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Klik på et bogstav for at se de begreber, der er forklaringer til.
- ACE-hæmmere: Angiotensin Converting Enzyme hæmmere. ACE-hæmmere nedsætter aktiviteten af renin-angiotensin-aldosteron-systemet ved at hæmme omdannelsen af angiotensin I til II, hvorved universel vasodilatation uden sympatikusaktivering indtræder og medfører fald i blodtrykket. Anvendes typisk mod forhøjet blodtryk og hjerteinsufficiens.
- Antacida: Stoffer der neutraliserer syre produceret i mavesækken. Eller: Syreneutraliserende stoffer, der medfører neutralisering af mavesækkens pH.
- AUC: Area under the curve. Det grafiske areal under en plasmakoncentrations-tids-kurve for et lægemiddel. AUC bruges til at beskrive, hvordan kroppen eksponeres for et givent lægemiddel og anvendes til at estimere biotilgængeligheden og clearence.
- BID: Medicinsk forkortelse for bis in die = to gange dagligt.
- Biotilgængelighed, F: Den del af et oralt administreret lægemiddel, der i forhold til en intravenøs dosis når det systemiske kredsløb. Omfatter også den hastighed, hvormed dette sker. Biotilgængelighed omfatter både absorptionen over tarmvæggen (absorptionen sensu strictiori) og en evt. førstepassagemetabolisme.
- Bredspektret antibiotika: Antibiotika med virkning på et bredt spektrum af mikroorganismer, i modsætning til smalspektrede antibiotika, der kun er virksomme over for specifikke typer af mikroorganismer.
- Clearance (Cl): Forholdet mellem et lægemiddels (eller andet stofs) eliminationshastighed (mængde per tidsenhed) og dets koncentration i plasma (eller blod).
Clearance er konstant, dvs. koncentrations-uafhængig, for stoffer, der elimineres efter en 1. ordens-reaktion. Clearance bestemmer sammen med fordelingsrummet halveringstiden. Clearance fra forskellige eliminationsorganer er additiv.
- Cmax: Den maksimale koncentration i plasma, der opnås efter lægemiddelindgift.
Ved i.v. indgift er Cmax lig Co, mens Cmax efter peroral indgift oftest først opnås efter 1-2 timer (tmax).
- CYP P450: Cytochrom-P450. Enzymsystem, som metaboliserer adskillige lægemidler via oxidering.
Oxidering udgør den kvantitativt dominerende eliminationsvej for lægemidler. CYP-enzymerne forekommer i særlig høj koncentration i leveren.
- Fald i clearance: Lægemidlet tager længere tid at få renset ud af kroppen.
- Halveringstid, t1/2: Den tid, det tager organismen (efter fordeling) at eliminere halvdelen af den tilbageværende mængde lægemiddel i kroppen.
Størrelsen er konstant og koncentrationsuafhængig for lægemidler med 1. ordens-elimination.
- Hepatisk: Vedr. leveren.
- Hypertension: Forhøjet blodtryk.
- Hypoglykæmi: Lavt blodsukker. Symptomer optræder ofte ved blodsukker lavere end 2,5 mmol/L.
- Hypotension: Lavt blodtryk.
- Hypothyreose: Nedsat funktion af skjoldbruskkirtlen som fører til nedsat dannelse af hormon (thyroxin) og dermed for lavt stofskifte.
- Inducerende lægemiddel: Når et lægemiddel forårsager øget omsætning af et andet lægemiddel via induktion af f.eks. CYP450.
- Induktion: Øget omsætning af et lægemiddel via induktion af f.eks. CYP450.
- INR: International normalized ratio. INR er en standardiseringsmetode til sammenligning af koagulationstider (protrombintider, PT). INR er således et mål for blodets evne til at koagulere.
INR har til formål at minimere forskellene mellem tromboplastinreagenser ved hjælp af en kalibreringsproces, hvor alle kommercielle tromboplastiner sammenlignes med et internationalt referencemateriale. INR beregnes således: INR=((Patient PT)/(Middel normal PT))^ISI , og fortæller dermed hvor lang koagulationstiden er i forhold til den normale koagulationstid.
- ISI: International Sensitivity Index. Protrombintid målt med forskellige tromboplastiner kan ikke sammenlignes direkte med hinanden, f.eks. fordi sensitiviteten over for koagulationsfaktorer kan variere. For at få koagulationstider, der er så sammenlignelige som muligt, godkendte Verdenssundhedsorganisationen (WHO) i 1983 en standard reference-tromboplastin. Alle producenter af tromboplastin skal kalibrere deres reagens over for WHOs standard. Den fundne værdi betegnes International Sensitivity Index (ISI), og bruges til at beregne INR.
- Iskæmi: Ophævet eller nedsat blodforsyning af et væv i forhold til dets behov.
- Isoenzymer: Forskellige udtryksformer for et enzym. Opstår pga. af forskellige allelle gener. Eksempler ses inden for det lægemiddelomsættende system CYP450, hvor isoenzymer f.eks. er 2D6, 3A4 og 2C9.
- Kasuistik: I lægevidenskab en offentliggjort beskrivelse af et enkelt eller få sygdomstilfælde (casus (lat.): ”tilfælde, sag”).
- Lipidsænkende lægemidler: Lægemidler, der sænker visse af blodets fedtstoffer – kolesterolsænkende.
- Metabolisme: Metabolisme eller stofskifte er en generel betegnelse for den biokemiske omsætning af kemiske forbindelser i den levende organisme og dens celler. Bruges synonymt med biotransformation.
- P-gp: Permeability glycoprotein. P-gp er et cellemembran-protein, som er tilstede i epithelceller i bl.a. tarm, lever og nyrer, hvor det transporterer fremmede substanser fra blodet og ud i hhv. tarmen, galdegange og nyretubuli.
- Plasma: Plasma er den fraktion af blodet, der ikke indeholder celler. Plasma indeholder forskellige næringsstoffer, hormoner, antistoffer, koagulationsfaktorer og salte. 95% af plasma består af vand.
- PO: Per os. Via munden.
- PN medicinering: Pro re nata medicinering. Medicin, der gives efter behov.
- PT: Protrombintid. Tiden, det tager plasma at koagulere, efter tilsætning af tromboplastin (også kaldet tissue factor). Protrombintiden bruges til at vurdere blodets koagulationsevne, og anvendes især til monitorering af antikoagulationsbehandling.
- qd: Quaque die. Hver dag.
- QID: Quater in die. Fire gange dagligt.
- Renal: (af lat. renalis), vedr. nyrerne.
- Respirationsdepression: Respirationsdepression (også kaldet hypoventilation) er når frekvensen eller dybden af respirationen er utiltrækkelig til at opretholde den nødvendige gasudveksling i lungerne.
- Serotonergt syndrom: Et symptomkompleks, der skyldes overstimulering i centralnervesystemet med serotonergt aktive substanser. Symptomerne er muskelrykninger, skælven, kvalme, diarré, sved og forvirring.
- Serum: Plasma uden koagulationsfaktorer.
- SID: Semel in die. Én gang dagligt.
- SmPC: SmPC står for Summary of Product Characteristics, og er det engelske udtryk for produktresumé.
- TID: Ter in die. Tre gange dagligt.
- tmax: Det tidspunkt, hvor den maksimale plasmakoncentration af et lægemiddel indtræder. Des hurtigere absorptionshastighed, des mindre tmax.
- Total clearance: Summen af hepatisk og renal clearance. I hvilken grad disse fraktioner bidrager afhænger af, om lægemidlet primært udskilles renalt eller også undergår fase I (f.eks. via CYP) og fase II (f.eks. glukuronidering) biotransformation i leveren.
- UGT: Uridine 5'-diphospho-glucuronosyltransferase, eller UDP- glucuronosyltransferase. Glucuronyltransferaser er enzymer, som foretager konjugering (glucuronidering) af mange lægemidler og lægemiddelmetabolitter, hvorved de omdannes til stoffer, der er lettere at udskille.
- Vasodilatation: Udvidelse af kar.
- Vasokonstriktion: Sammentrækning af kar.
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Formålet med Interaktionsdatabasen er at gøre behandlingen med lægemidler mere effektiv og sikker, og fremme kvaliteten i patientbehandlingen, herunder bidrage til rationel farmakoterapi. Det har været til hensigt at udvikle et redskab, der er let at anvende i den kliniske hverdag og, hvor der på højt fagligt niveau er skabt konsensus om rekommandationer og beskrivelser af interaktioner mellem lægemidler.
Interaktionsdatabasens primære evidensgrundlag er offentligt publicerede, peer-reviewed original interaktionslitteratur (kliniske studier udført på mennesker og kasuistikker) publiceret i PubMed og Embase.
Der vil således kunne forekomme uoverensstemmelse mellem andre opslagsværker, som er opbygget efter andre principper og evidenskriterier.
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Etableringen af Interaktionsdatabasen var et fælles projekt mellem Danmarks Apotekerforening, Den Almindelige Danske Lægeforening, Dansk Lægemiddel Information A/S og Institut for Rationel Farmakoterapi. En projektleder og 2 farmaceuter stod for opbygningen af databasen bistået af et fagligt videnskabeligt udvalg. Desuden har der været tilknyttet eksperter indenfor forskellige fagområder. Efter en årrække under Sundhedsstyrelsen overtog Lægemiddelstyrelsen i 2015 driften og vedligeholdelsen af databasen.
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Vær opmærksom på, at alle anbefalinger på Interaktionsdatabasen.dk er vejledende.
Hjemmesiden giver desuden ikke oplysninger om bivirkninger ved hvert enkelt præparat. Her henviser vi til indlægssedlen i det enkelte præparat eller til Lægemiddelstyrelsens produktresuméer.
Der kan forekomme bivirkninger, du ikke kan finde informationer om her. Dem vil vi opfordre dig til at indberette til Lægemiddelstyrelsen. Det kan du gøre på:
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I denne database er lægemiddelinteraktion defineret som en ændring i enten farmakodynamikken og/eller farmakokinetikken af et lægemiddel forårsaget af samtidig behandling med et andet lægemiddel.
Interaktionsdatabasen medtager farmakodynamiske interaktioner, der ikke er umiddelbart indlysende additive (fx med forskellig virkningsmekanisme), og som kan have væsentlig klinisk betydning.
Andre faktorer, som interagerer med eller ændrer lægemiddelvirkningen så som næringsmidler (f.eks. fødemidler og kosttilskud) og nydelsesmidler (f.eks. alkohol og tobak), er ikke medtaget. Dog er medtaget lægemiddelinteraktioner med grapefrugtjuice, tranebærjuice og visse naturlægemidler.
Interaktionsdatabasens primære evidensgrundlag er offentligt publicerede, peer-reviewed original interaktionslitteratur (kliniske studier udført på mennesker samt kasuistikker) publiceret i PubMed og Embase. Desuden er interaktioner hvor data er beskrevet i produktresuméer medtaget.
I Interaktionsdatabasen findes fem forskellige symboler:
- Det røde symbol (tommelfingeren, der peger nedad) betyder, at den pågældende præparatkombination bør undgås. Denne anbefaling bliver givet i tilfælde hvor det vurderes, at den kliniske betydning er udtalt, og hvor dosisjustering ikke er mulig, eller hvis der er ligeværdige alternativer til et eller begge af de interagerende stoffer. Det røde symbol vælges også i tilfælde, hvor der vurderes at være ringe dokumenteret effekt af et eller begge stoffer, (hvor anvendelse derfor ikke findes strengt nødvendig), f.eks. for visse naturlægemidler.
- Det gule symbol (den løftede pegefinger) betyder, at kombinationen kan anvendes under visse forholdsregler. Denne anbefaling gives i tilfælde, hvor det vurderes, at den kliniske betydning er moderat til udtalt, samtidig med at den negative kliniske effekt af interaktionen kan modvirkes, enten gennem ned- eller opjustering af dosis, eller ved at forskyde indtagelsestidspunktet for det ene præparat. Anbefalingen gives også, hvis det vurderes, at kombinationen kan anvendes under forudsætning af øget opmærksomhed på effekt og/eller bivirkninger.
- Det grønne symbol (tommelfingeren, der peger opad) betyder, at kombinationen kan anvendes. Denne anbefaling gives i tilfælde, hvor det vurderes, at den kliniske betydning er uvæsentlig eller ikke tilstede.
- Det blå symbol (udråbstegnet) fremkommer i tilfælde, hvor der søges på et specifikt præparat eller en præparatkombination, som ikke findes beskrevet i Interaktionsdatabasen, men hvor der findes andre beskrevne interaktioner mellem stoffer i stofgruppen, som muligvis kan være relevante for søgningen.
- Det grå symbol (spørgsmålstegnet) fremkommer i tilfælde, hvor der er søgt på et præparat eller en præparatkombination, som (endnu) ikke er beskrevet i Interaktionsdatabasen, og hvor der heller ikke findes beskrivelser af andre præparatkombinationer mellem de to stofgrupper. En manglende beskrivelse er ensbetydende med, at Lægemiddelstyrelsen ikke har kendskab til videnskabelige undersøgelser, der undersøger en interaktion mellem den pågældende præparatkombination, og heller ikke til kasuistiske beskrivelser af en mulig interaktion. Der kan også være tale om en kombination, hvor der ikke kan drages konklusioner på baggrund af nuværende viden.
Opdatering af databasens faglige indhold foregår via litteratursøgninger som leveres via Det Kongelige Bibliotek. Litteratursøgningerne er struktureret efter veldefinerede søgekriterier og bliver løbende evalueret. Endvidere foretages yderligere håndsøgning i referencelister som kvalitetssikring af litteratursøgningerne.
Databasen bliver opdateret løbende.
Lægemiddelstyrelsens enhed Regulatorisk & Generel Medicin står for opdatering og vedligehold af Interaktionsdatabasens indhold.
Vedligehold og opdatering af databasen foretages af den faglige arbejdsgruppe, som består af 1 akademisk medarbejder og 2 studerende.
Arbejdsgruppen samarbejder med en deltidsansat speciallæge i klinisk farmakologi omkring den kliniske vurdering af lægemiddelinteraktionerne.
Interaktionsdatabasen er et opslagsværktøj, der beskriver evidensbaserede interaktioner, det vil sige interaktioner, der er dokumenteret ved publicerede kliniske studier og/eller kasuistikker. Der vil således kunne forekomme uoverensstemmelse mellem andre opslagsværker, som er opbygget efter andre principper og evidenskriterier.
Der inkluderes kun interaktioner fra offentligt publicerede, peer-reviewed original interaktionslitteratur (kliniske studier udført på mennesker samt kasuistikker) publiceret i PubMed og Embase. Desuden er interaktioner hvor data er beskrevet i produktresuméer også medtaget. Det tilstræbes at databasen opdateres snarest efter publicering, men der kan forekomme forsinkelser.
Interaktionsdatabasen beskriver interaktioner for markedsførte lægemidler, naturlægemidler samt stærke vitaminer og mineraler. I interaktionsbeskrivelserne skelnes som udgangspunkt ikke mellem forskellige dispenseringsformer. For udvalgte lægemidler skelnes dog mellem dermatologiske og systemiske formuleringer. Handelsnavnene for stærke vitaminer og mineraler, naturlægemidler samt lægemidler som ikke figurerer på medicinpriser.dk (dvs. SAD præparater) kan ikke findes på interaktionsdatabasen.
Interaktionsdatabasen omhandler ikke kosttilskud, vacciner, parenteral ernæring, elektrolytvæsker, lægemidler uden systemisk effekt og priktest (ALK).
Ja, du kan slå både lægemidler, naturlægemidler, stærke vitaminer, mineraler og enkelte frugtjuice op.
Naturlægemidler er en særlig gruppe lægemidler, der typisk indeholder tørrede planter eller plantedele, udtræk af planter eller andre naturligt forekommende bestanddele. Naturlægemidler er i lovgivningen defineret som "lægemidler, hvis indholdsstoffer udelukkende er naturligt forekommende stoffer i koncentrationer, der ikke er væsentligt større end dem, hvori de forekommer i naturen". Naturlægemidler skal godkendes af Lægemiddelstyrelsen inden de må sælges.
Stærke vitaminer og mineraler er en gruppe lægemidler, hvis indholdsstoffer udelukkende er vitaminer og/eller mineraler, og hvor indholdet af vitamin eller mineral er væsentligt højere end det normale døgnbehov hos voksne mennesker. Stærke vitaminer og mineraler kan kun godkendes til at forebygge og helbrede såkaldte mangeltilstande (og altså ikke til at behandle sygdomme). Stærke vitaminer og mineraler må kun sælges i Danmark, hvis de er godkendt af Lægemiddelstyrelsen.
Ja, du kan søge på så mange lægemidler/indholdsstoffer, du ønsker samtidig. Det gør du ved at bruge søgeboksen til højre på forsiden med overskriften ”Søg på flere præparater i kombination”. Her kan du tilføje flere felter med knappen nederst. Hvis du søger på kombinationer med mere end to slags lægemidler/indholdsstoffer, skal du være opmærksom på, at du ikke kun får ét resultat, men et antal 1+1 kombinationer. Et eksempel: Hvis du søger på samtidig brug af en p-pille, et blodtrykssænkende lægemiddel og et sovemiddel, får du 3 mulige resultater:
A: kombinationen af p-pille og blodtrykssænkende lægemiddel
B: kombinationen af p-pille og sovemiddel
C: kombinationen af blodtrykssænkende lægemiddel og sovemiddel
Du får de parvise kombinationer, der er videnskabeligt undersøgt.
Nej, du skal ikke angive dosis (500mg paracetamol) eller interval (2xdaglig), når du skal søge på et præparat eller indholdsstof. Det er kun selve præparatnavnet eller navnet på indholdsstoffet, du skal skrive. Vælg eventuelt bare navnet fra listen.
Det er desværre sådan, at der indtil videre kun kan søges på indholdsstof, når det gælder naturlægemidler.
Dette sker, når du søger på et kombinationspræparat. Når du søger på et kombinationspræparat, får du præsenteret et resultat for hvert af disse indholdsstoffer.
Indholdet i databasen er resultatet af grundige vurderinger af videnskabelige artikler og konklusioner fra humane forsøg. Hvis du kun får én interaktion på trods af, at du har indtastet flere præparater eller indholdsstoffer, skyldes det, at der endnu ikke er beskrevet (eller fundet) interaktioner af de andre indholdsstoffer i den videnskabelige litteratur.
På Lægemiddelstyrelsens hjemmeside, og i månedsbladet Rationel Farmakoterapi, juni 2015.
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Lægemiddelstyrelsen
Axel Heides Gade 1
2300 København S
Tlf.nr 44 88 95 95
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Interaktionsoplysninger
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1. Præparat: Marevan - Aktivt indholdsstof: warfarin |
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Interaktionsoplysninger for tegafur og warfarin |
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Dosisreduktion ved indledning og dosisøgning ved ophør af tegafur-behandling kan blive nødvendigt. Det anbefales hyppig kontrol af INR ved indledning og ophør af kombinationsbehandlingen.
Aktiviteten af warfarin forstærkes af tegafur, formodentligt som følge af en reduktion i antallet af CYP2C9 enzymer, der metaboliserer warfarin.
mulig
dokumenteret
vitamin K antagonister, perorale phenprocoumon, warfarin cytostatika, antimetabolitter azacitidin, capecitabin, cladribin, clofarabin, cytarabin, decitabin, fludarabin, fluoruracil, gemcitabin, methotrexat, nelarabin, pemetrexed, tegafur, Trifluridin
Studier og kasuistikker viser, at fluorouracil, capecitabin og tegafur (begge prodrugs, som omdannes til fluoruracil) samt gemcitabin kan øge warfarins antikoagulerende effekt med rapporterede stigninger i INR helt op til en faktor 16. Årsagen til interaktionerne menes at være nedsat syntese af CYP2C9, som metaboliserer warfarin. Der er ingen rapporter for phenprocoumon men interaktioner for warfarin forventes også at gælde for phenprocoumon.
Der er i litteraturen ikke lokaliseret yderlige undersøgelser eller kasuistikker, som beskriver antimetabolitters påvirkning af vitamin K antagonister.
Litteraturgennemgang - Vis
Warfarin og fluoruracil Studier En lille retrospektiv undersøgelse omhandlende 5 patienter i behandling med warfarin og fluoruracil viste at warfarin dosis gennemsnitlig skulle reduceres med 44 % (18-74 %) for at holde INR i terapeutisk niveau. INR havde max værdi (3,66-23,7) 16-41 dage efter start på kemoterapi. To patienter havde alvorlig blødning, Kolesar JM, Johnson CL et al, 1999. I en retrospektiv undersøgelser med 95 cancerpatienter, som fik fluoruracil, og som fik warfarin minidosis (1mg/dag) som profylakse for kateter-relateret thrombose, steg INR hos 31 patienter med mere end 1,5 og INR >3 hos 25 patienter. Næseblødning og hæmaturi forekom hos 8 patienter, Masci 2003 12586814. I en prospektiv undersøgelse med cancerpatienter, som fik fluoruracil, og som fik warfarin minidosis (1mg/dag) som profylakse for kateter-relateret thrombose, steg INR gennemsnitlig med 2,9 (1,5-9,4) hos 103 ud af 247 patienter efter gennemsnitlig 95 dages behandling med fluoruracil. Blødning forekom hos 8 patienter. Mekanismen er formentlig en hæmning af enzymet CYP2C9, som omsætter warfarin, Magagnoli M, Masci G et al, 2006 Kasuistikker To kasuistikker beskriver betydeligt forlængelse af protrombintiden hos patienter i warfarinbehandling efter infusion af fluoruracil, Davis DA og Fugate SE, 2005; Wajima T og Mukhopadhyay P, 1992b. En dosisreduktion af warfarin på 33-42 % var nødvendig ved hver fluouracil-cyclus-behandling, Davis DA og Fugate SE, 2005. En kasuistik rapporterer om en patient i AK-behandling for en aortastenose, hvor kemoterapi med cyclophosfamid, methotrexat og fluorouracil medførte en stigning i INR til fra 2-2,8 til 4,15-10, Malarcana P og Maestri A, 1996. En kasuistik rapporterer om en patient med lungecancer, der får profylaktisk AK-behandling for katetertrombose. Patientens INR steg fra 1 til 8 ti dage efter infusion af fluoruracil. INR var normaliseret efter 8 dage, Brown MC, 1999. En kasuistik (Brown MC, 1997) beskriver en patient med coloncancer i behandling med warfarin for venøs thrombose. Patienten blev en måned efter start af behandling med fluoruracil indlagt med blødninger, og der sås en forøgelse af INR med en faktor 16 (2,2 – 35,9). Warfarin-behandling blev ophørt og INR faldt til normal værdi efter 48 timer. En kasuistik beskriver stigning i INR til 5,5 på 3.-dagen af behandling med fluorouracil-infusion, Aki Z, Kotiloglu G et al, 2000b. Hos en ældre patient i stabil behandling med warfarin steg INR fra 3 til næsten 40 fire uger efter behandling med fluororacil+levimasol blev begyndt for behandling af coloncancer. Warfarin dosis blev 2/3 reduceret. I den følgende fem ugers periode, hvor kemoterapien blev pauseret, faldt INR til subterapeutisk niveau og steg igen, da kemoterapibehandlingen blev genoptaget, Scarfe MA og Israel MK, 1994. Warfarin og capecitabin Studier Capacitabin er et prodrug og omdannes til fluoruracil i tumorcellerne. Ved samtidig indgift af en enkelt dosis warfarin 20 mg og en cyklus capecitabin hos 4 cancerpatienter (Camidge R, Reigner B et al, 2005) observeres stigning i AUC for S-warfarin på ca. 57 % (90 % KI: 32-88 %). Halveringstiden for S-warfarin blev forlænget med 51 % (90 % KI: 32-74 %). Der var ingen ændring for plasmakoncentrationerne af R-warfarin og capecitabin. Under kombinationsbehandlingen observeres stigning i patienternes AUC-INR med en faktor 2,8 (90 % KI 1,33-5,70). En retrospektiv analyse af 77 cancerpatienter i capecitabin-behandling, hvoraf 21 fik warfarin, fandt at risikoen for INR >3 og blødning var signifikant højere hos warfarin brugere end hos patienter, som ikke var i warfarinbehandling (henholdsvis 32 % vs 4 % og 18 % vs 2 %). Hos 11 patienter i warfarinbehandling var INR >3, og hos 6 patienter var reduktion af warfarindosis dosis nødvendig og 4 patienter fik alvorlige blødninger, som krævede transfusion, Shah 2006 16512995. I modsætning hertil viste et register-kobling-studie, hvor 99 ud 883 (11 %) capecitabin-brugere samtidig fik warfarin ingen markant forskel i INR stigning og blødning med og uden warfarin. Forfatterne pointerer dog, at dette ikke udelukker en biologisk interaktion, men derimod kan afspejle korrekt håndtering af interaktion ved brug af INR monitorering, Yood 2006 PMID: 16466602. Kasuistikker En kasuistik beskriver en interaktion mellem warfarin og capecitabin hos to patienter, hvor INR steg fra terapeutiske niveauer til omkring 10, 6-8 uger efter start på capecitabin behandling, Copur MS, Ledakis P et al, 2001. En anden kasuistik beskriver en reduktion af warfarin-dosis med >85 % (fra 5,7 mg/dag til 0,78 mg/dag) i løbet af 3 capecitabin-/ironotecan-cykluser for at vedligeholde en terapeutisk INR-værdi. Efter afsluttet behandling, blev warfarindosis opjusteret til vedligeholdsdosis, Janney LM og Waterbury NV, 2005. Hos yderligere fem patienter i behandling med warfarin og capecitabin rapporteres om stigninger i INR og blødninger, Yildirim Y, Ozyilkan O et al, 2006; Buyck HC, Buckley N et al, 2003; Isaacs K og Haim N, 2005. En anden kasuistik beskriver en levertransplanteret patient i behandling med tacrolimus, mycophenolinsyre, prednison, warfarin og capecitabin. Patienten udviklede fatal leverskade, som menes at kunne skyldes interaktion mellem warfarin og capecitabin.Zhu LQ, Jiang WT et al, 2014a Warfarin og gemcitabin Studier Fra en producents register er der oplysninger om 4 tilfælde af mistænkt interaktion mellem warfarin og gemcitabin ud af 724 patienter i gemcitabinbehandling, som samtidig fik AK-behandling, Kilgour-Christie J og Czarnecki A, 2002. Kasuistikker En kasuistik beskriver en interaktion mellem warfarin og gemcitabin, hvor den ugentlige dosis af warfarin reduceres fra 57,5 mg til 48,5 mg unders gemcitabinbehandling for at holde det terapeutiske niveau, Kinikar SA og Kolesar JM, 1999. En kasuistik omhandler en 70-årig kvinde (Saif MW og Wasif N, 2008), som pga. atrieflimmer har været i behandling med warfarin igennem længere tid. Pga. pancreascancer sættes kvinden i behandling bla. gemcitabin og capecitabin. Dosis af warfarin var 7,5 mg og 5 mg ugentlig. For denne patient var der interaktion mellem warfarin og gemcitabin-capecitabin og senere kun med gemcitabin, som resulterede i en forhøjet INR (fra ca. 2 til max. 6) og et fald i hæmatokrit. Der blev ikke fundet gastrointestinal blødning. Supplerende litteratur: Carabino J og Wang F, 2002; Gilard M, Arnaud B et al, 2008a. Tegafur og warfarin Tegafur er et pro-drug af 5-FU med god oral biotilgængelighed. Efter peroral indgivelse konverteres tegafur gradvist til 5-FU in vivo, hovedsageligt af CYP2A6-enzymaktivitet i leveren. Brug af coumarin-derivative antikoagulantia hos patienter i behandling med Teysuno er i kliniske forsøg blevet associeret med forhøjet INR og gastrointestinal blødning, blødningstendens, hæmaturi og anæmi. SPC for Teysuno, 2013
En kasuistik beskriver tre tilfælde (to mænd og en kvinde på hhv. 79, 71 og 59 år), hvor stigning i INR er blevet set i forbindelse med co-administration af tegafur (tegafur og hjælpestofferne gimeracil og oteracil; 80-120 mg/dag) og warfarin (1,5-3,5 mg/dag). INR steg fra normalniveau (2,0-3,0) til supraterapeutisk niveau (3,79-4,92) 8-17 dage efter påbegyndelse af kombinationsbehandlingen, Yamamuro F, Miki A et al, 2011
Aki Z;Kotiloglu G;Ozyilkan O, Am J Gastroenterol, 2000, b, 95:1093-1094; A patient with a prolonged prothrombin time due to an adverse interaction between 5-fluorouracil and warfarin Shah HR;Ledbetter L;Diasio R;Saif MW, Clin Colorectal Cancer, 2006, 5:354-358; A retrospective study of coagulation abnormalities in patients receiving concomitant capecitabine and warfarin BACKGROUND: The extent and complications of the interaction between capecitabine and warfarin are not fully known. PATIENTS AND METHODS: A retrospective study of 77 patients who received capecitabine was performed to analyze coagulation abnormalities with or without warfarin. RESULTS: Twenty-one patients received warfarin with capecitabine. Twelve were on an average warfarin dosage of 19.4 mg per week (range, 7-35 mg) before capecitabine treatment, with a stable international normalized ratio (INR; range, 0.9-3.3). The dose of capecitabine ranged from 1.6 g/m2 to 2 g/m2 per day. Thirteen patients (11 on warfarin) had an INR > 3 (range, 3.23-11.5), resulting in a probability of an INR > 3 of 32% in the warfarin group versus 4% for those not on warfarin (P = 5.1 x 10(-14)) at 130 days. Six patients required a warfarin dose reduction (1-2.5 mg decrease). There were 7 episodes of bleeding (all gastrointestinal; 5 with warfarin). Seven patients who experienced bleeding had INRs ranging from 1.06 to 8 (average, 3.31) at the time bleeding occurred. Of the 7 bleeding episodes, 5 patients required transfusions, averaging 3.25 units of red blood cells and 2.4 units of fresh frozen plasma. The incidence of bleeding at 130 days of treatment with capecitabine was 18% with warfarin versus 2% without (P = 4 x 10(-13)). Bleeding episodes were not significantly different between patients with or without liver involvement (4 of 40 episodes vs. 3 of 37 episodes, respectively; P = 0.12). Patients with an INR > 3 were evenly distributed between those with or without liver involvement (6 of 40 patients vs. 7 of 37 patients, respectively). No INR increases persisted after discontinuation of capecitabine. CONCLUSION: This study confirms a clinically significant interaction between warfarin and capecitabine-based chemotherapy akin to that already known for 5-fluorouracil. In addition to altered coagulation parameters, bleeding can be a complication. These events occurred in patients with and without liver metastases. We recommend weekly monitoring of coagulation parameters for all patients receiving concomitant warfarin and capecitabine, with an appropriate adjustment of warfarin dose. The nature and extent of this interaction requires further investigation Isaacs K;Haim N, J Chemother, 2005, 17(3): 339-342-342; Adverse interaction between capecitabine and warfarin resulting in altered coagulation parameters and bleeding: Case report and review of the literature Capecitabine can interact with warfarin, resulting in altered coagulation parameters and bleeding. Four cases have been reported. We describe a fifth case with life-threatening interaction between these two drugs. A 67-year-old female with metastatic breast cancer developed hemorrhagic blisters, purpura and ecchymoses. She had been well controlled on long-term warfarin (5 mg/day). Capecitabine was initiated 4.5 weeks prior to the bleeding episode. Laboratory work-up revealed an international normalized ratio of 8.56, partial prothrombin time of 61 seconds and prothrombin time of 5.2%. The coagulation parameters gradually normalized within 4 days following vitamin K administration and discontinuation of capecitabine and warfarin. Careful monitoring of coagulation parameters and proper adjustment of the warfarin dose are required in patients taking warfarin and capecitabine concomitantly. < copyright > E.S.I.F.T. srl - Firenze Brown MC, Chemotherapy, 1999, a, 45:392-395; An adverse interaction between warfarin and 5-fluorouracil: A case report and review of the literature Adverse interactions between warfarin and 5-fluorouracil (5-FU) have been reported. Such an interaction occurred in a patient with lung cancer receiving vinblastine and 5-FU. This case is the first involving a patient taking minidose warfarin for prophylaxis of catheter- associated thrombosis. Although the mechanism of the interaction is unclear, it has been postulated that 5-FU interferes with the synthesis of hepatic cytochrome P-450 2C9. Because warfarin and 5-FU are regularly coadministered, this adverse interaction might be occurring more frequently than is realized. Clinicians should be aware of this interaction and should regularly monitor the prothrombin time of patients receiving warfarin and 5-FU Copur MS;Ledakis P;Bolton M;Morse AK;Werner T;Norvell M;Muhvic J;Chu E, Clin Colorectal Cancer, 2001, 1:182-184; An adverse interaction between warfarin and capecitabine: a case report and review of the literature Warfarin is one of the most commonly used oral anticoagulants in the clinic. It is well established that a wide range of antineoplastic drugs interact with warfarin, resulting in altered coagulation parameters and/or bleeding sequelae. While altered coagulation parameters have been observed in patients taking the oral 5- fluorouracil prodrug, capecitabine, in combination with warfarin, no report to date has described clinically overt evidence of bleeding. Herein, we report 2 cancer patients who presented with bleeding episodes that most likely resulted from an adverse interaction between capecitabine and warfarin after 6 weeks of concomitant therapy. In each case, there was a marked elevation in both the prothrombin time and international normalized ratio (> 10), with subsequent gastrointestinal bleeding. The exact mechanism of this interaction is yet unknown, but it is possible that capecitabine might, in some manner, reduce the hepatic metabolism of warfarin. Close monitoring of coagulation parameters is recommended for all patients receiving concomitant warfarin and capecitabine, with appropriate adjustment of warfarin dosage. The nature and extent of this interaction requires further investigation Yood MU;Quesenberry CP;Alford SH;Tsai AL;Wells KE;Yood SM;Ackermann Shiff SP, Curr Med Res Opin, 2006, 22:307-314; An observational study examining the impact of capecitabine on warfarin antithrombotic activity and bleeding complications OBJECTIVE: The objectives of this study are to quantify the frequency of concomitant use of capecitabine and warfarin, and to quantify the rate of bleeding events and elevated international normalized ratio (INR) among concomitant users of warfarin and capecitabine. RESEARCH DESIGN AND METHODS: We conducted a retrospective population-based study within the Henry Ford Health System (Detroit, MI) and the Kaiser Permanente Medical Care Program of Northern California (Oakland, CA). The study population included patients prescribed concomitant capecitabine and warfarin from 1 April 1997 through 31 July 2002. Data from the medical records of concurrent users were extracted through 31 August 2002. MAIN OUTCOME MEASURES: Concomitant use of capecitabine and warfarin, bleeding events, and INR laboratory results, collected from computerized databases and medical record review. RESULTS: Overall, 11% of capecitabine users also received warfarin (99 / 883). Among 17 patients who received warfarin for venous access device prophylaxis, one bleeding event occurred during concomitant capecitabine/warfarin use (rate = 35.7 bleeding events per 100 person-years, 95% confidence interval [CI] 0.9-198.9), and no events occurred during use of warfarin alone (95% CI 0.0-136.2) (p = 0.50). Among patients prescribed warfarin for indications other than port prophylaxis, no bleeding events occurred during concomitant use of capecitabine and warfarin (95% CI 0.0-34.6), and one event occurred during warfarin use alone (rate = 9.2 bleeding events per 100 person-years, 95% CI 0.2-51.3) (p = 0.54). We found one INR elevation > 3.0 among concomitant capecitabine/warfarin users receiving warfarin for port prophylaxis (rate = 35.7 per 100 person-years) and no INR elevations > 3.0 during use of warfarin alone (p = 0.46). Among patients using warfarin for indications other than port prophylaxis, the rates of INR > 3.0 were 309.7 per 100 person-years (95% CI 213.2-434.9) during concomitant capecitabine/warfarin use and 193.5 events per 100 person-years (95% CI 119.8-295.8) during use of warfarin alone (p = 0.09). CONCLUSIONS: The results of our study show a low prevalence of capecitabine and warfarin concomitant use. We did not find large differences in the rates of bleeding events and elevated INR in patients receiving concomitant capecitabine and warfarin when compared with use of warfarin alone. While these results do not imply a lack of biologic interaction, our findings indicate that patients appear to be appropriately managed in clinical practice Buyck HC;Buckley N;Leslie MD;Plowman PN, Clin Oncol (R Coll Radiol ), 2003, 15:297; Capecitabine-induced potentiation of warfarin Janney LM;Waterbury NV, Ann Pharmacother, 2005, 39:1546-1551; Capecitabine-warfarin interaction OBJECTIVE: To report a case of concomitant warfarin therapy with consecutive cycles of capecitabine therapy, providing time of onset, magnitude, and assessment of the interaction. CASE SUMMARY: A 59-year-old man receiving chronic warfarin therapy for a mechanical mitral valve replacement was diagnosed with stage IV metastatic colon cancer. He was started on capecitabine/irinotecan after his cancer progressed with fluorouracil/leucovorin and the FOLFOX 6 regimen (oxaliplatin, leucovorin, and continuous fluorouracil infusion). He received 3 consecutive cycles of capecitabine/irinotecan with concomitant oral anticoagulation and, with each cycle, the warfarin dose was reduced. Over the course of these 3 cycles, the total weekly dose of warfarin was reduced by >85%. DISCUSSION: The capecitabine-warfarin interaction is clinically significant, requiring a black box warning in the package insert. The mechanism of action for the interaction is not clear, but may be related to down-regulation of CYP2C9 by capecitabine or its metabolites or a pharmacodynamic interaction with warfarin. A common response to this interaction, as discussed in previously published case reports, is the discontinuation of warfarin, capecitabine, or both. In this case, the Naranjo probability scale indicates a highly probable drug interaction between warfarin and capecitabine. CONCLUSIONS: As more patients require anticoagulation, and as chemotherapy agents such as capecitabine become available, the likelihood for these drug interactions increases. In our patient, close monitoring of therapy allowed successful use of warfarin and capecitabine Yildirim Y;Ozyilkan O;Akcali Z;Basturk B, Int J Clin Pharmacol Ther, 2006, 44(2): 80-82-82; Drug interaction between capecitabine and warfarin: A case report and review of the literature Objective: To report on possible adverse interaction between capecitabine and warfarin in a patient with cancer, who developed subconjunctival and nose bleeding during treatment with these drugs and review of the previously reported five cases in the literature. Case summary: In the second week of capecitabine treatment the patient was hospitalized owing to subconjunctival hemorrhage and nose bleeding. Her international normalized ratio (INR) level was found to have increased, and both drugs were discontinued. Fresh frozen plasma replacement was administered. Warfarin and capecitabine treatment were restarted again but the warfarin dose was decreased. The patients INR was kept between 2.5-3 with the reduced dose of warfarin. Discussion: Capecitabine is an orally active prodrug of fluorouracil (FU) and is extensively used as an antineoplastic agent. It is converted to 5-FU in the liver and tumor tissues. Warfarin is an antithrombolytic agent and is metabolized by liver cytochorom P450 (CYP) isoenzymes in liver. Preclinical in vitro studies using human liver microsomes report no inhibitory effects between capecitabine and substrates of CYP. However, the concomitant administration of capecitabine and warfarin resulted in gastrointestinal, retroperitoneal bleeding and hemorrhagic blisters in the five cases previously reported. The exact mechanism of this interaction is unknown; however, a significant pharmacokinetic interaction between capecitabine and S-warfarin resulting in exaggerated anticoagulant activity has recently been demonstrated. Here, we describe another case and use of the Naranjo adverse drug reaction (ADR) probability scale, which indicated a probable relationship between subconjunctival bleeding and epistaxis in this patient after concomitant warfarin and capecitabine use. Conclusion: Capecitabine is extensively used in outpatient clinics, and physicians should be aware of ADRs arising from combined used of capecitabine and warfarin. In the light of the current data, INR levels should be closely monitored in patients using this medication regimen. < copyright > 2006 Dustri-Verlag Dr. K. Feistle Kilgour-Christie J;Czarnecki A, Lancet Oncol, 2002, 3:460; Gemcitabine and the interaction with anticoagulants 4 tilfµlde af interaction mellem warfarin og gemcitabin er rapporteret. Opg°relser viser at der er interaktion i 0.8% af de tilfµlde der behandles. Magagnoli M;Masci G;Castagna L;Morenghi E;Santoro A, Ann Oncol, 2006, 17:174-176; High incidence of INR alteration in gastrointestinal cancer patients treated with mini-dose warfarin and 5-fluorouracil-based regimens Kinikar SA;Kolesar JM, Pharmacotherapy, 1999, 19:1331-1333; Identification of a gemcitabine-warfarin interaction A man anticoagulated with warfarin 57.5 mg/week (international normalized ratio [INR] 1.94) was diagnosed with nonsmall cell lung cancer and prescribed weekly gemcitabine. With the first dose of the first cycle, his INR rose to 3.52, and his weekly warfarin dose was decreased to 52.5 mg. The lower warfarin dose was continued during the 2-week rest period between cycles 1 and 2 of gemcitabine therapy, and his INR decreased to 2.08. The patient resumed gemcitabine while taking warfarin 52.5 mg/week; however, the warfarin dosage had to be reduced to 48.5 mg/week to achieve a therapeutic INR. After gemcitabine was discontinued, the patient was restabilized at the prechemotherapy baseline dosage. We conclude that an interaction between warfarin and gemcitabine occurred with the first dose of the latter and recommend weekly INRs for anticoagulated patients receiving gemcitabine Davis DA;Fugate SE, Pharmacotherapy, 2005, 25:442-447; Increasing warfarin dosage reductions associated with concurrent warfarin and repeated cycles of 5-fluorouracil therapy Concurrent use of warfarin and 5-fluorouracil has resulted in elevated international normalized ratios (INRs). Although this drug interaction is well established in the literature, we found no documented cases that address its effects on anticoagulation parameters in patients requiring repeated cycles of 5-fluorouracil and continuous warfarin therapy. We describe the effect of multiple cycles of 5-fluorouracil administration in a patient receiving warfarin therapy. The patient's INR increased 11-14 days after each cycle of chemotherapy with 5-fluorouracil and leucovorin. In addition, she required additive reductions of 33-42% in her weekly warfarin dose with each chemotherapy cycle to maintain a therapeutic INR (goal range 2.0-3.0). After three cycles of chemotherapy over a 10-week period, the patient's dosage requirements returned to her baseline level (before treatment with 5-fluorouracil and leucovorin had started). Pertinent literature was reviewed to provide supporting evidence for the mechanism and clinical implications of the drug interaction. Based on this report and previous case reports, caution is advised when concurrent warfarin and 5-fluorouracil are prescribed. In addition, patients should be closely monitored for a possible delayed interaction that may occur with each repeated cycle of 5-fluorouracil chemotherapy Yamamuro F;Miki A;Kondo G;Maeda T;Satoh H;Hori S;Sawada Y, Int J Clin Pharmacol Ther, 2011, 49:700-704; Individual differences in prothrombin time-international normalized ratio variation following coadministration of the anticancer agents S-1 and warfarin: 3 case reports OBJECTIVE: We report three cases of elevated prothrombin time-international normalized ratios (PT-INR) following the initiation of coadministration of warfarin and S-1, a preparation containing tegafur (FT), gimeracil (CDHP), and oteracil potassium (Oxo). CASE SUMMARIES: The three cases included 2 men and 1 woman aged 79, 71, and 54 y, respectively. PT-INRs were in the range of 2.0 - 3.0 before therapy but were elevated to values in the range of 3.79 - 4.92 within 8 - 17 days after initiating the coadministration of warfarin (1.5 - 3.5 mg/d) and S-1 (80 - 120 mg/d). When the drug interactions in Cases 1 - 3 were evaluated using the Drug Interaction Probability Scale, each of these cases was assessed as 'probable'. DISCUSSION: The drug interaction between warfarin and S-1 presumably leads to elevated PT-INR because the 5-fluorouracil (5-FU), which is metabolite of FT in S-1, inhibits the metabolic processing of S-warfarin by cytochrome P450 (CYP) 2C9. However, individual differences in the metabolic production of 5-FU from FT because of genetic polymorphisms in CYP2A6 and individual variation in the levels of renal function may lead to complications when 5-FU is coadministered with warfarin as compared to when 5-FU is administered alone. CONCLUSION: It is essential that the dosage level of warfarin is appropriately adjusted by frequent PT-INR measurements when warfarin and S-1 are coadministered Gilard M;Arnaud B;Cornily JC;Le Gal G;Lacut K;Le Calvez G;Mansourati J;Mottier D;Abgrall JF;Boschat J, J Am Coll Cardiol, 2008, a, 51:256-260; Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study OBJECTIVES: This trial sought to assess the influence of omeprazole on clopidogrel efficacy. BACKGROUND: Clopidogrel has proved its benefit in the treatment of atherothrombotic diseases. In a previous observational study, we found clopidogrel activity on platelets, tested by vasodilator-stimulated phosphoprotein (VASP) phosphorylation, to be diminished in patients receiving proton pump inhibitor (PPI) treatment. METHODS: In this double-blind placebo-controlled trial, all consecutive patients undergoing coronary artery stent implantation received aspirin (75 mg/day) and clopidogrel (loading dose, followed by 75 mg/day) and were randomized to receive either associated omeprazole (20 mg/day) or placebo for 7 days. Clopidogrel effect was tested on days 1 and 7 in both groups by measuring platelet phosphorylated-VASP expressed as a platelet reactivity index (PRI). Our main end point compared PRI value at the 7-day treatment period in the 2 groups. RESULTS: Data for 124 patients were analyzed. On day 1, mean PRI was 83.2% (standard deviation [SD] 5.6) and 83.9% (SD 4.6), respectively, in the placebo and omeprazole groups (p = NS), and on day 7, 39.8% (SD 15.4) and 51.4% (SD 16.4), respectively (p < 0.0001). RESULTS: Omeprazole significantly decreased clopidogrel inhibitory effect on platelet P2Y12 as assessed by VASP phosphorylation test. Aspirin-clopidogrel antiplatelet dual therapy is widely prescribed worldwide, with PPIs frequently associated to prevent gastrointestinal bleeding. The clinical impact of these results remains uncertain but merits further investigation Saif MW;Wasif N, JOP , 2008, 9:739-743; Interaction between capecitabine and gemcitabine with warfarin in a patient with pancreatic cancer Gemcitabine is the only chemotherapeutic agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced pancreatic cancer. 5-fluorouracil or its oral pro-drug, capecitabine is the second most commonly used agent in this malignancy. Capecitabine or 5-fluorouracil is the second most common agent used either in second-line or as a radiosensitizer. Thromboembolism requiring anticoagulation is a common paraneoplastic complication in these patients. We report a patient with pancreatic cancer, challenged with maintaining the international normalized ratio (INR) with gemcitabine-capecitabine combination, and later with gemcitabine monotherapy with concomitant warfarin, as well as, a brief review of the literature. Patients with pancreatic cancer who receive warfarin and gemcitabine should be monitored for any potential drug interactions. Frequent prothrombin time and INR evaluations are suggested for anticoagulated patients receiving gemcitabine, especially when combined with capecitabine Carabino J;Wang F, Am J Health Syst Pharm, 2002, 59:875; International Normalized Ratio fluctuation with warfarin-fluorouracil therapy Zhu LQ;Jiang WT;Pan C;Liu YH;Thian Y, Tomt indhold, 2014, a, 39:August; Liver injury possibly related to drug interaction after liver transplant: A case report What is known and objective Drug-induced hepatotoxicity is potentially lethal. Liver transplant patients receive a large number of medications and adverse drug reactions, and drug-drug interactions must be closely monitored. Case summary We report a case of a 29-year-old liver transplant patient who suffered liver injury most likely induced by drug interaction between capecitabine and warfarin. Vitamin K1 caused skin rash possibly because of the distribution and metabolism characteristic of the drug in this patient. What is new and conclusion Close monitoring and prompt discontinuation of the drugs with high volume of distribution and metabolized through the liver are necessary to avoid drug-drug interaction in liver transplant patients. Close monitoring and prompt discontinuation of the drugs with high volume of distribution and metabolized through the liver are necessary to avoid drug-drug interaction in liver transplant patients. 2014 John Wiley & Sons Ltd Masci G;Magagnoli M;Zucali PA;Castagna L;Carnaghi C;Sarina B;Pedicini V;Fallini M;Santoro A, J Clin Oncol, 2003, 21:736-739; Minidose warfarin prophylaxis for catheter-associated thrombosis in cancer patients: can it be safely associated with fluorouracil-based chemotherapy? PURPOSE: The use of prophylactic low-dose oral warfarin in cancer patients with a central venous catheter (CVC) in place has an established role in the prevention of thrombotic complications and is associated with a low hemorrhagic risk. Despite the literature indicating an adverse interaction between warfarin and fluorouracil (FU), the frequency of this interaction and whether it occurs when minidose warfarin is used is unknown. We analyzed the incidence of alterations in the International Normalized Ratio (INR) and bleeding in cancer patients given minidose warfarin during treatment with continuous-infusion FU-based regimens. PATIENTS AND METHODS: Between July 1999 and August 2001, 95 cancer patients were evaluated. Forty-one patients (43%) had liver metastases. Seventy-nine patients (83%) had a Groshong CVC (Bard Access System, Salt Lake City, UT), and 16 (17%) had a Port-a-Cath device (Bard Access System). All patients received oral warfarin at a dose of 1 mg/daily as prophylaxis beginning the day after the catheter was positioned. An INR of more than 1.5 was considered significantly elevated. RESULTS: INR elevation occurred in 31 patients (33%), with 18 patients (19%) having an INR more than 3.0. Twelve (39%) of the 31 patients had liver metastases. Bleeding was observed in eight patients (8%); seven of these patients had elevated INR levels. We observed INR elevations in 12 of 21 patients treated with a FU, folinic acid, and oxaliplatin (FOLFOX) regimen, 11 of 40 treated with a de Gramont regimen (FU and folinic acid), and five of 19 treated with a FU, folinic acid, and irinotecan (FOLFIRI) regimen. CONCLUSION: A high incidence of INR abnormalities was observed in our cohort of patients, especially those treated with FOLFOX regimen. Clinicians should be aware of this interaction and should regularly monitor the prothrombin time in patients receiving warfarin and FU Brown MC, Pharmacotherapy, 1997, 17:631-633; Multisite mucous membrane bleeding due to a possible interaction between warfarin and 5-fluorouracil A 59-year-old man being treated for colon cancer experienced epistaxis, hematemesis, hematuria, and hematochezia. Laboratory evaluation revealed a greatly prolonged prothrombin time. It is possible that the bleeding was due to an interaction between 5-fluorouracil and warfarin. The former may inhibit the synthesis of cytochrome P-4502C9, leading to impaired metabolism of the latter Scarfe MA;Israel MK, Ann Pharmacother, 1994, 28:464-467; Possible drug interaction between warfarin and combination of levamisole and fluorouracil OBJECTIVE: To report a possible drug interaction between the combination of fluorouracil (5-FU), levamisole, and warfarin. CASE SUMMARY: An elderly patient with chronic atrial fibrillation and prosthetic valve replacements had been taking warfarin 22.5 mg/wk. Following the diagnosis of colon cancer (Duke´s classification D), a chemotherapy regimen of 5-FU and levamisole was started. Within four weeks after initiation of chemotherapy, the International Normalization Ratio (INR) increased from 3.04 to 39.56. Warfarin was discontinued and restarted at 7.5 mg/wk. Discontinuation of levamisole and 5-FU for a five-week period resulted in the INR falling to a subtherapeutic level. Reinstitution of the chemotherapeutic regimen once again led to an increase in INR. DISCUSSION: A literature search showed no reports of an interaction between warfarin and levamisole. However, prolongation of 5-FU half-life and an increase in INR have been reported with the concurrent use of 5-FU and warfarin. Inhibition of the hepatic metabolism of warfarin by 5-FU and levamisole is the postulated mechanism of this drug interaction. CONCLUSIONS: This case describes the clinically significant increase of INR in an elderly patient after adding a chemotherapy regimen of levamisole and 5-FU to a previous regimen of warfarin alone. The increasing incidence of both atrial fibrillation and colon cancer with age could potentially require the concomitant use of 5-FU, levamisole, and warfarin. Because of the potential severity of this interaction, close monitoring of INR and warfarin dosage adjustment is recommended in patients receiving warfarin along with levamisole and 5-FU Malarcana P;Maestri A, Recenti Progressi in Medicina, 1996, 87:135-135; Possible interactions between antiblastic agents and warfarin inducing prothrombin time abnormalities Our cases confirms an interaction between warfarin and antiplastic drugs with PT prolungation. Furthermore this clinical observation underlines how this adverse effect may appear after a long period, suggesting that this hemostatic alterations is more common than previously reported. Wajima T;Mukhopadhyay P, Am J Hematol, 1992, b, 40:238; Possible interactions between warfarin and 5-fluorouracil En kasuistik omhandlende en 75-Õrig mand med colon cancer, som fik warfarin pga af en dyb vene trombose. Han fik 5 mg warfarin og havde stabil protrombintid. Under behandling med fluoruracil steg protrombintiden trods reduktion og senere seponering af warfarin Camidge R;Reigner B;Cassidy J;Grange S;Abt M;Weidekamm E;Jodrell D, J Clin Oncol, 2005, 23:4719-4725; Significant effect of capecitabine on the pharmacokinetics and pharmacodynamics of warfarin in patients with cancer PURPOSE: Clinical cases of capecitabine and other fluorouracil-based chemotherapies potentiating the effects of coumarin derivatives have been reported. This study assessed the influence of capecitabine on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin. PATIENTS AND METHODS: Four patients with advanced/metastatic cancer completed the study, receiving a single oral dose of 20 mg warfarin before the start of standard capecitabine treatment (day 1), and again during the third cycle of capecitabine (day 61). PK parameters of warfarin and capecitabine and PD parameters of warfarin were assessed on days 1 and 61. RESULTS: During capecitabine treatment, the area under the plasma concentration time curve from 0 to infinity (AUC(0-infinity)) of S-warfarin increased by 57% (90% CI, 32% to 88%) with a 51% prolongation of the elimination half-life (t(1/2); 90% CI, 32% to 74%). Exposure to R-warfarin was not significantly affected. Plasma concentrations of capecitabine and its metabolites were not influenced by warfarin. During capecitabine treatment, the effect of warfarin on the baseline corrected AUC of the International Normalized Ratio (INR) increased by 2.8 times (90% CI, 1.33 to 5.70), with the maximum observed INR value almost doubling. Because of the administration of vitamin K to some patients with elevated INRs, these figures are likely to underestimate the true PD effect. Mean baseline factor VII levels dropped while on capecitabine therapy, potentially contributing to the observed PD interaction, though this effect did not reach statistical significance. CONCLUSION: There is a significant pharmacokinetic interaction between capecitabine and S-warfarin, resulting in exaggerated anticoagulant activity. Patients receiving warfarin anticoagulant therapy concomitantly with capecitabine should have their INR closely monitored and warfarin doses adjusted accordingly SPC for Teysuno, Produktresume, 2013; Teysuno (tegafur, gimeracil, oteracil), hårde kapsler Kolesar JM;Johnson CL;Freeberg BL;Berlin JD;Schiller JH, Pharmacotherapy, 1999, 19:1445-1449; Warfarin-5-FU interaction--a consecutive case series Five patients from a single institution received concomitant warfarin and 5-fluorouracil (5-FU) during a 3-year period. The mean weekly warfarin dose before starting chemotherapy was 40.66 mg and during chemotherapy it was 24 mg (p=0.0026). All patients required a warfarin dosage reduction (range 18-74%, mean 44%). Two patients were hospitalized, one with a major retroperitoneal bleed, the other for fresh-frozen plasma administration and observation. Maximum international normalized ratios (INRs) ranged from 3.66-23.7. This series confirms a common, clinically significant interaction between warfarin and 5-FU. An interaction between capecitabine, the orally available prodrug of 5-FU, and warfarin also has been reported. We recommend weekly monitoring of prothrombin time and INR for all patients receiving concomitant warfarin and 5-FU or capecitabine
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