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Drug safety issues in clinical practice –
drug interactions & adverse drug reactions
Kari Laine, MD, PhD
CEO, medbase Ltd
www.medbase.fi
Patient 1
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Bisoprolol 10 mg x1
Amlodipine 5 mg x1
Metformin 500 mg 2+3
Cholestyramine 1 bag x2
Low-dose ASA 50 mg x1
Arcoxia 120 mg x1
Tramadol dep 100 mg x3
Tizanidine 2 mg x2
Estradiol 2 mg x1
Nitrofurantoin C 75 mg x1
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Pantoprazole 20 mg x1
Perfenazine 8 mg x2
Mianserine 25 mg x1
Sertraline 100 mg x1
Levomepromazine 50 mg x1
Stesolid 10 mg 1x1
Flagyl vagit. 1x/vecka
Seretide Discus
Multitabs 1x1
19 medicines in regular use, yearly cost 4000€
Juurlink DN et al. JAMA 2003;289:1652-8
Hospitalization in the elderly due to
commonly known drug interactions
Glibenclamide
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Digoxin
+
ACE-inhibitor
+
Clarithromycin
Spironolactone
Hypoglycemia
Digitalis toxicity
Hyperkalemia
6.6 x risk
12 x risk
20 x risk
Sulfamethoxazole
Amoxycillin – no
elevated risk
Cefuroxim – no
elevated risk
Indapamide – no
elevated risk
Interaction could have been avoided !
Effect of itraconazole on
the bioavailability of various statins
1000 to 1500 new publications on drug interactions
evidence-based information is poorly
penetrated to clinical practice
Warfarin - metronidazole
Kazmier FJ. A significant interaction
between metronidazole and warfarin.
Mayo Clin Proc. 1976;51:782-4.
O’Reilly RA. The stereoselective interaction of warfarin and metronidazole
in man. N Engl J Med. 1976;295:354-7
Holm et al.
Eur J Clin Pharmacol 2014
The 15 most prevalent D-interactions
 Register based study
 Population: the whole Swedish
population 9,340,682 inhabitants
 34% (n=3,243,419) dispensed more
than one drug during 4-month period
 Setting: analysis of level C and D
interactions utilizing Sfinx
 94,267 D-interactions detected
 953,898 C-interactions detected
 About 50% of all C and D interactions
related to potential therapeutic failure
 Top 15 interactions (Table) explained
about 80% of D-interactions
Drug combination
Quinolone/tetracycline-metal ion
Prevalence
11158
Potassium-potassium-sparing diuretics
9902
Warfarin-acetylsalicylic acid
9523
(Es)omeprazole-clopidogrel
9042
Diltiazem/verapamil-beta blocker
6985
Tramadol-antidepressant (CYP2D6 inhibitor)
6439
Codeine/ethylmorphine-antidepressant (2D6 inh)
5415
Warfarin-NSAID
4512
Verapamil-digoxin
2052
Diazepam-carbamazepine
1869
Calcium antagonist-carbamazepine
1799
SSRI-SSRI
1659
Warfarin-econazole/fluconazole
1581
Risperidone/quetiapine-carbamazepine
1456
Dopamine antagonist-dopamine agonist
1409
TOTAL
74788
QUALITY OF CARE – not only ADRs
• Number of generic drugs covered 1500
– All have been checked regarding interactions
• Number of interactions over 20.000
Alert fatigue
Classification – clinical relevance
A
Minor interaction of no clinical relevance
B
Clinical outcome of the interaction is uncertain
and/or may vary
Alert threshold
C
Clinically relevant interaction that can be
handled by for example dose adjustments
D
Clinically relevant interaction that is best
avoided
Clear clinical & scientific basis – fully referenced
Classification – level of documentation
0
1
2
3
4
Data derived from extrapolation on the basis of
studies with similar drugs.
Data derived from incomplete case reports
and/or in vitro studies.
Data derived from well-documented case reports.
Data derived from studies among healthy
volunteers and/or on pilot studies among
patients.
Data derived from controlled studies in relevant
patient population.
Retrospective chart review
0,30%
D-interactions per drug pair
0,25%
0,20%
*p = 0.008
0,15%
ns p=0.53
0,10%
Control
0,05%
SFINX
0,00%
SFINX-group: RR 0.80, 95% CI: 0.68-0.94
Control:
RR 0.88, 95% CI: 0.59-1.31
The prevalence of potentially
serious drug-drug interactions
decreased by 20 percent
immediately when SFINX was
integrated into EHR
Portals
Penetration of most important portals to public
health care in Finland is 100%
• Survey on usability & perceptions of
database in Sweden
• 1871 (23%) answers from prescribers or pharmacists
• Used at least weekly or more often by 45% of the
prescribers and 51% of the pharmacists
• Among the prescribers, 74% reported that the
information received made them change their action at
least sometimes
• Sfinx was typically used in a direct patient consultation
situation, i.e. at POINT OF CARE
International journal of medical informatics 2015:84;327–333.
What is
lacking ?
• Interactions obvious based on the PD of drugs
• Additive sedative effects (Pharao)
• Obvious agonist-antagonist –interactions (e.g. metoprolol-salbutamol)
• Activated charcoal
• Interactions where clinical relevance has not been
established in clinical studies
• There are drugs that do not have interactions
• One cannot warn on everything, the signal has to be clear –
reduction of alert fatigue
Pharmacological Assessment
On-line
Purpose
• A tool to analyse 9 clinically important
adverse drug effects from patient’s medication:
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Anticholinergic effect
QT-prolongation
Sedation
Orthostatic hypotension
Renal toxicity
Seizure risk
Risk for bleeding
Constipation
Serotonergic overstimulation
• More than 1500 drugs analysed/characterised
• Scoring based on SOP specifically designed for
each adverse effect
• Scoring:
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0 - No effect
1 - Mild
2 - Moderate
3 - Severe
• Over 13000 scores
• A specific algorithm designed to relate the
score to the level of severity (A-D) for each
adverse effect:
• Standard phrases (easy to translate) for each
adverse effect, e.g. anticholinergic effect:
Consequence
There is a high risk for anticholinergic effects such as dry mouth,
constipation, urinary impairment or retention, risk of falling, cognitive
impairment and confusion.
Recommendation
The risk is additive. Consider reducing the number of anticholinergic
drugs.
Alert fatigue
The PRIMA-eDS Consortium
Polypharmacy in chronic diseases: Reduction of
Inappropriate Medication and Adverse drug events in
elderly populations by electronic Decision Support
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Witten-Herdecke University
Rostock University
Salzburg Paracelsus University
Manchester University
South Tyrolean GP Academy
Duodecim Medical Publications
Germany
Germany
Austria
UK
Italy
Finland
• Funded by major a EU-grant (5 million €)
PRIMA-eDS
-DDI (INXBASE)
-renal dosing (renbase)
-hepatic dosing (heparbase)
-cross allergies
-contraindications
-adverse events (RISKBASE)
-Indications and dosing
Why
?
• Adverse drug reactions and inappropriate
prescribing constitute a major health hazard and
increased cost to health care
• Those based on drug interactions/renal failure
could be most often avoided by right choice of
medication/dose/ monitoring
• Information overflow – evidence does not benefit
doctor/patient