X__
carvedilol
218
20
–1
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________________________________________________________________________________
carvedilol
warfarin
phenprocoumon warfarin
phenprocoumon protein binding warfarin Cardiovascular agent.Drug Today(1991) 27,465-92.) carvedilol
warfarin
warfarin
carvedilol
carvedilol carvedilol warfarin carvedilol
in vitro (SmithKline, et al. A Novel Multiple Action
carvedilol
warfarin INR
warfarin
219
20
–1
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________________________________________________________________________________
Timolol
:
blocker sympatholytic
non-selective beta(1) renin
Timolol maleate
:
:
_____
__X__
:
aqueous humor
beta(2) adrenergic receptor cardiac output
bioavailability
90 not extensive : / cytochrome P450 CYP2D6; partially metabolized, approximately 50% via first pass : 4 timolol
timolol
warfarin
timolol
timolol
warfarin
warfarin
warfarin
Drug interaction
case report
1. MICROMEDEX® [Database on the internet]. Colorado: Thomson Reuters (Healthcare). DRUGDEX® System, Timolol;[cited 23 Jun 16]. Available from: http://www.thomsonhc.com
220
20
–1
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Nebivolol
: Nebivolol
long-acting cardioselective beta-1 adrenoceptor antagonist diminution
of tonic sympathetic outflow to the periphery from cerebral vasomotor centers, suppression of renin activity, and vasodilation and decreased peripheral vascular resistance : _____ __X__
:
(poor metabolizers) : : 12-19
bioavailability
12% (extensive
metabolizers) to
96%
98
: glucuronidation
N-dealkylation
oxidation
CYP2D6
13-44
38-67
: Nebivolol
Nebivolol
warfarin warfarin
Nebivolol
Nebivolol
warfarin
warfarin
Drug interaction
case report
1. MICROMEDEX® [Database on the internet]. Colorado: Thomson Reuters (Healthcare). DRUGDEX® System, Nebivolol;[cited 23 Jun 16]. Available from: http://www.thomsonhc.com
221
20
–1
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________________________________________________________________________________
Esmolol hydrochloride inj. (Brevibloc®)
:
:
Selective beta-1-adrenergic receptors blocker _____ __X__
:
:
bioavailability
:
( injection 10055 form) esterases
:
:
9
esmolol
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
-88 73
warfarin
1
Clinical pharmacology, pharmacodynamics and interactions with esmolol
Lowenthal DT, Porter RS, Saris SD, Bies CM, Slegowski MB, Staudacher A. 1985 Am J Cardiol. 1985 Oct 23;56(11):14F-18F. Descriptive study , N=10 esmolol warfarin clinical trials -3 2 esmolol esmolol warfarin esmolol warfarin warfarin esmolol esmolol warfarin
esmolol
warfarin
esmolol
warfarin
esmolol
warfarin INR
warfarin
222
20
–1
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________________________________________________________________________________
Nadolol
:
beta1
beta2receptor
:
:
_____
__X__
:
10–24
20-40
: /
beta-adrenergic agonists
bioavailability 28-30
:
70
Nadolol
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
warfarin
Nadolol warfarin Nadolol warfarin Nadolol
warfarin
Observational studies / case reports:
Nadolol
Nadolol
warfarin
Nadolol
warfarin
warfarin
223
20
–1
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________________________________________________________________________________
Doxazosin
:
postsynaptic alpha-1-adrenoceptors
:
:
_____
sympathetic
__X__
65
O-demethylation hydroxylation CYP2D6 CYP2C9 biphasic 63
warfarin
Doxazosin warfarin vitro Doxazosin warfarin . Doxazosin warfarin
Clinical trials: Observational studies / case reports:
Doxazosin
Doxazosin
warfarin
warfarin
Doxazosin
Doxazosin
Drug Interaction Facts: Leaflet / package insert:
Doxazosin
CYP3A4
9 22
:
bioavailability 98
CYP450
: /
tone
competitive
:
selective
warfarin
warfarin
224
20
–1
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________________________________________________________________________________
Prazosin
:
quinazoline derivative
alpha-adrenoceptor blocker
:
:
total peripheral
resistance
_____
__X__
:
bioavailability 92-97
56-63
: /
demethylation
conjugation
2–3
:
prazosin
prazosin prazosin
prazosin
warfarin warfarin
warfarin
warfarin
Drug interaction
case report
1. MICROMEDEX® [Database on the internet]. Colorado: Thomson Reuters (Healthcare). DRUGDEX® System, Prazosin;[cited 23 Jun 16]. Available from: http://www.thomsonhc.com
225
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Fosinopril
: Fosinopril
Angiotensin I
:
sodium ester prodrug fosinoprilat Angiotensin II Aldosterone)
(
___ __ X __ 3 Bioavailability 75% : 99.4 volume of distribution : Prodrug / hydrolysis active drug glucuronide conjugate fosinoprilat 20-30 p-hydroxy metabolite 1-5 0 5 : 12 11.5 :
failure 14 heart 11 - 13 Fosinopril warfarin Drug Interaction Facts: Fosinopril warfarin Leaflet / package insert: Fosinopril warfarin Clinical trials: Fosinopril Fosinopril warfarin Fosinopril warfarin
warfarin
226
20
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Lisinopril
: Lisinopril long-acting angiotensin-converting enzyme (ACE) inhibitor Angiotensin I Angiotensin II Aldosterone) (
:
: 25
___ __ X__
: 12
Lisinopril
6 - 60 volume of distribution
Lisinopril
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
6-8
Bioavailability:
warfarin
Lisinopril warfarin Lisinopril warfarin Lisinopril
warfarin
warfarin
Lisinopril
: /
:
warfarin
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Perindopril
:
angiotensin-converting enzyme
:
:
angiotensin I
Perindopril 75 – 95
_____
__X__
:
Perindopril
Drug Interaction Facts: Leaflet / package insert:
Clinical trials: Observational studies / case reports:
Perindopril
angiotensin II
prodrug peak concentration 1 p erindoprilat plasma concentration peak protein binding perindoprilat 20 : / Peridopril 20 – 50 hepatic esterase active metabolite Perindoprilat 17 state 4
Perindopril
perindopril
Perindoprilat
steady
warfarin
perindopril warfarin perindopril warfarin perindopril perindopril
warfarin warfarin
warfarin
perindopril
b ioavailability prodrug 3–4
warfarin
warfarin
warfarin
228
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Ramipril
:
ramiprilat(active drug)
(Aldosterone)
Angiotensin II
ramiprilat active drug
28% 2-4
73%
Ramiprilat (active drug),
44%g
56%
Ramipril (prodrug)
active drug
r amiprilat
Ramipril (prodrug),
40%
Ramipril (prodrug),
60%
Ramiprilat (active drug)
Ramiprilat (active drug): 13-17
: 23.5
:
Ramipri
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
40
Ramipri
warfarin
Ramipril warfarin Ramipril warfarin Ramipril warfarin Ramipri
Ramipril (prodrug),
prodrug Bioavailability
: ___ _ X _
:
Angiotensin I
warfarin
warfarin
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Quinapril
:
angiotensin-converting enzyme
:
:
_____
__X__
angiotensin I
angiotensin II
:
bioavailability 97
25 – 30
: / metabolized
50
active metabolite
deesterification
quinaprilat
50 – 60 prodrug metabolite q uinaprilat
:
Quinapril
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
Observational studies / case reports:
Quinapril
Quinapril
quinapril
33 CHF
3.7
warfarin
quinapril warfarin quinapril warfarin quinapril quinapril
warfarin warfarin
warfarin
quinapril
0.8 2 – 25
warfarin
warfarin warfarin
230
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Olmesartan
:
Angiotensin II
:
_____
Olmesartan
Drug Interaction Facts: Leaflet / package insert:
13
26
99
active
olmesartan
50-63
ester hydrolysis
35-50
warfarin
Olmesartan warfarin Olmesartan warfarin
/
1999
1
Clinical trials:
: /
:
bioavailability
II receptortype1 Aldosterone
__X__
:
:
Angiotensin
Laeis P, et al
J Hypertens
40
/
randomised,crossover
1
2001;19(Suppl
1):S21–S32.
Quick value
Quick value
study
partial
prothrombin time
1.4-1.8
(N=24)
AUC
Cmax
R-,S-warfarin
Observational studies / case reports:
Olmesartan
Olmesartan crossover study R-,S-warfarin Olmesartan
Olmesartan
warfarin
warfarin
warfarin randomised AUC Quick value partial prothrombin time
warfarin
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Irbesartan
:
irbesartan
:
vasopressin : _____
angiotensin II type 1 (AT 1)
__X__
60 - 80
90
: /
50-70% irbesartan ( 20
Metabolites
Irbesartan
Drug Interaction Facts:
cytochrome P450 2C9 i rbesartan glucuronide conjugate 65
6 %)
: 11 - 15
Leaflet / package insert:
warfarin
1
Clinical trials:
aldosterone, catecholamine
bioavailability
:
Irbesartan
warfarin
Irbesartan
warfarin
/
1999
Mangold B, et al (double-blind , randomised ,placebocontrolled trial)
Eur J Clin Pharmacol. 1999 Oct;55(8):593-8..
Observational studies / case reports:
Irbesartan
Warfarin 10 mg 2.5-10 mg 2-21 Irbesartan 300 mg/day 15-21
Warfarin 10 mg Irbesartan 2.5-10 mg 2-21 placebo pharmacodynamic 15-21 pharmacokinetic warfarin
Irbesartan
warfarin
warfarin
Irbesartan warfarin double-blind , randomised , placebo-controlled trial 16 warfarin 10 mg 2.5-10 mg 2-21 Irbesartan 300 mg/day placebo 15-21 Irbesartan pharmacodynamic ( prothrombin time prothrombin time ratio) pharmacokinetic ( C max , tmax , t1/2 , AUC) warfarin Irbesartan
irbesartan
warfarin
warfarin
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Telmisatan
: telmisartan
:
nonpeptide angiotensin receptor blocker (ARB) angiotensin II AT1 receptor aldosterone catecholamine arginine vasopressin hypertrophic (anti-proliferative effect) _____ __X__ :
: /
:
bioavailability 99.5 conjugation
:
24
42
telmisartan
58
warfarin
telmisartan telmisartan telmisartan telmisartan
severity : minor R enantiomer warfarin trough concentration
Drung information Handbook: Clinical trials: 1
telmisartan
telmisartan trough concentration
warfarin warfarin warfarin warfarin stereoselective effect (less potent)
warfarin warfarin
warfarin
Stangier J, et al open-label, singleperiod study conducted over 30 days. (N=12 healthy young
INR
INR
/
J Clin Pharmacol . 2000 Dec;40(12 Pt 1):13317.
males)
Phase 1:Phase 2: 120mg
warfarin 10 Phase 3: off
Phase 1: loading dose warfarin 14 target INR 1.21.8 Phase 2 : warfarin
telmisartan
prothrombin phase 1,2 3 trough concentrations warfarin telmisartan ratio phase 2/phase 1 0.89 (95% CI: 0.84 to 0.95)
warfarin warfarin
time (INR)
INR target phase 1
telmisartan
10 Phase 3:
inactive metabolite
2000
Drug.com:
97
Drug Interaction Facts: Micromedex: Leaflet / package insert: Medscape:
warfarin
telmisartan
warfarin
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telmisartan (less potent)
INR telmisartan
telmisartan
1. 2.
stereoselective effect R enantiomer trough concentration warfarin
warfarin warfarin
warfarin telmisartan
warfarin
intervention
"Product Information. Micardis (telmisartan)." Boehringer-Ingelheim, Ridgefield, CT. Stangier J, Su CAPF, Hendriks MGC, vanLier JJ, Sollie FAE, Oosterhuis B, Jonkman JHG "Steady-state pharmacodynamics and pharmacokinetics of warfarin in the presence and absence of telmisartan in healthy male volunteers." J Clin Pharmacol 40 (2000): 1331-7
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Valsartan
: angiotensin receptor blocker (ARB) angiotensin II AT1 receptor aldosterone catecholamine arginine vasopressin
:
:
hypertrophic effect) (anti-proliferative Angiotensin converting enzyme inhibitors __X__ _____
: 6
: /
bioavailability 95 inactive metabolite
: 13
25
83
Valsartan
Drug Interaction Facts: Micromedex: Leaflet / package insert: Clinical trials: valsartan
valsartan
warfarin
valsartan valsartan
warfarin warfarin
valsartan valsartan
warfarin warfarin
warfarin
warfarin
intervention
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Azilsartan
:
renin-angiotensin-aldosterone system angiotensin angiotensin II type I (AT1)receptor
_____
active form
–
:
Azilsartan
Azilsartan
Azilsartan
Azilsartan
42
55
warfarin
Azilsartan warfarin
warfarin
warfarin
pharmacokinetics
60
%
O-dealkylation and decarboxylation
Drug Interaction Facts: Leaflet / package insert: drug interaction Clinical trials: Observational studies / case reports: -
Azilsartan
bioavailability
3 1.5 99
: /
inactive metabolites 11
prostaglandin
h ydrolysed
CYP2C9
Bradykinin __X__
:
:
angiotensin II Angiotensin II aldosterone
pharmacodynamics
warfarin
warfarin
warfarin
Drug interaction
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Candesartan
:
renin-angiotensin-aldosterone system angiotensin type I (AT1)receptor
II
solution cilexetil
Bradykinin
bioavailability 14% hydrolysed
active
warfarin
drug interaction
Leaflet / package insert:
Candesartan
Drug Interaction Facts:
Clinical trials:
– 4 3 99
: / 9
:
bioavailability 40% ester prodrug
form
:
__X__
:
angiotensin II
Angiotensin
angiotensin II
aldosterone prostaglandin : _____
candesartan
warfarin
warfarin
1
/
2001
Hanatani T, et
Pharmacogenomics
al
J. 2001;1(4):288-92..
Candesartan
candesartan
CYP2C9*1/*1
CYP2C9*1/*3
S-
warfarin 7-hydroxylation
human liver
microsomes
s-warfarin metabolism
candesartan
Observational studies / case reports: -
Candesartan
Candesartan Candesartan
Candesartan
warfarin
warfarin pharmacokinetics
warfarin warfarin
metabolism pharmacodynamics
candesartan warfarin
Drug interaction
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Felodipine
:
dihydropyridines
inotropic)
Ca2+ Ca2+ transmembrane (Negative
: _____ __X__ : – 20 13 Cmax %60 : 99 : / substrate CYP3A4, % 10 : 11 – 16 extended-release26.7 , – 33.2 Felodipine warfarin Drug Interaction Facts: Felodipine warfarin Drug interaction Leaflet / package insert: warfarin
Clinical trials:
70
%,
-
Observational studies / case reports: -
Felodipine
Felodipine
Felodipine
Felodipine
warfarin
pharmacokinetics
pharmacodynamics
warfarin
warfarin
warfarin
Drug interaction
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Lercanidipine
:
d ihydropyridine
Lercanidipine
vascular resistance
:
_____
__X__
: /
lercanidipine
lercanidipine
1.5-3
98
peripheral
warfarin
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
inactive metabolites CYP3A4 isoenzyme ( ) % 50inactive metabolites
8 – 10
:
:
:
calcium antagonist
lercanidipine lercanidipine lercanidipine
warfarin warfarin
warfarin
warfarin
lercanidipine
warfarin
warfarin lercanidipine
lercanidipine
warfarin
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Manidipine
:
dihydropyridine calcium antagonist L T- type calcium channels
Manidipine
:
_____
__X__
manidipine
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
dehydrogenation
oxidation
31
warfarin
manidipine
99%
cytochhrome P450 % 63 %
: /
:
:
manidipine
manidipine manidipine manidipine
warfarin
manidipine
warfarin
warfarin warfarin warfarin
warfarin
manidipine
manidipine
warfarin
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Nitrendipine
:
__X__
:
:
Nitrendipine (arteriolar dilation) : _____
Absolute bioavailability 10-30% 1-3 Plasma protein binding 98% : / first-pass metabolism substrate CYP 3A4
(as inactive metabolites, <0.1% as unchanged drug) : 10-22
nitrendipine
nitrendipine
warfarin
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
nitrendipine nitrendipine nitrendipine
warfarin warfarin warfarin
warfarin
nitrendipine
warfarin
warfarin nitrendipine
nitrendipine
warfarin
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Theophylline
:
phosphodiesterase (PDE)
monophosphate (cAMP)
:
_____
__X__ gastric mucosa Oral solution
Micro-crystalline uncoated tablets 0.45 L/kg body fat
:
:
: /
()
theophylline
17-43
(
9.4-30.6
) (
6.1-12.8 (
) )
warfarin
Drug Interaction Facts: drug interaction not found Drug information handbook: Metabolism/Transporter effect substance of CYP1A2 (major), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (major), CYP3A4 (major) Enzyme inhibitor CYP1A2 (weak) AHFS drug information: theophylline oral anticoagulant plasma prothrombin factor V therapeutic index theophylline anticoagulant response Micromedex: drug interaction not found More information: theophylline Citrate-Theophylline-Adenosine-Dipyridamole (CTAD) 15mM theophylline (Sigma) Macey EDTA CTAD 4 60-180
CYP3A4
Premature infants, postnatal age 25-57 days : 20 ) Children 6-17 : 3.7 1.5-5.9 ( 16-60 : 8.7
cyclic adenine
40
CYP1A2, CYP2E1
ideal body weight 2
Premature infants, postnatal age 3-15 days : 30
:
theophylline
warfarin
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theophylline warfarin oral anticoagulant plasma prothrombin therapeutic index theophylline anticoagulant response theophylline millimole 2 metabolite CYP theophylline
inhibitor CYP1A2 (weak) warfarin CYP2C9 theophylline form theophylline
theophylline factor V warfarin theophylline
metabolite
theophylline oral anticoagulant enzyme inhibitor CYP1A2 (weak)
enzyme
metabolite
warfarin
S-form warfarin
theophylline factor V
plasma prothrombin warfarin
Reference 1. Drug information handbook 22nd edition 2. Drug interaction fact 2008 3. AHFS drug information 2008 4. Medscape application Marion M., Urooj A., Desmond M., Lee W., E. Sabrinah C., David O., et. al. Evaluation of the Anticoagulants EDTA and Citrate, Theophylline, Adenosine, and Dipyridamole (CTAD) for Assessing Platelet Activation on the ADVIA 120 Hematology System. Clinical chemistry. 2002. 48(6). 891-899.
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Salbutamol (Albuterol Sulfate)
cyclase
: Short acting 2 agonist cyclic AMP
2 adrenergic receptor
adenyl
m ast cell
:___ __X__ : bioavailability 100% : 10% : / ester 4-O-sulfate : 3.7–5 Salbutamol (Albuterol Sulfate) warfarin
244
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Terbutaline Sulfate
:
protein kinase receptor
ionized calcium
:
33-50
25
sulfate
conjugated
terbutalinel
ionized calcium protein kinase
__X__
desensitized
bioavailability
: / first pass metabolism 60% : 11-16
sulfate
__
:
:
inactive
warfarin
Drug Interaction Facts: Martindale : Micromedex: Drug information : Google scholar : 3. Procaterol
:long acting 2 adrenergic receptor agonist 2 receptor 1 adrenergic receptor EKG ST- segment , T wave
: _
:
:
:
4.2
: /
__X__
10 – 25
procaterol
warfarin
245
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Montelukast
:
cysteinyl leukotriene receptor
receptor antagonist
:
_____
__X__
inflammatory process
metabolite CYP2C9 warfarin 30 mg single dose
9 9
<0.2%
(mild to moderate)
montelukast warfarin pharmacokinetic profile
CYP3A4
warfarin
PT, INR
/
Van H, et al
64 (oral 10 mg tablets)
Drug information handbook: Enzyme inhibitor CYP2C8, CYP2C9 (weak) Metabolism/Transporter effect substance of CYP2C9 (major), CYP3A4 (major) montelukast AHFS drug information: drug interaction study Pharmacokinetics warfarin metabolism CYP2C9 CYP3A4 99% montelukast 2 PT INR montelukast 10 mg daily steady state warfarin 30 mg single dose montelukast AUC peak plasma concentration warfarin S R form montelukast time to peak plasma concentration warfarin elimination half-life R-form 2 form Clinical trials: 1
1999
Drug Interaction Facts: drug interaction not found Leaflet / package insert: montelukast 10 mg
bioavailability 73 (chewable 5 mg tablets) : 8-11 L : / Metabolite CYP3A4 CYP2C9 86% : 2.7-5.5 7.4 montelukast warfarin :
selective leukotriene
J ClinPharmacol.
10 mg once daily
dose 1999 May;39(5):495-
30 mg single PT, ING
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500.
montelukast warfarin montelukast 10 mg once daily
pharmacokinetic warfarin 30 mg single dose time to peak plasma concentration warfarin S R form elimination half-life R-form PT INR competitivemetabolic pathways CYP2C9 CYP3A4 2 substrate warfarin 1 dose warfarin 6 pharmacokinetic clinical 2 montelukast
anticoagulant
montelukast warfarin
warfarin
10 mg once daily)
(
pharmacokinetic
Reference 1. Drug information handbook 22nd edition 2. Drug interaction fact 2008 3. AHFS drug information 2008 4. 5.
Medscape application Van H.A., Depré M, Verbesselt R, Wynants K, De Lepeleire I, Arnout J, et. al. Effect of montelukast on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.J ClinPharmacol. 1999. 39(5) : 495-500
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Chlorpheniramine
:
:
H1 (Inhibit H1 receptor)
:
_____
__X__
:
2 – 3
cerebral fluid
: /
29 – 37%
chlorpheniramine
(50%)
warfarin
Drug Interaction Facts : No drug interaction Leaflet / package insert : No drug interaction Clinical trials : No drug interaction Observational studies / case reports: No drug interaction
Bioavailability 25 – 50%
CYP2D6 Monodesmethylchlorpheniramine,didesmethylchlorpheniramine (< 1%) : 20
( Antihistamine)
bioavailability
chlorpheniramine
warfarin
interaction drug chlorpheniramine
chlorpheniramine
warfarin
warfarin
248
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Diphenhydramine
:
:
(central) _____
:
4–8
Inactive
: Oral bioavailability 65 – 100 % 76– 85 % : : /
(nonselective H1 receptor) (peripheral) __X__
H1
(Antihistamine)
50% unchanged
(Inactive)
diphenhydramine
warfarin
Drug Interaction Facts : No drug interaction Leaflet / package insert : No drug interaction Clinical trials : No drug interaction Observational studies / case reports: No drug interaction
diphenhydramine
warfarin
drug interaction diphenhydramine
diphenhydramine
warfarin
warfarin
249
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Loratadine
:
H1
:
selective H1 receptor)( __X__ _____
(peripheral)
1.3 1 : 97 % : / descarboethoxyloratadine : 8 – 18 Loratadine warfarin AHFS: loratadine warfarin :
CYP3A4
CYP2D6 %
metabolite active
, PT
,
, tertiary
loratadine
(melena) secondary
40
digoxin Drug interaction fact : No drug interaction Leaflet / package insert : No drug interaction Observational studies / case reports: No drug interaction Website http://drug-data.com/combinations/L/P/loratadine-warfarin-sodium.html : loratadine warfarin
INR
warfarin
interaction drug loratadine
warfarin
loratadine
warfarin
250
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Fexofenadine
:
selective H1 receptor)( __X__ _____
H1
:
(peripheral)
60– 70 % absolute bioavailability alpha-1-acid : / %3.5 0.5– 1.5 % 80 Methyl ester metabolite % : 14 – 18 fexofenadine warfarin :
:
Drug Interaction Facts: No drug interaction Leaflet / package insert: US FDA 3 fexofenadine warfarin (http://www.fda.gov/ohrms/dockets/ac/01/briefing/3737b_03_risk.html.) Observational studies / case reports: No drug interaction
fexofenadine fexofenadine
Tertiary
fexofenadine
warfarin
fexofenadine
11
warfarin
warfarin
Secondary
CYP3A(4) %
warfarin
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Hydroxyzine Hydrochloride
: Hydroxyzine :
:
:
_____
__X__
histamine
H1 – receptor
bioavailability
Hydroxyzine
Hydroxyzine
80
BBB
: / Hydroxyzine (45 % of oral dose) Metabolite H1 -antagonist Metabolite CYP3A4/5 Inactive metabolite : 7 -20
Hydroxyzine interaction drug Hydroxyzine
Alcohol dehydrogenase N-dealkylation O-dealkylation
warfarin warfarin
252
20
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Brompheniramine Maleate
: Brompheniramine
:
:
_____
histamine
H1 – receptor
bioavailability 39-49
70
: /
52
Oxidative deamination acid metabolite : 25
__X__
:
1.5
mono- and di-N-demethylated brompheniramine, the carboxylic
Brompheniramine drug interaction Brompheniramine
warfarin warfarin
253
20
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Cetirizine Hydrochloride
: Cetirizine
:
:
_____
__X__
: 7 -8
bioavailability
Cetirizine
histamine H1 – receptor Acetylcoline
:
: / 10
93
Oxidative O-dealkylation
Cetirizine drug interaction Cetirizine
70
70
warfarin warfarin
254
20
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Estrogen(Conjugated Estrogen, Estradiol)
: Estrogen
__X__ _____ : : : 67% 37% : / Oxidaton Hydroxylated CYP3A4 enterohepatic recirculation estrone estrone ( estriol ) Estrogen warfarin
estrogen receptor)
(
Conjugation metabolites estriol
Drug Interaction Facts:
Significant rating: 4Onset:Delayed, Severity:Moderate, Documentation: Possible, Mechanism:Unknow Leaflet / package insert: Estrogen warfarin Clinical trials: warfarin
oral contraceptive 12 ( 11 ) ( ) 1 nicoumalone Bjork-Shiley valve disease (9 ) embolic mitral valve disease ( 3 ) 374 230 144 2.05 mg (Phase A) 2.53 mg (Phase B) phase A phase B p (<0.01) prothrombin time phase A 1.67 phase B 1.5 p <0.01) Estrogen ( Observational studies / case reports: warfarin 33 warfarin 38.5 mg/wk ( 42 mg/wk ) aortic valve monophasic EE 0.02 mg/norestrindrone 1 mg/day thrombosis estonogestrel 55.8% (60mg/wk) INR 10 ( warfarin 2.5-3.5) 9 INR 48 6.5 warfarin 55.5 mg/wk Norethindone 0.35 mg/wk warfarin 53.5 mg/wk Norethindone 39 warfarin Ethinyl estradiol CYP1A2 CYP2C19
estrogen
warfarin
255
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estrogen
Thromboembolism
coagulation
estrogen
thromboembolism estrogen
warfarin fibrinolysis
anticoagulant
warfarin
warfarin
INR
Reference 1. de Teresa E, Vera A, Ortigosa J, et al; Interaction between anticoagulants and contraceptive: an unexpected finding. Br Med J 1979; 2:1260-1261. 2. Zingone MM, Guirguis AB, Airee A, et al: probable drug interaction between warfarin and hormonal contraceptive. Ann Pharmacother 2009; 43 (12):2096-2102
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Medroxyprogesterone
:
gonadotropins pituitary gland, mammary tissues : _____ __X__
:
Urine
(bioavailability) .6-10 : 86 – 90 enzymes : CYP450 glucuronide conjugates : 50 (IM)
medroxyprogesterone
follicular maturation
,
0 : Metabolites
warfarin
Micromedex: Onset: Delayed, Severity: Moderate, Substantiation: Probable, Mechanism: Unknown Clinical trials: 1
/
79
Vera A, et al
19
British Medical
11
Journal.1979,2,12601261.
Prothrombin
time ratio 2 phase (phase A: 2 , phase B:
Phase A
Prothrombin
time ratio 1.67
,1
phase B (1.5)
anticoagulant
p < 0.01 Estrogen
hepatic enzyme
(nicoumalone))
metabolism anticoagulant
case reports: levonorgestrel
35
Warfarin 7 mg/ day INR 8.1
INR 2.1
3
Warfarin 2
INR et al. Apparent interaction between warfarin and Bleeding contraception. (Ellison 2000J, Dec;321:1382.) levonorgestrel2.5 used for emergency
medroxyprogesterone
Combination contraceptive
CYP2C19
Warfarin
warfarin
metabolism
warfarin Ethinyl estradiol Warfarin
CYP1A2
257
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medroxyprogesterone
2
warfarin
PT/INR
warfarin
258
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Testosterone
:
:
:
:
__X__
transdermal gel Intramuscular sex hormone blinding globulin (SHBG) SHBG, 2% free form, albumin
: 10-100
6% testosterone
conjugation
glucoronic
10%
albumin
40% protein 98%) : /
_____
sulfuric acid
30blinding (
90%
warfarin
Drug Interaction Facts: drug interaction not found Drug information handbook: Enzyme inhibitor CYP3A4 (weak)
AHFS drug information:
Rxlist.com:
Metabolism/Transporter effect substance of CYP2B6 (major), CYP2C19 (minor), CYP2C9 (minor), CYP3A4 (minor) warfarin testosterone warfarin testosterone oral anticoagulant testosterone oral anticoagulant oral anticoagulant hypoprothrombinemic INR testosterone warfarin warfarin serious
Drugs.com:
testosterone androgenic hypoprothrombinemic
warfarin
Major anabolic steroids anticoagulants
2-3 case report INR warfarin androgenic agents danazol, oxymetholone, testosterone, methyltestosterone, stanozolol 15 warfarin oxandrolone 10 to 20 mg S-warfarin 26 per day 48 AUC 4.55 12.08 ng-hr/mL warfarin 80-85%
259
20
–1
2559
________________________________________________________________________________
INR
warfarin Observational studies / case reports:
93
INR w arfarin oxandrolone 2.5 mg 2
15.6 65 sec warfarin androgenic agents 69 warfarin 16 PT 2% testosterone propionate ointment warfarin 25% PT oxandrolone5 10 mg 2 warfarin AUC Cmax 2.8 2.2 S-warfarin 2.2 2.3 R-warfarin INR 1.3-2.0 warfarin 84% warfarin androgenic 2
2 androgenic agents
androgenic agents
PT
agents
testosterone
warfarin warfarin 25-84%
1
2-3 10-20%
INR
PT, INR
INR
warfarin androgenic agents androgenic agents warfarin
testosterone
warfarin
androgenic agents
2 2
bleeding
warfarin
INR
warfarin
260
20
–1
2559
________________________________________________________________________________
Cyproterone Acetate
: Cyproterone acetate
testosterone androgen receptor stimulating hormone (FSH) : __ __X__
:
Progestogen antiandrogen testosterone, luteinizing hormone (LH), and follicle
:
: 40
: /
Cyproterone
warfarin
261
20
–1
2559
________________________________________________________________________________
Acarbose
:
complex oligosaccharide complex carbohydrate oligosaccharide
glycosylated hemoglobin
_____ :
__X__
alpha-glucosidase monosaccharide
Bioavailability <2% : 14–24 1 (active drug) / : Major metabolites sulfate, methyl, and glucuronide conjugates IV 89% :2 Acarbose warfarin Drug Interaction Facts: Significant rating: 4, Onset: Delayed, Severity: Moderate, Documentation: Possible, Mechanism: Unknown, Effect: warfarin :
Micromedex :
Onset: Delayed Severity: Moderate Documentation: Good Mechanism: unknown Effect:
increased risk of bleeding Leaflet / package insert: Clinical trials: Observational studies / case reports:
66
acarbose
INR
42.5 mg/wk fosinopril, warfarin hydrochlorothiazide, glipizide, regular insulin, diphenhydramine acarbose 25 mg 1 mg 25 2 2 mg 25 3 3 acarbose 10 INR 2.53- 3.13 4 Acarbose INR 3.09 acarbose 2 INR 4.85 1 40mg/wk acarbose 7 14 INR 3.28 2.84 Morreale ( AP &Janetzky K: Probable interaction of warfarin and acarbose. Am J Health Syst Pharm 1997 ; 54:1551 -2.)
acarbose
report Case acarbose INR
7-14
3
2 acarbose
acarbose
INR warfarin 1
warfarin (Morreale &
Janetzky, 1997). Acarbose
warfarin
25mg
warfarin
262
20
–1
2559
________________________________________________________________________________
warfarin
Acarbose
INR
1-2
263
20
–1
2559
________________________________________________________________________________
Pioglitazone
:
:
proliferator-activated peroxisome receptor gamma (PPAR γ) insulin
_____ :
__X__
: / Metabolism 39), CYP3A4 (minor 2C19 (weak), 2D6 (moderate)
insulin
bioavailability
:
50
99
15-30
–7
Hydroxylation CYP1A1 CYP3A4 (weak)
17)
CYP450 system C YP2C8 (major CYP2C8 (moderate), 2C9 (weak), -90 80
:3 Pioglitazone
warfarin
Drug Interaction Facts: Significant rating: 4, Onset: Delayed, Severity: Major, Documentation: Possible, warfarin Mechanism: Unknown, Effect: Leaflet / package insert: pioglitazone AUC R-warfarin S-warfarin 3 1 pioglitazone Clinical trials:
Cmax R-warfarin prothrombin time 1
2,
Cmax
S-warfarin
1
/
2007
Andre J. Scheen
REVIEW ARTICLE,Clin Pharmacokinet 2007; 46 (1)
1/
45
45
/
INR
pioglitazone INR INR 84 atrial fibrillation warfarin 1 pioglitazone 15 mg INR -3 2 12 INR 1.2 mg/wk 16mg/wk 8.5 (88%) INR 1.2 2.3 18 INR 1.9 -3.2 (www.theannals.com The Annals of Pharmacotherapy n 2006 May, Volume 40 n 994-996) pioglitazone warfarin pioglitazone reports Clinical trials warfarin case pioglitazone INR INR pioglitazone Observational studies / case reports: pioglitazone
264
20
–1
2559
________________________________________________________________________________
3
case report
pioglitazone
Warfarin
warfarin pioglitazone
INR
warfarin INR
warfarin 3
80%
265
20
–1
2559
________________________________________________________________________________
Repaglinide
:
repaglinde ATP-dependent potassium channels characterizable calcium influx insulin site : _____ __X__
:
bioavailability 98
:
60
beta-cell membrane
: /
aromatic amine, a dicarboxylic acid,
oxidized C YP3A4
CYP450 system
acyl glucuronide
90
8
:
1
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
Repaglinide
warfarin
1
/
2007
REVIEW ARTICLE Clin Pharmacokinet 2007; 46 (2)
Andre J. Scheen
Repaglinide
ARTICLE warfarin
Repaglinide
Repaglinide
Repaglinide
/
3
INR
warfarin
2
Observational studies / case reports:
Repaglinide
warfarin
warfarin
REVIEW
Repaglinide
warfarin
warfarin
warfarin
Repaglinide
266
20
–1
2559
________________________________________________________________________________
Sitagliptin
:
dipeptidyl peptidase-4 (DPP-4) peptide (GLP-1) glucose-dependent insulinotropic peptide (GIP) glucose-dependent
: _____
M etabolism 13
12.4
87
INR
: sitagliptin
Clinical trials:
2009
__X__
warfarin Drug Interaction Facts: Leaflet / package insert: sitagliptin warfarin S(-) or R(+) warfarin enantiomers S(-) warfarin metabolized warfarin 1 sitagliptin CYP2C9 inhibitor
glucagon-like
Bioavailability 87 38 / : CYP450 system CYP3A4, CYP2C8
: :
/
1
Wright DH, et al. randomized, open-label, 2part, 2-period crossover study
CYP2C9
J Clin Pharmacol. Sitagliptin 200 mg/d 2009 Oct;49(10):1157 11 67.
Warfarin 30 mg AUC (0-infinity), Cmax 5 R(+) S(-) warfarin
PT
warfarin
Observational studies / case reports:
sitagliptin
sitagliptin
warfarin
warfarin warfarin CYP2C9
warfarin
INR 30 mg sitagliptin
RCT INR 1 warfarin INR AUC (0-infinity), Cmax R(+) S(-) metabolized S(-) warfarin sitagliptin metabolized 267
20
–1
2559
________________________________________________________________________________
organic cationic transporter (OCT) sitagliptin
sitagliptin sitagliptin warfarin
warfarin substrates CYP3A4, CYP2C8, CYP2C9, (Wright DH, et al. J Clin Pharmacol. 2009 Oct;49(10):1157-67.) warfarin
warfarin
warfarin
sitagliptin
268
20
–1
2559
________________________________________________________________________________
Methimazole
:
iodination intermediate T4
MMI
: __ X __ myelopoiesis
thyroid peroxidase
(substrate) iodothyronine
T 3
____ granulopenia, aplastic anemia agranulocytosis,
thrombocytopenia
:
: / Methbolized : 4-6
bioavailability
:
- 90%
80
Methimazole
80
warfarin
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: suspected , Mechanism: Unknown. Leaflet / package insert: Clinical trials:
Methimazole 3
warfarin
/
1964
Loeliger EA, et al Observationa l study (N=26) Myxoedema 10 thyrotoxicosi s5
Thrombosis et diathesis Haemorrhagica. 1964;10:267-77.
-
Loading dose Acenocoumar ol 80-100 mg then at least 40 mg OD
5 Control 6
2006
Busenbark LA, et al
Ann Pharmacothera
Start MMI 30 mg/day
Start 35mg/wk
Thyrotoxicosis
fever factor activity
(2.5 hr,4-8 hr), PT 2 (thyroroxicosis 18hr, fever 13 hr, control 24 hr) control 2 control Myxoedema factor activity1(15, 4-8 hr),PT 2 (50,24hr) control 2 warfarin Antithyroid medication
269
20
–1
2559
________________________________________________________________________________
py.2006;40(6); 1 200-3.
Then thyroid function
2008
Akin F, et al
then INR ( mg/wk)
Warfarin
85
2.4
Blood
Start MMI
Start 5 mg/
Coagulation & Fibrinolysis. 2008;19(1):8991.
30 mg/day Then
day then INR
thyroid function
( 105 mg/wk)
Warfarin
warfarin
Antithyroid medication Warfarin Warfarin
3
Methimazole INR hyperthyroidism 22 deep vein warfarin Methimazole INR 1.2 0.95 Warfarin 12.5 mg/day (87.5 mg/wk) 2.5 2.0 (Akin F, et al. Blood Coagulation & Fibrinolysis. 2008;19(1):89-91.)
Observational studies / case reports:
thrombosis
INR
Methimazole
1-2
INR
Warfarin INR
INR
INR
2.4 -2.5
3- 10
Case report Methimazole
Hyperthyroidism clotting factor Antithyroid medication Warfarin (Loeliger EA, et al. Thrombosis et diathesis Haemorrhagica. 1964;10:267-77.)
Methimazole
warfarin
INR
catabolism
Methimazole
warfarin
warfarin
Methimazole
Hyperthyroidism
270
20
–1
2559
________________________________________________________________________________
Propylthiouracil
:
PTU
: __ X __ myelopoiesis
thyroid peroxidase triiodothyronine peripheral tissues
iodination intermediate thyroxine
(substrate) iodothyronine T 3 ,T4
____ granulopenia, aplastic anemia agranulocytosis,
thrombocytopenia
:
bioavailability 75-80%
:
: / Methbolized
75%
Propylthiouracil
35
warfarin
Drug Interaction Facts:
Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: suspected , Mechanism: Unknown. Leaflet / package insert: Propylthiouracil warfarin 7 Clinical trials:
1964
/ Loeliger EA, et al Observational study (N=26) Myxoedema1 0 thyrotoxicosis 5
Thrombosis et diathesis Haemorrhagica . 1964;10:26777.
-
Loading dose Acenocoumarol 80-100 mg then at least 40 mg OD
5 Control 6
2006
Busenbark LA, et al
Ann Pharmacothera py. 2006;40(6); 120 0-3.
Start MMI 30 mg/day Then thyroid function
Start 35mg/wk then 85 INR ( mg/wk)
Thyrotoxicosis
fever factor activity (2.5 hr,4-8 hr), PT 2 (thyroroxicosis 18hr, fever 13 hr, control 24 hr) control 2 control Myxoedema factor activity1(15, 4-8 hr),PT (50,24hr) 2 control 2
warfarin Antithyroid medication Warfarin Warfarin 2.4
271
20
–1
2559
________________________________________________________________________________
2008
1960
1964
1972
Akin F, et al
Greenstein
Start MMI 30 mg/day Then thyroid function Propylthiou
RH.
1014-5
racil
Gilbert DK.
JAMA. 1964; 189:855.
Propylthiou racil 300 mg
-
Propylthiou racil 200 mg every 6 hr.
-
Propylthiou racil 1000 mg
7.5 mg/day PT 30
mg/day
Hypoprothrombinemia
Gotta AW. Et al.
Anesthesiology .1972;37(5): 562-3
Start 5 mg/ day then INR ( 105 mg/wk) -
warfarin Antithyroid medication Warfarin Warfarin 3 PTU
Blood Coagulation & Fibrinolysis. 2008;19(1):8991. JAMA. 1960;17:
Hypoprothrombinemia PT PTU Hypoprothrombinemia PT 4.6 thyroid PTU Hypoprothrombinemia Bleeding
Self T. et al
JAMA. 1975;2311(11): 1165-6
1975
Warfarin
PTU INR Warfarin 4
Propylthiouracil INR 57 hyperthyroidism Atrial Fibrillation warfarin Propylthiouracil Warfarin 30 mg/day (210 mg/wk) 4 Hypoprothrombinemia (Self T. et al,JAMA. 1975;2311(11): 1165-6)
Observational studies / case reports:
Propylthiouracil
INR
Propylthiouracil Warfarin
1-2
INR 4
Case report
5
Antithyroid medication Warfarin Thrombosis et diathesis Haemorrhagica. 1964;10:267-77.) Propylthiouracil
warfarin
INR
PT
Propylthiouracil
INR
Hyperthyroidism (Loeliger EA, et al.
warfarin
272
20
–1
2559
________________________________________________________________________________
catabolism
clotting factor Hypoprothrombinemia
Propylthiouracil INR
Hyperthyroidism warfarin
273
20
–1
2559
________________________________________________________________________________
Levothyroxin
:
thyroid hormone
:
:
____
__ X __
99%
: / Metabolism
metabolism
:
40-80%bioavailability
64%
%
50
Active metabolite (T3)
20
%
: 9-10 Levothyroxine
warfarin
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Probable Leaflet / package insert: Levothyroxine warfarin 3
Clinical trials:
2014
1975
1964
/
Wood M.D, et al Retrospective, self-controlled study (N =119)
Journal of Thrombosis and Hemostasis. 2014;12: 1313-9
Levothyroxin 25, 50, >50 µg (TSH< 10 mIU/L)
Self T. et al
JAMA. 1975;2311(11): 1165-6
Propylthiouracil 1000 mg
Loeliger EA, et al Observational study (N=26) Myxoedema10 thyrotoxicosis 5
5
Thrombosis et diathesis Haemorrhagica. 1964;10:267-77.
-
stable INR 2-3
7.5 mg/day PT 30 mg/day
Loading dose Acenocoumarol 80-100 mg then at least 40 mg OD
Warfarin
Warfarin
PTU INR Warfarin 4
Hypoprothrombinemia fever factor activity (2.5 hr,4-8 hr), PT 2 (thyroroxicosis 18hr, fever 13 hr, control 24 hr) control 2 control
Thyrotoxicosis
274
20
–1
2559
________________________________________________________________________________
Myxoedema factor activity1(15, 4-8 hr),PT 2 (50,24hr) control 2
Control 6
2014
Walderez P.G. et al
Central European Journal of Medicine.2014;9( 2): 231-4.
Levothyroxin 50 µg
Phenprocoumon stable INR 2.5-3.5
warfarin 2 Vitamin K Anticoagulant INR (Walderez P.G. et al, Central European Journal of Medicine.2014;9(2): 231-4.)
Levothyroxine
Levothyroxine
frozen plasma Fresh 5.0 (TSH =12)
warfarin
INR Retrospective, self INR ( TSH INR case reports INR ( ) Retrospective INR 3-4 2 INR 1-2 Hypothyroidism catabolism vitamin K-dependent clotting factor INR warfarin (Loeliger EA, et al. Thrombosis et diathesis Haemorrhagica. 1964;10:267-77.) Levothyroxine warfarin Hypothyroidism INR warfarin controlled study <10 mIU/)
fibrillation Heart failure Levothyroxin 50 µg
Levothyroxine INR 62 Severe mitral valve insufficiency,atrial Phenprocoumon INR 2.5 -3.5 INR 2.8
Observational studies / case reports:
Anticoagulant
warfarin Levothyroxine Anticoagulant
INR
275
20
–1
2559
________________________________________________________________________________
SSKI (saturated solution of potassium iodide)
:
: _____
No data
S porothrix
__X__
schenckii
SSKI
SSKI
warfarin
Drug Interaction Facts: Severity: Moderate, Documentation: Good, Mechanism: no data Leaflet / package insert: SSKI warfarin Observational studies / case reports: SSKI INR hyperthyroid 54 Grave’s disease atrial fibrillation MMI (30 mg/day) warfarin ( ) 3 warfarin 85 mg/wk INR 2-3 12 MMI 10 mg/day warfarin dose hypothyroidism MMI MMI 5 mg/day INR (micromedex 2016) warfarin 60 mg/wk
SSKI
SSKI
SSKI
thyroid SSKI
warfarin
INR
warfarin
warfarin
INR
warfarin
276
20
–1
2559
________________________________________________________________________________
Esomeprazole
: esomeprazole proton pump inhibitor H+/K+ ATPase parietal cell : ____ __ X __
:
bioavailability 97 CYP450 system
:
: / CYP 3 A4 Metabolite <1% active drug) : –1.5 1 Esomeprazole
90 CYP2C19 ( inactive 80
20
warfarin
Drug Interaction Facts: Onset: Not Specified, Severity: Moderate, Documentation: Good, Mechanism: unknown Leaflet / package insert: Esomeprazole warfarin Clinical trials: 1
2001
/
double-blind, randomized, 2-way crossover study (AstraZeneca)
Clin Pharmacokine t 2001; 40 (7): 523-537
40
/
3
13%
esomeprazole
2
plasma concentration (R)-warfarin
placebo
(S)-warfarin (
potent form)
esomeprazole
Observational studies / case reports:
esomeprazole warfarin esomeprazole INR RCT R-warfarin S-warfarin S-warfarin R-warfarin Esomeprazole CYP2C19 R-warfarin
5
277
20
–1
2559
________________________________________________________________________________
esomeprazole
warfarin
INR warfarin
Esomeprazole
Warfarin
278
20
–1
2559
________________________________________________________________________________
Omeprazole
:
H+/K+ ATPase enzyme enzyme H+( lumen )
Omeprazole
basal
stimulated acid secretion _____ __X__
:
:
bioavailability 95 – 96
30-40
: /
first pass metabolism 70-77 substrate CYP2C19 CYP3A4 inhibits CYP1A2, 2C9, 2C19, 2D6, 3A4 induce CYP1A2 : 0.5 – 1
16-19
:
enzyme H+/K+ ATPase (proton pump) parietal cell (dose-related)
membrane
omeprazole
18-23
warfarin
Drug Interaction Facts: Significant rating: 4 Onset: Delayed, Severity: Moderate, Documentation: Possible, Mechanism: Stereoselective inhibition of the hepatic metabolism of the less potent R-WARFARIN enantiomer metabolized Leaflet / package insert:
3
Clinical trials:
1989
1992
cytochrome P450 (warfarin) omeprazole PT INR
/
SulfinT,et al double-blind placebocontrolled, randomized, crossover study (N=21)
TherDrug Monit. 1989;11:176
Unge P, et al Randomized double-blind, placebocontrolled, crossover study (N=28)
Br. J. clin. Pharmac. 1992 May;(34) :509-512
20
/
/
2.5 -8.125
(
2
R-warfarin
coagulation factor 10-20 %
3
/
warfarin
) 20
S-
warfarin % warfarin
R 9.5 S-
279
20
–1
2559
________________________________________________________________________________
/
Coagulation time
2008
Uno et al Randomized, double-blind, two-
Ther Drug Monit 2008 June;(30):276-281
phase crossover study (N=27)
20
/
10 mg
omeprazole
Warfarin
R-
CYP2C19 omeprazole S-warfarin Observational studies / case reports: 78 deep vein thrombosis 60INR – 2.5 3 acenocoumarol (oral vitamin K antagonist) omeprazole / 20 Hematuria) ( INR O meprazole INR therapeutic range acenocoumarol Garcia ( B, et al. Pharm World Sci. 1994; 16:231)
omeprazole
5 5.7
warfarin
R- warfarin omeprazole warfarin 2 Omeprazole warfarin 1-2 warfarin PPI warfarin S-warfarin
omeprazole INR
INR
280
20
–1
2559
________________________________________________________________________________
Lansoprazole
:
Parietal cell _____ __X__
:
:
bioavailability
80
97
: /
2
:
H+/k+ATPase enzyme
CYP2c19
3A4
parietal cell
67
33
:
1.5
2-3
lansoprazole
warfarin
Micromedex drug interaction : onset : not specified, Seerity Moderate, Documentatic : Good Mechanism : unknown Clinical trials:
1995
1
/
DelhotalLandes etal, double-blind placebocontrolled,randomized,cross over study ( N=24 healthy volunteers
Clin.Pharmacokinetic 1995:48(6):458-470
60mg/
1
warfarin 9
warfarin
PT Observational studies/case report : Lansoprazole Retrospective , Observation analysis 75 (Lansoprazole Rebeprazole) artery bypass grafting warfarin 2 INR 1.5 5.68 (hemothorax)
lansoprazole
2
INR
Warfarin 15 mg/
PPI coronary 2
warfarin
observation studies
lansoprazole
INR
) 281
(
20
–1
2559
________________________________________________________________________________
lansoprazole
INR
warfarin
lansoprazole
warfarin
warfarin
282
20
–1
2559
________________________________________________________________________________
Pantoprazole
:
:
H+/K+ ATP pump parietal cell
__X__
/
bioavailability 98, albumin
77
:
CYP450 system
(minor)
CYP2C19
71
CYP2D6 CYP2C9 CYP3A4, unchange) (
18
_____
:
:
1
:
Pantoprazole
warfarin
Micromedex drug interaction: Onset: Not specified , Severity: Moderate, Documentation: Good, Mechanism: inhibition of CYP2C9-mediated warfarin metabolism by pantoprazole Leaflet / package insert: Pantoprazole INR Clinical trials: 1
/
1995
Duursema, et al double-blind, randomised, placebocontrolled, two-period, crossover study (N=26 )
Br J clinPharmac. 1995;39: 700-703
INR
-
PT
warfarin
pantoprazole
CYP2C9
pantoprazole
warfarin
25
S-warfarin
/ 8
R-
pantoprazole
warfarin
-
Observational studies / case reports:
40
warfarin
warfarin
INR
pantoprazole
283
20
–1
2559
________________________________________________________________________________
Rabeprazole
:
:
5%
proton pump inhibitor _____ __X__ :
/
gastric acid
parietal cell H+/K+ ATP pump
1
, :96.3%
4
CYP3A : 2C19 inactive metabolites; CYP2C19 (3% Caucasians 17% 20% Asians) metabolism : - Dose dependent - Adolescents: ~0.55 1 - Adults: 1 2 ; mild-to-moderate hepatic impairment - :Adolescents: : 3.3 4.1 - Adults: : 2 5 ; : 1 6.5 (90% : thioether carboxylic acid metabolites);
rabeprazole
warfarin
Drug Interaction Facts: rabeprazole warfarin Micromedex: Onset: Delayed, Severity: Moderate, Documentation: Fair, Probable Mechanism: unknow Leaflet / package insert:
3
Clinical trials:
INR
prothrombin time
/
2015
Hata M, et al. Prospective randomized and interventional trial.
Thorac Cardiovasc Surg. 2015 Feb;63(1):45-50. doi: 10.1055/s0034-1383814. Epub 2014 Jul 28.
rabeprazole 10 mg/day lansoprazole 15 mg/day
Target INR 1.6-2.6 3 mg
PPI INR
Lansoprazole rabeprazole INR Bleeding Lansoprazole
Rabeprazole over 2 INR (>3.5) lansoprazole 15
2
rabeprazole bleeding 2 rabeprazole 3.10±1.06
284
20
–1
2559
________________________________________________________________________________
/
lanzoprazole 3.04±1.68 Max INR rabeprazole 2.29±0.55
lansoprazole 3.32±0.99
1
INR
2014
Wedemeyer RS1, Blume H. Review.
Drug Saf. 2014 Apr;37(4):20111. doi: 10.1007/s40264014-0144-0.
2008
Hata M1, et al.
Thorac cardiovasc Surg
Humphries TJ, Nardi RV, Spera rabeprazole AC, et al. Coadministration of metabolic drug rabeprazole sodium (E3810) does interactions warfarin. not affect the pharmacokinetics of anhydrous theophylline or warfarin. Gastroenterology. 1996;110:A138. 3 mg rabeprazole INR 10 mg/day INR ( 4 )
Retrospective, observational analysis.
2008; 56(5): 274-277.
lansoprazole 15 mg/day
Lansoprazole Rabeprazole
rabeprazole (1.66±0.87)
Lansoprazole
rabeprazole
lansoprazole (2.06±1.03) delayed bleeding lansoprazol INR 3.95 ( 3 .11-5.86) rabeprazole delayed bleeding rabeprazole minor CYP2C19 INR INR >3
Observational studies / case reports:
INR
Case Report
warfarin
285
20
–1
2559
________________________________________________________________________________
lanzoprazoe ( metabolism INR
rabeprazole warfarin INR rabeprazole warfarin r abeprazole metabolism minor CYP2C19 nonenzymatic reduction) R-warfarin R-warfarin S-warfarin CYP2C19 competitive inhibitor CYP2C19
rabeprazole
warfarin
rabeprazole 1
warfarin
INR >3
rabeprazole
INR
INR
286
20
–1
2559
________________________________________________________________________________
Cimetidine
:
parietal cell :
receptors
Histamine H2 Antagonist
:
_____
50
: /
: 2
histamine
sulfoxide 48
H2
bioavailability 3 – 26 1
cimetidine
__X__
:
70 – 76
5-hydroxymethyl derivatives 2-3
warfarin
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Established, Mechanism: stereoselective inhibition of the hepatic metabolism of the less potent (R)-warfarin enantiomer Leaflet / package insert: cimetidine warfarin Clinical trials: 3
/
Cimetidine
warfarin
1984
O'Reilly RA Randomized, Cross-over study (N=11)
Arch Intern Med. 1984 May;144(5):98991.
1,200 8
/
1.5
/
cimetidine 3
AUC the onestage prothrombin times plasma concentrations warfarin cimetidine + warfarin
warfarin ± 6 84 (mean ± SEM) 101 ±8 units (P = . 01) ± 38 467 (mean ± SEM) 589 ±51 mg-hr/L (P<.001) cimetidine S
1986
Choonara IA,
Br J Clin
1
/
15
287
20
–1
2559
________________________________________________________________________________
/
Cimetidine
warfarin
et al (N=8)
Pharmacol. 1986 Mar;21(3):271-7.
enantiomer warfarin R enantiomer warfarin
cimetidine
3
cimetidine
halfplasma
life hr
R warfarin 57.8 hr
47.8
plasma clearance 2.3 1.7 ml h-1 kg-1 (P < 0.02) 1987
Toon S, et al Placebocontrolled, Randomized,
Eur J Clin Pharmacol. 1987;32(2):16572.
three-way crossover design (N = 9)
800 9
/
25
cimetidine elimination half-life R-warfarin 55.2 + 11.0 hr (mean
cimetidine 3
±SD; control) 69.7 ± 16.3 hr (mean + SD; cimetidine; p < 0.01) clearance a 234+42.6ml/hr 187+38.6ml/hr, (p < 0.001)
cimetidine prothrombin time 19 nephrotic syndrome, renal vein thrombosis pulmonary embolism warfarin 6 mg/day, prednisolone 15 mg twice daily furosemide 250 mg twice daily prothrombin time therapeutic range 18-26 seconds cimetidine 300 mg 3 12 3 140/100 mmHg, pulse rate 78 beats /min, Hb 16.4 g/dl Observational studies / case reports:
leukocyte count 34.5 X 10./l, platelet count 546 X 1 0./l., prothrombin time 51 seconds partial thromboplastin time 91 seconds (control time 35 seconds) pulse rate 156 beats/min, respiratory rate of 40/mm Hb 9.8 g/dl, prothrombin time 90 seconds partial thromboplastin time 110 seconds IV vitamin k 50 mg, fresh frozen plasma 2 fluid (Saline), Albumin red cell concentrates factor II, VII, IX X concentrate 2200 units (Kerley B, Ali M. Can Med Assoc J. 1982 Jan 15;126(2):116.)
288
20
–1
2559
________________________________________________________________________________
20%
cimetidine
26 % plasma clearance
warfarin
cimetidine
prothrombin times warfarin R warfarin plasma half-life R warfarin case reports cimetidine prothrombin times 1-2 1
cimetidine
warfarin
cimetidine
warfarin
warfarin INR, PT
metabolism (moderate cimetidine ), 2C9 (weak), hepatic enzyme inhibitors : CYP1A2 3A4 (moderate)
warfarin
cytochrome P450 enzyme system
famotidine cimetidine
289
20
–1
2559
________________________________________________________________________________
Famotidine
:
H2-receptor antagonist partial cell H2-receptor gastric : _____ __X__
histamine
:
Bioavailability
/
competitive inhibition
:
35
30
oxide metabolites
40% to 45% 15% to 20%
:
metabolized (IV: 65-70%, oral: 25-30%)
Oxidation
S-
: Adult: 2.5 – 4 Children: 3 - 4 Infant 3-12 : 4.5 Infant <3 : 8-10.5
famotidine
Drug interaction fact: Micromedex:
CrCl<10 ml/min: 20 warfarin
Medscape: AHFS drug information: unlike cimetidine and ranitidine, famotidine does not appear to inhibit the metabolism of drug, include warfarin, theophylline, phenytoin, diazepam, or procanamide, by hepatic cytochrome P-450 enzyme system Clinical trials:
/
1990
De Lepeleire, I., Van Hecken, A., Verbesselt, R. et al. (N=8)
1987
Clin. Pharmacol. Res.;1990;10(3): 167–71
Humphries TJ
famotidine
famotidine
cimetidine warfarin famotidine
7
NA
subtherapeutic doses of warfarin (mean daily dose = 4.0 mg)
PT
NA PT
warfarin
famotidine
Scand J Gastroenterol Suppl. 1987;134: 55-60 Observational studies / case reports:
40 mg 1
guanylthiazole ring
PT,INR
Cytochrome P-450
warfarin 290
20
–1
2559
________________________________________________________________________________
H2-receptor antagonist
Famotidine
PT, INR
291
20
–1
2559
________________________________________________________________________________
Ranitidine Hydrochloride
:
inhibition
histamine H2-receptor antagonist partial cell H2-receptor gastric
histamine
:
bioavailability 15
/
:
N-desmethyl metabolites N-oxide < 4%
ranitidine (1%) cirrhosis)
1.9 – 3
:
Clinical trials:
1981
1984
4
competitive
39-88 metabolized
Oxidation
1%
warfarin
(probable)
/
N-
warfarin
severity : moderate Ranitidine Hydrochloride
S-oxide (1%) desmethyl hepatic dysfunction (compensated bioavailability
_____ : __X__ ranitidine Hydrochloride Drug Interaction Facts: none found Micromedex: warning onset : delayed Leaflet / package insert :
4%, 1%
:
oxide, S-oxide
M.J. SERLIN, R.G. SIBEON & A.M. BRECKENRIDGE (N=5*Five healthy male volunteers)
Br. J. clin. Pharmac. 200 mg (1981), 12, 791-794
Desmond PV, Mashford ML, Harman PJ, et al
ClinPharmacolTher. 150 mg 1984 Mar;35(3):338 41. 750 mg
2
Mean dose =3.4 mg/day (range 2.54.5mg)
14
2
stable INR 2-3
not a significant change in prothrombin time or plasma warfarin concentration
750 mg
150 mg
2
(dose related to warfarin
292
20
–1
2559
________________________________________________________________________________
/
clearance)
1984
O'Reilly, Robert A.MD(N=11)
Arch Intern Med. 1984;144(5):989991
300 mg
1.5 mg/kg single oral dose
ranitidine Hypoprothrombinemia ( prothrombin
prothrombin time (PT)
) 1987
S. Toon, K.J. Hopkins, F. M.
Eur J ClinPharmacol
Garstang, and M. Rowland
(1987)
300 mg
25 mg
Ranitidine pharmacodynamics
32:165-172
pharmacokinetics
enantiomers 2 Observational studies / case reports Ranitidine Hydrochloride INR 66 hemattemesis) ( prothrombin time 36.7 sec ( sec.) 10.8-12.4 ranitidine 600 mg 5 mg 11 ranitidine 300 mg prothrombin time 19-20 sec ranitidine warfarin ranitidine ranitidine Hydrochloride warfarin prothrombin prothrombin time ranitidine Hypoprothrombinemia (
(PT)
ranitidine Hydrochloride
150 mg interaction INR
warfarin
famotidine nizatidine warfarin 2
Ranitidine
drug
293
20
–1
2559
________________________________________________________________________________
Lactulose
:
synthetic disaccharide osmotic pressure : _____ __X__
acid
: -
lactic acid, acetic acid and formic
: -
/
:
:
3
Lactulose
warfarin
Drug Interaction Facts: no data* Leaflet / package insert: no data* Micromedex interaction : Onset: unspecified, Severity moderate , Substantiation: probable Probable Mechanism: reduced intestinal absorption of vitamin K, Summary: Coadministration of lactulose with either acenocoumarol or phenprocoumon (coumarin derivatives related to warfarin) resulted in a significantly higher risk of excessive anticoagulation in patients receiving prophylactic anticoagulation therapy (adjusted relative risk =3.4 Interaction Effect: elevated International Normalized Ratio serum values with potentiation of anticoagulation effects Observational studies / case reports:
Population-based cohort anticoagulation clinic acenocoumarol 1 1991 31 1124 351 phenprocoumon 1998 INR 6 51 INR 6 15 Lactulose 36 Lactulose over anticoagulation 2.2,5.3) 3.4 (95%CI: (RR=0.5, 95% CI: 0.3, 0.8) 28-97 1.7 27 (95% CI: 0.9, 3.0) 98 2.1 (95% CI: 1.2, 3.7)
294
20
–1
2559
________________________________________________________________________________
Visser LE, Penning-van Beest FJA, Wilson JHP et al: Overanticoagulation associated with combined use of lactulose and acenocoumarol or phenprocoumon. Br J Clin Pharmacol 2003; 57(4):522-524. Lactulose
warfarin
warfarin
Lactulose
INR warfarin
27
295
20
–1
2559
________________________________________________________________________________
Milk of Magnesia (MOM)
:
lumen (
: :
peristalsis
magnesium hydroxide lumen
:
lumen
intestinal lumen bowel distension
_____
__X__
contents
-30
15
-
: / Magnesium : –
30
Milk of Magnesia
warfarin
Drug Interaction Facts: Significant rating: 4 Onset: Delayed, Severity: Moderate Documentation: Possible Mechanism: Possible increase in absorption of MAGNESIUM DICUMAROL chelate Leaflet / package insert: Micromedex interaction: 1
Clinical trials:
/
1973
Ambre JJ, Fischer LJ (N=6)
Clin Pharmacol Ther (1973) 14, 231–7 Observational studies / case reports: -
Magnesium hydroxide (Milk of Magnesia) 15 mL
magnesia milk of
Bishydroxycouma rin(BHD) 300 mg single dose
monitor
PTs
75% 50%
AUC
warfarin
magnesium hydroxide Warfarin MAGNESIUM DICUMAROL chelalate
milk of magnesia
BHD 3
AUC anticoagulant activity
warfarin
296
20
–1
2559
________________________________________________________________________________
Psyllium seed (mucillin)
:
:
: _____ Psyllium seed
2016
(
__x__ warfarin
1
/
Laxative)
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
:
Donald S.Robinson
Clinical Pharmacology and Therapeutics Volume 12, Issue 3, pages 491–495, May 1971
M.D.†, David M.
Benjamin M.S. andJohn J. McCormack Ph.D.
-
single oral dose of warfarin 40 mg.
(N=6) Observational studies / case reports:
6
Psyllium seed warfarin seed warfarin Psyllium Psyllium seed warfarin Psyllium seed
40 Psyllium
warfarin
297
20
–1
2559
________________________________________________________________________________
Senna
:
:
:
stimulant laxative
_____
anthraquinones
__X__
: unknown (Ref: Micromedex) : unknown / (Ref: Micromedex) : unknown (Ref: Micromedex)
Senna
warfarin
Drug Interaction Facts: no data Micromedex: no data
298
20
–1
2559
________________________________________________________________________________
Dicyclomine
:
:
:
time to peak : Vd 3.65 L/kg : / 79.5 : 1.8
anticholinergic agent
_____
antispasmodic
dicyclomine
warfarin
8.4
warfarin
dicyclomine
dicyclomine
60-90
Drug Interaction Facts: Leaflet / package insert: Clinical trials: Observational studies / case reports:
__X__
warfarin
warfarin
dicyclomine
warfarin
dicyclomine
299
20
–1
2559
________________________________________________________________________________
Hyoscine N-butylbromide
:
acetylcholine
parasympathetic
:
_____ __X__ : bioavailability : : / : injection 3.5 , oral 7.47
hyoscine
30
warfarin
Drug Interaction Facts: * Leaflet / package insert: * Clinical trials: * Observational studies / case reports: * Drug fact and comparisons, Drug Interaction fact, Micromedex, US FDA, Pub med *
thioguanine
hyoscine
hyoscine
warfarin
warfarin
warfarin
300
20
–1
2559
________________________________________________________________________________
Mebeverine
:
:
musculotropic agent gastrointestinal tract : _____ __X__
: / esterases
direct effect
: metabolized
75
ester bond
veratric acid
mebeverine alcohol
: 2
mebeverine
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
* * *
warfarin
Observational studies / case reports:
*
* Micromedex, Medscape, Pubmed, US FDA, European Medicines Agency, Japan Pharmaceutical Reference, AHFs Drug Information 2013, Drug Interaction Facts 2015, Drug Information Handbook with International, Drug Facts and Comparisons 2012
mebeverine
mebeverine
warfarin
mebeverine
warfarin
warfarin
mebeverine
warfarin
INR, PT
301
20
–1
2559
________________________________________________________________________________
Prokinetic drugs Cisapride
:
serotonin 5-HT4 receptors
acetylcholine
gastric
esophageal sphincter lower : _____ __X__ tone sophageal peristalsis : bioavailability 35-65 : 98, albumin / : CYP450 system CYP3A4 6-12 : Pantoprazole warfarin
emptying
Micromedex drug interaction: Onset: delayed , Severity: Moderate, Documentation: Good, Mechanism: unknown Drug interaction analysis and management: cisapride Hypoprothrombinemia Clinical trials: 1
1990
/
Daneshmend, et al
The World Congress of Gastroenterology:1990 Aug 26-31; Sydney, PD 169
40
/
cisapride warfarin cisapride INR INR cisapride 3 INR 10.7 2.2 -2.5
INR 1.5
warfarin
10%
Observational studies / case reports: cisapride GRED , 75 warfarin 3 cisapride 10 4 10.7 warfarin 2 INR 2.3 3 / Raburn ( M.Am J Health syst Pharm.1997;54(3) : 320)
cisapride
Hypoprothrombinemia
3
INR warfarin
warfarin 40 /
1
INR
warfarin
302
20
–1
2559
________________________________________________________________________________
cisapride
INR
warfarin
303
20
–1
2559
________________________________________________________________________________
Domperidone
:
:
lower esophageal sphincter emptying time : _____ __X__
bioavailability 15 : 91 – 93 : / N-dealkylation 66 31 : 7 – 9 domperidone warfarin Micromedex®: no data
gastric
hydroxylation
Drug Interaction Facts: no data Drug Interactions Analysis and Management: no data Leaflet / package insert: no data Clinical trials: Pubmed, Sciencedirect Warfarin
Observational studies / case reports: Drug interaction Warfarin
domperidone
domperidone domperidone
domperidone
CYP3A4
Pubmed, Sciencedirect
Drug interaction
warfarin
warfarin warfarin
warfarin
Drug interaction
304
20
–1
2559
________________________________________________________________________________
Metoclopramide hydrochloride
:
cholinomimetic
:
: _____ __X__
: Vd /
:
3-5 L/kg
dopamine antagonistic
80
78-85
30
2
: 5– 6
metoclopramide hydrochloride
warfarin
Drug Interaction Facts: no data* Leaflet / package insert: no data* Micromedex: no data*
305
20
–1
2559
________________________________________________________________________________
Mosapride citrate
:
serotonin 5-HT4 receptor acetylcholine
5-HT4
_____ __X__ : : Absolute data in humans are unavailable. : (Protein binding) 97 / : : des- 4-fluorobenzyl CYP3A4 0.1 7.0 : 1.3-2 Mosapride warfarin Drug interaction fact: Micromedex: Medscape: Clinical trials: Observational studies / case reports: mosapride warfarin mosapride warfarin Drug Interaction Facts, Micromedex, medscape warfarin mosapride mosapride warfarin drug interaction 2 INR
306
20
–1
2559
________________________________________________________________________________
Activated charcoal
data : No :
phenobarbital
alcohol digitoxin
enterohepatic recirculation theophylline :
:
:- / Activated charcoal
Drug Interaction Facts: no data Documentation: no data Leaflet / package insert:Activated charcoal
warfarin
warfarin
Clinical trials: Observational studies / case reports:-
Activated charcoal
warfarin
charcoal Activated
warfarin clinical
warfarin
307
20
–1
2559
________________________________________________________________________________
Aluminum Hydroxide
:
Neutralized hydrochloric acid
- :
phosphate
_____ :
__X__
-:
/ : : Aluminum hydroxide Drug Interaction Facts: Aluminum hydroxide
-
warfarin
warfarin
Hypoprothrombinemia action
Leaflet / package insert: no data* Micromedex: no data*
308
20
–1
2559
________________________________________________________________________________
Alum milk
:
Al(OH) 3
:
:
:
_____
Mg(OH) 2
__X__
-
: Aluminium / oxide Magnesium oxide 1-3 Alum milk warfarin
:
Drug Interaction Facts: Magnesium salt Significant rating: 4 Onset: Delayed, Severity: Moderate Documentation: Possible Mechanism: Possible increase in absorption of MAGNESIUM DICUMAROL chelate Leaflet / package insert: Micromedex interaction: Clinical trials: 2
/
1971
Robinson DS, Clin Pharmacol Benjamin DM, Ther McCormack JJ. (1971) 12, 491– (N=6) 5. 1973 Ambre JJ, Clin Pharmacol Fischer Ther (1973) 14, LJ (N=6) 231–7 Observational studies / case reports: -
Alum milk
alum milk hydroxide Magnesium anticoagulant effect
monitor
Single oral dose 40 mg
warfarin
pharmacologic BHD 3
Bishydroxycouma rin (BHD) 300 mg single dose
BHD
warfarin
Alum milk
Aluminium/ magnesium Hydroxide 30 mL Aluminium hydroxide gel (Antacid) 15 mL
warfarin
warfarin
PTs
MAGNESIUM DICUMAROL chelate
309
20
–1
2559
________________________________________________________________________________
Bismuth subsalicylate
:
(antisecretory action)
:
hydrolyzed acid salicylic bismuth subsalicylate
:
_____
__X__
bioavailability bismuth subsalicylate plasma protein : / bismuth oxychloride bismuth 99 : 2-5
subsalicylate bismuth
toxins
prostaglandin E.coli
90
90 salicylic acid salicylate
active form
warfarin
Drug Interaction Facts: Micromedex: Severity: moderate, Onset: delayed, Documentation: Fair, Mechanism: bismuth subsalicylate INR protein binding site Leaflet / package insert: salicylate bleeding warfarin Coumadin anticoagulant Clinical trials:
Observational studies / case reports: 57 kg (126% of ideal body weight) BMI of 25 kg/m2 Caucasian 56 chronic obstructive pulmonary admit enoxaparin warfarin deep vein loperamide, thrombosis diphenoxylate hydrochloride/atropine sulfate, titrate multivitamin, vitamin D, prednisone nebulized ipratropium/ albuterol warfarin dose INR 2-3 bismuth subsalicylate 30 mL 4 INR 2.56 3.54 3 bismuth subsalicylate bismuth subsalicylate bismuth subsalicylate warfarin INR 3 ( Bingham AL, et al. Nutrition in Clinical Practice.2013 Dec; 28(6):766-769.)
bismuth subsalicylate
:
warfarin
warfarin bismuth subsalicylate Micromedex INR severity; moderate, onset ; delayed, Documentation; Fair bismuth subsalicylate protein binding site 1 case report INR 2.56 3.54 minor bleeding 3 bismuth subsalicylate titrate dose warfarin 2-3 2.56 ( ) 2 warfarin bismuth subsalicylate INR 3 ( AL, et al. Nutrition in Clinical Practice. 2013 Dec; Bingham
28(6):766-769.)
310
20
–1
2559
________________________________________________________________________________
bismuth subsalicylate
INR
warfarin
bismuth subsalicylate 3
warfarin
2
311
20
–1
2559
________________________________________________________________________________
Itopride
:
benzamide
( peristalsis
)
: 60 %
gastroprokinetic
:
pyloric sphincter
GI tract plasma protein
:
anti-acetylcholinesterase actions
anti-dopaminergic
gastric fundus
96%
albumin
15%
alpha-1-acid-
glycoprotein
: /
89.41%
N-oxidation
Flavin-containing monooxygenase
(FMO)
Itopride Drug Interaction Facts: no data Documentation: no data Leaflet / package insert:-
warfarin
Clinical trials: Observational studies / case reports:-
itopride hydrochloride
hydrochloride itopride
warfarin
warfarin
itopride hydrochloride
warfarin
312
20
–1
2559
________________________________________________________________________________
Loperamide
:
Peristalsis
Circular
time transit : _____
__X__
longitudinal intestinal muscle
opioid receptor
: Bioavaibility 0.3% Gastrointestinal : tract, 85% Liver, 5% Tissues, 0.04 to 0.2% : first pass biotransformation (Prod Info Imodium(R), pathway oxidative n-desmethylation oxidative n-dealkylation 7-15 : 50% unchanged feces Loperamide warfarin Drug Interaction Facts: docetaxel Leaflet / package insert: docetaxel Clinical trials: docetaxel Observational studies / case reports: Loperamide warfarin docetaxel warfarin Loperamide warfarin docetaxel warfarin
2000)
metabolic
:
warfarin warfarin warfarin docetaxel
warfarin
313
20
–1
2559
________________________________________________________________________________
Polidocanol
:
endothelium __X__
:
____
5
(
TM
: T max (Varithena ): 15 ( : Vd: 35 to 82 L : Clearance: / 0.2 to 0.4 L/min : 1.5 hr
Polidocanol
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
Polidocanol
)
)
warfarin
Polidocanol
warfarin
Polidocanol
warfarin
Polidocanol
warfarin
warfarin
314
20
–1
2559
________________________________________________________________________________
Smecta® (dioctahedral smectite)
: Smectite
smecta mucous mucous
1.
mucous
toxin
rota virus endotoxin exotoxin toxin mucous : _____ __X__ :
2. toxin 3.
toxin
-
:
:
mucous
: / Smecta®
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
warfarin
*
*
smecta
Observational studies / case reports: Drug fact and comparisons, Drug Interaction fact, Micromedex, US FDA, Pub med *
Smecta® Smecta®
Smecta® 2
warfarin
warfarin
warfarin
warfarin
Smecta®
Smecta®
warfarin
Smecta®
warfarin
315
20
–1
2559
________________________________________________________________________________
Sucralfate
:
albumin
sucralfate sucralfate prostaglandin E 2
fibrinogen
__X__ : non-systemic drug 0.005% aluminum) : / m etabolized : unknown sucralfate warfarin
:
_____
gastric mucus
octasulfate
5% (5%
Drug Interaction Facts: Significant rating: 5 Onset:Delayed Severity:Minor Documentation : Possible Mechanism: Sucralfate may reduce warfarin absorbtion. Effect: the hypoprothrombinemic effectof warfarin may be decreased Micromedex: warfarin sucrafate warfarin Probable machamism: decreased warfarin absorption Leaflet / package insert: Subtherapeutic prothrombin times with concomitant warfarin Clinical trials: 1
1985
1985
1988
/
Neuvonen PJ, Jaakkola A, Totterman J, et al A prospective crossover study (N=8) 68-75. Talbert RL, DalmadyIsrael C, Bussey HI, et al. A prospective study Braverman SE & Marino MT
Br J Clin Pharmacol 1985; 20:178180.
1g
Drug Intell Clin Pharm 1985; 19:45645
1g
Drug Intell Clin Pharm 1988; 22:913.
1g
3
14
4
the individual daily dose ranging from 1.5 mg to 4.5 mg.
stable INR 2-3
4
5 mg
PTT, PT, warfarin plasma levels
PT, PTT, warfarin plasma levels
sucralfate
warfarin
4 Subtherapeutic prothrombin times
316
20
–1
2559
________________________________________________________________________________
sucralfate
bioavailability
warfarin
Observational studies / case reports: time digoxin, quinidine sulfate 71 sucralfate Prothrombin warfarin sodium sucralfate sucralfate digoxin quinidine prothrombin time s ucralfate prothrombin time digoxin quinidine sucralfate digoxin, quinidine warfarin sucralfate bioavailability Rey ( AM, Gums JG.DICP. 1991 Jul-Aug;25(7-8):745-6. Subtherapeutic prothrombin times 4 (warfarin 5 mg daily sucralfate 4 . indomethacin phytonadione intake warfarin 17.5 mg , prothrombin times sucralfate indomethacin warfarin dose 10 mg therapeutic prothrombin times 1.5 2 sucralfate arfarin w bioavailability warfarin (Braverman & Marino, 1988).
sucralfate
(Neuvonen et al, 1985; Talbert et al, 1985) interaction sucralfate warfarin case report interaction Sucralfate Braverman & warfarin Marino, 1988; Rey & Gums, 1991). sucralfate warfarin sucralfate prothrombin time sucralfate bioavailability warfarin
sucralfate
warfarin
warfarin sucralfate
warfarin
warfarin
sucralfate warfarin
sucralfate 2
PT,INR
warfarin
317
20
–1
2559
________________________________________________________________________________
Ursodiol (Ursodeoxycholic acid)
:
:
:
_____
: –
: Conjugated / Ursodiol
bioavailability
:
__X__
70 Gluycine
90
Taurine
warfarin
Drug Interaction Facts: no data* Leaflet / package insert: no data* Clinical trials: no data* Observational studies / case reports: no data* * Drug fact and comparisons, Drug Interaction fact, Micromedex, Pub med
318
20
–1
2559
________________________________________________________________________________
Tacrolimus
:
(FKBP-12) cytosol (dephosphorylation)
IL-2 Calcineurin tacrolimus-FKBP-12 complex NF-AT IL-2
50 ( extended-release tablet)
:
:
_____
__X__ bioavailability
receptors calcineurin
F K-binding protein-12
-31(immediate-release 17 capsule)
:
99 / -: 99 98 metabolism immediate-release : 23 ( capsule) 34.5-41 extended-release ( tablet) Tacrolimus warfarin Drug Interaction Facts: Leaflet / package insert: Clinical trials:
-46
Tacrolimus
warfarin
Tacrolimus
CYP 3A4
warfarin
319
20
–1
2559
________________________________________________________________________________
Mycophenolatemotetil
: active metabolite
MPA (mycophenolic acid) inhibits purine synthesis inosinemonophosphate dehydrogenase (IMPDH) T B lymphocyte antibody
:
_____
__X__
noncompetitive inhibits
: 94% Bioavailability: Effects of food: delayed absorption :
-97 82 Metabolism / : enterohepatic recirculation
excretion: of active MPA may occur in human; feces , Urine
-18
: 16
Mycophenolatemotetil Drug Interaction Facts: Leaflet / package insert: Clinical trials: Mycophenolatemotetil
warfarin
warfarin
Mycophenolatemotetil
warfarin
320
20
–1
2559
________________________________________________________________________________
Basiliximab
: Basiliximab murine/human chimeric monoclonal antibody (IgG) (CD25 antigen Tacantigen ) interleukin-2 receptor –chain subunit lymphocyte interleukin-2 proliferation
:
_____
__X__
T-
:
30
unknownsystemic : : vd 8.6 L unknown / :
: 7.2
Basiliximab warfarin Drug Interaction Facts: Leaflet / package insert: Clinical trials: Basiliximab warfarin Basiliximab
warfarin
T-cell
321
20
–1
2559
________________________________________________________________________________
Azathioprine
: Azathioprine
imidazolyl derivative of 6-mercaptopurine immunosuppressive antimetabolite purine nucleotide metabolism T-cell B-cell activity
antibody production ___X___ _____
Azathioprine
RNA
DNA
cell-mediated hypersensitivities
: Prodine : binding 30% , Azathioprine / : Prodrug erythrocyte oxidation methylation 6-mercaptopurine (Active metabolites) 6thioguaninenucleotides Parent drug : :12 , mercapio purine : 0.73-3 , :
Azathioprine warfarin Drug Interaction Facts : - Significant rating : 2, Onset : Delayed, Severity = Modurate, Documentation : Suspected - Mechanism : Unknown ; however THIOPURINES have been reported to increase the synthesis or activation of prothrombin, as well as reduce plasma Wafarin concentrations Leaflet / package insert : azathioprine warfarin Clinical trials: 4
/
2001
2006
2008
Havrda DE1,Rathbun S, Scheid D. (Case report
Pharmacothera py. 2001 ar;21(3):355
postpartum course to treat an initial DVT azathioprine for a steroid-sparing effect
Ng HJ, CrowtherMA.(Cas e report)
Pharmacother. 2006Mar;4(1):75 -7.
150 – 200 mg/day
Vazquez SR, et al.
Ann harmacother.
Azathioprine 35 mg/wk Azathioprine 120 mg/wk
150 mg /
24 mg/wk
Azathioprine 60-75 mg/wk 130 mg/wk
Warfarin 3-4 Target INR
Azathioprine
Azathioprine INR 1.8 14
4
INR
322
20
–1
2559
________________________________________________________________________________
(Case report)
100 mg
2008 Jul;42(7):111823.
39 mg/wk
LFT
1.0 (2-3 wk)
1.9
/
Azathioprine
Warfarin
39
INR 2.5 mg/wk
112
112 mg/wk (2.9
)
Azathioprine 100 mg/day INR 3.4 Warfarin 105 mg/wk 2011
Pushpakom SP, et al. (Case report)
azathioprine INR
old AfroCaribbean man with Crohn disease with recurrent deep vein thrombosis and pulmonary emboli
ClinApplThrom b Hemost. 2011 Jun;17(3):293-6.
azathioprine warfarin
warfarin
INR
Azathioprine Azathioprine 3
INR
2-3
Warfarin
INR 2.4-5.4
warfarin
(25 mg/day)
warfarin
Warfarin Azathioprine
INR Azathioprine 8-10 Azathioprine75-200 mg/day Azathioprine 75 mg/day azathioprine warfarin Azathioprine international normalized ratio (INR) warfarin INR
>140 mg/wk
prothrombin time ratio
323
20
–1
2559
________________________________________________________________________________
Sirolimus
:
T-lymphocyte
IL-2, Il-4, IL-5 ) immunophilin F K Binding Protein-12 ( FKBP-12 ) therapy maintenance :
:
______
:
(2%) :62 ± 6
sirolimus The sirolimus:FKBP-12 complex
___X__ bioavailability
sirolimus
Medscape: Clinical trials: Observational studies / case reports:
14
CYP3A4
P-glycoprotein (91%)
warfarin
sirolimus warfarin sirolimus warfarin
sirolimus sirolimus
Drug Interaction Facts: Leaflet / package insert: Micromedex:
cytokine (
92%
: / substrate
the mammalian Target Of Rapamycin (mTOR)
warfarin warfarin
324
20
–1
2559
________________________________________________________________________________
Immune globulin (human) intravenous – ( IGIV, IVIG )
: primary humoral immunodeficiency,chronic immune thrombocytopenic purpura,
Kawasaki disease
:
:
______
___X__
: /
:
Guillain barre syndrome
Vd 0.6 dL/kg
:5-6
IVIG
Drug Interaction Facts: Leaflet / package insert: Micromedex: Medscape:
warfarin
Clinical trials: Observational studies / case reports: IVIG warfarin IVIG warfarin IVIG IVIG
warfarin warfarin
325
20
–1
2559
________________________________________________________________________________
Live BCG for intravesicle use ( TICE BCG )
:
:
:
______
:
:
superficial bladder cancer
___X__
: / TICE BCG
warfarin Drug Interaction Facts: Leaflet / package insert: Micromedex: Medscape: Clinical trials: Observational studies / case reports: TICE BCG warfarin TICE BCG warfarin TICE BCG TICE BCG
warfarin warfarin
326
20
–1
2559
________________________________________________________________________________
Busulfan
:
Alkylating agents
immunosuppressive
replication
DNA
RNA
:
_____
__X__
0.5-2
2.3-3.4
Busulfan Micromedex drug interaction: Clinical trials :
warfarin
327
20
–1
2559
________________________________________________________________________________
Chlorambucil
Alkylating agent
: alkylation
cross-linking the strands : _____ __X__
:
replication DNA
DNA
transcription
RNA
, >70% :Vd: ~ 0.3 L/kg ~: 99%; albumin (extensively); : active metabolite, phenylacetic acid mustard : ~1.5 ; Phenylacetic acid mustard: ~ 1.8 : 1 ; Phenylacetic acid mustard: 1.9 ± 0.7 : (~20% 60% 24 , inactive metabolites, <1% unchanged drug phenylacetic acid mustard) chlorambucil warfarin Drug Interaction Facts: chlorambucil warfarin Leaflet / package insert: chlorambucil warfarin Clinical trials: chlorambucil warfarin Observational studies / case reports: chlorambucil warfarin
chlorambucil
chlorambucil
warfarin
chlorambucil
warfarin
warfarin chlorambucil
warfarin
328
20
–1
2559
________________________________________________________________________________
Cyclophosphamide
:
guanine
DNA
crosslink DNA alkyl group (CnH2n+1) nitrogen atom 7 imidazole DNA replication ring cyclophosphamide thrombocytopenia
7 Bao.2003 Dec;23(12):1277-9,1282) : _____
200 mg/kg (Zhang Q, et al. Di Yi Jun Yi Xue Xue
__X__
:
>75%
:
24
: /
cyclophosphamide prodrug CYP450 CYP2B6, CYP2C9 and CYP3A4 -25% 5 cyclophosphamide reabsorbtion tubular excretion 3–12 :
metabolism active form ionized
Cyclophosphamide
non
warfarin
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Good, Mechanism: No established Leaflet/package insert: warfarin Clinical trials: Case reports: 1. 70 breast cancer cyclophosphamide,methotrexate 5-FU prothrombin time baseline 15 cycle base line PT treat (8.2-21 sec) 15 PT 44.2,39,31 29 sec case hematuria dose warfarin (Seifter et,al 1985) 2. 57 breast cancer cyclophosphamide,methotrexate 5-FU PT PT range 14.8-17.2 sec 3 week PT 24.6-26 sec 15 cycle 1 3. 62 lymphoma
cyclophosphamide,Doxorubicin,Etoposide,Mechalorethamine,Vincristine,Procarbazine,Methotrexate
PT CMT 1 cycle (Seifter et, al 1985)
Prednisolone
sec
sign bleed analysis ,RCT
8
baseline
case report cyclophospham ide gross hematuria mg dose warfarin
18-20sec
PT
45,30,36
trial support meta 329
20
–1
2559
________________________________________________________________________________
bleeding
mechanism side effect
2
PT cyclophosphamide
hemorrhagc cystitis
Cyclophosphamide warfarin Warfarin
PT Cyclophosphamide regimen chemotherapy cyclophosphamide
1 interaction identify chemotherapy bleeding dose
warfarin
15 bleeding 1
(gross hematuria)
warfarin
Cyclophosphamide
1
warfarin regimen chemotherapy contraindication monitor INR INR
warfarin
warfarin
INR
330
20
–1
2559
________________________________________________________________________________
Melphalan
:
Crosslink
: Bioavaibility
:
:
DNA :
1.2-1.5 h
, oral: 1-1.25 h (~20% 35 % Melphalan
Drug Interaction Facts: Leaflet / package insert: Clinical trials: Observational studies / case reports:
DNA and RNA synthesis
-2 1 39-45 0.5L/kg -90 60 : hydrolysis nonactive
:
nitrogen mustard-derivative alkylating agent N7 _____ __X__
Melphalan
Melphalan
24
,
(~20%
35 %
6
warfarin
melphalan warfarin melphalan warfarin melphalan warfarin melphalan
warfarin
warfarin
melphalan
warfarin
melphalan
warfarin
warfarin
331
20
–1
2559
________________________________________________________________________________
Ifosfamide
Alkylating agent sulfur, nitrogen, oxygen phosphorus DNA(DNA strand break) DNA :
:
:
_____
:
-100% 90 Tmax 3 blood brain barrier
: /
:
alkyl group
bioavailability
__X__
active alkylating moiety DNA
61%
7 ifosfamide
warfarin
Drug Interaction Facts: Significant rating: 4 Onset: Delayed, Severity: Moderate, Documentation: Possible, Mechanism: Unknown. However, inhibition of Warfarin metabolism and displacement of warfarin from its protein-binding site by ifosfamide are suspected to be involved. Leaflet / package insert: Clinical trials: Observational studies / case reports:
1.)
16
ifosfamide warfarin INR malignant ovarian endodermal sinus tumor left femoral INR 4mg/day 2 84 etoposide, ifosfamide/mesna cisplatin,
vien thrombosis warfarin IV Chemotherapy INR 8.4 (Hall G, et al. Postgrad Med J. 1990;66(780):860.) 2.) 61 breast cancer axillary vein thrombosis warfarin 4mg/day INR=2.3 doxorubicin ifosfamide/mesna 48 INR 8.4 warfarin 2 INR 1.3 warfarin 10mg/day INR (INR=2.0) (Hall G, et al. Postgrad Med J. 1990;66(780):860.) 3.) 25 retroperitoneal malignancy warfarin 4mg/day v doxorubicin, INR=2.3 48 incristine, ifosfamide/mesna I NR warfarin 5 5.5 warfarin (4mg/day) INR=2.0 INR 4.8 INR ifosfamide/mesna warfarin I NR (INR=1.0) (Hall G, et al. Postgrad Med J. 1990;66(780):860.) rhabdomyosarcoma 4.) 15 VCD Vincristine, doxorubicin cyclophosphamide ifosfamide/etoposide (IE therapy) VCD therapy cerebral
332
20
–1
2559
________________________________________________________________________________
warfarin INR 2.61 INR 5.45 IE therapy (ifosfamide+etoposide) (Okada N, et al. Journal of Clinical Pharmacology and Therapeutics. 2016;54,58-61.)
ifosfamide warfarin ifosfamide warfarin ifosfamide
INR protien binding warfarin
INR
warfarin ifosfamide INR warfarin
ifosfamide
warfarin monitorINR prothrombin time(PT)
333
20
–1
2559
________________________________________________________________________________
Bleomycin
:
DNA
: 45 – 80 :
: _____
Thymidine
__X__
DNA
Intrapleural Bioavailability
17.5 L/m 2
: 2 – 8.6
1
: /
Bleomycin
DNA
RNA
Intraperitoneal
SubQ
IM
40 – 45
double-strand
DNA single-strand
active drug
warfarin
Drug Interaction Facts: no data Micromedex: no data
334
20
–1
2559
________________________________________________________________________________
Dactinomycin
: Dactinomycin Dactinomycin base guanine DNA DNA cross-link DNA
:
25:
1 -
___x__
2
RNA
-
15
(intercalate)
6
-
:
5
Volume of distribution ( :
Vd) 59-714 L
:
: /
30
36 Dactinomycin
warfarin
Drug Interaction Facts: no data* Leaflet / package insert: no data* Clinical trials: no data* Observational studies / case reports: no data* Drug fact and comparisons, Drug Interaction fact, Micromedex, US FDA, Pub med * Dactinomycin
warfarin
warfarin
Dactinomycin
warfarin
Dactinomycin I NR
INR
335
20
–1
2559
________________________________________________________________________________
Doxorubicin Hydrochloride
:
polymerases
: -
malignancy cell nucleotide and action of DNA and RNA topoisomerase form DNA-cleavable complexes II to : _____ __X__
: Vd 809-1214 L/m(2) : / : 20-48
doxorubicin
75
cerebrospinal fluid 40-50%, 5 -12%
warfarin
Drug Interaction Facts: no data* Leaflet / package insert: no data* Micromedex: no data*
336
20
–1
2559
________________________________________________________________________________
Idarubicin
:
DNA) (
DNA replication) (
: :
oral ,variable (4 %-70%) 30% Vd : 64 L/kg; : 94% 97% : idarubicinol : oral: 14-35 I.V:12-27 oral:: (8%) %) (5 IV.: (17%) (13%) Idarubicin warfarin Drug Interaction Facts: Leaflet / package insert: Clinical trials: : _____ _x___ Idarubicin warfarin Idarubicin Warfarin Idarubicin platelets cell Idarubicin
warfarin
INR
-14 10
Idarubicin
337
20
–1
2559
________________________________________________________________________________
Mitomycin
:
active alkylating moiety phosphorus DNA cell
sulfur, nitrogen, oxygen strand break)
:
: :
_____
alkyl group
DNA (DNA
__X__
Vd: 11 to 48 L/m(2)
: 23-78
/
:
mitomycin
Drug interaction fact: Micromedex: Medscape: Clinical trials: Observational studies / case reports:
mitomycin
mitomycin
10%
warfarin
mitomycin
medscape
warfarin
mitomycin
warfarin
warfarin
Drug Interaction Facts, Micromedex,
warfarin
INR
338
20
–1
2559
________________________________________________________________________________
Mitoxantrone hydrochloride
:
:
antineoplastic drug DNA-reactive agent intercalates DNA hydrogen binding interferes crosslinks strand breaks DNA RNA topoisomerase II enzyme DNA : plot
_____
:
: /
23 – 215
:
dose area under the concentration-time curve (AUC) ) ( linear 78
__X__
Clinical trials:
mitoxantrone hydrochloride
65
(
75
warfarin
hydrochloride mitoxantrone mitoxantrone hydrochloride
warfarin warfarin
Pubmed warfarin
hydrochloride mitoxantrone CYP450
mitoxantrone hydrochloride
mitoxantrone hydrochloride
(
)
mitoxantrone hydrochloride
Pubmed
Observational studies / case reports:
25 11
mitoxantrone hydrochloride
Drug Interaction Facts: Leaflet / package insert:
warfarin
warfarin
warfarin
339
)
20
–1
2559
________________________________________________________________________________
Cytarabine
:
intracellular
antineoplastic DNA nucleotide (ara-CTP, cytosine, arabinoside triphosphate)
S phase
DNA
:
20 : Blood-brain barrier 40-50 : / m etabolite deoxycytidine kinase aracytidine triphosphate (active form) 86-96 ARA-U 24 : IV 7-20 1-3 IT 2-6
cytarabine
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
nucleotide kinase ARA-U (inactive form)
warfarin
Observational studies / case reports: 49 ( 174 ; 68 kg) malignant lymphoma (diffuse large B cell lymphoma, clinical stage IV) 20 r ituximab, etoposide, cisplatin, high-dose cytarabine, methylprednisolone (R-ESHAP). warfarin secondary pulmonary embolism with deep venous thrombosis. R-ESHAP 2 INR 1 5 R-ESHAP INR (1.05; normal range: 0.81–1.09) 2.44 4.71 5 Suzuki ( T, et al. Clinical Therapeutics. 2008 Jun; 30(6):1055-59.)
cytarabine
warfarin
cytarabine warfarin 1 case report R-ESHAP) ( Rituximab, Etoposide, Cisplatin, high-dose Cytarabine, Methylprednisolone
cytarabine
INR
warfarin
INR
cytarabine
340
20
–1
2559
________________________________________________________________________________
Fluorouracil
S phase DNA RNA
: fluorouracil
antimetabolite pyrimidine analog active metabolite
cell cycle
__ X __ ____ : : Topical: 5.98% of the topical dose 3 mucosa , ( : , intestinal uracil catabolism) : / (90%) active metabolite floxuridine monophosphate 7-20% 90% carbon dioxide : 16 (6–20 ) Fluorouracil warfarin
IV
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Suspected, Mechanism: Possible protein displacement, inhibition of warfarin metabolism or inhibition of clotting-factor synthesis Leaflet / package insert:
2
Clinical trials:
/
1999
2010
Jill M. Kolesar, et al. Retrospectiv e, A Consecutive Case Series
Pharmacothera py 1999;19(12):144 5–1449
Sachin R. Shah, et al. Retrospectiv e medical record review
Pharmacothera py 2010;30(12):125 9–1265
5-FU 450 -600 mg/m2
27.5-60 (44.6) mg/wk.
5
31-39 mg/wk.
Capecitabine
%( -7418 2 major bleeding FFP INR – 3.66 23.7 warfarin 5-FU significant interaction warfarin
44%)
Fluorouracil
INR FU warfarin warfarin Capecitabine 67% fluoropyrimidine (5-FU, Capecitabine) INR
- 5
341
20
–1
2559
________________________________________________________________________________
3
% 20 9 - FU 5 Capecitabine INR Baseline 2.8 2.5 INR
Observational studies / case reports:
/
1997
Michael C. Brown
Pharmacothera py 1997;17(3):631633
Case report
stable INR 2-3 warfarin 3.75 mg/day Fluorouracil 1200 mg iv push leucovorin 1400 mg iv infusion 2 25 ,1 . , 8 . 15 . 2 INR 3,4 INR 5.4 6.5 warfarin 1 INR content 35.9 coffee ground 300mL w arfarin indomethacin FFP 4 u INR INR 2.2
1999
Michael C. Brown
Chemotherapy 1999;45:392– 395
2002
Carabino & Wang
AM J HealthSystem Pharm 2002; 59:875 (Micromedex)
59
vitamin K
15 mg iv 48 warfarin 1 mg/day
24-48 small cell lung carcinoma 24 warfarin 1mg/day (mini-dose) catheter-associated thrombosis (PT/INR baseline 11.6/1) 4 vinblastine 5 -FU 5 cycle 16 62.3/8.4 CBC PT/INR ultrasound intrahepatic biliary ductal dilation warfarin b ilirubin K iv 10 mg bilirubin PT vitamin
58
PT/INR
, 60 6
1
,
14.1/1.1) (19.6/1.7 14.8/1.4 5-FU leucovorin 5
DVT
INR baseline 1.1
warfarin
fluorouracil
INR
2
3 – 4
3
342
20
–1
2559
________________________________________________________________________________
INR
20-70%
INR 4.2
(2-3) metabolism
1 7 mg/wk.
7 mg/wk.
INR
14 mg/wk. Fluorouracil warfarin
9 mg/wk. 1.58 INR CYP 2C9
30
fluorouracil
fluorouracil warfarin fluorouracil INR CYP 2C9 metabolism warfarin case reports INR 3 – INR 4 35.9 major bleeding fluorouracil FFP vitamin K
K
fluorouracil warfarin INR warfarin 20 – 70%) INR
warfarin
major bleeding
3
–
4
fluorouracil fluorouracil
FFP vitamin 3 fluorouracil 2 warfarin (
343
30
20
–1
2559
________________________________________________________________________________
Mercaptopurine
:
purine nucleotide
metabolism
RNA
DNA
B-cell activity
T-cell
:
:
__ X ___
:
methylmercaptopurine 2
/
:
____
bioavailability 50 19 6-thioguanine nucleotides
6-thiouric acid
46
:
Mercaptopurine warfarin Micromedex drug interaction: Onset: Not specified , Severity: Major, Documentation: Good, Mechanism: unknown AHFS drug interaction: mercaptopurine anticoagulant warfarin Clinical trials: Observational studies / case reports: mercaptopurine anticoagulant warfarin Mercaptopurine w arfarin induce hepatic enzymes
anticoagulant
warfarin recurrent thromboembolism 81 (deep vein thrombosis, pulmonary embolism with inferior vena caval filter placement) mercaptopurin acute promyelocytic leukemia alcohol K 2-3 INR warfarin 5.5 mg/day mercaptopurine INR 2 3 1.1 warfarin 7.5 mg/day 3 5.5 mg/day drug interaction warfarin mercaptopurine mercaptopurine 10 INR 1.2 warfarin 10 mg/day 2 INR 1.6 neutropenic fever 3 mercaptopurine warfarin 5.5 mg/day mercaptopurine 100 mg/day 3 warfarin cycle warfarin mercaptopurine warfarin 11 mg/day 2 mercaptopurine warfarin 8.5 mg/day (Pharmacotherapy 2003;23(2):260 –264) 62 warfarin 4-10 mg/day venous thrombosis 3 mercaaptopurine thrombolism warfarin mercaptopurine thrombolism mercaptopurine thrombolism Spiers ( & Mibashan, 1974)
mercaptopurine
warfarin
344
20
–1
2559
________________________________________________________________________________
mercaptopurine Mercaptopurine anticoagulant INR mercaptopurine
anticoagulant w arfarin warfarin INR
warfarin
prothrombin time
induce hepatic enzymes
warfarin
345
20
–1
2559
________________________________________________________________________________
Methotrexate
:
:
dihydrofolate reductase proliferation _____
__X__
:
DNA cycle specific cell epithelial cell
s phase
cycle
bioavailability 60 ≤ 30 mg/m2 bioavailability >80 mg/m2 Cmax : 50 , Vd: 0.4 to 0.8 L/kg / : Intracellular Polyglutamates 7-hydroxymethotrexate active form 48-100 3 :– 10 30 mg/m2 8 – 15 0.7 – 5.8 Methotrexate warfarin
Drug Interaction Facts: no data Drug Interactions Analysis and Management: no data Micromedex: Onset: Delayed, Severity: Major ,Documentation: Good, Management: Concurrent use of methotrexate and warfarin may result in increased risk for elevated INR and subsequent bleeding. Leaflet / package insert: no data Clinical trials: Observational studies / case reports: 70 CMF (cyclophosphamide, methotrexate, fluorouracil) warfarin Prothrombin Time (PT) 15 warfarin cycle 4 PT 44.2, 39, 31, and 29 PT 48 – 72 warfarin (Seifter et al, Cancer Treat Rep. 1985 Feb;69(2):244-245.) 57 CMF (cyclophosphamide, methotrexate, fluorouracil) 15 warfarin PT 24.6 14.8 1 PT – 26 ( warfarin PT0tvp^j.o=j;’ 17.2 3 ) PT 48 Seifter et (al, Cancer Treat Rep. 1985 Feb;69(2):244-245.) 62 cyclophosphamide, doxorubicin, etoposide, mechlorethamine, PT vincristine, procarbazine, methotrexate, prednisone 1 8 chemotherapy cycle subconjunctival hemorrhage cycle PT
346
20
–1
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________________________________________________________________________________
45, 30, 36 cycle 1 – 3 PT warfarin (Seifter et al, Cancer Treat Rep. 1985 Feb;69(2):244-245.) Methotrexate warfarin methotrexate warfarin methotrexate PT Methotrexate warfarin
methotrexate PT/INR bleeding PT
warfarin
bleeding
bleeding
INR
1
347
20
–1
2559
________________________________________________________________________________
Capecitabine
: Capecitabine :
cell
:
: :
_____
Metabolism
cell
cell
Capecitabine
__X__
enzyme
active 5- fluorouracil
thymidylate synthase
5-FU analog
/
60% (35% bound to human albumin)
:
95.5% (3% as unchanged drug)
2.6%
:
38-45
capecitabine warfarin Micromedex drug interaction: Onset:Delayed Severity:Major Documentation:Excellent Mechanism: INR CYP2C9 Excellent Leaflet / package insert: capecitabine
PT
2006
Shah HR, et al. / A retrospective study (N=77 patients receiving Capecitabine with or without Warfarin Retrospective
warfarin
1.6–2 g/m2 per day
Clinical Colorectal Cancer 2006; 5(5): 354-358.
77
anticoagulants
- AUC warfarin 57% INR 91% Clinical trials: 1 Capecitabine Warfarin / Capecitabine
capecitabine
Warfarin 18.8 (2.5-70) mg/week
Capecitabine
Warfarin 21
348
20
–1
2559
________________________________________________________________________________
Capecitabine warfarin
events) bleeding
Warfarin 1-2.5 mg 7 major 5 4 warfarin Capecitabine 1-1.1
18.8 mg/week
1
INR
INR 1-11.5
3.31 minor 3 acetylsalicylic acid 1 INR
6
bleeding ( major INR 4 5.9 4
7 Capecitabine 5 3.25 unit fresh frozen plasma 2.4 unit) 1 Capecitabine Warfarin Capecitabine Cytochrome P450 metabolism Warfarin Warfarin Capecitabine Warfarin INR Capecitbine Capecitabine Warfarin INR
pack ( red cell
1
349
20
–1
2559
________________________________________________________________________________
Gemcitabine
:
Pyrimidine (Antimetabolite)
ribonucleotide reductase
S-phase Cell cycle ( : _____ __X__
DNA
DNA polymerase
G1/S-phase )
:Infusions <70 : 50 L/m 2; Long infusion times (70-285 ): 370 L/m 2 : : nucleoside kinases diphosphate (dFdCDP) triphosphate (dFdCTP) : - Gemcitabine: Infusion time ≤70 : 42 to 94 ; infusion time 3 4 4 10.5 : ( ) Metabolite (gemcitabine triphosphate) terminal phase: 1.7 19.4 :30 infusion : 92% 98%; ( inactive uracil metabolite ; ) <1%
Gemcitabine
warfarin
Drug Interaction Facts: Significant rating: 1, Onset: Delayed, Severity: Major, Documentation: Suspected, Mechanism: Possible protein displacement, inhibition of Warfarin metabolism, or inhibition of clotting-factor synthesis Leaflet / package insert: Clinical trials: Observational studies / case reports: Case report 3 65 atrial fibrillation warfarin 57.5 mg/wk stable INR 1.94 multiple liver metastases Gemcitabine Obstructive jaundice staged T4N0M0 new 1,000 mg/m 2 1 Gemcitabine 2 (1 week ) 1 3 INR=1.5 INR=1.8 7 bright red blood per rectum 2 INR=8.0 (M. Wasif Saif, MD, MBBS, J Appl Res. 2005 January 1; 5(3): 434–437.) 82 cancer of the papilla of Vater thrombosis left internal jugular vein Gemcitabine Warfarin S-1 INR Warfarin 11 Warfarin INR 1.7 pulmonary ebolism 13 INR Heparin Genotype homozygous Cyp2c9 1/1 A/A VKORC1 Genotype INR Coadministration S-1/Gemcitabine and Warfarin (Yasui Y1, et al. Gan To Kagaku Ryoho. 2008 Aug;35(8):1367-70.) 65 atrial fibrillation INR target 2-3 Stage 4 nonsmall cell lung cancer Gemcitabine 2380 mg/ 3 2 (Dose 3 cycle 1985 mg) mg/wk INR 1.94 2 cylce Warfarin 57.5 mg/wk Wafarin Gemcitabine 59.23±1.57, INR 2.74±0.73 2 cycle 50.75±3.13 INR 2.74±0.70 INR 3 ( 57.5mg/wk INR 1.94
350
20
–1
2559
________________________________________________________________________________
) cycle 2 ( 52.5mg/wk INR 2.13 3.17 ) Warfarin cycle ( 8.7% 57.5 52.5 mg/wk ,) cycle 2 ( 4.8% 52.5 50.0mg/wk INR 3.17 3.58 7 3% 50.0 48.5 mg/wk INR 3.58 2.2 7 ) Gemcitabine INR 5-7 ( 52.5mg/wk INR 2.37 2.08 2 48.5mg/wk INR 2.2 1.77 7 ) (Kinikar SA1, Kolesar JM. Pharmacotherapy. 1999 3.52
3
Nov;19(11):1331-3.)
Gemcitabine warfarin Case Report Gemcitabine Warfarin INR 3 INR Gemcitabine Cycle Warfarin Gemcitabine cycle Cycle Gemcitabine reversible elevations hepatic transaminases Gemcitabine AST 53 U/L, alkaline phosphatase 132 U/L Gemcitabine AST 180 U/L, alkaline phosphatase 130 U/L AST (240%) Cytotoxicity hepatic cells 1. metabolic CYP enzymes Warfarin 2. Clotting factors INR warfarin Gemcitabine INR 2 INR 1 Warfarin ( 8%) INR ( 3 INR ) INR Cycle Warfarin Cycle Gemcitabine 1 INR Warfarin Warfarin INR target 2
351
20
–1
2559
________________________________________________________________________________
Oxaliplatin
:
transcription
:
- :
: Vd=440L / Nonenzymatic, :
platinum DNA cell cycle non specific
DNA
DNA replication
plasma protein >90% 54 % Oxaliplatin warfarin Drug Interaction Facts: no DI Documentation: no Leaflet / package insert:Clinical trials: Observational studies / case reports: Oxaliplatin warfarin Oxaliplatin warfarin
albumin 2%
Oxaliplatin
gamma globulin
warfarin
352
20
–1
2559
________________________________________________________________________________
Tegafur+Uracil
:
prodrug Fluorouracil Thymidine phospholytase Dihydropyrimidine dehydrogenase (DPD) : __ X __ ____
Rapid, : Tmax = 1-2 hour : Tegafur 52%, Uracil: Negligible Hepatic / (Oxidation) : CYP2A6 Tegafur = 11h,: Uracil 20-40 minutes : Urine (<20% as parent drug) Tegafur+Uracil warfarin
Tegafur
DNA
Hydrolysis
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Suspected, Mechanism: Possible protein displacement, inhibition of warfarin metabolism or inhibition of clotting-factor synthesis Leaflet / package insert: Clinical trials: 1 case report 72 warfarin myocardial infraction (Control INR 2.2-2.5) lung cancer Tegafur+Uracil
1
admit Hemoptysis Dyspnea CT scan diffuse alveolar hemorrhage (DAH) INR 8.9 K INR DAH1.4 2 fluorouracil warfarin fluorouracil INR CYP 2C9 metabolism INR warfarin case reports Tegafur+Uracil 4 fluorouracil
INR Tegafur+Uracil
warfarin 3–4 Tegafur+Uracil 2 3 - 4 fluorouracil warfarin ( 30 INR
353
20
–1
2559
________________________________________________________________________________
Thioguanine
:
6-thioguanilyic acid (TGMP)
:
: : : / : 80
purine
_____
DNA
__X__ bioavailability
pathway de novo RNA
30
thioguanine
thioguanine nucleothides
metabolite
warfarin
Drug Interaction Facts: * Leaflet / package insert: * Clinical trials: * Observational studies / case reports: * Drug fact and comparisons, Drug Interaction fact, Micromedex, US FDA, Pub med *
thioguanine
thioguanine
thioguanine
warfarin
warfarin
warfarin
354
20
–1
2559
________________________________________________________________________________
Etoposide
:
cells
topoisomerase 2 DNA _____ : __X__
: bioavailability :
mitochondrial
nucleosides
HeLa
50 (
7-17 L/m
25
– 75)
2
- 98 94 / : 44 - 11 :4 Etoposide
CYP3A4
3A5
56
Warfarin
Drug Interaction Facts: Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Suspected, Mechanism: Possible protein displacement, inhibition of warfarin metabolism or inhibition of clotting-factor synthesis Micromedex: Onset: Rapid, Severity: Major, Documentation: Good, Probable Mechanism: Unknown INR Leaflet / package insert: Etoposide Warfarin
case reports: reports Warfarin case 74 42.5 Carboplatin Etoposide 16 INR baseline 12.6 1.15-2.11 Carboplatin Etoposide metabolism warfarin Etoposide (Le AT, Hasson NK, Lum BL. Enhancement of warfarin response in a patient receiving etoposide and carboplatin chemotherapy. Ann Pharmacother. 1997;31(9):1006-8.)
Etoposide warfarin case reports Etoposide PT INR 1 case report Etoposide Warfarin warfarin Etoposide Etoposide Warfarin warfarin
INR
355
20
–1
2559
________________________________________________________________________________
Vinblastine sulfate
:
microtubule
:
tubulin __X__
beta subunit tubulin depolymerization
-
: distribution : Vd) 27.3 L/Kg : 14% : 24.8
metaphase
polymerization : _____
/
43 – 99
CYP450 system
CYP 3A4
Volume of
10
(
Vinblastine sulfate
warfarin
Drug Interaction Facts: no data* Leaflet / package insert: no data* Clinical trials: no data* Observational studies / case reports: no data* *
Drug fact and comparisons, Drug Interaction fact, Micromedex, Pub med
356
20
–1
2559
________________________________________________________________________________
Vincristine sulfate
:
tubulin depolymerization
polymerization microtubules
tubulin subunit microtubules microtubule assembly cellular
metaphase arrest
: _____
: -
:
cerebrospinal fluid
Vd 325 L/m(2)
/
85
__X__
:
80
:
3
vincristine
Cytochrome P450 CYP3A4 10 – 20 with initial, middle, and terminal t(1/2) 5 2.3
warfarin
Drug Interaction Facts: no data* Leaflet / package insert: no data* Drug.com : Warfarin because the risk of bleeding may be increased Micromedex interaction : Onset: Delayed, Severity major, Substantiation: probable Probable Mechanism: unknown , Summary: Concurrent use of vincristine and warfarin may result in increased risk for elevated INR and subsequent bleeding Observational studies / case reports: lymphoma vincristine, cyclophosphamide, doxorubicin, etoposide, 62 PT mechlorethamine, procarbazine, methotrexate prednisone warfarin 1 8 1 subconjunctival hemorrhage PT 18 - 20 45, 30 and 36 3 warfarin 1 PT (Seifter EJ, Brooks BJ, & Urba WJ: Possible interactions between warfarin and antineoplastic drugs. Cancer Treat Rep 1985; 69(2):244-245.)
vincristine
warfarin warfarin
warfarin
vincristine
INR
357
20
–1
2559
________________________________________________________________________________
Asparaginase (Crisantapase)
: L-Asparaginase (L-ASNase) ( Asparagine, ASN) ASN
:
:
:
__x___
aspartic ( acid)
____
80%
asparaginase
Drug Interaction Facts: Leaflet / package insert: Clinical trials:
IV
50
CSF
plasma volume
%1
warfarin
asparaginase
Fibrinogen protein C
warfarin
Asparaginase Warfarin L-Asparaginase
thrombotic
asparaginase
warfarin
INR
protein S 1,2
asparaginase
events
IM Vd :4-5 L/kg; 70% : /
systemically degraded Half life elimination : IM 39-49 IV : 8-30
1. Pornsri I, et al. Adverse drug reaction from L-Asparaginase Therapy in Pediatric Cancer. Thai Pediatric Journal .Vol.18 No.3 Sep.-Dec. 2011:194-198. 2.Rinne ML, Lee EQ, Wen PY. Central nervous system complications of cancer therapy. J Support Oncol 2012; 10: 133 - 41. 3. Chirawadee S, Arunee D. Neurological Complications of Chemotherapy and Radiotherapy in Cancer Patients. Songkla Med J Vol. 32 No. 4 Jul-Aug 2014:259-270.
358
20
–1
2559
________________________________________________________________________________
Cisplatin
:
DNA
DNA
:
- :
platinum-DNA adduct Apoptosis _____ __X__
Intrastrand crosslink
:
90 Volume of distribution: 11-12 L/m2 / : 90 10 Initial 25 – 49: Secondary t1/2 58 – 73 cisplatin warfarin Micromedex: Onset: Delayed, Severity: Moderate, Documentation: Good Mechanism: unknow Summary: cisplatin warfarin INR Clinical Management: INR , , Medscape: Observational studies / case reports: 1.
Cisplatin 50
INR cancer, disseminated intravascular coagulation ovarian (DIC), deep vein thrombosis (DVT), renal thrombosis and cerebellar thrombosis DIC DVT Heparin warfarin 3.25 mg/day (goal INR 2 to 2.5) INR ovarian cancer irinotecan 60 1, 8 15 cisplatin 60 mg/m(2) 1 4 mg/m(2) aprepitant 1 3 3 1 INR 3.43 warfarin 1 warfarin 3 mg/day 10 INR warfarin 3.75 mg/day INR 2 3 INR
2.
recurrent uterine cervical adenocarcinoma with liver paclitaxel carboplatin Iliac venous thrombosis warfarin 1 g/day (goal INR 1.2 to 1.5) pulmonary embolism irinotecan cisplatin 60 mg/m2 1 4 supportive care aprepitant 2 warfarin 2.0 mg/day 21 INR INR 1.30 1.77 3 1.88 8 15 INR 43
metastasis
359
20
–1
2559
________________________________________________________________________________
3
4
INR
cisplatin warfarin Cisplatin INR Cisplatin warfarin INR 2
3
INR 90 warfarin Cisplatin warfarin INR cisplatin warfarin warfarin Cisplatin INR INR bleeding 2 warfarin I NR
INR cisplatin INR case report
INR
warfarin
360
20
–1
2559
________________________________________________________________________________
Carboplatin
:
platinum compound alkylating agent interstrand DNA cross-links : _____ __X__
DNA
:
:
peak plasma time : 2 – 4 carboplatin irreversible : /
DNA cell cycle-phase nonspecific
platinum (
carboplatin)
carboplatin ( 70 24 ; platinum 3-5 1-4 ) : CrCl > 60 ml /min : carboplatin : 2.6 – 5.9 based on (a dose of 300-500 mg /m2) platinum ( Carboplatin) : ≥ 5
carboplatin
Drug Interaction Facts:
warfarin
Significant rating: 1 Onset: Delayed, Severity: Major, Documentation: Suspected, Mechanism: Possible protein displacement, inhibition of warfarin metabolism, or inhibition of clotting-factor synthesis (Antineoplastic agents)
Leaflet / package insert: Clinical trials:
carboplatin
warfarin
carboplatin INR 74 warfarin (42.5 mg/wk) atrial INR 8 (1.15-2.11) right fibrillation INR testicular non-seminoma mixed germ cell tumor chemotherapy c arboplatin 180 mg/m2 IV 1 etoposide 150 mg/m2 IV 1-3 INR 2.11, Hb 12.6 g /dl platelets 228 x 103/mm3 follow-up 11 chemotherapy bleeding, , , INR Hb 11.1 g/dl 16 chemotherapy admit INR = 12.6, Hb 10.5 g/dl, platelets 348 x 103/mm3 warfarin 2 phytonadione IV fresh frozen plasma INR 2 (LeAT, et al. The Annals of Pharmacotherapy. 1997
Observational studies / case reports:
Sep;31(9):1006-8.)
carboplatin
warfarin
Case report
carboplatin
carboplatin
long plasma half-life) warfarin warfarin carboplatin
etoposide
free drug warfarin
warfarin platinum (
INR
361
20
–1
2559
________________________________________________________________________________
2
warfarin
carboplatin
warfarin
INR
362
20
–1
2559
________________________________________________________________________________
Hydroxyurea (Hydroxycarbamine)
:
antimetabolite
DNA
ribonucleotide
reductase
:
1-4 : Tmax :
__X__
: 2-4.5
60
75-80
40 (sickle cell anemia)
hydroxyurea
Drug Interaction Facts:
Clinical trials:
Observational studies / case reports:
hydroxyurea
hydroxyurea
warfarin
Leaflet / package insert:
plasma protein : /
_____
hydroxyurea
warfarin
hydroxyurea
warfarin
warfarin
warfarin
363
20
–1
2559
________________________________________________________________________________
Dacarbazine
:
alkylating agent
:
/
5
0-5
:
40
unchange )
(
: Dacarbazine
Micromedex drug interaction: Clinical trials: Observational studies / case reports:
purine analog
:
DNA
SH group _____ __X__
:
Dacarbazine
Dacarbazine
warfarin
warfarin
Dacarbazine
warfarin
warfarin Dacarbazine
warfarin
364
20
–1
2559
________________________________________________________________________________
tretinoin
:
cytodifferentiation proliferation of acute promyelocytic leukemia cells complete remission initial maturation primitive tretinoin promyelocytes leukemic clone remission ( complete ) : _____ __X__ : Bioavailability 50 : 95 , Vd, oral: unknown / : cytochrome 450 glucuronidation
acid, 4-oxo cis retinoic acid, 4-oxo trans retinoic acid 63, 0.5 – 2 :
tretinoin Micromedex®: no data
31
13-cis retinoic
warfarin
Drug Interaction Facts: no data Drug Interactions Analysis and Management: no data Leaflet / package insert: Drug interaction Warfarin ( Japan Pharmaceutical References) Drug Clinical trials: Pubmed, Sciencedirect interaction Warfarin Observational studies / case reports: Pubmed, Sciencedirect Drug interaction Warfarin tretinoin warfarin tretinoin warfarin tretinoin warfarin tretinoin warfarin
Drug interaction
365
20
–1
2559
________________________________________________________________________________
Paclitaxel
:
Paclitaxel antimicrotubule agents polymerization tubulin stable tubulin : _____ __X__
:
89-98% : /
alpha-hydroxypaclitaxel : 5.3 - 17.4
Paclitaxel Micromedex drug interaction :
B-subunit
tubulin microtubules depolymerization
0.1-50mcg/ml
CYP2C8 and CYP3A4 : 1.3% - 12.6%
Major metabolite: 6-
Warfarin
/
2003
Thompson ME, et al. / Case report
Annals of Oncology 2003;
14: 500
Paclitaxel
Warfarin
175 mg/m2
2 mg/day
INR 3
5.2 2 Paclitaxel
cycle
75
2 Deep vein thrombosis INR Paclitaxel ( mg/m175 2) Carboplatin 2 warfarin Dexamethasone mg 20 Ondansetron 8 2 mg Cimetidine (300 mg infusion over 15 Paclitaxel ranitidine mg150 2 duodenal ulcer 2 cycle INR 5.23 Warfarin 8 cycle INR warfarin Paclitaxel Carboplatin Paclitaxel 135mg/m 2 cycle 3 ranitidine cimetidine INR warfarin mg/d 5 cycle 4 Paclitaxel Warfarin Paclitaxel Warfarin plasma protein Warfarin INR Paclitaxel Warfarin INR -3 2.5
warfarin ovarian cancer
mg
366
)
20
–1
2559
________________________________________________________________________________
Docetaxel
:
tubulin
tubulin dimers microtubules stabilizes microtubules M phase cell cycle
:
_____
__X__
depolymerization
DNA, RNA
Extensive : extravascular distribution tissue / binding; Vdss: 113 L (mean steady state) : 97%, ~94% alpha1-acid glycoprotein, albumin, lipoproteins ; oxidation : CYP3A4 metabolites : Terminal: ~11 : ~75%, <8% ( unchanged drug); ~6%) ( docetaxel warfarin Drug Interaction Facts: docetaxel warfarin Leaflet / package insert: docetaxel warfarin Clinical trials: docetaxel warfarin Observational studies / case reports: docetaxel warfarin docetaxel warfarin docetaxel warfarin
docetaxel
warfarin docetaxel
warfarin
367
20
–1
2559
________________________________________________________________________________
Imatinib
:
tyrosine protein( kinase) bcr-abl tyrosine kinase apoptosis bcr-abl positive cell lines fresh leukemic cell
proliferation
:
Rapid : F=98% : protein binding 95% metabolism / :
CYP1A2,CYP2D6,CYP2C9,CYP2C19)
albumin alpha1-acid glycoprotein enzyme CYP3A4 (minor 68% ) 13% metabolites
Imatinib warfarin Drug Interaction Facts:Onset: Not Specified, Severity: Major, Documentation: Good, Mechanism: Probable competitive enz. CYP3A4 enz. CYP2C9 metabolism warfarin Documentation: Good Leaflet / package insert: risk bleeding warfarin Clinical trials:
2010
5%
/
Lin.et.al
CYP2D6
Leukemia research
Imatinib 400 mg OD
Warfarin 2 mg OD
2
prothrombin time grade 3
hemorrhagic INR value variation
Observational studies / case reports: 3 progressive,metastasis,hormone-refractory prostate cancer fixed dose estramustine 280 mg 3 Day 1-5 ,Imatinib 400 mg OD ,Dexamethasone Warfarin 2 mg prothrombin time 3 Imatinib warfarin Imatinib warfarin Imatinib warfarin monitor LMWH standard heparin
368
20
–1
2559
________________________________________________________________________________
Nilotinib (Tasigna®)
:
BCR-ABL kinase ATP-binding protein site of BCR-ABL, c-kit Platelet derived growth factor receptor (PDGFR) Selective inhibit proliferation Leukemic cell Imatinib-resistant BCR-ABL kinase mutations
: High fat meal :
:
:
_____
__X__
Bioavaibility 82 98 / Oxidation 93 CYP450 system
inactive metabolites CYP2C9 inducer ( : 15-17 Nilotinib
in vitro)
3
Hydroxylation CYP3A4 (Major), CYP2C8 (minor)
warfarin Drug Interaction Facts: Onset: Not specified Severity: Major Documentation: Fair , Mechanism: Nilotinib may also have inhibitory effects on the CYP2C9-mediated metabolism of warfarin warfarin Leaflet / package insert: paracetamol Clinical trials: 1
2011
/
Q.P. Yin, et al A Randomized, Single-Blind, Two-Period Crossover Study in Healthy Subjects
Clin Drug Investig. 2011;31(3):16979
Single oral dose of warfarin 25 mg with either a single oral dose of nilotinib 800mg
25 mg Single dose
PT
INR
Monitor INR
2
Nilotinib
Observational studies / case reports: Crossover study Healthy subject 24 Treatment A (Single dose Single dose Nilotinib 800 mg) Treatment B (Single dose warfarin 25 mg + warfarin 25 mg Placebo) subject intervention 2 Crossover wash out period 3 PT INR intervention Bleeding Monitor INR 2 Nilotinib
369
20
–1
2559
________________________________________________________________________________
Nilotinib
Nilotinib
bleeding
warfarin
Nilotinib Warfarin INR CYP3A4, CYP2C9 substrate High protein binding INR Monitor PT/INR Sign of bleeding ( Onset ) Offset warfarin
INR warfarin
Monitor PT/INR
Sign of
370
20
–1
2559
________________________________________________________________________________
Dasatinib
:
tirosine kinase transduction inhibitor
(molecular targeted therapy)
:
_____ __X__ : oral, time to peak concentration 0.5 -6 hours 96 (Vd in adults = 2505L) : : / CYP450 3A4 (85%) : 3-5
signal
dasatinib
dasatinib
Drug Interaction Facts: Leaflet / package insert:
bleeding
warfarin
warfarin
CYP450 3A4
Clinical trials: Observational studies / case reports:
dasatinib
dasatinib
warfarin
warfarin
cytochrome450 3A4
dasatinib
monitor PT
warfarin
dasatinib INR
warfarin
371
20
–1
2559
________________________________________________________________________________
Trastuzumab
:
monoclonal antibody growth factor receptor 2 protein (HER-2) _____ : __X__
- :
44 ml/kg
human epidermal
:
Extracellular domain
3
-
/ : : 6 ( 16 ( 11-23
Trastuzumab
1-32
)
)
Warfarin
Drug Interaction Facts: Significant rating: 4 Onset: Delayed, Severity: Moderate, Documentation: possible, Mechanism: Unknown Micromedex: Onset: Delayed, Severity: Moderate, Documentation: Good, Probable Mechanism: Unknown Leaflet / package insert: nodata case reports: case reports : Case 1 75 1989
5 deep venous thrombosis pulmonary embolism 1990 Warfarin 2.1 - 2.8 1995 Trastuzumab INR 2 10 dose INR 6 Case 2 47 1996 6 2.2 – Warfarin 7 INR 2.6 1998 Trastuzumab 8 INR 5.8 2 case 2 case Trastuzumab 2 albumin warfarin (Nissenblatt MJ, Karp GI. 7.5
Bleeding risk with trastuzumab (Herceptin) treatment. JAMA. 1999;282(24):2299-301.)
case reports
Trastuzumab
Trastuzumab
warfarin
warfarin
Trastuzumab Trastuzumab
Trastuzumab
INR albumin
warfarin
warfarin
Warfarin
INR
372
20
–1
2559
________________________________________________________________________________
373
20
–1
2559
________________________________________________________________________________
374
