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Aim Patients receiving lamotrigine therapy frequently use paracetamol concomitantly. While one study suggests a possible, clinically relevant drug–drug interaction, practical recommendations of the concomitant use are inconsistent. We performed a systematic pharmacokinetic study in healthy volunteers to quantify the effect of 4 day treatment with paracetamol on the metabolism of steady-state lamotrigine. Methods Twelve healthy, male volunteers participated in an open label, sequential interaction study. Lamotrigine was titrated to steady-state (100 mg daily) over 36 days, and blood and urine sampling was performed in a non-randomized order with and without paracetamol (1 g four times daily). The primary endpoint was change in steady-state area under the plasma concentration–time curve of lamotrigine. Secondary endpoints were changes in total apparent oral clearance, renal clearance, trough concentration of lamotrigine and formation clearance of lamotrigine glucuronide conjugates. Results Co-administration of lamotrigine and paracetamol decreased the steady-state area under the plasma concentration–time curve of lamotrigine by 20% (95% CI 10%, 25%; P

Purpose Generic switching of warfarin was recently repealed in Denmark, as adverse drug reaction (ADR) reports suggested risk of excessive anticoagulation following switches from branded to generic warfarin. We investigated this putative association in a formalized pharmacoepidemiological analysis. Methods We conducted a nationwide cohort study based on Danish healthcare registries, including data from the introduction of generic warfarin until the repeal (January 2011–April 2015). We followed Danish warfarin users over time and compared the rate of incident hospitalizations due to excessive anticoagulation (i.e. increased INR or any bleeding requiring hospitalization) in periods following a recent switch to generic warfarin to the rate in periods without a recent switch. Results We included 105 751 warfarin users, filling a total of 1 539 640 prescriptions for warfarin (2.5% for generic warfarin). This constituted 89.0% of all warfarin prescriptions in Denmark during the study period. We observed 19 362 switches to generic warfarin during the study period. The adjusted hazard ratio for excessive anticoagulation following a recent switch from branded to generic warfarin was 1.1 (95%CI, 0.8–1.4). The result was robust within subgroups and several sensitivity analyses. Conclusion Switching from branded to generic warfarin is not associated with an increased risk of hospitalization with excessive anticoagulation. However, a minor excess risk of transient INR increase cannot be excluded. Pharmacoepidemiological studies provide an effective method for swift evaluation of hypotheses generated by ADR-reports. Copyright © 2015 John Wiley & Sons, Ltd.

ObjectivesTo examine the association between use of second-generation antipsychotics (SGA) and the risk of chronic kidney disease (CKD).DesignPopulation-based case-control study.SettingRoutinely collected laboratory, prescription and diagnostic information on all inhabitants with creatinine measurements residing on the island of Funen, Denmark (2001 to 2015).Participants21 434 cases with incident CKD matched with 85 576 CKD-free population controls by risk-set sampling using age, sex and calendar year.Primary and secondary outcome measuresCKD was defined as an estimated glomerular filtration rate below 60 mL/min/1.73 m2 in a period longer than 3 months. Information on drug exposure and comorbidities were obtained from the Danish National Prescription Register and the Danish National Patient Register. We calculated OR for the association between SGA use and CKD using conditional logistic regression.ResultsUse of SGAs was associated with increased risk of CKD among ever users (OR 1.24, 95% CI: 1.12 to 1.37) and current users (OR 1.26, 95% CI: 1.12 to 1.42). We found no clear evidence of dose-response relationship. Both short duration (one to two antipsychotic prescriptions; OR 1.22, 95% CI: 1.01 to 1.48) as well as long-term use (>30 prescriptions; OR 1.45, 95% CI 1.19 to 1.76) were associated with an increased risk of CKD. Both use of SGAs with mild and high risk of metabolic disturbances was associated with increased risk of CKD (OR 1.21, 95% CI: 1.06 to 1.39 and OR 1.36, 95% CI: 1.11 to 1.68, respectively). Recent use of non-steroidal anti-inflammatory drugs, prior use of lithium, hypertension or prior acute kidney injury were not clearly associated with development of CKD connected to SGA exposure. The highest risk of CKD was found for clozapine (OR 1.81, 95% CI: 1.22 to 2.69).ConclusionUse of SGA is associated with a small-to-moderately increased risk of incident CKD. All investigated SGAs, except for aripiprazole, were associated with an increased risk of CKD.

AIMS: Some antipsychotics increase prolactin levels, which might increase the risk of breast cancer. Existing evidence is conflicting and based on sparse data, especially for the increasingly used second-generation antipsychotics. We conducted a nationwide case-control study of the association between antipsychotic use and incident breast cancer.METHODS: From the Danish Cancer Registry, we identified women with a first-time diagnosis of breast cancer 2000-2015 (n = 60 360). For each case, we age-matched 10 female population controls. Using conditional logistic regression, we calculated odds ratios (ORs) for breast cancer associated with use of antipsychotics. We stratified antipsychotics by first- and second-generation status and by ability to induce elevation of prolactin.RESULTS: In total, 4951 cases (8.1%) and 47 643 controls (7.9%) had ever used antipsychotics. Long-term use (≥10 000 mg olanzapine equivalents) was associated with breast cancer, with an adjusted OR of 1.18 [95% confidence interval (CI), 1.06, 1.32]. A weak dose-response pattern was seen, with ORs increasing to 1.27 (95% CI 1.01, 1.59) for ≥50 000 mg olanzapine equivalents. Associations were similar for first- and second-generation antipsychotics (ORs 1.17 vs. 1.11), but also for nonprolactin inducing-antipsychotics (OR 1.17). Stratifying by oestrogen receptor status, positive associations were seen for oestrogen receptor-positive cancers (long-term use: OR 1.29; 95% CI 1.13, 1.47) while no associations were observed for oestrogen receptor-negative cancers.CONCLUSIONS: Overall, our results do not suggest a clinically important association between antipsychotic use and risk of breast cancer. The importance of drug-induced prolactin elevation is unclear but may lead to a slightly increased risk of oestrogen receptor-positive breast cancer.

Use of tobacco, alcohol, addictive medicines, and illegal substances in pregnancy increases the risk of pregnancy complications and temporary and persistent damage to the unborn child. Early detection and intervention may mitigate these adverse effects. The Danish Family Clinics are specialist centres for counselling and treatment of such families at risk. Results from a pilot study indicate that the number of pregnant women, who may benefit from treatment and counselling in the Family Clinics, is underestimated. In this project, we will conduct an anonymous nationwide screening of 3000 pregnant women to detect use of tobacco, alcohol, addictive medicines, and illegal substances. We will use a new, improved dipstick screening supported by validated confirmation analyses. As a new initiative, the dipstick is promising to detect a wider range of relevant substances, but also a small alcohol intake down to two units three days after intake. Also, we will validate all the substance components of the dipstick with confirmation analyses among 200 pregnant women, who are already affiliated to the Family Clinics comprising a known and much higher prevalence of substance use. This study will inform future, national strategies to identify women at risk and therefore may benefit from the support offered by the Family Clinics. The results are important contributions to research within screening for, and treatment of, substance use in the entire population.

Tamoxifen reduces the rate of breast cancer recurrence by about one-half. It is converted to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6) and transported by ATP-binding cassette transporters. Genetic polymorphisms that confer reduced CYP2D6 activity or concurrent use of CYP2D6-inhibiting drugs may reduce the clinical efficacy of tamoxifen. The issue of the clinical utility of CYP2D6 genotype testing is subject to considerable and ongoing academic and clinical controversy. In this chapter, we outline tamoxifen's clinical pharmacology and give an overview of the research to date on the association between CYP2D6 inhibition and tamoxifen effectiveness. Based on the evidence to date, the impact of drug-induced and/or gene-induced inhibition of CYP2D6 activity is likely to be null or small, or at most moderate in subjects carrying two reduced function alleles. Future research should examine the effect of polymorphisms in genes encoding enzymes in tamoxifen's complete metabolic pathway, should comprehensively evaluate other biomarkers that affect tamoxifen effectiveness, such as the transport enzymes, and focus on subgroups of patients, such as premenopausal breast cancer patients, for whom tamoxifen is the only guideline approved endocrine therapy.

AIMS: Some antipsychotics increase prolactin levels, which might increase the risk of breast cancer. Existing evidence is conflicting and based on sparse data, especially for the increasingly used second‐generation antipsychotics. We conducted a nationwide case–control study of the association between antipsychotic use and incident breast cancer. METHODS: From the Danish Cancer Registry, we identified women with a first‐time diagnosis of breast cancer 2000–2015 (n = 60 360). For each case, we age‐matched 10 female population controls. Using conditional logistic regression, we calculated odds ratios (ORs) for breast cancer associated with use of antipsychotics. We stratified antipsychotics by first‐ and second‐generation status and by ability to induce elevation of prolactin. RESULTS: In total, 4951 cases (8.1%) and 47 643 controls (7.9%) had ever used antipsychotics. Long‐term use (≥10 000 mg olanzapine equivalents) was associated with breast cancer, with an adjusted OR of 1.18 [95% confidence interval (CI), 1.06, 1.32]. A weak dose–response pattern was seen, with ORs increasing to 1.27 (95% CI 1.01, 1.59) for ≥50 000 mg olanzapine equivalents. Associations were similar for first‐ and second‐generation antipsychotics (ORs 1.17 vs. 1.11), but also for nonprolactin inducing‐antipsychotics (OR 1.17). Stratifying by oestrogen receptor status, positive associations were seen for oestrogen receptor‐positive cancers (long‐term use: OR 1.29; 95% CI 1.13, 1.47) while no associations were observed for oestrogen receptor‐negative cancers. CONCLUSIONS: Overall, our results do not suggest a clinically important association between antipsychotic use and risk of breast cancer. The importance of drug‐induced prolactin elevation is unclear but may lead to a slightly increased risk of oestrogen receptor‐positive breast cancer.

The issue of antipsychotic treatment during pregnancy is subject to substantial uncertainty and some controversy among healthcare providers, specifically pertaining to second-generation antipsychotics (SGAs) that are subject to a large gap in safety data during pregnancy compared with antidepressants. The amount of safety data for the use of SGAs during pregnancy is rapidly increasing, thus constantly changing the level of evidence. We performed a clinically focused review on the safety of SGA during pregnancy. Twenty-three studies provided various pregnancy outcomes for 14,382 pregnant women exposed to an SGA during pregnancy. In utero exposure to aripiprazole, olanzapine, and quetiapine is not associated with increased risks of major congenital malformations, whereas risperidone and paliperidone may be associated with a very minor increased risk of congenital malformations. Safety data on ziprasidone and clozapine remain scarce and insufficient for a quantitative safety evaluation. No or minimal safety data are available for amisulpride, asenapine, lurasidone, and sertindole. For other pregnancy outcomes of interest, e.g. miscarriage, stillbirth, and small for gestational age, the available data overall do not suggest a clinically important increased risk, and do not allow for a meaningful stratification on individual drug level. Furthermore, for neonatal adaption and childhood neurodevelopment, the data do not allow for a meaningful risk assessment. It is imperative that factors in addition to safety data, e.g. individual disease history, characteristics and treatment response, adverse reaction profile, and patient preferences, be considered for the individual patient when choosing specific SGA treatment during pregnancy.

Tamoxifen reduces the rate of breast cancer recurrence by about one-half. It is converted to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6) and transported by ATP-binding cassette transporters. Genetic polymorphisms that confer reduced CYP2D6 activity or concurrent use of CYP2D6-inhibiting drugs may reduce the clinical efficacy of tamoxifen. The issue of the clinical utility of CYP2D6 genotype testing is subject to considerable and ongoing academic and clinical controversy. In this chapter, we outline tamoxifen's clinical pharmacology and give an overview of the research to date on the association between CYP2D6 inhibition and tamoxifen effectiveness. Based on the evidence to date, the impact of drug-induced and/or gene-induced inhibition of CYP2D6 activity is likely to be null or small, or at most moderate in subjects carrying two reduced function alleles. Future research should examine the effect of polymorphisms in genes encoding enzymes in tamoxifen's complete metabolic pathway, should comprehensively evaluate other biomarkers that affect tamoxifen effectiveness, such as the transport enzymes, and focus on subgroups of patients, such as premenopausal breast cancer patients, for whom tamoxifen is the only guideline approved endocrine therapy.

Aims: To analyse prescribing patterns during pregnancy for antipsychotics (APs), antidepressants (ADs) and mood-stabilizing antiepileptics (AEDs) in Denmark from 2000 to 2016. Methods: Data were obtained from the Danish Medical Birth Register, the Register for Legally Induced Abortions, the Danish National Patient Register and the Register of Medicinal Product Statistics. Data were linked through a unique personal identifier by Statistics Denmark. Results: The use of APs increased 2.5-fold from a prevalence of 1.5 per 1000 pregnancies to 3.8 for pregnancies ending in a delivery. Use of mood-stabilizing AEDs increased from a prevalence of 0.1 to 2.1 during the study period. The prevalence for APs and mood-stabilizing AEDs was nearly twice as high for pregnancies ending in miscarriage or termination compared to pregnancies ending in delivery. A marked increase in the prevalence of ADs use during pregnancy was seen from 2000–2011 (from 6 to 41 per 1000 pregnancies ending in a delivery) but appears slightly in decline. Age, smoking, obesity and social status were generally associated with increased use of psychotropic drugs. Conclusions: The use of APs, ADs and mood-stabilizing AEDs during pregnancy has increased substantially in Denmark from 2000–2016. The use of ADs appears to be slightly in decline since 2011.

Objective To explore safety in adipose-derived regenerative cells (ADRC) therapy, treating erectile dysfunction (ED). Methods Twenty-one patients with ED after radical prostatectomy, with no signs of recovery using conventional therapy, received a single intracavernous injection of autologous ADRC and were followed for 1 year. Six men were incontinent, and 15 were continent at inclusion. The primary (safety of ADRC therapy) and secondary endpoints (sexual function) were evaluated at 1, 3, 6, and 12 months after ADRC injection by registration of adverse events and validated questionnaires using the international index of erectile function-5 and erection hardness score. Results No serious adverse events occurred, but 8 reversible minor events related to the liposuction were noted. Eight out of 15 (53%) patients in the continent group reported erectile function sufficient for intercourse at 12 months. Baseline median international index of erectile function-5 scores (6.0; interquartile range [IQR] 3) were unchanged 1 month after the treatment, but significantly increased after 6 to 7 (IQR 17). This effect was sustained at 12 months (median 8; IQR 14). We did not see any improvements in erectile function in the group of incontinent men or among men with ED prior to radical prostatectomy. Conclusion Intracavernous injection of ADRC is safe in this phase 1 study with a 12-month follow-up.

The antibiotic dicloxacillin has been shown to induce drug-metabolizing CYP enzymes to a clinically relevant extent. In this study, we investigated whether the use of dicloxacillin confers an increased risk of unwanted pregnancy among oral contraceptive users. The study population comprised Danish women falling pregnant (1997–2015) during oral contraceptive use, defined as having filled a prescription for an oral contraceptive within 120 days both before and after the estimated date of conception. Data were analysed using a case-crossover approach. For each woman, we assessed the use of dicloxacillin preceding the date of conception and during 10 previous control periods and estimated the odds ratio for such unintended pregnancies associated with the use of dicloxacillin. Among 364 women using dicloxacillin prior to conception, 40 (11%) were exposed to dicloxacillin at the time of conception, yielding an odds ratio (OR) associating use of dicloxacillin to unintended pregnancy of 1.18 (95% CI 0.84–1.65). Supplementary and sensitivity analyses generally returned similar estimates, except for a slightly increased risk among users of progestogen-only oral contraceptives (OR 1.83, 95% CI 0.63–5.34). Analysis of other antibiotics as negative controls yielded results close to unity (ORs ranging from 0.83 to 1.13). In conclusion, our study found no evidence for an increased risk of oral contraceptive failure when using dicloxacillin. However, acknowledging study limitations, we suggest the use of supplementary barrier methods during treatment with dicloxacillin, until our findings are confirmed in further studies.

BACKGROUND: Myriad reports suggest that frequently used prescription drugs alter the viability of breast cancer cells in pre-clinical studies. Routine use of these drugs, therefore, may impact breast cancer prognosis, and could have important implications for public health.METHODS: The Danish Breast Cancer Group (DBCG) clinical database provides high-quality prospectively collected data on breast cancer diagnosis, treatment, and routine follow-up for breast cancer recurrence. Individual-level linkage of DBCG data to other population-based and medical registries in Denmark, including the Danish National Prescription Registry, has facilitated large population-based pharmacoepidemiology studies. A unique advantage of using DBCG data for such studies is the ability to investigate the association of drugs with breast cancer recurrence rather than breast cancer mortality - which may be misclassified - or all-cause mortality. Here we summarize findings from pharmacoepidemiological studies, based on DBCG data, on the association between routinely used prescription drugs and risk of breast cancer recurrence.RESULTS: Our findings suggest that concurrent use of glucocorticoids, ACE inhibitors, aspirin, NSAIDs, selective COX-2 inhibitors, digoxin, and opioids has little impact on breast cancer recurrence. Similarly, patients who use SSRIs concurrently with tamoxifen treatment are not at increased risk of recurrence. In contrast, post-diagnostic use of simvastatin, a lipophilic statin, correlates with a decreased risk of breast cancer recurrence, providing a rationale for a prospective randomized clinical trial investigating simvastatin as an adjuvant therapy for breast cancer.CONCLUSION: As a whole, findings of pharmacoepidemiological studies based on DBCG data provide reassurance to physicians and healthcare personnel who provide supportive care during and after cancer (including prescriptions for comedications) and to breast cancer survivors for whom the risk of breast cancer recurrence is a major concern.

Background Proton pump inhibitors (PPIs) have been suggested to increase the effect of warfarin, and clinical guidelines recommend careful monitoring of international normalized ratio (INR) when initiating PPI among warfarin users. However, this drug–drug interaction is sparsely investigated in a clinical setting. The aim was to assess whether initiation of PPI treatment among users of warfarin leads to increased INR values. Methods The study was an observational self-controlled study from 1998 to 2012 leveraging data on INR measurements on patients treated with warfarin from primary care and outpatient clinics and their use of prescription drugs. Data were analyzed in 2015. We assessed INR, warfarin dose, and dose/INR ratio before and after initiating PPI treatment using the paired student's t-test. Results We identified 305 warfarin users initiating treatment with PPIs. The median age was 71 years (interquartile range 63–78 years), and 64% were men. The mean INR in the 70 days prior to PPI initiation was 2.6 (95%CI 2.5–2.8) and 2.6 (95%CI 2.5–2.7) in the period 1–3 weeks after PPI initiation (p = 0.67). Further, neither mean warfarin dose nor the dose/INR ratios were significantly different before and after PPI initiation. Sensitivity analyses revealed no differences among individual PPIs. Conclusions We found no evidence of a clinically meaningful drug–drug interaction between PPIs and warfarin in a Northern European patient population of unselected patients from an everyday outpatient and primary care clinical setting. Thus, we do not support the recommendation to “cautiously monitor” users of warfarin initiating PPI treatment. Copyright © 2015 John Wiley & Sons, Ltd.

PURPOSE: It is well documented that drug-drug interaction databases (DIDs) differ substantially with respect to classification of drug-drug interactions (DDIs). The aim of this study was to study online available transparency of ownership, funding, information, classifications, staff training, and underlying documentation of the five most commonly used open access English language-based online DIDs and the three most commonly used subscription English language-based online DIDs in the literature.METHODS: We conducted a systematic literature search to identify the five most commonly used open access and the three most commonly used subscription DIDs in the medical literature. The following parameters were assessed for each of the databases: Ownership, classification of interactions, primary information sources, and staff qualification. We compared the overall proportion of yes/no answers from open access databases and subscription databases by Fisher's exact test-both prior to and after requesting missing information.RESULTS: Among open access DIDs, 20/60 items could be verified from the webpage directly compared to 24/36 for the subscription DIDs (p = 0.0028). Following personal request, these numbers rose to 22/60 and 30/36, respectively (p < 0.0001). For items within the "classification of interaction" domain, proportions were 3/25 versus 11/15 available from the webpage (P = 0.0001) and 3/25 versus 15/15 (p < 0.0001) available upon personal request.CONCLUSION: Available information on online available transparency of ownership, funding, information, classifications, staff training, and underlying documentation varies substantially among various DIDs. Open access DIDs had a statistically lower score on parameters assessed.

Purpose: Deaths among drug addicts are frequently caused by intoxication with methadone and/or morphine. These drugs are often used in combination with other drugs, such as buprenorphine. In addition, methadone is generally used as a mixture of R- and S-enantiomers. To date, a method for separation and quantitation of these specific drugs has not been developed. The aim of this study was to develop a sensitive enantioselective method for quantitation of morphine, its active metabolite morphine 6-glucuronide, buprenorphine, and R- and S-methadone, in a single analytical run. Methods: Whole blood samples were diluted with 0.5 mol/L ammonium carbonate buffer and extracted on a Bond Elut C18 solid-phase extraction column with an automatic solid-phase extraction system. Chromatographic separation was performed on a chiral alpha-1-acid glycoprotein column with an acetonitrile/ammonium acetate buffer (10 mmol/L, pH 7.0, 22:78 v/v) mobile phase. The whole blood concentrations of the drugs were quantified by mass spectrometry using their stable isotope-labeled compounds as internal standards. Results: The method was validated with respect to specificity, linearity, precision, limits of detection, and quantification and matrix effects. The precision (coefficient of variation) was below 15 %, and the accuracy was between 90 and 115 %. Conclusions: This method will be useful for routine analyses in forensic laboratories where blood samples are frequently analyzed for drugs of abuse. In some cases, sudden death from methadone overdose is caused by the enantiomeric form of the methadone, which makes the enantiomer separation capability of this method important.

Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, and VEGFR-3. Based on the positive opinion from the European Medicines Agency (EMA), a marketing authorization valid throughout the European Union (EU) was issued for the treatment of advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. The demonstration of clinical benefit for axitinib was based on a phase III, randomized, open-label, multicenter study of axitinib compared with sorafenib in patients with advanced RCC after failure of a prior systemic first-line regimen containing one or more of the following agents: sunitinib, bevacizumab plus interferon-α, temsirolimus, or cytokines. In the primary analysis, a 2-month increase in median progression-free survival (PFS) was observed for axitinib compared with sorafenib (hazard ratio [HR]: 0.665; 95% confidence interval [CI]: 0.544–0.812; p < .0001). In the subgroup of patients with a prior cytokine-containing regimen, the increase in median PFS associated with axitinib was 5.4 months (updated analysis, HR: 0.519; 95% CI: 0.375–0.720; p < .0001). In the subgroup of patients with prior sunitinib treatment, the increase in median PFS was 1.4 months (updated analysis, HR: 0.736; 95% CI: 0.578–0.937; p = .0063). The analysis of overall survival showed no statistically significant survival benefit of axitinib over sorafenib in patients previously treated with cytokine-containing regimens (HR: 0.813; 95% CI: 0.556–1.191) or sunitinib (HR: 0.997; 95% CI: 0.782–1.270). The most common treatment-related adverse events associated with axitinib included diarrhea, hypertension, fatigue, nausea, decreased appetite, dysphonia, and palmar-plantar erythrodysesthesia. Most of these events were mild or moderate in severity. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).

Aims Our objective was to investigate the steady-state pharmacokinetic and pharmacodynamic interaction between the antidepressive herbal medicine St John's wort and the antidiabetic drug metformin.

AIMS: Up to 50‐fold higher levels of urinary phthalate metabolites have been observed in users of phthalate‐containing drug products compared with non‐users. This is of concern, as phthalates are suspected endocrine disrupters and have been associated with cancer development. This study aims to quantify annual cumulated phthalate exposure from drug products among users of phthalate‐containing oral medications in Denmark throughout the period of 2004–2016. METHODS: We conducted a Danish nationwide cohort study using The Danish National Prescription Registry and an internal database held by The Danish Medicines Agency. These databases hold information on drug products; date of dispensing, and the type and quantity of excipients in drugs with Danish marketing permission. We present the number of users over time and their distribution of exposure to enteric phthalate polymers and ortho‐phthalates. RESULTS: The annual number of individuals exposed to phthalate‐containing products declined during 2004–2016. The total number of individuals exposed to dibutyl phthalate declined from 21 499 in 2004 to 5400 in 2016. However, among those exposed, the median dibutyl phthalate exposure remained above European regulatory limit of exposure ranging between 380–1710 mg/year throughout the study period. Lithium‐products constituted the majority of dibutyl phthalate exposure. Diethyl phthalate exposure, mainly caused by erythromycin, theophylline and diclofenac products, did not exceed the EMA regulatory limit. CONCLUSION: While the number of individuals exposed to phthalates from oral medications during 2004–2016 declined, the use of phthalate‐containing drugs is still considerable.

AIM: The aim of this study was to study potential cytochrome P450 (CYP) induction by dicloxacillin. METHODS: We performed an open‐label, randomized, two‐phase, five‐drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1 g dicloxacillin three times daily for 10 days. Plasma and urine were collected over 24 h and the concentration of all five drugs and their primary metabolites was determined using a liquid chromatography coupled to triple quadrupole mass spectrometry method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48 h and changes in gene expression and the activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 were investigated. The activation of nuclear receptors by dicloxacillin was assessed using luciferase assays. RESULTS: A total of 10 days of treatment with dicloxacillin resulted in a clinically and statistically significant reduction in the area under the plasma concentration–time curve from 0 to 24 h for omeprazole (CYP2C19) {geometric mean ratio [GMR] [95% confidence interval (CI)]: 0.33 [0.24, 0.45]}, tolbutamide (CYP2C9) [GMR (95% CI): 0.73 (0.65, 0.81)] and midazolam (CYP3A4) [GMR (95% CI): 0.54 (0.41, 0.72)]. Additionally, other relevant pharmacokinetic parameters were affected, indicating the induction of CYP2C‐ and CYP3A4‐mediated metabolism by dicloxacillin. Investigations in primary hepatocytes showed a statistically significant dose‐dependent increase in CYP expression and activity by dicloxacillin, caused by activation of the pregnane X receptor. CONCLUSIONS: Dicloxacillin is an inducer of CYP2C‐ and CYP3A‐mediated drug metabolism, and we recommend caution when prescribing dicloxacillin to users of drugs with a narrow therapeutic window.

Venlafaxine is a commonly used antidepressant agent. We aimed to provide detailed information on the associations between venlafaxine dose and concentrations of venlafaxine, by patient age and sex. From a therapeutic drug monitoring (TDM) database located at Odense University Hospital, Denmark, we identified all adults for whom the treating physician had requested clinical advice on the TDM result for venlafaxine between 2002 and 2012. We identified 1077 TDM samples of venlafaxine from 334 males and 743 females (median age 45 years), and the median daily dose was 225 mg. Median plasma concentration of venlafaxine and o-desmethylvenlafaxine (ODV) was 306 nmol/L and 861 nmol/L, respectively. The median dose-corrected serum level for venlafaxine was 1.49 nmol/L/mg., while the dose-corrected serum level of men and women were 1.21 nmol/L/mg and 1.60 nmol/L/mg, respectively. The dose-corrected sum of venlafaxine and ODV was 8.91 nmol/L/mg (IQR 6.56–12.26) versus 5.52 nmol/L/mg (IQR 4.16–7.52) for patients above 64 years and below the age of 65 years, respectively. Dose-corrected plasma concentrations of venlafaxine and ODV are increased to a clinically significant degree in patients above the age of 64, and initiation of venlafaxine therapy in the elderly should be made cautiously and supported by drug measurements.

Background: Some studies indicate a reduced risk of serious upper gastrointestinal bleeding (UGIB) for users of beta-blockers, but the association remains to be confirmed in larger studies and characterized with respect to differences among beta-blockers. We aimed to assess whether beta-blocker use decreases the risk of UGIB.Methods: We conducted a register-based, population-based case-control study in Denmark. We identified cases with a first validated discharge diagnosis of UGIB during the period 1995-2006. Controls were selected by risk-set sampling in a ratio of 10:1. We estimated crude and adjusted odds ratios (ORs) of the association between current beta-blocker use and the risk of UGIB by using conditional logistic regression and further stratified by selective and non-selective beta-blockers, respectively.Results: We identified 3571 UGIB cases and 35,582 controls. Use of beta-blockers was not found to be associated with a decreased risk of UGIB (adjusted OR 1.10; 95% CI: 1.00-1.21). The association remained neutral after stratification by selective and non-selective beta-blockers, and by single beta-blocker substances. Similarly, we found no association between current beta-blocker use and the risk of UGIB within different subgroups.Conclusions: We found no association between beta-blocker use and UGIB.

Treatment for oral candidiasis in warfarin users may be complicated by drug-drug interactions (DDIs) between warfarin and topically applied antimycotics. However, current knowledge of these putative DDIs is merely based on case series. We therefore performed a cohort cross-over study with the objective to evaluate the potential DDIs between warfarin and miconazole oral gel or nystatin oral solution. The cohort consisted of individuals using warfarin in the period of 1998-2012 (n ≈ 7400). We collected data on cohort members' measurements of the international normalized ratio (INR) from a clinical database, and obtained information on their use of topically applied miconazole and nystatin from a regional prescription register. Potential DDIs were assessed by comparing INR values before and after initiation of an antimycotic drug. Among 17 warfarin users exposed to miconazole oral gel, the mean INR increased from 2.5 (95% CI: 2.1-2.8) to 3.8 (95% CI: 2.8-4.8) after exposure, corresponding to a mean INR increase of 1.4 (95% CI: 0.3-2.4). Among 30 warfarin users exposed to nystatin oral solution, the mean INR was 2.7 (95% CI: 2.3-3.1) before and 2.5 (95% CI: 2.2-2.9) after exposure. In conclusion, we found evidence supporting a clinically relevant drug-drug interaction between warfarin and miconazole oral gel. In contrast, we did not find any indication of an interaction between warfarin and nystatin oral solution. Nystatin rather than miconazole should be preferred when treating warfarin users for oral candidiasis.

Much preclinical and epidemiological evidence supports the anticancer effects of statins. Epidemiological evidence does not suggest an association between statin use and reduced incidence of breast cancer, but does support a protective effect of statins-especially simvastatin-on breast cancer recurrence. Here, we argue that the existing evidence base is sufficient to justify a clinical trial of breast cancer adjuvant therapy with statins and we advocate for such a trial to be initiated without delay. If a protective effect of statins on breast cancer recurrence is supported by trial evidence, then the indications for a safe, well tolerated, and inexpensive treatment can be expanded to improve outcomes for breast cancer survivors. We discuss several trial design opportunities-including candidate predictive biomarkers of statin safety and efficacy-and offer solutions to the key challenges involved in the enrolment, follow-up, and analysis of such a trial.

A 47-year-old woman had been treated with high-dose simvastatin for several years. After systemic treatment with the antifungal agent itraconazole, she developed muscle pain and highly elevated levels of creatine kinase and myoglobin. Muscle biopsy was compatible with statin-associated rhabdomyolysis, probably caused by a drug-drug interaction between simvastatin and itraconazole. The patient made full recovery. Three commonly used statins-simvastatin, atorvastatin and lovastatin-are metabolised by the liver enzyme CYP3A4. Several potent inhibitors of this enzyme are known, for example, azole antifungal agents such as itraconazole and posaconazole. If antifungal treatment is indicated in a patient using a CYP3A4-metabolised statin, we recommend (1) topical administration of the antifungal agent if possible, (2) the use of a non-CYP3A4-inhibiting antifungal drug such as terbinafine or (3) temporary discontinuation of statin treatment.

Aim In Europe, pregabalin is approved for treatment of neuropathic pain, general anxiety disorder (GAD) and as adjunctive therapy for epilepsy. The purpose of this study was to assess utilisation of pregabalin in the UK, including patients with a recorded history of substance abuse, from a large general practice database. Methods This observational drug utilisation study (DUS) analysed pregabalin prescription data from the UK Health Improvement Network primary care database between September 2004 and July 2009. Patient demographics, diagnoses (by READ codes) and pregabalin dosing data were collected. Diagnosis codes were used as proxy for approved indication for pregabalin. Result A cohort of 18,951 patients was prescribed pregabalin; dosing information was available for 13,480 (71.1%). Median age of patients was 58 years, and majority were female (60.1%). Median (interquartile range) prescribed average daily dose (ADD) of pregabalin for all patients was 150.0 (162.5) mg/day; this was highest in patients with epilepsy (191.9 mg/day), followed by neuropathic pain (158.0 mg/day) and GAD (150.0 mg/day). Only 1.0% (136/13,480) of patients were prescribed an ADD of pregabalin over the maximum approved dose of 600 mg/day. Of these, 18.4% (25/136) of patients had a history of substance abuse compared with 14.0% (1884/13,480) in the full population. Conclusion Data from this DUS indicated that the majority of pregabalin prescribing in the UK was consistent with product labelling. The proportion of patients with prescribed ADD > 600 mg/day was small and with a similar proportion with a history of substance abuse as in the full population.

Purpose: The aims of this study were to assess the quality of responses produced by drug information centers (DICs) in Scandinavia, and to study the association between time consumption processing queries and the quality of the responses. Methods: We posed six identical drug-related queries to seven DICs in Scandinavia, and the time consumption required for processing them was estimated. Clinical pharmacologists (internal experts) and general practitioners (external experts) reviewed responses individually. We used mixed model linear regression analyses to study the associations between time consumption on one hand and the summarized quality scores and the overall impression of the responses on the other hand. Findings: Both expert groups generally assessed the quality of the responses as "satisfactory" to "good." A few responses were criticized for being poorly synthesized and less relevant, of which none were quality-assured using co-signatures. For external experts, an increase in time consumption was statistically significantly associated with a decrease in common quality score (change in score, -0.20 per hour of work; 95% CI, -0.33 to -0.06; P = 0.004), and overall impression (change in score, -0.05 per hour of work; 95% CI, -0.08 to -0.01; P = 0.005). No such associations were found for the internal experts assessment. Implications: To our knowledge, this is the first study of the association between time consumption and quality of responses to drug-related queries in DICs. The quality of responses were in general good, but time consumption and quality were only weakly associated in this setting. (C) 2016 The Authors. Published by Elsevier HS Journals, Inc. Funding Agencies|Nord University, Steinkjer, Norway; Norwegian Regional Medicines Information and Pharmacovigilance Centers (RELIS)

BACKGROUND: Several case reports and epidemiological studies have raised concern about the abuse potential of pregabalin, the use of which has increased substantially over the last decade. Pregabalin is, in some cases, used for recreational purposes and it has incurred attention among drug abusers for causing euphoric and dissociative effects when taken in doses exceeding normal therapeutic dosages or used by alternative routes of administration, such as nasal insufflation or venous injection. The magnitude of the abuse potential and the mechanism behind it are not fully known.OBJECTIVE: The aim of this study was to present a systematic review of the data concerning the abuse potential of pregabalin.METHODS: We performed a systematic literature search and reviewed the preclinical, clinical and epidemiological data on the abuse potential of pregabalin.RESULTS: We included preclinical (n = 17), clinical (n = 19) and epidemiological (n = 13) studies addressing the abuse potential of pregabalin. We also reviewed case reports (n = 9) concerning abuse of pregabalin. The preclinical studies indicated that pregabalin possesses modulatory effects on the GABA and glutamate systems, leaving room for an abuse potential. Further, clinical studies reported euphoria as a frequent side effect in patients treated with pregabalin. The majority of case reports concerning abuse of pregabalin involved patients with a history of substance abuse and, similarly, epidemiological studies found evidence of abuse, especially among opiate abusers.CONCLUSIONS: Overall, the available literature suggests an important clinical abuse potential of pregabalin and prescribers should pay attention to signs of abuse, especially in patients with a history of substance abuse.

The Danish Society of Clinical Pharmacology was founded in 1976, and mainly thanks to the persistent efforts of the society, clinical pharmacology became an independent medical speciality in Denmark in 1996. Since then, clinical pharmacology has gone from strength to strength. In the Danish healthcare system, clinical pharmacology has established itself as an indispensible part of the efforts to promote the rational, safe and economic use of drugs. Clinical pharmacologists are active in drug committees both in hospitals and in the primary sector. All clinical pharmacology centres offer a local medicines information service. Some centres have established an adverse drug effect manager function. Only one centre offers a therapeutic drug monitoring service. Clinical pharmacologists are responsible for the toxicological advice at the Danish Poison Information Centre at Bispebjerg University Hospital in the Capital Region. The Department of Clinical Pharmacology at Aarhus University Hospital works closely together with forensic toxicologists and pathologists, covering issues regarding illicit substances, forensic pharmacology, post-mortem toxicology, expert testimony and research. Therapeutic geriatric and psychiatric teach-inns for specialist and junior doctors are among the newest initiatives organized by clinical pharmacologists. Clinical pharmacologists work also in the Danish Medicines Agency and in the Danish pharmaceutical industry, and the latter has in particular a great growth potential for creating new jobs and career opportunities for clinical pharmacologists. As of July 2016, the Danish Society of Clinical Pharmacology has 175 members, and 70 of these are specialists in clinical pharmacology corresponding to approximately 2.5 specialists per 1000 doctors (Denmark has in total 28,000 doctors) or approximately 12 specialists per one million inhabitants.

INTRODUCTION: Pregabalin is currently approved for the treatment of epilepsy, generalized anxiety disorder and neuropathic pain with a licensed dosage range of 150 mg to 600 mg/day. Growing concern about the abuse potential of pregabalin is partly based on reports of pregabalin being used in dosages that exceed the approved therapeutic range.METHODS: To identify predictors of pregabalin use above recommended dosage, we conducted a pharmacoepidemological drug utilization study using the Danish nationwide registers. We deployed 4 measures of abuse: high use (≥600 mg/day) or very high use (≥1 200 mg/day) over a 6- or 12-month period, respectively. Multiple logistic regression was used to identify patient and treatment characteristics that were associated with either abuse marker.RESULTS: Out of 42 520 pregabalin users 4 090 (9.6%) were treated with more than 600 mg/day for 6 months and 2 765 (6.5%) for more than 12 months. Male gender and prescription of antipsychotics and benzodiazepines were associated with increased risk of use of above the recommended dosage.DISCUSSION: Use of pregabalin above recommended dosages was rare but abuse may occur in susceptible patients.

BACKGROUND: A protective effect of tricyclic antidepressants (TCAs) against gliomas has been suggested by a small number of studies. We investigated this putative association in a nationwide setting.METHODS: Using a case-control design, we identified all patients with histologically verified glioma (cases) in Denmark between 2000 and 2012 and matched these 1 : 20 to population controls. Conditional logistic regression was used to estimate adjusted odds ratios (ORs) for glioma associated with long-term (⩾3 years) use of TCAs. Similar analyses were performed for selective serotonin reuptake inhibitors (SSRIs).RESULTS: We identified 3767 glioma cases and 75 340 population controls. Long-term use of TCAs was inversely associated with risk of glioma (OR 0.72, 95% CI: 0.41-1.25). Long-term SSRI use was not associated with glioma risk (OR 0.93, 95% CI: 0.75-1.16).CONCLUSIONS: Our study indicated that long-term use of TCAs may be associated with a reduced risk of glioma, however, the statistical precision was limited. A similar pattern was not observed for use of SSRIs.

INTRODUCTION: Electroconvulsive treatment (ECT) is an effective treatment for severe depression but carries a risk of relapse in the following months.METHODS: Major depressive disorder patients in a current episode attaining remission from ECT (17-item Hamilton Depression Rating Scale (HAM-D17) score≤9) received randomly escitalopram 10 mg, 20 mg, 30 mg or nortriptyline 100 mg as monotherapies and were followed for 6 months in a multicentre double-blind set-up. Primary endpoint was relapse (HAM-D17≥16).RESULTS: As inclusion rate was low the study was prematurely stopped with only 47 patients randomised (20% of the planned sample size). No statistically significant between-group differences could be detected. When all patients receiving escitalopram were compared with those receiving nortriptyline, a marginal superiority of nortriptyline was found (p=0.08). One third of patients relapsed during the study period, and one third completed.DISCUSSION: Due to small sample size, no valid efficacy inferences could be made. The outcome was poor, probably due to tapering off of non-study psychotropic drugs after randomisation; this has implications for future study designs. ClinicalTrials.gov Identifier: NCT00660062.

Letter in resonse to: Del Re M, Rofi E, Citi V, Fidilio L, Danesi R. Should CYP2D6 be genotyped when treating with tamoxifen? Pharmacogenomics 17(18), 1967–1969 (2016).

The standard treatment for ovarian cancer in advanced stages is post-surgery treatment with taxane-platin chemotherapy. Despite an initial high response rate, most patients eventually relapse. The dose-limiting toxicities of paclitaxel are neutropenia and neuropathy, but the inter-individual variability is large. The aim of this prospective study was to investigate the impact of genetic variants in key drug metabolizing/transporter genes on toxicity and compliance. CYP2C8*3 and three ABCB1 polymorphisms were chosen for primary analysis, and a host of other candidate genes was explored in 92 prospectively recruited Scandinavian Caucasian women with primary ovarian cancer who were treated with paclitaxel and carboplatin. A single investigator assessed the clinical toxicity in 97% of the patients. Patients carrying variant alleles of ABCB1 C3435T experienced more pronounced neutrophil decrease (63%, 72% and 80% for 3435CC, CT and TT, respectively; p-value 0.03). A similar association was found for G2677T/A, p-value 0.02. For C1236T, there was a trend with p-value 0.06. No statistically significant correlations were found for paclitaxel compliance and sensory neuropathy in the primary analysis. Variants in the drug transporter ABCB1 gene are possibly associated with the neutrophil suppressing effect of paclitaxel in patients with ovarian cancer. This finding has implications for the understanding of bone marrow suppression and future tailored chemotherapy.

Nielsen J, Damkier P, Lublin H, Taylor D. Optimizing clozapine treatment. Objective: Clozapine treatment remains the gold standard for treatment-resistant schizophrenia, but treatment with clozapine is associated with several side-effects that complicate the use of the drug. This clinical overview aims to provide psychiatrists with knowledge about how to optimize clozapine treatment. Relevant strategies for reducing side-effects and increasing the likelihood of response are discussed. Method: Studies of clozapine available in MEDLINE were reviewed. Results: A slow up-titration of clozapine is recommended in order to reach the optimal dosage of clozapine and diminish the risk of dose-dependent side-effects. Particularly, in case of partial response or non-response, the use of therapeutic drug monitoring of clozapine is recommended. Plasma levels above the therapeutic threshold of 350–420 ng/ml are necessary to determine non-response to clozapine. To ease the burden of dose-dependent side-effects, dose reduction of clozapine should be tried and combination with another antipsychotic drug may facilitate further dose reduction. For most side-effects, counteracting medication exists. Augmentation with lamotrigine, antipsychotics, or electroconvulsive therapy may be beneficial in case of partial response to clozapine. Conclusion: Treatment with clozapine should be optimized in order to increase the rate of response and to minimize side-effects, thus diminishing the risk of discontinuation and psychotic relapse.

PurposeThe Predictors of Breast Cancer Recurrence (ProBe CaRe) study was established to evaluate modification of tamoxifen (TAM) effectiveness in premenopausal women through reduced activity of TAM-metabolising enzymes. It comprehensively evaluates the effects of pharmacogenetic variants, use of concomitant medications and biomarkers involved in oestrogen metabolism on breast cancer recurrence risk.ParticipantsThe ProBe CaRe study was established using resources from the Danish Breast Cancer Group (DBCG), including 5959 premenopausal women diagnosed with stage I–III primary breast cancer between 2002 and 2010 in Denmark. Eligible participants were divided into two groups based on oestrogen receptor alpha (ERα) expression and receipt of TAM therapy, 4600 are classified as ERα+/TAM+ and 1359 are classified as ERα−/TAM−. The ProBe CaRe study is a population-based cohort study nested in a nearly complete source population, clinical, tumour and demographic data were abstracted from DBCG registry data. Linkage to Danish registries allows for abstraction of information regarding comorbid conditions, comedication use and mortality. Formalin-fixed paraffin-embedded tissue samples have been prepared for DNA extraction and immunohistochemical assay.Findings to dateTo mitigate incorrect classification of patients into specific categories, we conducted a validation substudy. We compared data acquired from registry and from medical record review to calculate positive predictive values (PPVs) and negative predictive values. We observed PPVs near 100% for tumour size, lymph node involvement, receptor status, surgery type, receipt of radiotherapy, receipt of chemotherapy and TAM treatment. We found that the PPVs were 96% (95% CI 83% to 100%) for change in endocrine therapy and 61% (95% CI 42% to 77%) for menopausal transition.Future plansThe ProBeCaRe cohort study is well positioned to comprehensively examine pharmacogenetic variants. We will use a Bayesian pathway analysis to evaluate the complete TAM metabolic path to allow for gene–gene interactions, incorporating information of other important patient characteristics.

The objective of the study was to develop, implement and evaluate two treatment algorithms for schizophrenia and depression at a psychiatric hospital department. The treatment algorithms were based on available literature and developed in collaboration between psychiatrists, clinical pharmacologists and a clinical pharmacist. The treatment algorithms were introduced at a meeting for all psychiatrists, reinforced by the project psychiatrists in the daily routine and used for educational purposes of young doctors and medical students. A quantitative pre-post evaluation was conducted using data from medical charts, and qualitative information was collected by interviews. In general, no significant differences were found when comparing outcomes from 104 charts from the baseline period with 96 charts from the post-intervention period. Most of the patients (65% in the post-intervention period) admitted during the data collection periods did not receive any medication changes. Of the patients undergoing medication changes in the post-intervention period, 56% followed the algorithms, and 70% of the patients admitted to the psychiatric hospital department for the first time had their medications changed according to the algorithms. All of the 10 interviewed doctors found the algorithms useful. The treatment algorithms were successfully implemented with a high degree of satisfaction among the interviewed doctors. The majority of patients admitted to the psychiatric hospital department for the first time had their medications changed according to the algorithms.

Conflict of interest: None. Correspondence to: Per Damkier, Department of Clinical Chemistry & Pharmacology, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense, Denmark E-mail: pdamkier@health.sdu.dk Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2015 DOI 10.1002/ajmg.a.37153 How to Cite this Article: Damkier P, Kaplan YC. 2015. In utero exposure to methotrexate and risk of congenital malformations.

Patients receiving lamotrigine therapy frequently use paracetamol concomitantly. While one study suggests a possible, clinically relevant drug-drug interaction, practical recommendations of the concomitant use are inconsistent. We performed a systematic pharmacokinetic study in healthy volunteers to quantify the effect of 4 day treatment with paracetamol on the metabolism of steady-state lamotrigine.Twelve healthy, male volunteers participated in an open label, sequential interaction study. Lamotrigine was titrated to steady-state (100 mg daily) over 36 days, and blood and urine sampling was performed in a non-randomized order with and without paracetamol (1 g four times daily). The primary endpoint was change in steady-state area under the plasma concentration-time curve of lamotrigine. Secondary endpoints were changes in total apparent oral clearance, renal clearance, trough concentration of lamotrigine and formation clearance of lamotrigine glucuronide conjugates.Co-administration of lamotrigine and paracetamol decreased the steady-state area under the plasma concentration-time curve of lamotrigine by 20% (95% CI 10%, 25%; P 0.001) from 166 to 127 μmol l(-1) . Concomitant administration of paracetamol increased the formation clearance of lamotrigine glucuronide conjugates by 45% (95% CI 18%, 79%, P = 0.005) from 1.7 to 2.8 l h(-1) , while the trough value of lamotrigine was reduced by 25% (95% CI 12%, 36%, P = 0.003) from 5.3 to 3.9 μmol l(-1) .Paracetamol statistically significantly induced steady-state lamotrigine glucuronidation, resulting in a 20% decrease in total systemic exposure and a 25% decrease in trough value of lamotrigine. This interaction may be of clinical relevance in some patients.

Essentials It is not known if initiation of glucose-lowering drugs alters the efficacy of vitamin K antagonists (VKA). We examined if glucose-lowering drugs affected international normalized ratio (INR) in VKA-treated patients. Upon initiating glucose-lowering drugs, 51% of patients had INR values below the therapeutic window. Monitoring of INR levels should be intensified upon initiation of glucose-lowering drugs. SummaryBackground It is not known whether initiation of antidiabetic treatment affects the effect of vitamin K antagonists (VKAs). It was previously shown that metformin affects the effect of one VKA, phenprocoumon. Objectives The aim of this study was to determine if initiation of glucose-lowering treatment affects the international normalized ratio (INR) and dose requirements of the anticoagulant VKAs warfarin and phenprocoumon. Patients/methods We performed a self-controlled retrospective register-based study. A total of 118 patients commencing glucose-lowering treatment while being treated with warfarin or phenprocoumon were included in the study. We compared INR, dose/INR and proportion of patients with at least one sub-therapeutic INR measurement before and after initiation of glucose-lowering treatment. Results Initiation of glucose-lowering treatment caused mean INR to decrease from 2.5 to 2.2 (decrease of −0.3 [95% CI: −0.1; −0.5]) and led to more than half of the patients having at least one sub-therapeutic INR measurement. Six to 12 weeks later, the VKA dose/INR was increased by 11%, indicating a weakened effect of the VKA. Conclusion Initiation of glucose-lowering treatment reduces the anticoagulant effect of VKAs to an extent that is likely to be clinically relevant. This finding needs confirmation and mechanistic explanation.