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Some data indicate that simvastatin may increase the anticoagulative effect in patients treated with warfarin, but the evidence is scarce. The aim of the present study was to investigate how the anticoagulative effect of warfarin is affected by the initiation of simvastatin in a very large patient sample. In a retrospective cohort study, we included 5637 individuals on warfarin treatment initiating simvastatin. INR values and warfarin doses were calculated week-by-week during co-treatment. Data were obtained from two large Swedish warfarin registers and from the Swedish Prescribed Drug Register. INR increased from 2.43 at baseline to 2.58, 4 weeks after simvastatin initiation, and did not stabilize until the last quarter of the year studied. Consequently, the proportion of patients with an INR above 3 increased from around 8 to 15%. In conclusion, initiation of simvastatin resulted in moderately increased INR values and subsequent dose decreases in patients already on warfarin. In order to avoid the increased risk of bleeding, the initiation of simvastatin may be accompanied by closer INR monitoring.

Janusmed interactions is a drug-drug interactions (DDI) database available online for healthcare professionals (HCP) at all levels of the healthcare system including pharmacies. The database is aimed at HCP but is also open to the public for free, for those individuals who register for a personal account. The aim of this study was to investigate why and how patients use the database Janusmed interactions, how they perceive content and usability, and how they would react if they found an interaction. A web-based questionnaire was sent by email to all users who had registered for Janusmed interactions as a &ldquo, patient&rdquo, (n = 3219). A total of 406 patients completed the survey (response rate 12.6%). The study shows that there is an interest among patients to use a DDI database to check their own or a relative&rsquo, s medication. The respondents found the database easy to use and perceive they understand the information aimed at HCP. Most patients stated they would talk to their HCP if they found an interaction and not adjust their treatment by themselves. However, the respondents in this study are actively searching for information and seem to have high health literacy. Thus, the findings are not generalizable for the general population.

Drug-drug interactions are increasingly common, as patients are getting older and the number of drugs per patient is increasing. In this study, we investigated to which extent potential drug-drug interactions originated from single or multiple prescribers. All patients attending any of 20 primary healthcare centres were included in a retrospective observational cohort study. Data on all prescriptions to these patients, irrespectively of the prescriber, were collected for two 4-month periods. Potential drug interactions were identified using the drug-drug interaction database SFINX. Interactions were classified with respect to the workplace of the prescriber, and the prevalence of interactions according to origin was analysed. We found that the drug interactions were significantly more common when the drugs were prescribed from different healthcare centres, compared with drugs prescribed from the patients' primary healthcare centre only. One explanation for this increased risk of drug interactions could be that the prescribers at different primary healthcare centres do not share the same information concerning the total medication list of the patient.

Purpose The aims of this study are to describe the development of PHARAO (Pharmacological Risk Assessment Online), a decision support system providing a risk profile for adverse events, associated with combined effects of multiple medicines, and to present data from a pilot study, testing the use, functionality, and acceptance of the PHARAO system in a clinical setting. Methods About 1400 substances were scored in relation to their risk to cause any of nine common and/or serious adverse effects. Algorithms for each adverse effect score were developed to create individual risk profiles from the patient’s list of medication. The system was tested and integrated to the electronic medical record, during a 4-month period in two geriatric wards and three primary healthcare centers, and a questionnaire was answered by the users before and after the test period. Results A total of 732 substances were tagged with one or more of the nine risks, most commonly with the risk of sedation or seizures. During the pilot, the system was used 933 times in 871 patients. The most common signals generated by PHARAO in these patients were related to the risks of constipation, sedation, and bleeding. A majority of responders considered PHARAO easy to use and that it gives useful support in performing medication reviews. Conclusions The PHARAO decision support system, designed as a complement to a database on drug-drug interactions used nationally, worked as intended and was appreciated by the users during a 4-month test period. Integration aspects need to be improved to minimize unnecessary signaling.

AimsTramadol, a widely used analgesic drug, inhibits the reuptake of noradrenaline and serotonin impairing the aggregation function of thrombocytes. However, the risk for severe bleeding has previously not been studied. The aim of the present study is to investigate the association between tramadol and bleeding peptic ulcer in the Swedish population.MethodsIn this register based case-control study based on the Swedish national patient registry and prescription drug registry, we included 18 306 patients hospitalized with a first-time diagnosis of bleeding peptic ulcer. For every case, 4 matched controls were included. To investigate the temporal aspects of tramadol induced bleeding ulcer, exposure was divided into patients with newly initiated and ongoing treatment. To explore a possible confounding by indication, the effect of codeine, a drug also prescribed for the treatment of moderate pain, but not known to affect thrombocyte function, was investigated. Univariable and multivariable logistic regression was used to analyse the association between tramadol use and bleeding ulcer.ResultsTramadol was associated with an increased risk of bleeding ulcer (adjusted odds ratio (aOR) 2.1, 95% confidence interval: (2.0-2.3). The association was stronger for newly initiated treatment with tramadol 2.8 (2.5-3.2) and weaker for ongoing treatment 1.7 (1.6-1.9). Codeine was also associated with an increased risk of bleeding ulcer 1.9 (1.7-2.1) and this association was also stronger for newly initiated treatment with codeine 2.3 (2.0-2.6) and weaker for ongoing treatment 1.7 (1.5-1.9).ConclusionTreatment with tramadol was associated with an increased risk of bleeding peptic ulcer. Most of this association may be mediated by factors related to the pain condition rather than the pharmacologic effect per se.

To investigate the impact of interacting drugs on the dispensed doses of warfarin in the Swedish population. This was a retrospective, cross-sectional population based register study of patients being dispensed warfarin. Warfarin doses were estimated in different age groups, in men and women, and in patients using interacting drugs. The influence of interacting drugs on the dispensed warfarin dose was analyzed using multiple regression. All 143,729 patients dispensed warfarin were analyzed. The dispensed dose of warfarin was highest in patients 30-39 years old and decreased with age. Co-medication with carbamazepine, simvastatin, paracetamol, amiodarone, fluconazole, lactulose, or bezafibrate was associated with significant changes in dispensed warfarin doses, by +40%, -3.4%, -7.3%, -8.2%, -8.8%, -9.0%, and -9.7%, respectively. After adjustment for age and gender, sulfamethoxazole was also found to significantly alter the dispensed warfarin dose (-6.1%). We provide new support for the previous scarce evidence of interactions between warfarin and carbamazepine, bezafibrate, and lactulose. Initiation or discontinuation of bezafibrate or lactulose in a patient on warfarin should warrant close clinical monitoring. The marked increased warfarin requirement associated with carbamazepine use supports moving from a more conservative reactive towards a proactive strategy including preventive warfarin dose adjustments to avoid potential adverse effects.

Information must be collected, evaluated and utilized to support every qualified activity. Medicine, with a written scientific tradition stretching back more than 2,000 years, is no exception. Here, we discuss a number of important items associated with the establishment of a drug information centre run by clinical pharmacologists and information pharmacists, serving a broad demand, mainly among clinical specialists. The working methods include a professional literature search, critical evaluation of the material, writing a structured answer, quality control, feedback to the inquirer and storage in a database which is publicly available. One can foresee even more complex systems wherein a number of active and specialized databases communicate to provide relevant advice and support at the point of care, supplying information on drug recommendations, reimbursement, environmental aspects, antimicrobial resistance, pharmacogenetics and adverse effects, and linked to a list of prescribed drugs for the individual patient. This will be possible in both rich and poor countries through the application of modern and developing information technology. However, research on the best and safest methods of such decision support systems will be needed to ensure that they really do improve the quality of drug prescribing and use.

In recent years the use of the opioid oxycodone has increased markedly and replacing morphine as the first-line choice of opioid in several countries. There are formulations for oral immediate, oral extended release and intravenous use. The bioavailability is higher than for morphine and less variable. Oxycodone is primarily metabolized in the liver by the cytochrome P450 (CYP) enzymes with CYP3A as the major metabolic pathway and CYP2D6 as the minor metabolic pathway to noroxycodone, oxymorphone and noroxymorphone. Oxycodone exerts its analgesic effect via the µ-opioid receptor. The metabolism of CYP2D6 substrates varies to a large degree between individuals as a result of allele functionality. Poor metabolizers (PM) have two non-functional alleles, extensive metabolizers (EM) are homozygous with two functional alleles or heterozygous with one functional allele and ultrarapid metabolizers (UM) have more than two functional alleles. There are pronounced interethnic differences in the allele distribution. On the basis of studies performed thus far, oxycodone concentrations in comparison with EM are similar in PM and reduced in UM. The pharmacokinetics in UM are insufficiently investigated. Simultaneous inhibition of both CYP3A and CYP2D6 results in increased oxycodone concentrations and such a combination should be avoided. A similar effect is to be expected with use of a CYP3A inhibitor in CYP2D6 PM. Concomitant use of enzyme inducers such as rifampicin, St John's wort and carbamazepine should be avoided because of the risk of subtherapeutic concentrations of oxycodone. When the dosage of morphine may result in unpredictable bioavailability, like in patients with severe hepatic cirrhosis, oxycodone might be beneficial because it has higher and less variability in bioavailability between patients than morphine.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Preliminary evidence from a single study indicates that co-medication with lamotrigine may reduce the serum concentration of quetiapine. Since both drugs are commonly used in bipolar disorder such a drug–drug interaction could be of great importance, but the findings need to be confirmed. WHAT THIS STUDY ADDS • The association between lamotrigine dosing and lowered quetiapine concentrations was confirmed in a small independent patient sample. The magnitude of the reduction (58%) indicated that the proposed drug–drug interaction may be of clinical importance. AIM The aim of the present study was to investigate a previously proposed interaction between quetiapine and lamotrigine resulting in reduced serum quetiapine concentrations. METHODS Data on 402 patients subjected to analysis of quetiapine concentration in serum were extracted from a routine therapeutic drug monitoring database. Among these patients, those concomitantly treated with lamotrigine (n= 22) were identified and matched with 22 controls receiving quetiapine while unexposed to lamotrigine. The dose-corrected quetiapine concentrations (C : D ratios) in the two groups were compared in both paired and unpaired analyses. RESULTS Patients co-treated with lamotrigine had a lower mean C : D ratio (0.71, 95% CI 0.46, 0.97) compared with controls (1.64, 95% CI 1.00, 2.28). Dose-corrected quetiapine concentrations were 58% lower in patients co-medicated with lamotrigine. CONCLUSIONS This study indicates that lamotrigine exposure is associated with substantially reduced serum concentrations of quetiapine, possibly due to induced glucuronidation. These findings need to be confirmed in experimental studies.

To quantify the influence of common cytochrome P450 2C9 (CYP2C9) polymorphisms on warfarin dose requirements. A systematic review and a meta-analysis, calculating the warfarin dose reduction associated with the five most common variant CYP2C9 genotypes. Thirty-nine studies (7,907 patients) were included in the meta-analysis. Compared to the CYP2C9*1/*1 genotype, the CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3, and CYP2C9*3/*3 required warfarin doses that were 19.6 (95% confidence interval 17.4, 21.9), 33.7 (29.4, 38.1), 36.0 (29.9, 42.0), 56.7 (49.1, 64.3), and 78.1% (72.0, 84.3) lower, respectively. The impact of CYP2C9 genotype tended to be larger in patients without interacting drugs. Previous studies have rarely been powered to determine the quantitative influence of specific CYP2C9 genotypes on warfarin dose requirements. The results from our pooled analysis are likely to be the most accurate to date and the methodology could serve as a model for future pharmacogenetic meta-analyses.

Essentials Data on the effect of introducing amiodarone in patients already using warfarin regime are scarce. Information on 754 patients was extracted from three nationwide registers in Sweden. With amiodaron, 37% of patients had an international normalized ratio (INR) over 3.0 To avoid bleeding, the initiation of amiodarone should be accompanied by closer INR monitoring. SummaryBackground Data indicate that the interaction between warfarin and amiodarone results in an increased warfarin effect. There are several large, well-performed studies using genetic and clinical factors such as co-medication to predict an adequate starting dose of warfarin. However, longitudinal data on the effect of introducing amiodarone in patients on an ongoing warfarin regime are more scarce. Objectives An investigation of how initiation of amiodarone affects the anticoagulant effect and dosing of warfarin, using data from three nationwide registries. Patients/Methods In a retrospective cohort study including 754 patients, warfarin doses were compared between two 4-week periods, before and 18–21 weeks after initiating co-treatment with amiodarone. In addition, warfarin doses and international normalized ratio (INR) values were calculated week-by-week after the initiation of amiodarone. Results The initiation of amiodarone increased the mean INR from 2.6 to 3.1. The proportion of patients with a supratherapeutic INR over 3.0 and 4.0 increased from 12% to 37% and 0.9% to 5.5%, respectively. The subsequent mean decrease in warfarin dose was 24.6% (95% confidence interval [CI], 23.5, 25.6). The frequency of INR monitoring within 1 and 2 weeks after initiation of amiodarone was 67% and 90%. Conclusions Although warfarin doses in most patients were within the therapeutic range, more than one in three patients initiating co-treatment with amiodarone were exposed to a supratherapeutic anticoagulative effect within 3 weeks. In order to further avoid severe unnecessary bleeding, the initiation of amiodarone should be accompanied by closer INR monitoring, anticipating an average dose reduction of 25%.

Purpose: The aim of the present study was to investigate how prescribers and pharmacists use and perceive the drug-drug interaction database SFINX in their clinical work. Methods: A questionnaire was developed with questions aimed at the usage of SFINX, and the perceptions of the database. The questionnaire was sent out to all registered users of the web application of SFINX. The anonymous answers from the target users, prescribers and pharmacists were summarized using descriptive statistics. Statistical analysis was performed on age and gender differences for some questions regarding different usage patterns. Results: The questionnaire was sent to 11,763 registered SFINX users. The response rate was 23%, including 1871 answers from prescribers or pharmacists. SFINX was reported to be used at least weekly or more often by 45% of the prescribers and 51% of the pharmacists. Many prescribers reported using the database during the patient consultation (60%) or directly before or after (56%). Among the prescribers, 74% reported that the information received made them change their action at least sometimes. About 20% of the prescribers and 25% of the pharmacists considered the information as irrelevant sometimes or more often. Conclusion: Most prescribers and pharmacists reported using SFINX in direct association with a patient consultation. Information received by using SFINX makes prescribers and pharmacists change their handling of patients. DDI databases with relevant information about patient handling might improve drug treatment outcome. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

PURPOSE: To investigate the extent to which clinicians avoid well-established drug-drug interactions associated with warfarin. We hypothesised that clinicians would avoid combining non-steroidal anti-inflammatory drugs (NSAIDs), tramadol and sulfamethoxazole with warfarin. METHODS: A cross-sectional analysis of nationwide dispensing data was performed in Swedish individuals 18 years or older (n = 7,563,649). Odds ratios of interacting NSAIDs, tramadol and sulfamethoxazole versus respective prevalence of comparator drugs codeine, and ciprofloxacin in patients co-dispensed interacting warfarin versus patients unexposed was calculated. RESULTS: The odds of receiving an interacting NSAID versus the comparator codeine was markedly lower in patients with warfarin than in the remaining population (adjusted OR 0.21; 95% CI 0.20 - 0.22). Also, the interacting drugs tramadol and sulfamethoxazole were less common among patients dispensed warfarin as compared to the remaining population, although the decrease was much more modest (adjusted OR 0.83; CI 0.80-0.87 and 0.81; CI 0.73 - 0.90). CONCLUSIONS: In conclusion, Swedish doctors in the vast majority of cases refrain from prescribing NSAIDs to patients already on warfarin. Tramadol and sulfamethoxazole are however rarely avoided.

Background: Simvastatin interacts with warfarin, but the strength of the interaction varies between individual patients, indicating a genetic predisposition. Patients & methods: The influence of the CYP2C9*2 and CYP2C9*3 polymorphisms on the interaction between simvastatin and warfarin was analyzed in data from 1132 patients. Results: Simvastatin use reduced warfarin dose requirements by 29% in carriers of the CYP2C9*3 allele, compared with 5% in noncarriers. A regression model showed a significant influence of CYP2C9*3 on the drug–drug interaction, predicting a warfarin dose reduction of 25% in CYP2C9*3 heterozygotes and 43% in CYP2C9*3 homozygotes. Conclusion: Our data indicate that the CYP2C9*3 polymorphism predisposes for a pharmacologic interaction between warfarin and simvastatin. Original submitted 5 January 2012; Revision submitted 15 February 2012

To investigate the impact of the integration of the drug-drug interaction database SFINX into primary health care records on the prevalence of potentially serious drug-drug interactions.The study was a controlled before-and-after study on the prevalence of potential drug-drug interactions before and after the implementation of SFINX at 15 primary healthcare centres compared with 5 centres not receiving the intervention. Data on dispensed prescriptions from health care centres were retrieved from the Swedish prescribed drug register and analysed for September-December 2006 (pre-intervention) and September-December 2007 (post-intervention). All drugs dispensed during each 4 month period were regarded as potentially interacting.Use of SFINX was associated with a 17% decrease, to 1.81 × 10(-3) from 2.15 × 10(-3) interactions per prescribed drug-drug pair, in the prevalence of potentially serious drug-drug interactions (p = 0.042), whereas no significant effect was observed in the control group. The change in prevalence of potentially serious drug-drug interactions did not differ significantly between the two study groups. The majority of drug-drug interactions identified were related to chelate formation.Prescriptions resulting in potentially serious drug-drug interactions were significantly reduced after integration of the drug-drug interaction database SFINX into electronic health records in primary care. Further studies are needed to demonstrate the effectiveness of drug-drug interaction warning systems.

The most important enzyme in hepatic drug metabolism is cytochrome P450 3A4. Published in vitro data indicate that vitamin D may up-regulate the expression of the CYP3A4 gene. Individual vitamin D levels are highly dependent on sunlight exposure and show great seasonal variability in northern countries. The aim of the present study was to investigate whether plasma concentrations of CYP3A4 drug substrates exhibit seasonal changes compatible with a stimulatory effect of vitamin D on drug metabolism. Three immunosuppressants (tacrolimus, sirolimus, and cyclosporine) were analyzed, because these CYP3A4 drug substrates are subject to long-term use and repeated concentration determinations. In addition, mycophenolic acid was included in the analysis as a control drug independent of CYP3A4 metabolism. Concentration-to-dose ratios were extracted from the Karolinska Therapeutic Drug Monitoring database and compared between the 3-month periods of lowest and highest vitamin D levels. Sirolimus and tacrolimus levels showed seasonal variability that was highly consistent with changes in vitamin D; for example, significantly lower drug concentrations in July to September than in January to March. As expected, no significant difference was evident for mycophenolic acid, but this result was also the case with cyclosporine, possibly due to cross-reactivity of CYP3A4-mediated metabolites with the immunoassay used for quantification. In conclusion, there is cyclic variation in blood levels of important immunosuppressants throughout the year that correlates with UV light-dependent changes in vitamin D levels. Even though a causal relationship remains to be established, it is suggested that individual differences in vitamin D may contribute to variability in drug metabolism and disposition.

Objective The aim was to develop a drug-drug interaction database (SFINX) to be integrated into decision support systems or to be used in website solutions for clinical evaluation of interactions. Methods Key elements such as substance properties and names, drug formulations, text structures and references were defined before development of the database. Standard operating procedures for literature searches, text writing rules and a classification system for clinical relevance and documentation level were determined. ATC codes, CAS numbers and country-specific codes for substances were identified and quality assured to ensure safe integration of SFINX into other data systems. Much effort was put into giving short and practical advice regarding clinically relevant drug-drug interactions. Results SFINX includes over 8,000 interaction pairs and is integrated into Swedish and Finnish computerised decision support systems. Over 31,000 physicians and pharmacists are receiving interaction alerts through SFINX. User feedback is collected for continuous improvement of the content. Conclusion SFINX is a potentially valuable tool delivering instant information on drug interactions during prescribing and dispensing.

A letter in response to: Botton MR, Hutz MA & Suarez-Kurtz G. Influence of the CYP2C9*3 allele on the pharmacological interaction between warfarin and simvastatin. Pharmacogenomics 13(14), 1557–1559 (2012).