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ADVERSE DRUG REACTIONADVERSE DRUG REACTION

Anna WielaAnna Wiela--HojeńskaHojeńska

Ewa JaźwińskaEwa Jaźwińska--TarnawskaTarnawska

Department of Clinical Pharmacology Department of Clinical Pharmacology

Wroclaw Medical UniversityWroclaw Medical University

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ADVERSE DRUG REACTIONADVERSE DRUG REACTION

as defined by WHO:as defined by WHO:

–– aanyny response to a drug which is response to a drug which is noxiousnoxious and and

unintendedunintended and which occurs at doses used in and which occurs at doses used in

man for prophylaxis, diagnosis or therapy.man for prophylaxis, diagnosis or therapy.

Directive Directive 2010/84/EU2010/84/EU of the of the EuropeanEuropean

ParliamentParliament and of the and of the CouncilCouncil

of 15 of 15 DecemberDecember 20102010amendingamending, as , as regardsregards pharmacovigilancepharmacovigilance, Directive , Directive

2001/83/EC on the 2001/83/EC on the CommunityCommunity codecode relatingrelating to to medicinalmedicinal

products for products for humanhuman useuse

aadversedverse reactionreaction –– noxiousnoxious and and unintendedunintended effectseffects

resultingresulting not not onlyonly for the for the authorisedauthorised useuse of a of a medicinalmedicinal

productproduct atat normalnormal dosesdoses, but , but alsoalso from from medicationmedication errorserrors

and and usesuses outsideoutside the the termsterms of the marketing of the marketing

authorisationauthorisation, , includingincluding the the misusemisuse and and abuseabuse of the of the

medicinalmedicinal productproduct

•• aacutecute

within 60 minuteswithin 60 minutes

•• ssubub--acuteacute

1 to 24 hours1 to 24 hours

•• llatentatent

> 2 days> 2 days

Onset of reactionOnset of reaction

•• mmildild

bothersome but requires no change in bothersome but requires no change in therapytherapy

•• mmoderateoderate

requires change in therapy, additional requires change in therapy, additional treatment, hospitalization treatment, hospitalization

•• ssevereevere

disabling or lifedisabling or life--threateningthreatening

SSeverityeverity of reactionof reaction

-- rresultesult in deathin death

–– llifeife--threateningthreatening

–– rrequireequire hospitalizationhospitalization

–– pprolongrolongeded hospitalizationhospitalization

–– ccauseause disabilitydisability

–– ccauseause congenital anomaliescongenital anomalies

–– medicallymedically significantsignificant

Serious ADRSerious ADR

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ExamplesExamples of of seriousserious reactionsreactions

BloodBlood: : bonebone marrowmarrow dyscrasiasdyscrasias, ,

coagulopathiescoagulopathies, , haemolitichaemolitic anaemiasanaemias

CardiovascularCardiovascular: : arrhythmiasarrhythmias, ,

cardiaccardiac arrestarrest, , cardiaccardiac failurefailure, ,

hypertensionhypertension

Central Central nervousnervous systemsystem: : depressiondepression, , epilepsyepilepsy, , myastheniamyasthenia

GastrointestinalGastrointestinal: : colitis, colitis, hepatichepatic

cirrhosiscirrhosis, , hepatichepatic dysfunctiondysfunction, , hepatichepatic

fibrosisfibrosis, , pancreatitispancreatitis

ImmunologicaImmunologicall:: anaphylaxisanaphylaxis, , drugdrug

feverfever, , graftgraft tejectiontejection, , vasculitisvasculitis

MetabolicMetabolic: : acidosisacidosis, , adrenaladrenal

dysfunctiondysfunction, , diabetesdiabetes, , hypercalcaemiahypercalcaemia, ,

hyperkalaemiahyperkalaemia, , hypokalaemiahypokalaemia, ,

hyponatraemiahyponatraemia

MusculoskeletalMusculoskeletal: : arthopathyarthopathy, ,

asepticaseptic bonebone necrosisnecrosis, ,

osteomalaciaosteomalacia

RenalRenal: : renalrenal dysfunctiondysfunction, ,

urinaryurinary retentionretention

ReproductionReproduction: : spontaneousspontaneous

abortionabortion, , congenitalcongenital abnormalitiesabnormalities, ,

eclampsiaeclampsia, , infertilityinfertility, , uterineuterine

haemorrhagehaemorrhage//perforationperforation

RespiratoryRespiratory: : bronchospasmbronchospasm, ,

pneumonitispneumonitis, respiratory , respiratory failurefailure, ,

thromboembolismthromboembolism

SkinSkin: : angioedemaangioedema, , bullousbullous

eruptionseruptions, , epidrmalepidrmal necrolysisnecrolysis, ,

exfoliationexfoliation

Special Special sensessenses: : cataractcataract

Classifications of ADRClassifications of ADR

Type:Type:

AA ((AAugmented)ugmented)

BB ((BBizzare)izzare)

CC ((CContinuous)ontinuous)

DD ((DDelayed)elayed)

EE ((EEnding Use)nding Use)

FF ((FFailure of Efficacy)ailure of Efficacy)

Type AType A reactionsreactions

aaugmentedugmented

Type B reactionsType B reactions

bbizzareizzare

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Type C Reactions Type C Reactions

ccontinuontinuinging

llong term effects are usually related to the ong term effects are usually related to the dosedose and and duration of treatmentduration of treatment

eexamplexampless:: eethambutol thambutol –– optical neuropathyoptical neuropathy, bisphosphonates , bisphosphonates –– osteonecrosisosteonecrosis

Type D reactionsType D reactions

ddelayedelayed

become apparent some time after the use of a medicinebecome apparent some time after the use of a medicine

examples: leucopoenia, which can occur up to six weeks after a dose of lomustineexamples: leucopoenia, which can occur up to six weeks after a dose of lomustine

Type E ReactionsType E Reactions

eend of nd of uusese

associated wassociated withith the withthe withdrawal drawal of a medicineof a medicine

examples: bexamples: barbiturates arbiturates –– restlessness, mental confusion, convulsionrestlessness, mental confusion, convulsion, c, clonidine lonidine –– rebound rebound

hypertensionhypertension, o, opioids pioids –– narcotic withdrawalnarcotic withdrawal, benzodiazepins , benzodiazepins –– insomnia, anxiety, perceptual insomnia, anxiety, perceptual

disturbancesdisturbances

Type F ReactionsType F Reactions

ffailure of ailure of eefficacyfficacy

can be attributed to lack of efficacy of drug productscan be attributed to lack of efficacy of drug products

eexamples:xamples: ffailure to control infection (microbial resistance)ailure to control infection (microbial resistance), u, uncontrolled hypertensionncontrolled hypertension, ,

iintractable painntractable pain

Limitations of Clinical TrialsLimitations of Clinical Trials

•• tootoo small small number of patientsnumber of patients-- averageaverage 1500 patients1500 patientsif a medicine has a risk that only occurs if a medicine has a risk that only occurs onceonce in in every 5.000every 5.000 patients you would patients you would

have to give the medicine to have to give the medicine to 15.00015.000 patients during the trials to be patients during the trials to be reasonably sure of identifying itreasonably sure of identifying it

•• tootoo sstrict trict conditionsconditions -- use patients without complications, use patients without complications,

other medicalother medical conditionsconditions

•• tootoo narrownarrow -- limited indicationslimited indications

•• tootoo brief brief -- limited timelimited time

•• tootoomedianmedian -- very old/very young patients, very old/very young patients,

pregnapregnant nt women not includedwomen not included

Drug administered

Pt develops a new condition/symptoms

Drug suspected?

Yes

Check literature

Documented ?– (for the product or similar class of products)

Yes

Highly suggestive of ADR

Not documented in literature

Drug continued Drug discontinued

Worsening of symptoms Symptoms improve (+ve dechallenge)

Drug restarted

Symptoms recur(+ve rechallenge)

Any other possible causes?• Concomitant therapy• Underlying conditions

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PharmacovigilancePharmacovigilance

drug safety monitoringdrug safety monitoringWHOWHO

European Medicines AgencyEuropean Medicines Agency

iis the science and activities relating to the s the science and activities relating to the

detectiondetection, , assessmentassessment, , understandingunderstanding and and

preventionprevention of of adverse effectsadverse effects andand other other

medicinemedicine--related problemsrelated problems

The European Union system of pThe European Union system of pharmacovigilanceharmacovigilance

European Medicines Agency, EMA/186974/2012European Medicines Agency, EMA/186974/2012

www.ema.europa.euwww.ema.europa.euNew EU pharmacovigilance legislation New EU pharmacovigilance legislation –– Key conceptsKey concepts

oversees the safety of medicines on the European marketoversees the safety of medicines on the European market

it has been established for a number of yearsit has been established for a number of years

this processes have evolved over timethis processes have evolved over time

The European CommissionThe European Commission has reviewed the current system has reviewed the current system and proposed and proposed new EU pharmacovigilance legislationnew EU pharmacovigilance legislation

This new legislation This new legislation was adoptedwas adopted by the by the European ParliamentEuropean Parliamentand and European CouncilEuropean Council in in December 2010December 2010 and will enter into and will enter into force in force in July 2012July 2012

EMAEMA, together with the , together with the European Member StatesEuropean Member States is responsible is responsible for implementing much of a new legislationfor implementing much of a new legislation

The European Union system of pThe European Union system of pharmacovigilanceharmacovigilance

European Medicines Agency, EMA/186974/2012European Medicines Agency, EMA/186974/2012

www.ema.europa.euwww.ema.europa.euNew EU pharmacovigilance legislation New EU pharmacovigilance legislation –– Key conceptsKey concepts

every country within the European Union has a every country within the European Union has a department department or or agency responsibleagency responsible for for national national pharmacovigilancepharmacovigilance

the reports that the national competent authorities the reports that the national competent authorities receive receive are transferredare transferred to a to a databasedatabase called called EudraVigilanceEudraVigilance and and evaluatedevaluated, together with additional , together with additional sources of information such as sources of information such as clinical trial dataclinical trial data, , medical literaturemedical literature or or data from international regulatorsdata from international regulators, , in order to identify new safety inormationsin order to identify new safety inormations

Aims of drug safety monitoringAims of drug safety monitoring

(pharmacovigilance)(pharmacovigilance)

collection, monitoring, discovering of ADRcollection, monitoring, discovering of ADR

analysisanalysis of all information related to ADR, of all information related to ADR, confirmationconfirmation or or

negationnegation of hypothesis of their occurence, of hypothesis of their occurence, evaluation of riskevaluation of risk

identification of risk factors identification of risk factors and and estimation estimation of probability of their of probability of their

occurrenceoccurrence

determinationdetermination of of increased risk increased risk of ADRof ADR

making decisions making decisions regarding changes in the therapyregarding changes in the therapy

propagationpropagation of information about ADR to physicians, of information about ADR to physicians,

pharmacists, patientspharmacists, patients

Pharmacovigilance by pharmaceutical

companies

www.ema.europa.eu

the company that holds the marketing

authorisation for a medicine has legal

obligations to continuously collect data and

conduct pharmacovigilance

data have to be transmitted to the authorities

within defined timelines, and any emerging

concern about the benefit-risk balance has to

be notified immediately

SPONTANEOUS REPORTINGSPONTANEOUS REPORTING

AdvantagesAdvantages

–– large population/not large population/not

specific pts groupsspecific pts groups

–– all medicinesall medicines

–– hospital and outhospital and out--patient patient

carecare

–– mmay generate rapid alertsay generate rapid alerts

–– lleast likely to influence east likely to influence

prescribing behaviourprescribing behaviour

–– llow setow set--up/costsup/costs

DisadvantagesDisadvantages

–– underreportingunderreporting

–– difficult to detectdifficult to detect

delayed reactionsdelayed reactions

reactions with high reactions with high

background incidencebackground incidence

–– number of exposed number of exposed

unknownunknown

–– biasbias

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What does the What does the �� black triangle mean?black triangle mean?

The Black Triangle indicates a medicine The Black Triangle indicates a medicine under under

additional monitoringadditional monitoring, a system to identify , a system to identify

medicines that are being monitored particularly medicines that are being monitored particularly

closely by regulatory authoritiesclosely by regulatory authorities

itit isis assigned toassigned to a medicine if:a medicine if:–– it contains a it contains a new new active substanceactive substance

–– it is a biological medicine, such as a vaccine or a medicine derived from it is a biological medicine, such as a vaccine or a medicine derived from

plasmaplasma

–– it has been given a conditional approval (where the company that it has been given a conditional approval (where the company that

markets the medicine must provide more data about it) or approved markets the medicine must provide more data about it) or approved

under exceptional circumstances (where there are specific reasons wht under exceptional circumstances (where there are specific reasons wht

the company cannot provide a comprehensive set of data)the company cannot provide a comprehensive set of data)

–– the company that markets the medicine is required to carry out additional the company that markets the medicine is required to carry out additional

studiesstudies

List of Black Triangle List of Black Triangle medicinesmedicines

hashas beenbeen publishedpublished by the by the EuropeanEuropean MedicinesMedicines

AgencyAgency

was was firstfirst publishedpublished in in AprilApril 2013 2013 and and willwill be be

reviewedreviewed everyevery monthmonth by the by the

PharmacovigilancePharmacovigilance RiskRisk AssessmentAssessment

CommitteeCommittee (PRAC)(PRAC)

tthe he upup--toto--datedate list of list of medicinesmedicines underunder additionaladditional

monitoring monitoring isis publishedpublished eacheach monthmonth on the on the

MHRAMHRA websitewebsite

mmedicinesedicines willwill be be typicallytypically assignedassigned a Black a Black

Triangle for a period of Triangle for a period of five five yearsyears

If in doubt

Fill a card out!

The The YellowYellow Card Card SchemeSchemeMHRA, http://www.mhra.gov.ukMHRA, http://www.mhra.gov.uk

wwas as introducedintroduced in 1964 in 1964

afterafter thalidomidethalidomide tragedytragedy

highlightedhighlighted the the urgenturgent needneed for for routineroutine

monitoring of monitoring of medicinesmedicines

pprincipallyrincipally actsacts as as anan earlyearly--warningwarning system system for for

identyfyingidentyfying previouslypreviously unrecognisedunrecognised ADRsADRs

pprovidesrovides valuablevaluable informationinformation on on recognisedrecognised

ADRsADRs, , allowingallowing to to identifyidentify and and refinerefine the the

understandingunderstanding of of riskrisk factorsfactors thatthat maymay affectaffect the the

clinicalclinical management of management of patientspatients

What information must I have to What information must I have to

complete a Yellow Card?complete a Yellow Card?

55 critical pieces of information are neededcritical pieces of information are needed::

11. Patient details (anonymised). Patient details (anonymised)

22. Suspect. Suspecteded drugdrug(s) (s)

33. Suspect. Suspecteded reactionreaction(s)(s)

4.4. Other drug(s) (including selfOther drug(s) (including self--medication andmedication and

complementary remedies)complementary remedies)

55. Reporter details. Reporter details

Do not delay reportingDo not delay reporting,,

even if you are in doubt even if you are in doubt

about causalityabout causality

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ADRsADRs findingsfindings cancan leadlead to to changeschanges in the in the

marketing marketing authorisationauthorisation of the of the medicinemedicine, , suchsuch as:as:

restrictionsrestrictions in in useuse

changeschanges in the in the specified dose specified dose of the medicineof the medicine

introductionintroduction of specific of specific warningswarnings of sideof side--effects effects

in the product informationin the product information

updatingupdating patient information patient information leafletsleaflets (PILs) and (PILs) and

Summaries of Product Characteristics Summaries of Product Characteristics (SPCs)(SPCs)

Yellow Card reports have helped identify:

Year Medicine Adverse Reaction Resulting action or

advice

August 2012 Simvastatin Drug interactions Updated warnings and

contraindications with

maximum dose

recommendations

July 2012 Dabigatran

(Pradaxa)

Serious haemorrhages Contraindications clarified

and reminder to monitor

renal function

April 2012 Proton pomp

inhibitors

Hypomagnesaemia Long-terms use warnings

and measurement of

magnesium levels

December 2011 Citalopram and

escitalopram

QT interval

prolongation

New maximum daily dose

restrictions (including in

elderly patients),

contraindications, and

warnings

SUMMARYSUMMARY

AAnyny drug can produce some form of ADRdrug can produce some form of ADR

Significant untoward risks, costs, and increased Significant untoward risks, costs, and increased

hospital stays associated with ADRshospital stays associated with ADRs

Allergy, Allergy, atopyatopy, or asthma p, or asthma paattientsients have been have been

suggested to be at an increased risksuggested to be at an increased risk

SUMMARY (2)SUMMARY (2)

Antibiotics, blood products, drug preservatives (sulfites Antibiotics, blood products, drug preservatives (sulfites

and methylparabens) and polypeptides (ie, aprotinin, and methylparabens) and polypeptides (ie, aprotinin,

latex, and protamine) may be associated with a higher latex, and protamine) may be associated with a higher

incidence of reactionsincidence of reactions

Drug avoidance whenever possible is still the best Drug avoidance whenever possible is still the best

method to avoid an ADRmethod to avoid an ADR

Undesirable drug interactions Undesirable drug interactions

in clinical practicein clinical practice

Department of Clinical Pharmacology Department of Clinical Pharmacology

Wroclaw Medical UniversityWroclaw Medical University

Criteria for clinical significanceCriteria for clinical significance

of interactionof interaction

hazard of interaction consequenceshazard of interaction consequences –– for for instance, mutual displacement of two drugs instance, mutual displacement of two drugs featuring high therapeutic range from protein featuring high therapeutic range from protein binding seldom leads to dangerous binding seldom leads to dangerous consequences, while the same phenomenon consequences, while the same phenomenon observed in the case of drugs characterized by observed in the case of drugs characterized by narrow therapeutic index is of considerable narrow therapeutic index is of considerable clinical significance (97% of warfarin bounds clinical significance (97% of warfarin bounds with proteins, displacement of merely 3% of the with proteins, displacement of merely 3% of the drug from these bonds increases the effect drug from these bonds increases the effect twice)twice)

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Criteria for clinical significance Criteria for clinical significance

of interactionof interaction (continuation)(continuation)

the degree of support by documentary evidence of particular interaction in clinical material –– it is important if this it is important if this interaction has been confirmed in patientsinteraction has been confirmed in patients



the frequency of particular interaction the frequency of particular interaction

in determined population of patientsin determined population of patients

(the factor is very useful for prognosis)(the factor is very useful for prognosis)



the frequency and degree of interaction the frequency and degree of interaction

documentationdocumentation –– mainly depends on how mainly depends on how

often a determined combination of drugs often a determined combination of drugs

is applied in medical practiceis applied in medical practice

Risk factors increasing the Risk factors increasing the

probability of undesirable interactionprobability of undesirable interaction

ppololypharmacotherapyypharmacotherapy –– the number of the number of

undesired interactions increases proportionally undesired interactions increases proportionally

to the number of drugs prescribed to one to the number of drugs prescribed to one

patient patient (4 or (4 or 5 5 drugs simultaneusly).drugs simultaneusly).

When When more than 5 drugsmore than 5 drugs are used at the same are used at the same

time, the time, the number of interactions increasesnumber of interactions increases, ,

excessing the proportional wayexcessing the proportional way


probability of undesirable interactionprobability of undesirable interaction(continuation)(continuation)

administration of drugs featuringadministration of drugs featuring

strong effects strong effects andand narrow therapeutic narrow therapeutic

indexindex, , as well asas well as the the drugsdrugs determined determined

as substances thatas substances that potentially potentially

endanger the highest interaction riskendanger the highest interaction risk



thethe useuse ofof drugsdrugs characterizedcharacterized byby nonnon--linearlinear

kineticskinetics,, ee..gg.. ttheophyllineheophylline,, phenytoinphenytoin

coexistence of other diseasescoexistence of other diseases, , especially especially

those disturbing the function of organs those disturbing the function of organs

eliminating drugs, like the liver or/and kidneyseliminating drugs, like the liver or/and kidneys

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advancedadvanced oror veryvery youngyoung ageage ofof patients,patients,

accompaniedaccompanied byby adequateadequate physiologicalphysiological

differencesdifferences inin thethe functionfunction ofof thethe circulatorycirculatory andand

centralcentral nervousnervous system,system, liver,liver, kidneyskidneys

elderlyelderly patientspatients sufferingsuffering fromfrom manymany diseasesdiseases

andand thereforetherefore takingtaking manymany drugsdrugs atat thethe samesame

timetime,, areare mostmost endangeredendangered byby undesirableundesirable drugdrug

interactionsinteractions



polytherapypolytherapy in critically ill patients taking in critically ill patients taking

many drugs, when the symptoms of the many drugs, when the symptoms of the

disease are difficult to differentiate from disease are difficult to differentiate from

complications resulting from drug therapy complications resulting from drug therapy

which becomes not tolerated by the which becomes not tolerated by the

patientspatients



therapy conducted by several doctorstherapy conducted by several doctors and and

the lack of detailed interview regarding the the lack of detailed interview regarding the

drugs administered previouslydrugs administered previously

takingtaking contraceptivecontraceptive drugsdrugs whichwhich cancan bebe thethe

reasonreason ofof theirtheir interactioninteraction withwith thethe drugsdrugs usedused

atat thethe samesame timetime


probability of undesirable probability of undesirable

interactioninteraction

drug advertisingdrug advertising in mass mediain mass media

general accessibility of drugsgeneral accessibility of drugs, , especially especially

those fromthose from OTCOTC ((OOver ver TThe he CCounter) ounter) group, group,

sold without doctor’s prescriptionsold without doctor’s prescription

dangerous phenomenon of dangerous phenomenon of patients’ patients’ selfself--

treatmenttreatment

Consequences of drug interactionsConsequences of drug interactions

Decrease in pharmacological drug effect Decrease in pharmacological drug effect

by:by:

pharmacodynamic antagonism,pharmacodynamic antagonism,

reduced absorption (decrease in reduced absorption (decrease in

bioavailability),bioavailability),

induction of metabolic processes,induction of metabolic processes,

increased excretion.increased excretion.

Consequences of drug interactionsConsequences of drug interactions

Increase in pharmacological drug effect Increase in pharmacological drug effect

by:by:

pharmacodynamic synergism,pharmacodynamic synergism,

displacement of drugs from protein displacement of drugs from protein

binding,binding,

inhibition of metabolic processes,inhibition of metabolic processes,

decreased excretion.decreased excretion.

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Drug absorption interactions Drug absorption interactions

after oral administrationafter oral administration

changes in gastrointestinal pHchanges in gastrointestinal pH

adsorbtion, chelation, complexes formation, adsorbtion, chelation, complexes formation,

malabsorption syndromemalabsorption syndrome

changes in gastrointestinal motilitychanges in gastrointestinal motility

inhibiting activity of CYP3A cytochrom P450 inhibiting activity of CYP3A cytochrom P450

enzymes responsible for metabolism of the first enzymes responsible for metabolism of the first

passage in the intesine wallpassage in the intesine wall

Inhibiting activity of CYP3A cytochrome Inhibiting activity of CYP3A cytochrome

P450 enzymes responsible for the first P450 enzymes responsible for the first

pass metabolism in the intestine wallpass metabolism in the intestine wallThe components of The components of grapefruit grapefruit (naringenine, (naringenine, dihydroksybergamotine) inhibiting activity of CYP3A4 dihydroksybergamotine) inhibiting activity of CYP3A4 cytochrome P450 isoenzyme cytochrome P450 isoenzyme –– increase absorption increase absorption from intestines of from intestines of calcium channel blockerscalcium channel blockers((nifedipine, felodipine, isradipine, lacidipine, nifedipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nimodipine, verapamil), lercanidipine, nicardipine, nimodipine, verapamil), immunosuppressantsimmunosuppressants (cyclosporine, sirolimus, (cyclosporine, sirolimus, tacrolimus), tacrolimus), entocort which contains budesonide for entocort which contains budesonide for Crohn’s diseasCrohn’s diseas, , statinsstatins ((simvastatin, atorvastatinsimvastatin, atorvastatin), ), medicines used in the tratment of cancerousmedicines used in the tratment of cancerous((crizotinib, lapatinib, linotinib, sunitinibcrizotinib, lapatinib, linotinib, sunitinib, , everolimuseverolimus), ), aliskiren aliskiren which is used to which is used to treat high blood pressuretreat high blood pressure ––drugs undergoing first pass metabolism in the drugs undergoing first pass metabolism in the intestinal wallintestinal wall

amlodipine and grepefruit interactionamlodipine and grepefruit interaction

a male patient drank a male patient drank grapefrit juicegrapefrit juice three times three times

a day whilst taking a day whilst taking amlodipineamlodipine, prescribed for , prescribed for

high blood pressure, reported high blood pressure, reported severe swelling severe swelling

to his legs and feetto his legs and feet

the swelling resolved when he stoped drinking the swelling resolved when he stoped drinking

grapefruit juicegrapefruit juice

Drug transport interaction by cell membranes. Drug transport interaction by cell membranes.

Drugs effects on PDrugs effects on P--glicoprotein activity (Pglicoprotein activity (P--gp)gp)

PP--glycoproteinglycoprotein is a largeis a large--molecule protein molecule protein

detected in cell membranes of different detected in cell membranes of different

organs, which, by active transport organs, which, by active transport

(„pump”) push drugs out of the cells, („pump”) push drugs out of the cells,

preventing their accumulation.preventing their accumulation.

Induction of PInduction of P--gp activitygp activity

RifampicinRifampicin can inducecan induce PP--gp activity in gp activity in

intestinal epithelium cells, increasing the intestinal epithelium cells, increasing the

elimination of digoxin to the intestine elimination of digoxin to the intestine

lumen, what causes the decrease of its lumen, what causes the decrease of its

concentration in blood serum concentration in blood serum

Inhibition of PInhibition of P--gp activitygp activity

CiclosporinCiclosporin inhibits Pinhibits P--gp activity within gp activity within

the kidney tubule cells so that the amount the kidney tubule cells so that the amount

of digoxin pushed out into urine is of digoxin pushed out into urine is

reduced, therefore causing a rise in reduced, therefore causing a rise in

plasma digoxin levelsplasma digoxin levels

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Drug displacement (proteinDrug displacement (protein--binding) binding)

interactionsinteractions

Drugs of high affinity to blood proteins, soDrugs of high affinity to blood proteins, so--

called „called „displacing drugsdisplacing drugs" " –– the compounds of the compounds of

acidic propertiesacidic properties –– acetylsalicylic acid, acetylsalicylic acid,

ibuprofen, diclofenac, phenylbutazone, some ibuprofen, diclofenac, phenylbutazone, some

sulfonamides, chloral hydrate, trichloroacetic sulfonamides, chloral hydrate, trichloroacetic

acid, clofibrate, ethacrynic acid, quinidine, acid, clofibrate, ethacrynic acid, quinidine,

verapamil, amiodaroneverapamil, amiodarone

Drug metabolism interactionsDrug metabolism interactionsSubstances inhibiting metabolism of other drugs, Substances inhibiting metabolism of other drugs,

soso--calledcalled „„enzyme inhibitorsenzyme inhibitors”:”:

–– allopurinol allopurinol

–– amiodarone amiodarone

–– qunidine qunidine

–– chloramphenicol chloramphenicol

–– cimetidine cimetidine

–– ciprofloxacin ciprofloxacin

–– diltiazem diltiazem

–– disulfiram disulfiram

–– enoxacinenoxacin

–– erythromycin erythromycin

–– phenylbutazone phenylbutazone

–– fluconazolefluconazole

__-- fluoxetinefluoxetine

–– isoniazidisoniazid

–– indynavirindynavir

–– ketoconazole ketoconazole

–– clarithromycin clarithromycin

–– omeprazoleomeprazole

–– metronidazolemetronidazole

–– rytonavirrytonavir

–– sulfinpyrazone sulfinpyrazone

–– verapamil verapamil

–– alcohol once in high amountalcohol once in high amount

–– grapefruit juicegrapefruit juice

warfarin and cranberry juice interactionwarfarin and cranberry juice interaction

warfarin warfarin + + cranberry juicecranberry juice

interaction interaction -- ↑↑ International Normalised Ratio International Normalised Ratio

(INR), (INR), bleeding bleeding episodesepisodes

Cranberry juice Cranberry juice contains various antioxidants contains various antioxidants

including flavinoid, which inhibit CYP2C9, including flavinoid, which inhibit CYP2C9,

enzyme used to metabolise warfarin enzyme used to metabolise warfarin

Drug metabolism interactionsDrug metabolism interactions

Substances inducing metabolism of other drugs, Substances inducing metabolism of other drugs,

soso--called called „„enzyme inductorsenzyme inductors”:”:

barbiturates, especially phenobarbital barbiturates, especially phenobarbital

aminoglutethimide aminoglutethimide

carbamazepinecarbamazepine

phenytoin phenytoin

rifampicin rifampicin

griseofulvin griseofulvin

preparations of St. John’s wortpreparations of St. John’s wort (Hypericum (Hypericum perforatum)perforatum)

alcoholalcohol abused for a long timeabused for a long time

carbohydrates present in tobacco smokecarbohydrates present in tobacco smoke

Drug excretion interactionsDrug excretion interactions

changes in urinary pH changes in urinary pH

changes in active kidney tubule excretionchanges in active kidney tubule excretion

changes in kidney blood flowchanges in kidney blood flow

Drugs most commonly causing adverse Drugs most commonly causing adverse effects of interactionseffects of interactions

anticoagulantsanticoagulants

antidiabeticsantidiabetics

nonsteroidal antinonsteroidal anti--inflammatory drugs (NSAIDs)inflammatory drugs (NSAIDs)

drugs used in the diseases of circulatory systems, like: drugs used in the diseases of circulatory systems, like: cardiac insufficiency, cardiac ischemia, arterial cardiac insufficiency, cardiac ischemia, arterial hypertension, allorhythmia, (especially cardiac hypertension, allorhythmia, (especially cardiac glycosides, betaglycosides, beta--adrenolytic drugs, diuretics, adrenolytic drugs, diuretics, angiotensin converting enzyme inhibitors, antagonists , antagonists of angiotensin II receptors, calcium canal blockers, of angiotensin II receptors, calcium canal blockers, antiarrhythmic drugs, dilatators of peripheral vesselsantiarrhythmic drugs, dilatators of peripheral vessels––nitrates),nitrates),

hypolipemic drugshypolipemic drugs

antibacterial, antiviral and antifungal drugsantibacterial, antiviral and antifungal drugs

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Drugs most commonly causing adverse Drugs most commonly causing adverse effects of interactions effects of interactions (continuation)(continuation)

drugs affecting the central nervous system: drugs affecting the central nervous system:

psychotropic drugs psychotropic drugs -- antidepressants, antidepressants,

neuroleptics, anxiolytics (benzodiazepines), neuroleptics, anxiolytics (benzodiazepines),

antiepileptics, lithium saltsantiepileptics, lithium salts

theophyllintheophyllin

antineoplastic drugsantineoplastic drugs

immunosuppressive drugs immunosuppressive drugs -- cyclosporine, cyclosporine,

tacrolimus, syrolimus tacrolimus, syrolimus

Anticoagulant drugAnticoagulant drug interactionsinteractions with other drugs and with other drugs and substancessubstances

Drugs and other substances decreasing anticoagulant effect ofcoumarins

Drugs and other substances

simulataneously administered with

coumarins

Type and consequences of interaction

Aluminium hydroxide, neomycin,

colestyramine, metoclopramid

Reduction of coumarin absorption from

gastrointestinal tract, decrease of their

activity

Vitamin K, estrogens,

glycocortycosteroides, oral contraceptives

Antagonistic effect with coumarins,

diminishing their action

Phenobarbital, secobarbital,

aminoglutethimide, carbamazepine,

griseofulvin, rifampicin, nafcylin,

dicloxacylin, phenytoin, ethanol (abuse

for a long time)

Induction of coumarin metabolism,

diminishing their action

Anticoagulant drugAnticoagulant drug interactions with other drugs interactions with other drugs

Drugs increasing anticoagulant effect of coumarins

Magnesium hydroxide, magnesium trisilicate Increase in coumarins

gastrointestinal absorption,

enhancement of their activity

Neomycin, kanamycin, paromomycin The mentioned drugs through the

change in bacterial composition

in intestine flora, reduce vitamin

K production, intensify of

coumarin activity

Phenylbutazone, azapropazone, sulfinpyrazone,

indometacin, mefenamic acid, celecoxib, salicylates,

phenytoin, chloral hydrate, sulfonamides

Displacement of coumarins from

serum albumin binding, increase

in their activity, enhancement of

toxicity, higher risk of bleeding

Anticoagulant drugAnticoagulant drug interactions with other drugsinteractions with other drugs

Drugs increasing anticoagulant effect of coumarins

Anabolic steroids, thyroxin, other thyroxin preparations, quinin, quinidin, heparin, glucagon, clofibrate, some cefalosporin (cefazolin, cefamandole, cefonicid, cefoperazone, ceforanide, ceftriaxone, cefemenoxime, cefpiramide), flutamide, oral antibiotics cause vitamin K deficiency (tetracycline, chloramphenicol), ticlopidine

Synergic effect with

coumarins, increase of their

activity, higher risk of

hemorrhagic complications

Cimetidine, amiodarone, chloramphenicol, phenylbutazone, metronidazole, fluconazole, itraconazole, ketoconazole, miconazole, tamoxifen, ciprofloxacin, norfloxacin, erythromycin, clarithromycin

Inhibition of coumarinmetabolism, increase of theiractivity, enhancement of toxicity, higher risk of bleeding

Interactions of iInteractions of insulin nsulin andand oral antidiabetic drugsoral antidiabetic drugs with with other drugs and substancesother drugs and substances

Drugs and other substances diminishing antidiabetic drugs action

Drugs and other substances

simulataneously administered with

antidiabetic drugs


Glycocorticosteroids, sympathomimetics, thyroxin preparations, glucagon, diuretics(furosemide, ethacrynic acid), oral contracteptives

Antagonistic effect with antidiabetic drugs,

which diminish their action

Rifampicin Induction of the metabolism of oral

antidiabetic drugs, diminishing their

activity

InteractionsInteractions of of iinsulinnsulin andand oral antidiabetic drugoral antidiabetic drug with other drugswith other drugs

Drugs enhancing antidiabetic drugs activity

Magnesium hydroxide, sodium bicarbonate

Increase in oral antidiabetic drugs absorption, enhancement activity

Nonsteroidal anti-inflammatory drugs(phenylbutazone, oxyphenbutazone, salicylates – they have hypoglycaemicproperties in large doses), antibacterial sulfonamides

Displacement of antidiabetic drugs from serum albumin binding, enhancement activity

Chloramphenicol, dicoumarol, phenylbutazone, sulfaphenazole, anabolic steroids, H2 receptor blockers, ketoconazole, fluconazole

Inhibition of the metabolism of antidiabetic drugs, enhancement of their activity

12

InteractionsInteractions of of iinsulinnsulin and and oral antidiabetic drugoral antidiabetic drug with other drugswith other drugs

Drugs enhancing antidiabetic drugs activity

Beta-adrenolytic drugs(propranolol)

Synergic effect with antidiabetic drugs, enhancement of their activity

Salicylates, allopurinol Displacement of antidiabetic drugs from kidney tubular transport systems

�SAIDs�SAIDs phphaarmacodynamicrmacodynamic iinteraction nteraction of highest clinical significanceof highest clinical significance

Drugs and other substances simultaneously administered with

�SAIDs


Hypotensive drugs (beta-adrenolytics, angiotensin converting enzyme inhibitors, diuretics)

Reduction of hypotensive effect of these drugs due to increase in synthesis of vasodilatory prostaglandins by NSAIDs

Anticoagulant drugs (coumarin derivatives)

Higher risk of bleeding from gastrointestinal tract due to inhibition of platelets activity and prothrombin synthesis

Antidiabetic drugs Intensification of hypoglycemic activity by hypoglycemic action of some of NSAIDs

Fluoroquinolones Intensification of toxic effect on CNS

Cyclosporine, tacrolimus, angiotensin converting enzyme inhibitors

Enhancement of nephrotoxicity by NSAIDs

Lithium carbonate Enhancement of toxicity by NSAIDs

Alcohol Higher risk of bleeding from gastrointestinal tract

Thrombocyte aggregation inhibitors(ticlopidine, clopidogrel)

Higher risk of bleeding, synergic effect

�SAIDs�SAIDs pharmacokinetic interactionspharmacokinetic interactions

oof highest clinical significancef highest clinical significance

Drugs simultaneously administered with �SAIDs


Anticoagulant drugs(coumarin derivatives)

Higher risk of bleeding from gastrointestinal tract due tocoumarins displacement from blood protein binding

Antidiabetic drugs (oral, especially sulphonylureas derivatives)

Enhancement of hypoglicemic activity, by displacement ofantidiabetic drugs from blood protein binding and inhibition oftheir metabolism

Methotrexate Enhancement of methotrexate toxicity as a result of its displacement from protein binding and impairment of renal tubular secretion of this drug

Cardiac drugs (digoxin) Increase in digoxin concentration as a result of its displacementfrom protein binding and reduction of kidney excretion, leading to intensification of its activity and causing risk of adverse effects

�SAIDs�SAIDs phpharmaarmaccookkinetinetiic ic interactionsnteractions

of highest clinical significanceof highest clinical significance

Drugs simultaneously administered with �SAIDs


Aminoglycosides Increase in aminoglycosides concentration in serum leading to higher risk of adverse effects due to inhibition of their glomerular filtration, enhancement of oto- andnephrotoxicity

Drugs affecting CNS(phenytoin, valproic acid)

Increase in phenytoin and valproic acid concentration due to inhibition of their metabolism and their displacement fromblood protein binding

Corticosteroids Increase in cortycosteroids concentration due to decrease in their renal excretion, gastropathy, bleeding from gastrointestinal tract

Tricyclic antidepressants,selective serotonin reuptake inhibitors, neuroleptics, antiarrhythmic drugs

Increase in activity as a result of metabolism inhibition of the mentioned drugs by NSAIDs (celecoxib)

Cardiac Cardiac glglycycoosisiddeses interactioninteraction with other drugs and substanceswith other drugs and substances

Drugs and substances simultaneously

administered with cardiac glicosidesType and consequences of

interaction

Hypercalcemia: calcium compounds

Hypokalemia: diuretics (furosemide, etacrynic

acid), indapamide, glicocorticosteroids, laxatives,

amphotericin B, polymyxins

Enhancement of cardiac glycosides

activity and their arrhythmogenic effect

Hyperkalemia: potassium compounds

Hypokalcemia: sodium versenate, sodium citrate

Reduction of cardiac glycosides activity

Epinephrine, norepinephrine, reserpine,

monoamine oxidase inhibitors (MAOI)

Possibility of cardiac arrhythmia

Cardiac glycosidesCardiac glycosides interactions with other drugs and substancesinteractions with other drugs and substances

Drugs and substances simultaneously

administered with cardiac glycosidesType and consequences of

interaction

Drugs diminishing digoxin absorption from

gastrointestinal tract: activated charcoal,

metoclopramide, colestyramine, colestipol,

neomycin, sulphasalazine, aminosalicylic acid

Reduction of digoxin activity

Drugs stimulating cardiac glycosides

biotransformation: phenobarbital, phenylbutazone,

rifampicin, phenytoin, St. John’s wort (Hypericum

perforatum)

Reduction of cardiac glycosides activity

Drugs increasing plasma digoxin concentration:

verapamil, diltiazem, niphedypine, quinidine, amiodarone, indomethacin, spironolactone, trimethoprim, gentamicin, cefradine, tetracycline, erythromycin, clarithromycin, propafenone, cyclosporine, itraconazole

Decrease in digoxin renal clearance, inhibition of P-glicoprotein activityresponsible for renal and intestinal digoxin transport, intensification of digoxin activity

13

BetaBeta--adrenolytic drugadrenolytic drug interactionsinteractions with other drugs with other drugs

BetaBeta--adrenolytic adrenolytic

drugs (DBA)drugs (DBA)

Simultaneously administered Simultaneously administered

other drugs other drugs


Lipofilic DBA Lipofilic DBA

(propranolol, (propranolol,

metoprolol)metoprolol)

Quinidine, amiodarone, Quinidine, amiodarone,

propafenone, encainide, propafenone, encainide,

flecainide, hydralazineflecainide, hydralazine

InhibitionInhibition of DBA of DBA metabolismmetabolism, increase , increase

in DBA blood concentration, hypotonia, in DBA blood concentration, hypotonia,

bradycardia, ventricular arrhythmiasbradycardia, ventricular arrhythmias

TimololTimolol Quinidine, cimetidineQuinidine, cimetidine IncreaseIncrease in cardiac action frequency, in cardiac action frequency,

reduction of intraocular pressurereduction of intraocular pressure

PropranololPropranolol Propafenone, lidocainePropafenone, lidocaine IncreaseIncrease in propafenone, lidocaine in propafenone, lidocaine

bioavailabilitybioavailability, enhancement their , enhancement their

activityactivity

MetoprololMetoprolol PropafenonePropafenone InhibitionInhibition of metoprolol of metoprolol metabolismmetabolism, ,

increase in metoprolol concentration, increase in metoprolol concentration,

enhancement activity (hypotonia, enhancement activity (hypotonia,

bradycardia)bradycardia)




Simultaneously Simultaneously

administered other drugs administered other drugs

Type and consequences of

interaction

Metoprolol, Metoprolol,

carvedilol, carvedilol,

propranolol, propranolol,

timololtimolol

Antidepressive drugs: Antidepressive drugs:

amitriptyline, nortriptyline, amitriptyline, nortriptyline,

fluoxetinefluoxetine

InhibitionInhibition of DBA of DBA metabolismmetabolism, ,

increase in DBA activity, hypotoniaincrease in DBA activity, hypotonia

DBA (acebutolol, DBA (acebutolol,

atenolol,esmolol, atenolol,esmolol,

metoprolol, metoprolol,

timolol)timolol)

AlphaAlpha--adrenolytic drugs: adrenolytic drugs:

prazosin, doxazosinprazosin, doxazosin

Orthostatic hypotoniaOrthostatic hypotonia

Propranolol, Propranolol,

labetalollabetalol

ClonidineClonidine Rebound hypertension after clonidine Rebound hypertension after clonidine

discontinuationdiscontinuation

DBADBA Werapamil, diltiazemWerapamil, diltiazem EnhancementEnhancement of negative dromothropic of negative dromothropic

effect the mentioned drugs, Aeffect the mentioned drugs, A--V block, V block,

hypotoniahypotonia





administered other drugs administered other drugs


interaction

DBADBA DigoxinDigoxin Enhancement Enhancement of depressive influence of depressive influence

the mentioned drugs on cardiac impulsthe mentioned drugs on cardiac impuls--

conductive system, bradycardia, conductive system, bradycardia,

impairments of transmissionimpairments of transmission

DBA DBA Indomethacin, acetylsalicylic Indomethacin, acetylsalicylic

acidacid

InhibitionInhibition of prostaglandins synthesis, of prostaglandins synthesis,

increase in DBA hypotensive effectincrease in DBA hypotensive effect

PropranololPropranolol Oral hypoglycaemic drugsOral hypoglycaemic drugs InhibitionInhibition of insulin secretion, of insulin secretion,

reduction of insulinreduction of insulin--susceptibility susceptibility

tissues, worsening of diabetes tissues, worsening of diabetes

metabolic control, masking of metabolic control, masking of

hypoglycaemic symptoms by DBA, hypoglycaemic symptoms by DBA,

higher risk of hypoglycaemiahigher risk of hypoglycaemia

DiureticDiuretic interactionsinteractions with other drugs with other drugs

DiureticDiuretic Simultaneously administered Simultaneously administered



Loop diuretics Loop diuretics

(furosemide, (furosemide,

ethacrynic acid)ethacrynic acid)

Aminoglycosides, Aminoglycosides,

cephalosporinscephalosporins

IncreaseIncrease in aminoglycosides, in aminoglycosides,

cephalosporins cephalosporins nephrotoxicitynephrotoxicity, ,

aminoglycosides aminoglycosides otoxicityotoxicity

Amiloride Amiloride CiclosporinCiclosporin IncreaseIncrease in ciclosporin in ciclosporin nephrotoxicitynephrotoxicity

AmilorideAmiloride QuinidineQuinidine QT interval prolonging effects, QT interval prolonging effects, enhanced enhanced

proarythmic quinidine activityproarythmic quinidine activity, ,

ventricular tachycardia episodes of ventricular tachycardia episodes of

torsade de pointestorsade de pointes typetype

IndapamideIndapamide Quinidine, disopyramide, Quinidine, disopyramide,

amiodarone, bretylium, sotalol, amiodarone, bretylium, sotalol,

bepridil, erythromycin, bepridil, erythromycin,

pentamidinepentamidine

QT interval prolonging effects, QT interval prolonging effects,

ventricular tachycardia episodes of ventricular tachycardia episodes of

torsade de pointestorsade de pointes typetype

Diuretic Diuretic interactionsinteractions with other drugs with other drugs

DiureticDiuretic Simultaneously administered Simultaneously administered



FurosemideFurosemide Valproic acidValproic acid

PhenytoinPhenytoin

Displacement Displacement of furosemide of furosemide from proteinfrom protein

bindingbinding, increase in furosemide , increase in furosemide

concentration, enhancement its diuretic concentration, enhancement its diuretic

activityactivity

DecreaseDecrease in furosemide in furosemide diuretic activitydiuretic activity

Loop diuretics Loop diuretics

(furosemide, (furosemide,

torasemide, torasemide,

bumetanide)bumetanide)

NSAIDs NSAIDs –– indometacin, indometacin,

diclofenac, piroxicam, diclofenac, piroxicam,

naproxen, acetylsalicylic acidnaproxen, acetylsalicylic acid

Decrease in diuretic effectDecrease in diuretic effect

IndapamideIndapamide Indometacin, tienilic acidIndometacin, tienilic acid Acute renal insufficiencyAcute renal insufficiency

Interactions ofInteractions of angiotensin converting enzyme angiotensin converting enzyme

(ACE) inhibitors (ACE) inhibitors with other drugs with other drugs

and substancesand substances

Angiotensin Angiotensin

converting enzyme converting enzyme

(ACE) inhibitors(ACE) inhibitors



and substances and substances


Captopril, enalapril, Captopril, enalapril,

lisinopril, lisinopril,

perindopril perindopril

NSAIDs (acetylosalicylic acid, NSAIDs (acetylosalicylic acid,

indometacin, naproxen)indometacin, naproxen)

ReductionReduction of hypotensive action, of hypotensive action,

hemodynamic effects of ACE inhibitorshemodynamic effects of ACE inhibitors

ACE inhibitors ACE inhibitors Hypoglycaemic agentsHypoglycaemic agents DecreaseDecrease in glucose blood concentration in glucose blood concentration

in patients with diabetesin patients with diabetes

CaptoprilCaptopril General anesthetic agentsGeneral anesthetic agents ExcessiveExcessive reduction of blood pressurereduction of blood pressure

ACE inhibitorsACE inhibitors AllopurynolAllopurynol Neurologic disturbances, StevensNeurologic disturbances, Stevens--

Johnson syndrom, anaphylactic reactions, Johnson syndrom, anaphylactic reactions,

neutropenianeutropenia

14











ACE inhibitors ACE inhibitors

(captopril, (captopril,

cilizapril, cilizapril,

trandolapril)trandolapril)

Immunosuppressant drugs Immunosuppressant drugs

(azathioprine), cytostatics(azathioprine), cytostatics

NeutropeniaNeutropenia

ACE inhibitors ACE inhibitors CiclosporinCiclosporin Symptoms of acute renal insufficiencySymptoms of acute renal insufficiency

in patients after kidney transplantationin patients after kidney transplantation

ACE inhibitorsACE inhibitors Lithium saltsLithium salts Increase in lithium carbonate blood Increase in lithium carbonate blood

concentration, enhancement its toxicityconcentration, enhancement its toxicity

Captopril, enalaprilCaptopril, enalapril Chlorpromazine, clozapineChlorpromazine, clozapine Hypotonia, orthostatic syncopeHypotonia, orthostatic syncope











ACE inhibitors ACE inhibitors Thiazides, chlortalidone, Thiazides, chlortalidone,

furosemide, etacrynic acid furosemide, etacrynic acid

Rapid hypotension, acute renal Rapid hypotension, acute renal

insufficiencyinsufficiency

ACE inhibitors ACE inhibitors Diuretics potassiumDiuretics potassium--sparing sparing

(amiloride, triamterene, (amiloride, triamterene,

spironolactone)spironolactone)

Dangerous, sometimes lifeDangerous, sometimes life--threatening threatening

hyperkalemic symptomshyperkalemic symptoms

ACE inhibitorsACE inhibitors DiureticsDiuretics Increase in urea blood concentrationIncrease in urea blood concentration

Captopril at the Captopril at the

dose of 25 mgdose of 25 mg

FurosemideFurosemide Reduction of furosemide diuretic effectReduction of furosemide diuretic effect

Interactions ofInteractions of calciumcalcium--channel blockers channel blockers with other with other

drugs and substancesdrugs and substances

CalciumCalcium--channel channel

blockersblockers





Amlodipine, Amlodipine,

felodipine, felodipine,

isradipine, isradipine,

nicardipine, nicardipine,

nifedipine, nifedipine,

verapamil verapamil

Erythromycin, itraconazole, Erythromycin, itraconazole,

ketoconazole, cimetidine, ketoconazole, cimetidine,

indinavir, ritonavir, saquinavir, indinavir, ritonavir, saquinavir,

grapefruit juice grapefruit juice

InhibitionInhibition of of metabolismmetabolism, increase in , increase in

calciumcalcium--channel blockers blood channel blockers blood

concentration, enhancement of concentration, enhancement of

hypotonia, dizziness, headache, circular hypotonia, dizziness, headache, circular

edema edema

Diltiazem, Diltiazem,

verapamil, verapamil,

nifedipine nifedipine

Rifampicin, phenobarbitalRifampicin, phenobarbital AccelerationAcceleration of of metabolismmetabolism, decrease in , decrease in


concentration, reduction of their activityconcentration, reduction of their activity

Werapamil, Werapamil,

diltiazemdiltiazem

Qinidine, disopyramide, Qinidine, disopyramide,

amiodaroneamiodarone

InhibitionInhibition of werapamil, diltiazem of werapamil, diltiazem

metabolismmetabolism, increase in their , increase in their

concentration, bradycardia, hypotonia, concentration, bradycardia, hypotonia,

enhancement of cardiac failure enhancement of cardiac failure

symptomssymptoms




blockersblockers






amlodipine, amlodipine,

nifedipine, nifedipine,

verapamil verapamil

Ciclosporin, tacrolimus, Ciclosporin, tacrolimus,

sirolimussirolimus

InhibitionInhibition of of metabolismmetabolism, increase in , increase in

ciclosporin, tacrolimus, sirolimus blood ciclosporin, tacrolimus, sirolimus blood

concentration, enhancement of their concentration, enhancement of their

activityactivity


verapamil, verapamil,

nifedipine nifedipine

Rifampicin, phenobarbitalRifampicin, phenobarbital AccelerationAcceleration of of metabolismmetabolism, decrease in , decrease in


concentration, reduction of their activityconcentration, reduction of their activity

Werapamil, Werapamil,

diltiazemdiltiazem

Lovastatin, simvastatin, Lovastatin, simvastatin, InhibitionInhibition of of statins metabolismstatins metabolism, increase , increase

in their plasma concentration, higher risk in their plasma concentration, higher risk

of myopathy or rhabdomyolysisof myopathy or rhabdomyolysis




blockersblockers






verapamil verapamil

Carbamazepine, phenytoinCarbamazepine, phenytoin Inhibition Inhibition of carbamazepine, phenytoin of carbamazepine, phenytoin

metabolismmetabolism, increase in their blood , increase in their blood


neurotoxicityneurotoxicity


verapamilverapamil

BetaBeta--adrenolitic drugsadrenolitic drugs EnhancementEnhancement of negative dromothropic of negative dromothropic

effect the mentioned drugs, Aeffect the mentioned drugs, A--V block, V block,

arrhythmogenic effect of arrhythmogenic effect of torsade de torsade de

pointespointes typetype


blockersblockers

Tubocurarine, atracurium, Tubocurarine, atracurium,

vecuroniumvecuronium

Increase, prolongIncrease, prolong in muscle relaxant in muscle relaxant

effecteffect

Drugs prolonging Drugs prolonging QT QT interval in interval in EECCG G with the highest risk with the highest risk of of induinducing cing ventricular tachycardia episodes of ventricular tachycardia episodes of torsade de pointestorsade de pointes typetype

Antiarrhythmic drugs

Amiodarone, disopyramide, dofetilide, qunidine, sotalol

Antihistaminic drug

Ebastine

Antibacterial drugs

Erythromycin, clarithromycin, spiramycin, ciprofloxacin, gatifloxacin, norfloxacin, sparfloxacin, co-trimoxazole

Antimycotic drug

Ketoconazole

Antiprotozoan drugsMetronidazole, pentamidine, quinine, chloroquine

Antidepressant drugs

Tricyclic antidepressant drugs, fluoxetine, maprotiline

Antipsychotic drugsChlorpromazine, haloperidol, droperidol, thioridazine, mesoridazine, lithium carbonate, pimozide, sertindole

Calcium channel blocking drugs

Bepridil, prenylamine

Opiate receptor agonists

Methadone, levomethadyl

Other drugs

Chloral hydrate, ketanserin, succinylocholine, tamoxyfen, tacrolimus, vasopressin

15

StatinsStatins interactionsinteractions with other drugs and substanceswith other drugs and substances

StatinsStatins Simultaneously administered Simultaneously administered




LovastatinLovastatin FoodFood IncreaseIncrease in in absorptionabsorption (50%), (50%),

enhancement of activityenhancement of activity

Simvastatin, Simvastatin,

lovastatin, lovastatin,

atorvastatinatorvastatin

Erythromycin, clarithromycin, Erythromycin, clarithromycin,

itraconazole, ketoconazole, itraconazole, ketoconazole,

fluconazole, diltiazem, fluconazole, diltiazem,

verapamil, ciclosporinverapamil, ciclosporin

InhibitionInhibition of CYP3A4 isoenzyme of CYP3A4 isoenzyme

activity responsible for statins first pass activity responsible for statins first pass

metabolism in the intestine wall, metabolism in the intestine wall,

enhancement of their activity, higher enhancement of their activity, higher

risk of myopathy, rhabdomyolysisrisk of myopathy, rhabdomyolysis




Grapefruit juiceGrapefruit juice InhibitionInhibition of CYP3A4 isoenzyme of CYP3A4 isoenzyme

activity responsible for statins first pass activity responsible for statins first pass

metabolism in the intestine wall, metabolism in the intestine wall,

enhancement of their activity, higher enhancement of their activity, higher

risk of myopathy, rhabdomyolysisrisk of myopathy, rhabdomyolysis









Fibrates (especially Fibrates (especially

gemfibrozil), niacingemfibrozil), niacin

DecreaseDecrease in statins in statins eliminationelimination, increase , increase

in concentration, enhancement of in concentration, enhancement of

activity, higher risk of myopathy, activity, higher risk of myopathy,

rhabdomyolysisrhabdomyolysis

FluvastatinFluvastatin WarfarinWarfarin InhibitionInhibition of warfarin of warfarin metabolismmetabolism by by

fluvastatin, enhancement of warfarin fluvastatin, enhancement of warfarin

activityactivity



atorvastatin, atorvastatin,

pravastatin, pravastatin,

fluvastatinfluvastatin

Pectin, colestyraminePectin, colestyramine ReductionReduction of statinsof statins absorptionabsorption, , decrease decrease

in their activityin their activity









Rifampicin, barbituratesRifampicin, barbiturates AccelerationAcceleration of CYP3A4 isoenzyme of CYP3A4 isoenzyme

activity responsible for statins activity responsible for statins

metabolism, reduction of their activitymetabolism, reduction of their activity

FluvastatinFluvastatin RifampicinRifampicin AccelerationAcceleration of fluvastatin of fluvastatin metabolismmetabolism

by rifampicin, reduction of its activityby rifampicin, reduction of its activity

AtorvastatinAtorvastatin Norethisterone, estradiolNorethisterone, estradiol IncreaseIncrease inin hormoneshormones plasma plasma


activityactivity

Rules of antibiotic combinationRules of antibiotic combination

Do not combineDo not combine antibiotics with each other or antibiotics with each other or

antibiotics with other drugs antibiotics with other drugs featuring similar featuring similar

toxic propertiestoxic properties or mutually altering the or mutually altering the

destination in organism, thus affecting destination in organism, thus affecting

pharmacokinetic properties.pharmacokinetic properties.

Rules of antibiotic combination Rules of antibiotic combination (continuation)(continuation)

Antibiotic doses administered in combination Antibiotic doses administered in combination

can not be lowercan not be lower than the doses of these drugs than the doses of these drugs

administered individually.administered individually.

Rules of antibiotic combinationRules of antibiotic combination(continuation)(continuation)

CombinationCombination of of bactericidalbactericidal chemotherapeutics, which chemotherapeutics, which require effectively growing bacteria cells for their require effectively growing bacteria cells for their activity (penicillins, cephalosporins, aminoglycosides, activity (penicillins, cephalosporins, aminoglycosides, rifampicin, isoniazid, fluoroquinolones, polymyxins, rifampicin, isoniazid, fluoroquinolones, polymyxins, vancomycin, bacitracin, nitrofurans, macrolides at vancomycin, bacitracin, nitrofurans, macrolides at higher doses) with higher doses) with bacteriostaticbacteriostatic drugs (sulfonamides, drugs (sulfonamides, tetracyclines, macrolides, chloramphenicol, tetracyclines, macrolides, chloramphenicol, lincosamides, trimethoprim, ethambutol), inhibiting lincosamides, trimethoprim, ethambutol), inhibiting bacteria growth, at great sensitivity of microbacteria growth, at great sensitivity of micro--organism organism can leadcan lead to undesirable to undesirable antagonistic effectantagonistic effect; the ; the ranknest example of drug combination is that of ranknest example of drug combination is that of penicillins with tetracyclines, macrolides or penicillins with tetracyclines, macrolides or chloramphenicol.chloramphenicol.

16

Aminoglicoside antibioticsAminoglicoside antibiotics interaction with other interaction with other


Drugs and substances simultaneously Drugs and substances simultaneously

administered with aminoglicosidesadministered with aminoglicosidesType and consequences of interaction

Neuromuscular blockers (tubocurarine, Neuromuscular blockers (tubocurarine,

gallamine, pancuronium) gallamine, pancuronium)

Increase Increase inin muscle relaxation, prolong muscle muscle relaxation, prolong muscle

paralysis, resulting in possible fatal respiratory paralysis, resulting in possible fatal respiratory

depressiondepression

Furosemide, etacrynic acidFurosemide, etacrynic acid Increase Increase inin ototoxicity ototoxicity

Cefalotin, cefradine, vancomycin, Cefalotin, cefradine, vancomycin,

amphotericin, furosemide, etacrynic acid, amphotericin, furosemide, etacrynic acid,

methoxyflurane, cisplatin, ciclosporin methoxyflurane, cisplatin, ciclosporin

Increase Increase in nephrotoxicity in nephrotoxicity

Phenothiazines (thiethylperazine, Phenothiazines (thiethylperazine,

chlorpromazine, dimenhydrinate) chlorpromazine, dimenhydrinate)

Masking Masking ofof aminoglycosides aminoglycosides

ototoxic symptoms ototoxic symptoms

TetracyclinsTetracyclins interaction with other drugs and interaction with other drugs and

substancessubstances

Drugs and substances simultaneously Drugs and substances simultaneously

administered with tetracyclinesadministered with tetracyclinesType and consequences of interaction

Drugs containing the ions of calcium, iron, Drugs containing the ions of calcium, iron,

magnesium, aluminium, bismuth, zinc, copper, magnesium, aluminium, bismuth, zinc, copper,

milk, bases milk, bases

ReductionReduction of tetracyclins of tetracyclins absorptionabsorption from from

gastrointestinal tract, decrease in their activitygastrointestinal tract, decrease in their activity

Phenytoin, barbiturates, carbamazepine Phenytoin, barbiturates, carbamazepine InductionInduction of teracyclins of teracyclins metabolismmetabolism ––

doxycycline, diminishing of their activitydoxycycline, diminishing of their activity

Phenothiazines (chlorpromazine) Phenothiazines (chlorpromazine) IncreaseIncrease in in hepatotoxic activityhepatotoxic activity of tetracyclins of tetracyclins

Warfarin, phenindioneWarfarin, phenindione IncreaseIncrease in in anticoagulant drug activityanticoagulant drug activity due to due to

dysbacteriosis, decrease in vitamin K synthesis dysbacteriosis, decrease in vitamin K synthesis

by intestinal bacteria and decrease in by intestinal bacteria and decrease in

prothrombin concentrationprothrombin concentration

Digoxin, insulin Digoxin, insulin Tetracyclins enhancement of digoxin and Tetracyclins enhancement of digoxin and

insulin activityinsulin activity

Macrolides antibioticsMacrolides antibiotics interaction with other drugsinteraction with other drugs

AntibioticAntibiotic Type and consequences of interaction

Group IGroup I

Old genetation macrolides Old genetation macrolides

erythromycin, troleandomycin erythromycin, troleandomycin

EnhancementEnhancement of warfarin, digoxin, of warfarin, digoxin,

theophylline, ebastine, methylprednisolone, theophylline, ebastine, methylprednisolone,

carbamazepine, ciclosporin, disopyramide, carbamazepine, ciclosporin, disopyramide,

felodipine, benzodiazepines (triazolam, felodipine, benzodiazepines (triazolam,

midazolam) and bromocriptine midazolam) and bromocriptine activity activity due to due to

inhibitioninhibition of their of their metabolismmetabolism and and excretionexcretion

Group IIGroup II

josamycin, roxithromycin, josamycin, roxithromycin,

clarithromycin, flurythromycin, clarithromycin, flurythromycin,

miokamycin, midekamycin miokamycin, midekamycin

Enhancement Enhancement ofof theophylline, ebastine, theophylline, ebastine,

carbamazepine, coumarin derivatives, carbamazepine, coumarin derivatives,

bromocriptine, ciclosporin bromocriptine, ciclosporin activityactivity due to due to

inhibitioninhibition of their of their metabolismmetabolism

Group IIIGroup III

azythromycin, spiramycin,azythromycin, spiramycin,

dirithromycin, rokitamycin dirithromycin, rokitamycin

So far clinically significant interactions have So far clinically significant interactions have

not been observed in peoplenot been observed in people

FluoroquinolonesFluoroquinolones interactions with other drugsinteractions with other drugs

Drugs simultaneously Drugs simultaneously

administered with administered with

fluoroquinolonesfluoroquinolones


Theophyllin Theophyllin InhibitionInhibition of theophyllin of theophyllin metabolismmetabolism by enoxacin, by enoxacin,

pipemidic acid, in a less degree by ciprofloxacin, pipemidic acid, in a less degree by ciprofloxacin,

pefloxacin, norfloxacin, increase in theophyllin pefloxacin, norfloxacin, increase in theophyllin

concentration, concentration, enhancementenhancement in its activity and adverse in its activity and adverse

effects effects

Antihistaminic drugs Antihistaminic drugs

(ebastine) (ebastine)

EnhancementEnhancement of cardiotoxic effect by ciprofloxacin, of cardiotoxic effect by ciprofloxacin,

norfloxacin, sparfloxacin, prolongation of QT interval, norfloxacin, sparfloxacin, prolongation of QT interval,

risk of ventricular tachycardia episodes of risk of ventricular tachycardia episodes of torsade de torsade de

pointespointes typetype

FluoroquinolonesFluoroquinolones interactions with other drugsinteractions with other drugs

Drugs simultaneously administered Drugs simultaneously administered

with fluoroquinoloneswith fluoroquinolones


Anticoagulant drugs, NSAIDs, Anticoagulant drugs, NSAIDs,

antidiabetic drugs, cytostatic drugs antidiabetic drugs, cytostatic drugs --

substrates for isoenzyme CYP1A2 substrates for isoenzyme CYP1A2

and CYP3A4and CYP3A4

InhibitionInhibition of drug of drug metabolismmetabolism, which are , which are

substrates for isoenzyme CYP1A2 and substrates for isoenzyme CYP1A2 and

CYP3A4 by fluoroquinolones, enhancement of CYP3A4 by fluoroquinolones, enhancement of

their activity their activity

Antacids containing aluminium, Antacids containing aluminium,

magnesium, calcium, zinc, iron magnesium, calcium, zinc, iron

salts, sucralfate, salts, sucralfate,

ReductionReduction of fluoroquinolones of fluoroquinolones absorptionabsorption from from

gastrointestinal tract gastrointestinal tract

Tuberculostatic drugTuberculostatic drug interactions with other drugs interactions with other drugs


Tuberculostatic drugsTuberculostatic drugs Drugs and substances simultaneously Drugs and substances simultaneously

administered administered

Type and consequences

of interaction

Rifampicin Rifampicin Antifungal drugs (itraconazole, Antifungal drugs (itraconazole,

ketoconazole), antiviral drugs ketoconazole), antiviral drugs

(indinavir, saquinavir, nelfinavir), (indinavir, saquinavir, nelfinavir),

immunosuppressant drugs immunosuppressant drugs

(ciclosporin, tacrolimus), (ciclosporin, tacrolimus),

theophylline, narcotic analgesics theophylline, narcotic analgesics

(methadone), contraceptives, (methadone), contraceptives,

coumarins derivatives, oral coumarins derivatives, oral

antidiabetics, tricyclic antidiabetics, tricyclic

antidepressant drugs, antipsychotic antidepressant drugs, antipsychotic

drug (haloperidol), drug (haloperidol),

antihypertensive drug (enalapril), antihypertensive drug (enalapril),

corticosteroids corticosteroids

InductionInduction of the of the

mentioned drugs mentioned drugs


metabolismmetabolism by by

rifampicin, rifampicin,

reduction of their reduction of their

activityactivity

17

Tuberculostatic drugTuberculostatic drug interactions with other interactions with other

drugsdrugs

Tuberculostatic Tuberculostatic

drugsdrugs


administered other administered other

drugsdrugs

Type and consequences

of interaction

Rifampicin Rifampicin Digoxin Digoxin Decrease Decrease in digoxin in digoxin

concentration by rifampicin concentration by rifampicin

inductioninduction of of PP--glicoproteinglicoprotein

activity activity in gut epithelium cells, in gut epithelium cells,

reduction of digoxin activity reduction of digoxin activity

Antifungal drugAntifungal drug interactions with other drugs interactions with other drugs


Antifungal Antifungal

drugsdrugs


administered drugs administered drugs



interaction

Ketoconazole Ketoconazole Drugs prolonging QT intervalDrugs prolonging QT interval IncreasedIncreased risk ofrisk of lifelife--threateningthreatening

dysrrhythmia of dysrrhythmia of torsade de pointestorsade de pointes

typetype

Ketoconazole Ketoconazole Alcohol Alcohol Symptoms of alcohol Symptoms of alcohol intoleranceintolerance, ,

disulfiramdisulfiram--like reaction like reaction

Ketoconazole, Ketoconazole,

fluconazole, fluconazole,

itraconazole, itraconazole,

woriconazole woriconazole

Phenytoin, rifampicin, Phenytoin, rifampicin,

phenobarbital phenobarbital

InductionInduction of antifungal drugs of antifungal drugs

metabolismmetabolism by phenytoin, rifampicin, by phenytoin, rifampicin,

phenobarbital, reduction of antifungal phenobarbital, reduction of antifungal

drugs activity drugs activity





Drugs administered in Drugs administered in

chronic peptic ulcer disease, chronic peptic ulcer disease,

antagonists of H2 receptors, antagonists of H2 receptors,

omeprazol, sucralfate omeprazol, sucralfate

DecreaseDecrease in antifungal drugs in antifungal drugs

absorptionabsorption from gastrointestinal tractfrom gastrointestinal tract

Antifungal drugAntifungal drug interactions with other drugs interactions with other drugs


Antifungal drugsAntifungal drugs Simultaneously Simultaneously

administered drugs administered drugs



interaction

Griseofulvin Griseofulvin Anticoagulants, ciclosporin, Anticoagulants, ciclosporin,

oral contraceptives oral contraceptives

InductionInduction of the above drugs of the above drugs

metabolismmetabolism by griseofulvin, decrease by griseofulvin, decrease

in their activityin their activity

Griseofulvin Griseofulvin Barbiturates Barbiturates InductionInduction of griseofulvin of griseofulvin metabolism metabolism

by barbiturates, reduction of its by barbiturates, reduction of its

antifungal activity antifungal activity

Griseofulvin Griseofulvin Alcohol Alcohol IntensificationIntensification of alcohol effectof alcohol effect





Phenytoin, ciclosporin, Phenytoin, ciclosporin,

statins, anticoagulants, statins, anticoagulants,

antihistamines H1 II antihistamines H1 II

generation, cardiac generation, cardiac

glycosides, calcium channel glycosides, calcium channel

blocker drugsblocker drugs

Inhibition Inhibition of the above drugs of the above drugs

metabolismmetabolism by ketoconazole, by ketoconazole,

fluconazole, itraconazole, fluconazole, itraconazole,

woriconazole, enhancement of their woriconazole, enhancement of their

activity and toxicityactivity and toxicity

TheophyllineTheophylline interactions with other drugs and substancesinteractions with other drugs and substances

Simultaneously administered drugs Simultaneously administered drugs



Macrolides Macrolides –– erythromycin, erythromycin,

clarithromycin, josamycin; clarithromycin, josamycin;

fluoroquinolones fluoroquinolones –– enoxacin, enoxacin,

pipemidic acid, ciprofloxacin, pipemidic acid, ciprofloxacin,

pefloxacin, norfloxacin; moreover pefloxacin, norfloxacin; moreover

cimetidine, zileuton, oral cimetidine, zileuton, oral

contraceptivescontraceptives

InhibitionInhibition of theophyllin of theophyllin metabolismmetabolism

Enzyme inductors Enzyme inductors -- barbiturates, barbiturates,

rifampicin, phenytoin, St John’s wortrifampicin, phenytoin, St John’s wort

InductionInduction of theophyllin of theophyllin metabolismmetabolism, ,

reductionreduction ofof its pharmacological activityits pharmacological activity

Methotrexate Methotrexate interactions with other drugsinteractions with other drugs


with MTXwith MTX


Cholestyramine, neomycin, Cholestyramine, neomycin,

paromomycin paromomycin

DecreaseDecrease in MTX gastrointestinal in MTX gastrointestinal

absorptionabsorption, diminishing MTX action, diminishing MTX action

Hydrocortisone, prednisone, cefalotin Hydrocortisone, prednisone, cefalotin ReductionReduction of MTX of MTX cell uptakecell uptake, ,

diminishing of MTX activitydiminishing of MTX activity

Griseofulvin, rifampicin, phenobarbital Griseofulvin, rifampicin, phenobarbital Induction Induction of MTX of MTX metabolismmetabolism, ,

diminishing of MTX action diminishing of MTX action

Asparaginase Asparaginase Antagonistic effectAntagonistic effect in relation to MTX, in relation to MTX,

diminishing of MTX activitydiminishing of MTX activity

Kanamycin Kanamycin IncreaseIncrease in MTX gastrointestinal in MTX gastrointestinal

absorptionabsorption, increase in its bioavailability, , increase in its bioavailability,

enhancement of MTX activity enhancement of MTX activity

MethotrexateMethotrexate interactionsinteractions with other drugswith other drugs


with MTXwith MTX


NSAIDs, sulfonamides, probenecidNSAIDs, sulfonamides, probenecid DisplacementDisplacement of of MTX from MTX from serum serum

albumin bindingalbumin binding, increase in its activity, , increase in its activity,

enhancement of MTX toxicityenhancement of MTX toxicity

Salicylates, sulfonamides, cefalotin, Salicylates, sulfonamides, cefalotin,

penicillin, probenecid penicillin, probenecid

Competitive Competitive impairmentimpairment of renal tubular of renal tubular

secretion of MTX, increase in activity, secretion of MTX, increase in activity,

enhancement of toxicity enhancement of toxicity

Aminoglycosides, cisplatin, Aminoglycosides, cisplatin,

ciclosporin, procarbazin ciclosporin, procarbazin

Impairment Impairment of kidney function, decrease of of kidney function, decrease of

MTX excretion, increase in MTX MTX excretion, increase in MTX

pharmacological activity, enhancement of pharmacological activity, enhancement of

MTX toxicityMTX toxicity

18

MethotrexateMethotrexate interactions with other drugsinteractions with other drugs


with MTXwith MTX


CisplatinCisplatin DamageDamage of renal tubules, of renal tubules, decrease decrease in MTX in MTX

and folic acid reabsorptionand folic acid reabsorption, decrease in , decrease in

effectiveness of leucovorin rescueeffectiveness of leucovorin rescue

Phenylbutazone, amidopirinePhenylbutazone, amidopirine EnhancementEnhancement of MTX bone marrow of MTX bone marrow

depressiondepression

Azathioprine, sulfasalazineAzathioprine, sulfasalazine Increase Increase in hepatotoxicity riskin hepatotoxicity risk

Mercaptopurine Mercaptopurine InhibitionInhibition of mercaptopurine of mercaptopurine metabolismmetabolism by by

MTX, enhancement of mercaptopurine MTX, enhancement of mercaptopurine

activityactivity

Immunosuppressant drugImmunosuppressant drug interactions interactions ––

ciclosporin, tacrolimus, sirolimus with other drugsciclosporin, tacrolimus, sirolimus with other drugs

Immunosuppressant Immunosuppressant

drugsdrugs

Other simultaneously Other simultaneously

administered drugsadministered drugs


Ciclosporin, Ciclosporin,

tacrolimustacrolimus

Macrolides Macrolides --

erythromycin, erythromycin,

clarithromycin, clarithromycin,

josamycin josamycin

Inhibition Inhibition of ciclosporin andof ciclosporin and

tacrolimus tacrolimus metabolismmetabolism by macrolides, increaseby macrolides, increase in in

immunosuppressant drugsimmunosuppressant drugs effecteffect

Ciclosporin Ciclosporin Antifungal drugs Antifungal drugs --

ketoconazole, ketoconazole,


itraconazoleitraconazole

InhibitionInhibition of ciclosporin of ciclosporin metabolismmetabolism by by

antifungal drugs, increaseantifungal drugs, increase inin itsits activity. activity.

Necessity of 85% reduction in ciclosporin Necessity of 85% reduction in ciclosporin

dosages during simultaneous therapy with dosages during simultaneous therapy with

ketoconazole, and of 50% ketoconazole, and of 50% -- during therapy with during therapy with

fluconazolefluconazole

Tacrolimus Tacrolimus Fluconazole Fluconazole InhibitionInhibition of tacrolimus of tacrolimus metabolismmetabolism by by

fluconazole, enhancement of tacrolimus activity. fluconazole, enhancement of tacrolimus activity.

Necessity of 50% reduction in tacrolimus Necessity of 50% reduction in tacrolimus

dosages during simultaneously therapy with dosages during simultaneously therapy with

fluconazolefluconazole

Sirolimus Sirolimus Ketoconazole Ketoconazole Inhibition Inhibition of sirolimus of sirolimus metabolismmetabolism by by

ketoconazole, enhancement of sirolimusketoconazole, enhancement of sirolimus activityactivity




drugsdrugs





tacrolimus, tacrolimus,

sirolimussirolimus

Diltiazem Diltiazem InhibitionInhibition of immunosupressant drugs of immunosupressant drugs

metabolismmetabolism by diltiazem, increase in their by diltiazem, increase in their

activityactivity

CiclosporinCiclosporin Verapamil Verapamil InhibitionInhibition of ciclosporin of ciclosporin metabolismmetabolism by by

verapamil, enhancement of ciclosporin activityverapamil, enhancement of ciclosporin activity

TacrolimusTacrolimus Nifedipine, Nifedipine,

antiviral drugs antiviral drugs ––

protease inhibitors protease inhibitors

(nelfinavir, (nelfinavir,

ritonavir, ritonavir,

saquinavir) saquinavir)

InhibitionInhibition of tacrolimus of tacrolimus metabolismmetabolism by the by the

above drugs, enhancement of its activityabove drugs, enhancement of its activity



Grapefruit juiceGrapefruit juice InhibitionInhibition of ciclosporin and tacrolimus of ciclosporin and tacrolimus first first

pass metabolismpass metabolism in intestine, increase of in intestine, increase of

bioavailability, enhancement of activitybioavailability, enhancement of activity




drugsdrugs




Ciclosporin Ciclosporin Phenobarbital, Phenobarbital,

rifampicin, rifampicin,

phenytoin, phenytoin,

carbamazepine, carbamazepine,

St John’s wortSt John’s wort

Induction Induction of ciclosporinof ciclosporin metabolismmetabolism by the by the

above drugs, diminishing its activity, above drugs, diminishing its activity,

danger of graft rejectiondanger of graft rejection

Tacrolimus Tacrolimus Rifampicin, Rifampicin,

phenytoinphenytoin

InductionInduction ofof tacrolimus tacrolimus metabolismmetabolism by the by the

above drugs, diminishing its activity, above drugs, diminishing its activity,

danger of graft rejectiondanger of graft rejection

Sirolimus Sirolimus RifampicinRifampicin Induction Induction of sirolimus of sirolimus metabolismmetabolism by by

rifampicin, diminishing its activity, danger rifampicin, diminishing its activity, danger

of graft rejectionof graft rejection




drugsdrugs






Aminoglycosides, Aminoglycosides,

NSAIDs, amiloride, NSAIDs, amiloride,

sirolimus, other sirolimus, other

nephrotoxic drugsnephrotoxic drugs

IncreaseIncrease inin nephrotoxicity as a result nephrotoxicity as a result

of of additive effectadditive effect of these drugsof these drugs

CiclosporinCiclosporin Digoxin Digoxin Increase Increase inin digoxin concentration in digoxin concentration in

organism, enhancement of its activityorganism, enhancement of its activity

Some websitesSome websites

www.ema.europa.euwww.ema.europa.eu

www.adrreports.euwww.adrreports.eu

yellowcard.yellowcard.mhra.mhra.gov.ukgov.uk

www.dsru.orgwww.dsru.org

www.mhra.gov.ukwww.mhra.gov.uk

www.cks.nks.uk/adversewww.cks.nks.uk/adverse drug reactionsdrug reactions

19

Literature Sources for ADR InformationLiterature Sources for ADR Information

WHO PublicationWHO Publication

-- Pharmacovigilance A to ZPharmacovigilance A to Z

-- Dictionary of PharmacovigilanceDictionary of Pharmacovigilance

-- Stephen’s Detection of New Adverse Stephen’s Detection of New Adverse

Drug ReactionsDrug Reactions

-- To Heal and HarmTo Heal and Harm

-- WHO Pharmaceutical NewsletterWHO Pharmaceutical Newsletter

-- Signal Signal –– Analyses of ADR in WHO DatabaseAnalyses of ADR in WHO Database

Electronic Reference SearchesElectronic Reference Searches

EE--mail Alerts mail Alerts –– USFDA MedwatchUSFDA Medwatch

Electronic Table of Content (EElectronic Table of Content (E--ToC)ToC)

-- Lancet (Lancet (http://thelancet.comhttp://thelancet.com))

-- BMJ (BMJ (http://www.bmj.comhttp://www.bmj.com))

-- NEJM (NEJM (http://content.nejm.orghttp://content.nejm.org))

SCIRUS SCIRUS –– for scientific information onlyfor scientific information only

((http://www.scirus.com/srsapphttp://www.scirus.com/srsapp))

Free medical journalFree medical journal

((http://www.freemedicaljournals.comhttp://www.freemedicaljournals.com))

PLoS MedicinePLoS Medicine

((http://medicine.plosjournals.orghttp://medicine.plosjournals.org))

Medscape Medscape

((http://www.medscape.comhttp://www.medscape.com))

Medical �ews TodayMedical �ews Today

((http://www.medicalnewstoday.comhttp://www.medicalnewstoday.com))

Medsafe, �ew ZealandMedsafe, �ew Zealand

((http://www.medsafe.govt.nzhttp://www.medsafe.govt.nz))

Lareb Lareb -- �etherland Pharmacovigilance �etherland Pharmacovigilance

((www.lareb.comwww.lareb.com))

WHO WHO –– Vigisearch, Vigibase, Vigimed Vigisearch, Vigibase, Vigimed

(Sorry!!! This is for members only(Sorry!!! This is for members only))

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