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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 metronidazol og warfarin |
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Hyppig kontrol af INR ved indledning og ophør af kombinationsbehandlingen. Dosisjustering af warfarin kan blive nødvendig afhængig af INR. Interaktionen har evt. mindre klinisk betydning ved vaginal administration af metronidazol, hvor kun ca. 20% når det systemiske kredsløb.
Ved samtidig brug af metronidazol og warfarin øges effekten af warfarin og dermed risikoen for blødning. Et retrospektivt kohorte studie har fulgt INR værdier hos 705 warfarin behandlede patienter.
Mean INR steg med 0.75 (95%CI 0.65-0.84). I en gruppe, der fik warfarin men ikke metronidazole fandtes en stigning i mean INR på 0.22 (95%CI 0.21-0.24) Martin-Perez M, Gaist D et al, 2018. Mekanismen er ukendt.
udtalt
dokumenteret
vitamin K antagonister, perorale phenprocoumon, warfarin metronidazol metronidazol
Metronidazol potentiserer effekten af warfarin med stigning i INR/PT og blødninger til følge. Der er i litteraturen ikke lokaliseret referencer omhandlende interaktioner med phenprocoumon og metronidazol. Dog forventes de samme interaktioner at gælde for phenprocoumon som for warfarin,
Litteraturgennemgang - Vis
Warfarin og metronidazol Et prospektiv studie (O'Reilly RA, 1976b) beskriver, at der ved samtidig indtagelse af warfarin og metronidazol ses en signifikant stigning i plasmakoncentrationen af warfarin og i PT (ca. en fordobling ) hos 8 raske personer, sandsynlig pga. hæmning af warfarins omsætning i CYP2C9 i leveren. I et retrospektiv kohorte studie Laine K, Forsstrom J et al, 2000a hvor 32 patienter fik målt INR før og under samtidig metronidazol anvendelse steg den gennemsnitlige INR fra 2.2 til 4.3 på dag 8. Hos 14 af de 32 patienter var INR over 4 (4.5-10), men der var ingen tilfælde af blødning. Et epidemiologisk studie Zhang K, Young C et al, 2006 som analyserede sygesikringsdata viste at samtidig anvendelse af metronidazol og warfarin var associeret med en øget risiko for blødning (Odds ratio 1,6; 95% CI 1,3-1,9) I et retrospektivt single-center cohorte studie, bestående af 21 cases og 957 kontroller, sås en relativ risiko på 4,56 for stigning i INR til >4,5 ved kombinationsbehandling med warfarin og metronidazol sammenlignet med warfarin alene, Daniels LM, Barreto JN et al, 2015
To kasuistikker (Kazmier FJ, 1976; Dean RP og Talbert RL, 1980) rappporterer om blødning hos to patienter ved samtidig behandling med warfarin og metronidazol. Hos tre patienter (Tonna AP, Scott D et al, 2007) rapporteres der om stigninger i INR efter kombinationsbehandling med warfarin og metronidazol. En kasuistik (Howard-Thompson A, Hurdle AC et al, 2008) omhandler en 78-årig kvinde, som har været i stabil warfarin-behandling (7 mg dagligt med INR 2,5) i tre måneder, da hun får en infektion, der behandles med metronidazol (250 mg 3 gange dagligt i 5 dage) og levofloxacin (500 mg QD i 6 dage). Seks dage efter behandlingsstart bliver patienten indlagt med INR 9, næseblod samt cerebral blødning. Blødningen formodes at skyldes interaktion mellem warfarin og metronidazol. Et kohort studie beskriver en patient i behandling med warfarin som fik alvorlig blødning og en INR på 4,5 to dage efter at metronidazol behandling var begyndt Gasse C, Hollowell J et al, 2005. Supplerende litteratur for antikoagulantia, perorale og metronidazol: Harder S og Thurmann P, 1996 Lane MA, Zeringue A et al, 2014
Et retrospektivt kohorte studie har fulgt INR værdier hos 705 warfarin behandlede patienter der samtidig behandledes med oralt metronidazol. Mean INR steg med 0.75 (95%CI 0.65-0.84). I en gruppe, der fik warfarin men ikke metronidazole fandtes en stigning i mean INR på 0.22 (95%CI 0.21-0.24) (Martin-Perez M, Gaist D et al, 2018)
Et studie på 9 raske har sammenlignet den systemiske absorption af 500 mg metronidazol administreret hhv. oralt og vaginalt. Efter én oral dosis var mean peak koncentrationen 16 mikrog/mL og AUC 142 mikrog/h/mL. Efter én vaginal tilførsel var peak koncentrationen 2 mikrog/mL og AUC 30 mikrog/h/mL. Relativt AUC for vaginal administration var 21% af AUC værdien efter oral administration. Data viste dog stor variabilitet I den lille studiegruppe. Alper MM, Barwin BN et al, 1985
Kazmier FJ, Mayo Clin Proc, 1976, 51:782-784; A significant interaction between metronidazole and warfarin Interaction between metronidazole (Flagyl) and warfarin had been suggested based on the disulfiram-like effect of metronidazole and the known interaction of warfarin and disulfiram. This case report confirms that this interaction is clinically significant in man Zhang K;Young C;Berger J, J Manag Care Pharm , 2006, 12:640-648; Administrative claims analysis of the relationship between warfarin use and risk of hemorrhage including drug-drug and drug-disease interactions BACKGROUND: Despite the risk of hemorrhage, warfarin is the most commonly used oral anticoagulant today, both as monotherapy and when taken in combination with selected drugs. Warfarin is used most commonly for irregular heartbeat, after a heart attack, and after joint or heart valve replacement surgery. OBJECTIVE: To evaluate the relative risk of hemorrhage in health plan members who received warfarin concomitant with a drug known to cause an interaction or after diagnosis of liver disease or heart failure (HF). METHODS: A cohort study sample was drawn from an administrative database comprising medical and pharmacy claims for 1.7 million health plan members. A health plan member was defined as anyone who was eligible for pharmacy and medical benefits at any time from October 1, 2003, to September 30, 2004. To be included in the study, a member must have received at least 1 pharmacy claim for warfarin during the study period and been younger than 100 years. Hemorrhage was defined as a diagnosed bleeding episode recorded on a medical claim within 7 calendar days of a fill date for a pharmacy claim (new or refill) for warfarin. The following variables were used to predict the outcome measures: type of drug-drug or drug-disease interaction, patient age and gender, number of unique prescribers during the year for all drugs, specialty of the first prescriber for warfarin, average dose of warfarin, and days of warfarin therapy. Because individuals were followed only during the calendar year under study, the authors have interpreted the days of therapy measured primarily as a control on exposure. The outcome measures are prevalence of drug and disease interactions among members receiving warfarin therapy and the per-patient-per-year and per-member-per-month (PMPM) cost of medical treatment of hemorrhage associated with warfarin therapy including drug and disease interactions. Costs are defined as the total paid amount for a procedure or service after negotiated provider discounts and subtraction of patient copay and deductibles. Logistic regression was used to evaluate the relative risk of hemorrhage in users of warfarin monotherapy and of warfarin users with drug-drug and drug-disease interactions. The comparison group in the logistic regression comprised the members who were not diagnosed with either HF or liver disease and who received warfarin therapy but none of the drugs under study known to cause drug interactions. Therefore, the odds ratios [ORs] produced were estimates of the relative risk of hemorrhage when taking warfarin concomitant with selected drugs and diseases. RESULTS: Of the 17,895 patients who used warfarin during the study year, 2,634 (14.7%) were diagnosed with a hemorrhage event within 1 week after filling a prescription for warfarin. The factors associated with an increased risk of hemorrhage included female gender (OR 1.149; 95% confidence interval [CI], 1.053- 1.253), liver disease (OR 1.764; 95% CI, 1.360-2.288), and HF (OR 1.559; 95% CI, 1.373-1.770). Compared with the use of warfarin alone, the use of either cephalosporins (OR 1.157; 95% CI, 1.043-1.285) or metronidazole (OR 1.578; 95% CI, 1.321-1.886) was associated with increased risk of hemorrhage, whereas the risk of hemorrhage was not greater for concomitant use of warfarin with amiodarone, fibric acid derivatives, or nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors. There was no relationship between estimated average daily warfarin dose and prevalence of hemorrhage. Other variables associated with an increased risk of hemorrhage were increased patient age, female gender, 120 days or more of warfarin therapy during the year, 2 or more unique prescriber numbers, and the medical specialty of the first prescriber of warfarin. Over the population of 1.7 million members, the cost for all hemorrhage events within 7 days of a pharmacy claim for warfarin was 0.40 dollars PMPM. CONCLUSIONS: Only 2 of 5 combinations of warfarin with drugs in this study were found to be associated with a higher prevalence of hemorrhage compared with warfarin use alone. The absolute prevalence of hemorrhage in users of warfarin and metronidazole was 22.7% and 17.2% for warfarin and cephalosporins, respectively, versus 14.2% in users of warfarin alone. The prevalence of hemorrhage for concomitant use of warfarin and NSAIDs/COX-2 inhibitors, amiodarone, or fibric acid derivatives such as fenofibrate was not greater than for warfarin alone. Liver disease or HF in warfarin users was associated with a significant increase in the likelihood of hemorrhage Dean RP;Talbert RL, Drug Intell Clin Pharm, 1980, 14:864-866; Bleeding associated with concurrent warfarin and metronidazole therapy There are numerous drugs reported to interact with warfarin sodium. Reported drug interactions include decreased warfarin absorption, decreased vitamin K absorption, warfarin displacement from plasma protein binding sites, enhanced warfarin liver metabolism, and inhibition of warfarin liver metabolism. We would like to report a possible case of interaction between warfarin and metronidazole. Harder S;Thurmann P, Clin Pharmacokinet, 1996, 30:416-444; Clinically important drug interactions with anticoagulants. An update Coumarin derivatives combine 3 unfavorable properties which make them prone to potentially life threatening drug-drug interactions: (i) high protein binding; (ii) cytochrome P450 dependent metabolism; and (iii) a narrow therapeutic range. An entire list of drugs which are supposed to interact with coumarins (mostly with warfarin) comprises about 250 different compounds. Noteworthy are the interactions with cardiovascular or antilipidaemic drugs which are often coadministered with coumarins: amiodarone, propafenone and fibrates. Cardiovascular drugs which are obviously devoid or proven to be devoid of an interaction are angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, beta-blockers and cardiac glycosides. There are several other drugs which enhance the hypoprothrombinaemic response to coumarins by various mechanisms: inhibitors of the elimination of the eutomer S-(-)-warfarin (e.g. miconazole, phenylbutazone), combined with protein binding displacement (e.g., sulfinpyrazone, phenylbutazone), synergistic hypoprothrombinaemia (e.g. cefazoline). Furthermore, bleeding complications may occur with drugs affecting platelet function [aspirin (acetylsalicylic acid) and several nonsteroidal anti- inflammatories (NSAIDs)]. Strong inducers of coumarin metabolism are rifampicin (rifampin) and carbamazepine. Biphasic interactions may occur where a drug first enhances the hypoprothrombinaemic response to a coumarin but has a sustained inducing effect on coumarin metabolism (e.g. phenytoin or sulfinpyrazone). The complex response of coumarins to concomitant drug therapy makes it difficult to predict the occurrence and degree of a deterioration of anticoagulant control in individual patients. For clinical practice, it seems advisable that one should monitor for changes in prothrombin time when adding or deleting any newly approved drug or any drug suspected (e.g. on the basis of this review) to cause an interaction to patients on coumarin therapy. The onset of the adverse prothrombin time response might be from between 1 to 2 days up to 3 weeks (in case of phenprocoumon) after starting a concomitant drug regimen. With amiodarone, an adverse prothrombin time response might occur up to 2 months after initiating therapy. For heparins, only a drug interaction with aspirin or nitroglycerin seems clinically relevant due to the possibility of coadministration during acute cardiac events. Both drugs are shown to enhance the activated partial thromboplastin time response to heparin Gasse C;Hollowell J;Meier CR;Haefeli WE, Thromb Haemost, 2005, 94:537-543; Drug interactions and risk of acute bleeding leading to hospitalisation or death in patients with chronic atrial fibrillation treated with warfarin Although drug interactions with warfarin are an important cause of excessive anticoagulation, their impact on the risk of serious bleeding is unknown. We therefore performed a cohort study and a nested case-control analysis to determine the risk of serious bleeding in 4152 patients (aged 40-84 years) with nonvalvular atrial fibrillation (AF) taking long-term warfarin (> 3 months).The study population was drawn from the UK General Practice Research Database. More than half (58%) of eligible patients used potentially interacting drugs during continuous warfarin treatment. Among 45 identified cases of incident idiopathic bleeds (resulting in hospitalisation within 30 days or death within 7 days) and 143 matched controls, more cases than controls took > or = 1 potentially interacting drug within the preceding 30 days (62.2% vs. 35.7%) and used > 4 drugs (polypharmacy) within the preceding 90 days (80.0% vs. 66.4%). Conditional logistic regression analysis yielded an odds ratio (OR) of 3.4 (95% confidence interval [CI]: 1.4-8.5) for the risk of serious bleeding in patients treated with warfarin and > or = 1 drugs potentially increasing the effect of warfarin vs. warfarin alone adjusted for polypharmacy, diabetes, hypertension, heart failure, and thyroid disease; the adjusted OR for the combined use of warfarin and aspirin vs. warfarin alone was 4.5 (95% CI: 1.1-18.1). We conclude that concurrent use of potentially interacting drugs with warfarin is associated with a 3 to 4.5-fold increased risk of serious bleeding in long-term warfarin users Daniels LM;Barreto JN;Kuth JC;Anderson JR;Zhang B;Majka AJ;Morgenthaler TI;Tosh PK, Am J Health Syst Pharm, 2015, 72:1195-1203; Failure mode and effects analysis to reduce risk of anticoagulation levels above the target range during concurrent antimicrobial therapy PURPOSE: A failure mode and effects analysis (FMEA) was conducted to analyze the clinical and operational processes leading to above-target International Normalized Ratios (INRs) in warfarin-treated patients receiving concurrent antimicrobial therapy. METHODS: The INRs of patients on long-term warfarin therapy who received a course of trimethoprim-sulfamethoxazole, metronidazole, fluconazole, miconazole, or voriconazole (highly potentiating antimicrobials, or HPAs) between September 1 and December 31, 2011, were compared with patients on long-term warfarin therapy who did not receive any antimicrobial during the same period. A multidisciplinary team of physicians, pharmacists, and a systems analyst was then formed to complete a step-by-step outline of the processes involved in warfarin management and concomitant HPA therapy, followed by an FMEA. RESULTS: Patients taking trimethoprim-sulfamethoxazole, metronidazole, or fluconazole demonstrated a significantly increased risk of having an INR of >4.5. The FMEA identified 134 failure modes. The most common failure modes were as follows: (1) electronic medical records did not identify all patients receiving warfarin, (2) HPA prescribers were unaware of recommended warfarin therapy when HPAs were prescribed, (3) HPA prescribers were unaware that a patient was taking warfarin and that the drug interaction is significant, and (4) warfarin managers were unaware that an HPA had been prescribed for a patient. CONCLUSION: An FMEA determined that the risk of adverse events caused by concomitantly administering warfarin and HPAs can be decreased by preemptively identifying patients receiving warfarin, having a care process in place, alerting providers about the patient's risk status, and notifying providers at the anticoagulation clinic Laine K;Forsstrom J;Gronroos P;Irjala K;Kailajarvi M;Scheinin M, Ther Drug Monit, 2000, a, 22:503-509; Frequency and clinical outcome of potentially harmful drug metabolic interactions in patients hospitalized on internal and pulmonary medicine wards: focus on warfarin and cisapride Drug metabolic interactions present potential risks in patient care, but their frequency and relative importance as a clinical problem remains unclear. To assess the frequency and clinical outcome of potentially harmful drug metabolic interactions in hospitalized patients, the authors performed a survey of the medication data of patients treated on internal and pulmonary medicine wards in a university hospital. The database was searched for concomitantly administered drug pairs that would, according to Hansten and Horn´s drug interaction database, carry a high risk for a clinically harmful metabolic drug interaction. Coadministrations involving warfarin or cisapride were subjected to further analysis regarding clinical outcome. A total of 142 patients were exposed to 150 interactions with potentially harmful clinical outcome, resulting in a frequency of 0.9% (95% CI 0.7% to 1.0%). Inhibition of warfarin metabolism by metronidazole produced significant overanticoagulation as evidenced by elevated international normalized ratio values, whereas inducers (rifampicin and phenobarbital) of warfarin metabolism significantly reduced the efficacy of warfarin. One case of minor bleeding and one case of clavicular vein thrombosis were detected as possible consequences of disturbed anticoagulation. The coadministration of cisapride and erythromycin significantly prolonged the corrected QT (QTc) interval and was associated with clinical symptoms of cardiac arrhythmias. Coadministration of cisapride with fluconazole or miconazole was not associated with prolongation of the QTc interval or cardiac sequelae. Evaluations of patient materials are needed to assess the clinical relevance of metabolic drug interactions Howard-Thompson A;Hurdle AC;Arnold LB;Finch CK;Sands C;Self TH, Am J Geriatr Pharmacother , 2008, 6:33-36; Intracerebral hemorrhage secondary to a warfarin-metronidazole interaction Background: It has been >25 years since the interaction between warfarin and metronidazole was last reported in the literature. The current case report represents the first documentation of this interaction associated with intracerebral hemorrhage. Case summary: We present a case of a 78-year-old white woman started on metronidazole (250 mg every 8 hours for 5 days) and levofloxacin (500 mg QD for 6 days) for an upper respiratory tract infection after visiting a walk-in clinic. The patient did not notify any of the health care professionals involved that she was on concomitant warfarin therapy, which had been stable over the last 3 months. Her warfarin dose was 7 mg daily, and her most recent international normalized ratio (INR) reading was 2.5. Nine days after her clinic visit, the patient was admitted to the hospital for a profuse nosebleed with an INR of 8.0 and was found to have an intraparenchymal hemorrhage of the left occipital lobe. The Naranjo adverse drug reaction probability scale indicated that the association with metronidazole was probable and the association with levofloxacin was possible (scores of 7 and 4, respectively). After a 1-week hospital stay, she was discharged. Conclusions: This adverse event is highly suggestive of a drug interaction caused primarily by metronidazole, which produces an increase in S-warfarin concentrations. Treatment provided by health care providers who were not familiar with the patient and the use of a different pharmacy (where the pharmacist was unaware of her current medications) likely contributed to the event. copyright 2008 Excerpta Medica Inc Tonna AP;Scott D;Keeling D;Tonna I, Tomt indhold, 2007, 14(2): 65-67-67; Metronidazole causes an unexpected rise in INR in anticoagulated patients even after warfarin has been stopped Interaction between metronidazole and warfarin is thought to potentiate the anticoagulant effect of warfarin. In this article, the authors propose mechanisms for this interaction, based on three case studies Martin-Perez M;Gaist D;de Abajo FJ;Rodriguez LAG, Thromb Haemost, 2018, 118:461-470; Population Impact of Drug Interactions with Warfarin: A Real-World Data Approach1 OBJECTIVE: To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels. METHODS: Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 (N = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t-test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3). RESULTS: Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%). CONCLUSIONS: Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users Lane MA;Zeringue A;McDonald JR, Tomt indhold, 2014, 127:July; Serious bleeding events due to warfarin and antibiotic co-prescription in a cohort of veterans Background Antibiotics may interact with warfarin, increasing the risk for significant bleeding events. Methods This is a retrospective cohort study of veterans who were prescribed warfarin for 30 days without interruption through the US Department of Veterans Affairs between October 1, 2002 and September 1, 2008. Antibiotics considered to be high risk for interaction with warfarin include: trimethoprim/sulfamethoxazole (TMP/SMX), ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin. Low-risk antibiotics include clindamycin and cephalexin. Risk of bleeding event within 30 days of antibiotic exposure was measured using Cox proportional hazards regression, adjusted for demographic characteristics, comorbid conditions, and receipt of other medications interacting with warfarin. Results A total of 22,272 patients met inclusion criteria, with 14,078 and 8194 receiving high- and low-risk antibiotics, respectively. There were 93 and 36 bleeding events in the high- and low-risk groups, respectively. Receipt of a high-risk antibiotic (hazard ratio [HR] 1.48; 95% confidence interval [CI], 1.00-2.19) and azithromycin (HR 1.93; 95% CI, 1.13-3.30) were associated with increased risk of bleeding as a primary diagnosis. TMP/SMX (HR 2.09; 95% CI, 1.45-3.02), ciprofloxacin (HR 1.87; 95% CI, 1.42-2.50), levofloxacin (HR 1.77; 95% CI, 1.22-2.50), azithromycin (HR 1.64; 95% CI, 1.16-2.33), and clarithromycin (HR 2.40; 95% CI, 1.16-4.94) were associated with serious bleeding as a primary or secondary diagnosis. International normalized ratio (INR) alterations were common; 9.7% of patients prescribed fluconazole had INR value >6. Patients who had INR performed within 3-14 days of co-prescription were at a decreased risk of serious bleeding (HR 0.61; 95% CI, 0.42-0.88). Conclusions Warfarin users who are prescribed high-risk antibiotics are at higher risk for serious bleeding events. Early INR evaluation may mitigate this risk. 2014 Elsevier Inc. All rights reserved Alper MM;Barwin BN;McLean WM;McGilveray IJ;Sved S, Obstet Gynecol, 1985, 65:781-784; Systemic absorption of metronidazole by the vaginal route A study was designed to compare the systemic absorption of metronidazole by the oral and vaginal routes. Nine subjects received single 500-mg doses of the oral, vaginal insert, and vaginal cream preparations on three occasions. Approximately 20% bioavailability was demonstrated from both vaginal forms. Mean peak plasma concentrations were 15.56 micrograms/mL for the oral form, 1.86 micrograms/mL for the cream, and 1.89 micrograms/mL for the insert. The mean times to peak concentration were 1.23 hours for the oral dose and 11.11 hours and 20.11 hours for the cream and insert, respectively. The data demonstrate that some vaginal absorption occurs from both the cream and insert preparations of metronidazole O'Reilly RA, N Engl J Med, 1976, b, 295:354-357; The stereoselective interaction of warfarin and metronidazole in man Because of the known interaction of warfarin and disulfiram and the 'disulfiram effect' of metronidazole, the interaction with metronidazole of commercial racemic warfarin and its separated enantiomorphs was evaluated in eight normal subjects. Single oral doses of racemate, S(-)-warfarin, and R (+)-warfarin, were administered in the amounts of 1.5, 0.75 and 1.5 mg per kilogram of body weight, respectively, with and without metronidazole, 750 mg by mouth, beginning seven days before the warfarin dose and continuing seven days before the warfarin dose and continuing daily throughout the hypoprothrombinemia. Daily plasma samples were analyzed for warfarin in content and one-stage prothrombin time. A highly significant (P less than 0.01) augmentation of the mean warfarin level and hypoprothrombinemia with metronidazole occurred for racemic and S (-)- warfarin; none occurred with R (+)-warfarin. Thus, the interaction of racemic warfarin and metronidazole is stereoselective and can be lessened or even avoided by use of R (+)-warfarin alone for long-term therapy
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