Evidence- and consensus-based guidelines for drug-drug interactions with anticancer drugs; A practical and universal tool for management.

Drug-drug interactions (DDIs) with anticancer drugs are common and can significantly affect efficacy and toxicity of treatment. Therefore, a Dutch Multidisciplinary Expert group is assessing the clinical significance of DDIs in oncology and provides recommendations for the management of these DDIs. We present an overview of methodology and outcome of an evidence- and consensus-based assessment of DDIs between anticancer drugs and non-anticancer drugs. A literature search was performed through PubMed and EMA and FDA assessment reports, to identify potential DDI's involving anticancer drugs. For each potential DDI a concept report for risk analysis and practical advice for management was created. Subsequently, this risk analysis and the corresponding advice were assessed and weighed. A total of 290 potential DDIs have been identified in the literature thus far. Of these 290 potential DDIs, the Expert Group has identified 94 (32%) DDIs as clinically relevant, with a need for an automated alert and a suggested intervention. Furthermore, 110 DDIs have been identified as clinically not relevant. For 86 potential DDIs evidence supporting a relevant DDI was insufficient and in these cases neither an alert nor advice regarding a suggested intervention were formulated. A transparent risk analysis is presented for identification of clinically relevant DDIs with anticancer drugs. Integration of DDI guidelines into the national electronic prescribing system is essential to achieve optimal efficacy and minimal toxicity in patients receiving anticancer therapy. A clear overview of clinically relevant DDIs with anticancer therapy provides clinicians with a structured, evidence-based and consensus-built tool for anticancer therapy surveillance.

Recommendations for selecting drug-drug interactions for clinical decision support.

PURPOSE: Recommendations for including drug-drug interactions (DDIs) in clinical decision support (CDS) are presented. SUMMARY: A conference series was conducted to improve CDS for DDIs. A work group consisting of 20 experts in pharmacology, drug information, and CDS from academia, government agencies, health information vendors, and healthcare organizations was convened to address (1) the process to use for developing and maintaining a standard set of DDIs, (2) the information that should be included in a knowledge base of standard DDIs, (3) whether a list of contraindicated drug pairs can or should be established, and (4) how to more intelligently filter DDI alerts. We recommend a transparent, systematic, and evidence-driven process with graded recommendations by a consensus panel of experts and oversight by a national organization. We outline key DDI information needed to help guide clinician decision-making. We recommend judicious classification of DDIs as contraindicated and more research to identify methods to safely reduce repetitive and less-relevant alerts. CONCLUSION: An expert panel with a centralized organizer or convener should be established to develop and maintain a standard set of DDIs for CDS in the United States. The process should be evidence driven, transparent, and systematic, with feedback from multiple stakeholders for continuous improvement. The scope of the expert panel's work should be carefully managed to ensure that the process is sustainable. Support for research to improve DDI alerting in the future is also needed. Adoption of these steps may lead to consistent and clinically relevant content for interruptive DDIs, thus reducing alert fatigue and improving patient safety.

[Interaction between clopidogrel and proton pump inhibitors]. / Interactie tussen clopidogrel en protonpompremmers.

The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of omeprazole and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors omeprazole and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel.

Consensus-based evaluation of clinical significance and management of anticancer drug interactions.

BACKGROUND: Anticancer drug interactions can affect the efficacy and toxicity of anticancer treatment and that of the interacting drugs. However, information on the significance, prevention, and management of these interactions is currently lacking. OBJECTIVE: The purpose of this study was to assess the clinical significance of interaction among anticancer agents and comedications and to provide recommendations for the management of clinically significant interactions. METHODS: Members of a multidisciplinary expert group of hospital and community pharmacists, medical oncologists, internists, and clinical pharmacologists were selected by their professional organizations, which participated in this consensus project. Literature was extensively searched for any drug interactions with anticancer agents using registration files, reference books, handbooks, and electronic databases. Interactions between anticancer agents were not considered. Interactions were classified by level of best available evidence for the interaction and by severity of the clinical effect, according to a structured assessment procedure. This assessment distinguished 5 levels for the amount and quality of evidence available and 6 severity levels for classification of potential drug-to-drug interactions. RESULTS: A total of 88 drug interactions with anticancer agents were identified from 146 combinations of drugs with anticancer agents found in literature. For 58 combinations, there was insufficient evidence of an interaction. Of the identified interactions, 38 were classified as clinically significant, defined as necessitating an alert or intervention, such as dose adaptation, comedication, discontinuation of treatment, or additional monitoring of treatment. Recommendations were made for management of these interactions. CONCLUSION: Numerous interactions with anticancer agents are clinically significant and should be considered by pharmacists and doctors in daily oncology practice.

Clinical relevance of drug-drug interactions : a structured assessment procedure.

INTRODUCTION: Computerised drug interaction surveillance systems (CIS) may be helpful in detecting clinically significant drug interactions. Experience with CIS reveals that they often yield alerts with questionable clinical significance, fail to provide relevant information on risk factors for the adverse reaction of the interaction and fail to detect all significant drug interactions. These problems highlight the importance of transparency and selectivity in choosing the drug interactions to be included in CIS. In The Netherlands, the Working Group on Pharmacotherapy and Drug Information is responsible for maintenance of the CIS of the Royal Dutch Association for the Advancement of Pharmacy (KNMP). METHODS: The Working Group developed an evidence-based procedure for structured assessment of drug-drug interactions and revised all drug interactions in the CIS accordingly. RESULTS: For every drug interaction four core parameters were assessed: (i) evidence on the interaction; (ii) clinical relevance of the potential adverse reaction resulting from the interaction; (iii) risk factors identifying patient, medication or disease characteristics for which the interaction is of special importance; and (iv) the incidence of the adverse reaction. On the basis of this assessment the drug-drug interactions for inclusion in the CIS were selected. After revision of the drug combinations in the KNMP-CIS, the Working Group judged 22% of the combinations to be not interacting and another 12% to be interacting but not requiring action. On the basis of this assessment the subset of drug combinations for which interaction alerts are generated and the information on management of a drug interaction alert for users of the CIS were adapted. When an alert is generated by the CIS, the user of the system is supplied with comprehensive information on the four core parameters, the mechanism of the interaction and critical information for management of the interaction for the individual patient. DISCUSSION: This structured procedure offers the possibility for transparent and reproducible assessment of the clinical relevance of drug interactions. CONCLUSION: A CIS selectively generating interaction alerts based on this assessment may help in realising the goal of good clinical practice and may offer a methodology to further increase drug safety.