Evidence-Based Recommendations to Improve the Safe Use of Drugs in Patients with Liver Cirrhosis
Evidence-Based Recommendations to Improve the Safe Use of Drugs in Patients with Liver Cirrhosis
Rianne A. Weersink 0 1 2 3 4 5 6 7 8
Margriet Bouma 0 1 2 3 4 5 6 7 8
David M. Burger 0 1 2 3 4 5 6 7 8
Joost P. H. Drenth 0 1 2 3 4 5 6 7 8
S. Froukje Harkes-Idzinga 0 1 2 3 4 5 6 7 8
Nicole G. M. Hunfeld 0 1 2 3 4 5 6 7 8
Herold J. Metselaar 0 1 2 3 4 5 6 7 8
Margje H. Monster-Simons 0 1 2 3 4 5 6 7 8
Katja Taxis 0 1 2 3 4 5 6 7 8
Sander D. Borgsteede 0 1 2 3 4 5 6 7 8
0 Department of Guideline Development, Dutch College of General Practice , Utrecht , The Netherlands
1 Department of Pharmacy, Unit of Pharmacotherapy, Epidemiology and Economics, University of Groningen , Groningen , The Netherlands
2 & Rianne A. Weersink
3 Department of Clinical Pharmacy and Pharmacology, University of Groningen , Groningen , The Netherlands
4 Dutch Medicines Evaluation Board , Utrecht , The Netherlands
5 Department of Gastroenterology and Hepatology, Erasmus University Medical Center , Rotterdam , The Netherlands
6 Department of Pharmacy and Department of Intensive Care, Erasmus University Medical Center , Rotterdam , The Netherlands
7 Department of Gastroenterology, Radboud University Medical Center , Nijmegen , The Netherlands
8 Department of Pharmacy, Radboud University Medical Center , Nijmegen , The Netherlands
Introduction The presence of liver cirrhosis can have a major impact on pharmacodynamics and pharmacokinetics, but guidance for prescribing is lacking. Objective The aim of this study is to provide an overview of evidence-based recommendations developed for the safe use of drugs in liver cirrhosis. Methods Recommendations were based on a systematic literature search combined with expert opinion from a panel of 10 experts. The safety of each drug was classified as safe, no additional risks known, additional risks known, unsafe, unknown or the safety class was dependent on the severity of liver cirrhosis (Child-Pugh classification). If applicable, drug-specific dosing advice was provided. All recommendations were implemented in clinical decision support systems and on a website.
Department of Clinical Decision Support, Health Base
Foundation, Houten, The Netherlands
Center for Information on Medicines, Royal Dutch
Pharmacists Association (KNMP), The Hague, The
11 SIR Institute for Pharmacy Practice and Policy, Leiden, The
With a previously developed method, the safety and
optimal dosing of more than 200 drugs in patients
with liver cirrhosis were evaluated. In this study an
overview of the recommendations is given.
For the majority of the evaluated drugs, changes in
pharmacokinetics or pharmacodynamics occurred in
patients with liver cirrhosis. Overall, 30% of drugs
required dose adjustment and nearly 70 drugs were
classified as unsafe in (a stage of) liver cirrhosis.
Healthcare professionals in The Netherlands are
supported during the prescription or dispensing of
drugs to patients with liver cirrhosis by alerts from
their clinical decision support system and
information on a free website.
Adverse drug reactions (ADRs) are an important cause of
morbidity and mortality worldwide [
]. Patients with
hepatic impairment have an increased risk of adverse
outcomes with drug use due to the pharmacokinetic and
pharmacodynamic changes occurring in liver disease [
Most significant are the diminished first-pass effect caused
by altered liver blood flow and the decreased activity of
drug-metabolizing enzymes. Both result in a higher drug
exposure and an increased risk of concentration-dependent
ADRs. Furthermore, pathophysiological changes in
patients with hepatic impairment increase the risk of
specific ADRs, such as renal dysfunction or hepatic
]. These alterations are considered to be
clinically relevant when the liver disease has progressed to
liver cirrhosis [
Almost 30% of patients with liver cirrhosis experience
ADRs; 80% of the ADRs could probably be prevented [
Choosing appropriate drugs and doses for these patients is
very important, especially because they often use multiple
]. Practice guidelines can support healthcare
professionals in safe prescribing and can reduce the
number of inappropriate drug prescriptions, as seen in other
patient populations such as older people . For patients
with liver cirrhosis, literature regarding pharmacokinetic
alterations for several drugs is available [
however, we were not aware of a publicly available practice
guideline providing recommendations on the safe use of
specific drugs in liver cirrhosis [
]. We therefore
developed a systematic method to evaluate the safety and
dosing of medications to provide recommendations for safe
drug use in patients with liver cirrhosis [
]. The aim of
this study is to provide an overview of the
recommendations for safe drug use for 208 drugs that have been
In this study, we used our previously published method to
evaluate the safety and dosing of medications to provide
recommendations for safe drug use in patients with liver
]. This method consists of six steps per drug, as
described below. Overall, we evaluated 209 drugs, which
were chosen because they were (1) often prescribed for
complications of liver cirrhosis, or (2) frequently used in
the general population.
2.1 Step 1: Collection of Evidence
Data regarding the safety and pharmacokinetics of the drug
of interest in patients with liver cirrhosis were collected.
This evidence was collected in the official Dutch and
American product information and in the literature. The
literature searches for publications were conducted in
PubMed and EMBASE between January and October
2016, and no language restrictions were applied. Studies
were included if they related to patients with liver cirrhosis
taking the drug of interest and if they reported on outcome
data on safety or pharmacokinetics. Citation tracking was
used in the Web of Science database to retrieve additional
2.2 Step 2: Data Extraction and Presentation
The following data were extracted from the studies: study
design, number and characteristics of included patients and
controls (e.g. severity of liver cirrhosis), and information
on the intervention. We extracted the following
information on outcome(s):
Pharmacokinetics: pharmacokinetic parameters (e.g.
area under the curve [AUC], maximum plasma
Safety: number and type of adverse events and data on
discontinuation due to these adverse events
Literature was presented in summary tables and sorted
by level of evidence using the classification of the Oxford
Centre for Evidence-based Medicine [
]. All evidence
was included in an assessment report.
2.3 Step 3: Initial Safety Classification and Dosing
2.4 Step 4: Consensus of Recommendations by an Expert Panel
The collected data were used to propose an initial safety
classification and dosing advice if applicable. The safety
classification (Table 1) was designed to help healthcare
professionals efficiently judge the safety of a drug in liver
cirrhosis. We added the classification ‘safety class is
dependent on severity of cirrhosis’ to the earlier developed
classifications (see Table 1) [
]. Pharmacokinetic data
were used for the dosing advice. In general, this was
advised if the AUC was more than doubled. If the
pharmacokinetic alterations were so large that dose reductions
were unlikely to allow safe drug use, drugs were classified
as ‘unsafe’. The dosing advice could also depend on the
severity of liver cirrhosis, expressed as Child–Pugh class
(i.e. Child–Pugh A, B or C) [
These first three steps were performed by a pharmacist
with expertise in drug safety and clinical decision support
systems (CDSSs) (RW). Critical steps were verified by a
second pharmacist/epidemiologist (SB) and discussed with
the expert panel in cases of disagreement.
An expert panel was composed consisting of 10 members
with expertise in the treatment of patients with liver
cirrhosis, clinical pharmacology and/or evidence-based
medicine. The expert panel evaluated the validity and clinical
relevance of the proposed safety classification and dosing
advice. The panel concluded by consensus. The final
assessment report consisted of the recommendations,
supporting evidence and considerations of the expert panel.
2.5 Step 5: Implementation
The recommendations were implemented in all relevant
CDSSs in The Netherlands (G-standard and Pharmabase),
automatically reaching all pharmacists and numerous
general practitioners. If an evaluated medicine was
prescribed or dispensed to a patient marked with
contraindication ‘liver cirrhosis’, an alert was generated with a short
recommendation. Healthcare professionals were referred to
a website for more information (http://www.
geneesmiddelenbijlevercirrose.nl). This free website also
contained a part aimed at patients.
The drug has been evaluated in patients with liver cirrhosis, and
no increase in harm was found compared with persons without
liver cirrhosis. The safety of the drug is supported by
pharmacokinetic studies and/or safety studies over a long
period. It might be necessary to use an adjusted dose
The limited data suggest that this drug does not increase harm in
patients with liver cirrhosis in comparison with persons without
liver cirrhosis. It might be necessary to use an adjusted dose
The safety class and/or the dose adjustment of this drug depends
on the severity of liver cirrhosis of the patient, expressed by
The limited data suggest an increase in patient harm in patients
with liver cirrhosis compared with persons without liver
cirrhosis. However, the number of studies is limited and/or the
studies show contradicting results regarding the safety in
patients with liver cirrhosis
Data indicate this drug is not safe in patients with liver cirrhosis This drug should be avoided in patients with liver
For this drug, insufficient data are available to evaluate the safety This drug should preferably not be used in patients
in patients with liver cirrhosis with liver cirrhosis if there is a safer alternative
Individual judgement of therapeutic need versus
additional risks in patients with liver cirrhosis
Adverse drug reactions need to be monitored
Retrieve severity of liver cirrhosis (Child–Pugh
The drug can be used in patients with liver
Adverse drug reactions need to be monitored
This drug should preferably not be used in patients
with liver cirrhosis if there is a safer alternative
Adverse drug reactions need to be monitored
2.6 Step 6: Continuity
To ensure that recommendations remain up-to-date, the
expert panel will meet yearly to discuss new literature and
comments from healthcare professionals and patients. If
necessary, recommendations will be updated.
We determined the total number of recommendations for
the 209 drugs evaluated. We also determined the number of
drugs per safety class and the number of drugs with dosing
advice. It is outside the scope of this paper to show the
complete evidence-base we gathered during evaluation of
the 209 drugs. To give insight into the type and extent of
evidence available, we selected two drugs from every
safety class. For these drugs, we described the evidence
supporting the classification. This consisted of the number
of pharmacokinetic and safety studies and the number of
included patients with liver cirrhosis. We also included
information on whether the Summary of Product
Characteristics (SmPC) contained information on use of the drug
in patients with liver cirrhosis.
The safety of 209 drugs in patients with liver cirrhosis was
evaluated. A total of 218 recommendations were
formulated as nine drugs had a different recommendation per
route of administration or per indication. Figure 1
represents an overview of the recommendations. Twenty-nine
drugs were classified as ‘safe’ (13.3%), 60 as ‘no additional
risks known’ (27.5%), 3 as ‘additional risks known’
(1.4%), and 30 as ‘unsafe’ (13.8%). In 57 (26.1%) of the
recommendations, safety depended on the severity of liver
cirrhosis, and was ‘unknown’ in 39 (17.9%)
recommendations. In Table 2, all recommendations are presented.
Table 3 shows examples of the evidence supporting the
classification of two drugs per safety class. Besides
evidence from literature, the last column displays information
from the SmPC, which was often lacking or not specifically
aimed at patients with liver cirrhosis. The
recommendations were successfully implemented in the relevant CDSSs
in The Netherlands and on a website.
For 57 drugs, the recommendation depended on the
severity of liver cirrhosis, and dosing advice was given for
67 drugs (Fig. 1). The drug simvastatin illustrates the
recommendations that were given in such cases.
Simvastatin was classified as ‘safe’ for patients with liver cirrhosis
Child–Pugh class A or B, under the condition that the
patient is started on a low dose (20 mg) and the dose is
slowly increased until in the therapeutic range or until
ADRs develop. Because of a lack of studies in patients with
Child–Pugh class C, the safety of simvastatin was classified
as unknown for patients with Child–Pugh class C and no
dosing advice was given. All recommendations that
depended on the severity of liver cirrhosis, and those with
dosing advice, can be found in electronic supplementary
Tables 1 and 2, respectively.
We recommended avoiding the use of 30 drugs
(classification ‘unsafe’) in all patients with liver cirrhosis.
Another 38 drugs were considered unsafe as related to
certain Child–Pugh classes (n = 9 Child–Pugh B ? C, and
n = 29 Child–Pugh C) because of altered
pharmacodynamics (n = 41), altered pharmacokinetics (n = 24), or a
combination of both (n = 3). Examples of drugs
contraindicated because of altered pharmacodynamics were all
nonsteroidal anti-inflammatory drugs (NSAIDs). Literature
showed that patients with cirrhosis have an increased risk
of renal insufficiency with NSAID use compared with
healthy controls with more severe consequences. Even so,
cirrhotic patients are at risk for gastrointestinal bleeding.
Examples of drugs contraindicated due to altered
pharmacokinetics were several calcium antagonists (i.e.
barnidipine, isradipine). Most calcium antagonists are highly
cleared by the liver, resulting in largely increased exposure
in patients with cirrhosis compared with healthy controls.
In this study, we provide an overview of 218
evidencebased recommendations developed to improve safe drug
use in patients with liver cirrhosis. Overall, 30% of drugs
required dose adjustment and nearly 70 drugs were
classified as unsafe in (a stage of) liver cirrhosis. The main
reason for unsafe classification were pharmacodynamic
changes. The recommendations were implemented in all
relevant CDSSs in The Netherlands. In addition, all
recommendations are available on a free website (http://www.
In this study, we tried to tackle the problem of
insufficient information on safe prescribing in patients with liver
cirrhosis. A number of comparable studies are available
]. Most focus on altered pharmacokinetics, while
we show that pharmacodynamic changes are also relevant
in the decision process. This study is therefore unique in
using both pharmacokinetic and pharmacodynamic (safety)
literature to develop recommendations.
An important source of prescribing information is the
product information (SmPC). We noted a lack of
information on liver cirrhosis in the product information, which
was also recognized in a study from 2001 that classified the
SmPC information on liver disease as ‘‘often inconsistent,
unclear and unhelpful’’ [
]. Since 2003 and 2005, the
FDA and EMA, respectively, published guidelines for
pharmacokinetic research in patients with hepatic
impairment and how to present this data in the product
]. For further research it would be interesting
to study the quality of the information in these new SmPCs.
In addition, many agents were licensed before 2003–2005
and these product labels require updating based on these
new guidelines [
We developed and published the safety classification we
used to support healthcare professionals to efficiently judge
the safety of a drug in liver cirrhosis [
]. In our original
safety classification, there was also an option for
classifying drugs cleared for\20% by the liver as ‘no additional
risks known’, although no data were available. Based on
the important influence of pharmacodynamics, the expert
panel specified this to locally-acting drugs with no
systemic uptake (bioavailability [F]\1%, not based on an
extensive first-pass effect). The classification of drugs was
not always easy as the following two examples show.
Codeine is a prodrug that requires liver metabolism for
conversion to the active drug and it can be expected that
efficacy will decrease with the increasing severity of liver
cirrhosis. Azathioprine was associated with increased
adverse events in patients with liver cirrhosis, but is also
one of the only effective treatments for autoimmune
hepatitis. Our recommendation therefore includes explanations
in which we try to deal with such issues by
comprehensively discussing the details of the classification of a drug.
The recommendations were implemented on a website
and in all relevant CDSSs in The Netherlands. The
implementation revealed issues that need attention. First,
patients with liver cirrhosis need to be correctly marked in
the CDSSs. In The Netherlands, the contraindication
‘hepatic impairment’ was always used for this purpose;
however, we noted that most of the patients marked with
this contraindication did not have liver cirrhosis, causing an
incorrect signal in the CDSSs. Another difficulty is that in a
substantial part of the recommendations, the severity of
liver cirrhosis needs to be known (i.e. Child–Pugh class).
Before these recommendations can be used,
gastroenterologists need to determine the Child–Pugh class of their
patients and communicate this to the general practitioner
and pharmacist. These difficulties are also recognized in
literature about implementing contraindications into a
] and are important to consider when setting up
medication monitoring via a CDSS for these patients.
This study has its limitations. Although we evaluated
209 drugs, this is only a proportion of all drugs available.
The choice for these drugs was based on an estimation of
the most frequently used drugs in patients with liver
cirrhosis and is in good agreement with the literature [
We aim to eventually evaluate all drugs. Another limitation
is the amount of literature available. As stated in Table 3,
for some drugs there were several studies performed in
patients with liver cirrhosis, while for others, there were
only a few or no studies. Because of the limited literature,
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Two examples of drugs per safety class are shown
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39 drugs were classified as ‘unknown’, including
frequently used drugs such as nitrofurantoin. As the
recommendations are evidence-based, more research will
improve the quality of the recommendations and can better
support healthcare professionals. For now, the literature
review per drug identifies knowledge gaps and is a good
starting point for further research. A third limitation is that
the complete recommendations with detailed explanations
are currently only available in the Dutch language.
Nevertheless, in this study, we provided an overview in English
and plan to translate the recommendations in the future.
In this study, we provided evidence-based
recommendations to aid in prescribing for patients with liver cirrhosis.
This is the first study that applies a practical approach
providing recommendations that have been implemented in
all relevant CDSSs in The Netherlands and on a website.
Our advice aids healthcare professionals in tailoring
pharmacotherapy for the individual patient with liver cirrhosis,
which can possibly prevent ADRs and subsequent
morbidity and mortality in vulnerable cirrhotic patients.
Acknowledgements The authors would like to thank Minke
Kranenborg, Ton Lisman, Eline Okel, Sandra van Putten and Elise
Smolders for their contributions.
Open Access This article is distributed under the terms of the
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author(s) and the source, provide a link to the Creative Commons
license, and indicate if changes were made.
1. Thomsen LA , Winterstein AG , Søndergaard B , Haugbølle LS , Melander A . Systematic review of the incidence and characteristics of preventable adverse drug events in ambulatory care . Ann Pharmacother . 2007 ; 41 ( 9 ): 1411 - 26 .
2. Pirmohamed M , James S , Meakin S , Green C , Scott AK , Walley TJ , et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18,820 patients . BMJ. 2004 ; 329 ( 7456 ): 15 - 9 .
3. Verbeeck RK . Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction . Eur J Clin Pharmacol . 2008 ; 64 ( 12 ): 1147 - 61 .
4. Delco F , Tchambaz L , Schlienger R , Drewe J , Krahenbuhl S. Dose adjustment in patients with liver disease . Drug Saf . 2005 ; 28 ( 6 ): 529 - 45 .
5. Westphal J , Brogard J . Drug administration in chronic liver disease . Drug Saf . 1997 ; 17 ( 1 ): 47 - 73 .
6. Franz CC , Hildbrand C , Born C , Egger S , Bravo AER , Kra ¨ - henbu¨hl S. Dose adjustment in patients with liver cirrhosis: impact on adverse drug reactions and hospitalizations . Eur J Clin Pharmacol . 2013 ; 69 ( 8 ): 1565 - 73 .
7. Lucena IM , Andrade RJ , Tognoni G , Hidalgo R , de la Cuesta F. Multicenter hospital study on prescribing patterns for prophylaxis and treatment of complications of cirrhosis . Eur J Clin Pharmacol . 2002 ; 58 ( 6 ): 435 - 40 .
8. Zhang YJ , Liu WW , Wang JB , Guo JJ . Potentially inappropriate medication use among older adults in the USA in 2007 . Age Ageing. 2011 ; 40 ( 3 ): 398 - 401 .
9. Schlatter C , Egger SS , Tchambaz L , Kra¨henbu¨hl S. Pharmacokinetic changes of psychotropic drugs in patients with liver disease . Drug Saf . 2009 ; 32 ( 7 ): 561 - 78 .
10. Lewis JH , Stine JG . Review article: prescribing medications in patients with cirrhosis - a practical guide . Aliment Pharmacol Ther . 2013 ; 37 ( 12 ): 1132 - 56 .
11. Steelandt J , Jean-Bart E , Goutelle S , Tod M. A Prediction Model of Drug Exposure in Cirrhotic Patients According to Child-Pugh Classification . Clin Pharmacokinet . 2015 ; 54 ( 12 ): 1245 - 58 .
12. Rodighiero V. Effects of liver disease on pharmacokinetics . Clin Pharmacokinet . 1999 ; 37 ( 5 ): 399 - 431 .
13. Hilscher M , Odell L , Myhre L , Prokop L , Talwalkar J. The pharmacotherapy of cirrhosis: concerns and proposed investigations and solutions . J Clin Pharm Ther . 2016 ; 41 ( 6 ): 587 - 91 .
14. Weersink RA , Bouma M , Burger DM , Drenth JP , Hunfeld NG , Kranenborg M , et al. Evaluating the safety and dosing of drugs in patients with liver cirrhosis by literature review and expert opinion . BMJ Open . 2016 ; 6 ( 10 ): e012991 .
15. OCEBM Levels of Evidence Working Group. The Oxford Levels of Evidence 2 . Oxford Centre for Evidence-Based Medicine . Available at: http://www.cebm.net/index.aspx? 0 = 5653 . Accessed 2 Mar 2017 .
16. Pugh RN , Murray-Lyon IM , Dawson JL , Pietroni MC , Williams R . Transection of the oesophagus for bleeding oesophageal varices . Br J Surg . 1973 ; 60 ( 8 ): 646 - 9 .
17. Failings in treatment advice. SPCs and black triangles . Drug Ther Bull . 2001 ; 39 ( 4 ): 25 - 7 .
18. Food and Drug Administration . Guidance for Industry. Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis , and Impact on Dosing and Labeling . 2008 . Available at: https://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm072 123.pdf. Accessed 17 Jan 2017 .
19. European Medicines Agency. Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function . 2005 . Available at: http://www.ema.europa.eu/ docs/en_GB/document_library/Scientific_guideline/ 2009 /09/WC5 00003122.pdf. Accessed 17 Jan 2017 .
20. Kuperman GJ , Bobb A , Payne TH , Avery AJ , Gandhi TK , Burns G , et al. Medication-related clinical decision support in computerized provider order entry systems: a review . J Am Med Inform Assoc . 2007 ; 14 ( 1 ): 29 - 40 .
21. Lucena MI , Andrade RJ , Tognoni G , Hidalgo R , de La Cuesta FS. Drug use for non-hepatic associated conditions in patients with liver cirrhosis . Eur J Clin Pharmacol . 2003 ; 59 ( 1 ): 71 - 6 .
22. Franz CC , Egger S , Born C , Ratz Bravo AE , Krahenbuhl S. Potential drug-drug interactions and adverse drug reactions in patients with liver cirrhosis . Eur J Clin Pharmacol . 2012 ; 68 ( 2 ): 179 - 88 .