Abuse, dependence and withdrawal associated with fentanyl and the role of its (designated) route of administration: an analysis of spontaneous reports from Europe.

PURPOSE: Fentanyl, a highly potent synthetic opioid used in cancer and non-cancer pain, is approved for various routes of administration. In Europe, fentanyl consumption increased substantially in the last decades but information on abuse, dependence and withdrawal associated with fentanyl is scarce, especially with respect to its different formulations. METHODS: We analysed case characteristics of spontaneous reports of suspected fentanyl-associated abuse, dependence or withdrawal from European countries recorded in the EudraVigilance database up to 2018 with respect to the (designated) routes of administration and potential indications. RESULTS: A total of 985 reports were included (mainly from France and Germany) with 43% of cases referring to transdermal fentanyl. Median age was 45 years (48.8% female) and 21.6% had musculoskeletal disorders. Only 12.6% of those using transdermal fentanyl had a cancer diagnosis compared to 40.2% and 26.8% of those using intranasal and oral transmucosal fentanyl, respectively. Depression was common (10.7%) and highest in cases with musculoskeletal disorders (24.9%) as was the use of benzodiazepines. Overall, 39.5% of reports resulted in a prolonged hospital stay and for 23.2% a fatal outcome was recorded. The respective proportions were especially high in cases with musculoskeletal disorders (56.3% with prolonged hospitalisation) and in those using transdermal fentanyl (35.2% fatalities). CONCLUSIONS: In suspected cases of abuse, dependence or withdrawal, fentanyl was mainly used for non-cancer pain indications and most often as transdermal formulations. Depression and prolonged hospitalisations were common, especially in patients with musculoskeletal disorders, indicating a vulnerable patient group and complex treatment situations.

Global COVID-19 pandemic and reporting behavior - An analysis of the Food and Drug Administration adverse events reporting system.

PURPOSE: To describe the characteristics of adverse event reporting in the United States (US) Food and Drug Administration Adverse Event Reporting System (FAERS) before and after the outbreak of the COVID-19 pandemic. METHODS: We included all FAERS reports from the US and Canada from November 7, 2019 to July 15, 2020 and divided the study period into three equal time intervals (pre-pandemic, first pandemic, second pandemic). We focused on methotrexate, a broadly used drug unrelated to COVID-19, and (hydroxy)chloroquine, another broadly used drug implicated in COVID-19 treatment. Using descriptive statistics, we compared reporting characteristics before and after the COVID-19 outbreak. RESULTS: During the study period, 366 998 cases (60% female, median age: 59 years) were submitted to FAERS. The daily median number of reports (1796 in the pre-pandemic, 1810 in the second pandemic time interval) and other characteristics remained stable. The daily median number of reports for methotrexate decreased from 28 in the pre-pandemic to 15 in the second pandemic time interval, with no considerable differences in other characteristics. The daily median number of reports for (hydroxy)chloroquine increased slightly from 1 in the pre-pandemic to 3 in the second pandemic time interval, while there were also changes in the demographics of cases and an increase in the proportion of cases reported by health professionals. CONCLUSIONS: The overall reporting to FAERS did not change after the outbreak of the COVID-19 pandemic. However, some stimulated reporting was observed for (hydroxy)chloroquine, highlighting the need for caution when conducting pharmacovigilance analyses with substances related to COVID-19.

Treating epistaxis - who cares for a bleeding nose? A secondary data analysis of primary and secondary care.

BACKGROUND: The primary objective was to describe outpatient treatment of epistaxis among different physicians based on a large patient population over a period of 10 years. The secondary objective was to evaluate the value of the practice fee as an instrument of allocation in patients with epistaxis. METHODS: Anonymized statutory health insurance data (AOK Lower Saxony) of patients with a diagnosis of epistaxis treated between 2007 and 2016 were examined. Demographic data, accompanying diagnoses, medication and involved medical groups (general practitioners (GP), pediatricians, ear, nose and throat (ENT) specialists or other) were analyzed. Furthermore, we assessed whether the use of specialist groups changed after abolition of the practice fee in 2013. RESULTS: Epistaxis was responsible for 302,782 cases (160,963 patients). The distribution of cases was slightly in favor of ENT specialists vs. GP (119,170 vs. 110,352). The cases seen by GP and ENT specialists were comparable with regard to age and sex distribution. Hypertension, atrial fibrillation/flutter and an antithrombotic therapy were slightly more common among cases consulting a GP. The GP recorded more co-diagnoses than the ENT. The use of outpatient care and the proportions of the involved physicians scarcely fluctuated during the study period. Overall, 23,118 patients (14.4%) were diagnosed by both, GP and ENT during a relatively short time period. The practice fee remuneration had no impact on the consultation of the physician groups. CONCLUSION: The outpatient treatment of epistaxis constitutes a considerable medical and economic burden in Germany. Strengthening the primary medical sector (GP-centered care) is necessary to reach the goal of initially directing patients to primary care, providing specialists more time for severe cases and reducing the impact on public health balance sheets.

Use of oral anticoagulants in German nursing home residents: drug use patterns and predictors for treatment choice.

AIMS: Information on utilization of oral anticoagulants (OACs) in nursing homes is scarce. This study aimed to (i) describe OAC use in German nursing home residents, (ii) examine factors influencing whether treatment is initiated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) and (iii) assess which conditions predict switching to NOAC instead of continuing VKA. METHODS: Using claims data (2010-2014), we studied a cohort of new nursing home residents aged ≥65 years receiving OAC. Further, OAC use in patients with atrial fibrillation (AF) was examined over the years. RESULTS: Overall, 16 804 patients (median age: 85 years, 75% female, 44% with renal disease) were included. The majority received phenprocoumon as first OAC (58.0%), followed by rivaroxaban (28.1%). Over the study period, NOAC use increased substantially. Initiating NOAC instead of VKA was predicted by a previous stroke (adjusted odds ratio: 1.76; 95% confidence interval: 1.49-2.08). In contrast, renal disease predicted VKA initiation (0.66; 0.59-0.75) as did the presence of a prosthetic heart valve. Switching from VKA to NOAC was predicted by a stroke (2.55; 2.00-3.24), bleeding events and a recent hospitalization. During 2010-2014, the proportion of AF patients with a CHADS2 score ≥2 receiving OAC increased from 27% to 46%. CONCLUSIONS: NOACs are increasingly used in German nursing homes, both for initial anticoagulation but also in VKA pre-treated patients. Switching from VKA to NOAC was substantially influenced by aspects such as intended higher effectiveness and safety but probably also practicability due to less blood monitoring.

The impact of the lookback period and definition of confirmatory events on the identification of incident cancer cases in administrative data.

BACKGROUND: This cohort study examined the impact of the lengths of lookback and confirmation periods as well as the definition of confirmatory events on the number of incident cancer cases identified and age-standardized cumulative incidences (ACI) estimated in administrative data using German cancer registry data as a benchmark. METHODS: ACI per 100,000 insured persons for breast, prostate and colorectal cancer were estimated using BARMER Statutory Health Insurance claims data. Incident cancer cases were defined as having an in- or outpatient diagnosis in 2013, no diagnosis in a lookback period of 1 year and a second diagnosis (or death) in a confirmation period of 1 quarter. We varied lookback periods from 1 to 7 years, confirmation periods from 1 to 4 quarters as well as the definition of confirmatory events and compared ACI estimates to cancer registry data. RESULTS: ACI were higher for breast (138.7) and prostate (103.6) but lower for colorectal cancer (42.1) when compared to cancer registries (119.3, 98.0 and 45.5, respectively). Extending the lookback period to 7 years reduced ACI to 129.0, 95.1 and 38.3. An extended confirmation period of 4 quarters increased ACI to 151.3, 114.9 and 46.8. Including breast and colorectal surgeries as a confirmatory event reduced ACI to 114.9 and 37.1, respectively. CONCLUSIONS: The choice of lookback and confirmation periods and the definition of confirmatory events have considerable impact on the number of incident cancer cases identified and ACI estimated. Researchers need to be aware of potential misclassification when identifying incident cancer cases in administrative data. Further validation studies as well as studies using administrative data to estimate cancer incidences should consider several choices of the lookback and confirmation periods and the definition of confirmatory events to show how these parameters impact the validity and robustness of their results.

Characteristics and drug use patterns of older antidepressant initiators in Germany.

PURPOSE: The purpose of this study was to investigate characteristics, drug use patterns, and predictors for treatment choice in older German patients initiating antidepressant (AD) treatment. METHODS: Using the German Pharmacoepidemiological Research Database, we identified a cohort of AD initiators aged at least 65 years between 2005 and 2011. Potential indications, co-morbidity, and co-medication as well as treatment patterns such as the duration of the first treatment episode were assessed. In addition, a logistic regression model was used to identify independent predictors for initiating treatment with tricyclic ADs (TCAs) compared to selective serotonin reuptake inhibitors (SSRIs). RESULTS: Overall, 508,810 individuals were included in the cohort. About 55 % of patients initiated AD treatment with TCAs, followed by 22 % receiving SSRIs. During the study period, a decrease of treatment initiation with TCAs was observed. Higher age and male sex as well as being diagnosed with depression were highly associated with SSRI treatment, whereas pain and sleeping disorders were strong predictors for initiating TCA treatment. The duration of the first treatment episode was substantially longer in SSRI users compared to TCA initiators (median 119 vs. 43 days). CONCLUSIONS: Potential indications and drug use patterns in older German AD initiators varied substantially for different drug classes and single agents. Given the anticholinergic and sedative properties of TCAs, the frequent use of this drug class though probably related to indications such as pain was remarkable.

Pain, depressive symptoms and medication in German patients with rheumatoid arthritis-results from the linking patient-reported outcomes with claims data for health services research in rheumatology (PROCLAIR) study.

PURPOSE: Pain and depressive symptoms are common in patients with rheumatoid arthritis (RA). Information on the prevalence and treatment of both conditions in German RA patients is scarce. METHODS: Using data from a nationwide statutory health insurance fund (BARMER GEK), 6193 RA patients aged 18 to 79 years were provided with a questionnaire covering a variety of items such as demographics, medical condition and quality of life in 2015. Pain caused by the joint disorder (11-point scale) was classified as none existent/mild, moderate or severe. Depressive symptoms were determined using the World Health Organization's five-item Well-being Index and categorized as none existent, mild or moderate/severe. Another item covered additional use of over-the-counter drugs. Data were linked to dispensation records. RESULTS: A total of 3140 RA patients were included. Median age was 66 years (79% female). About 70% of patients were classified as having moderate or severe pain. Depressive symptoms were found in 52% and were far more common among patients with higher pain levels. Analgesic treatment ranged from 45% to 76% (non-opioid analgesics) and from 6% to 33% (opioids) in patients with no/mild pain and those reporting severe pain, respectively. In patients reporting moderate or severe pain, substantially higher prevalences of opioid use were observed among those with depressive symptoms. Depending on depressive symptoms, antidepressant use ranged from 7% to 37%. Overall, over-the-counter drug use varied between 30% and 59%. CONCLUSIONS: Pain and depressive symptoms are highly prevalent in German RA patients, often present together and influence each other's treatment. Copyright © 2017 John Wiley & Sons, Ltd.

Risk of venous thromboembolism in cancer patients treated with epoetins or blood transfusions.

AIMS: Anaemia is common in cancer patients, with treatments including epoetins and blood transfusions. Although an increased risk of venous thromboembolism (VTE) has been associated with both therapeutics, studies comparing the risk of VTE between epoetins and transfusions in cancer patients are lacking. METHODS: A nested case-control study investigated this risk using the German Pharmacoepidemiological Research Database. Cohort members were incident cancer patients receiving first time treatment with epoetin or transfusion. A subcohort including only patients receiving chemotherapy was created, since the formally approved indication of epoetins is chemotherapy-induced anaemia. Cases were defined as patients developing VTE. For each case up to 10 gender- and age-matched controls were selected from the cohort. Multiple confounder adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for VTE and recent treatment with epoetins or transfusions (last 28 days before index date) compared with past anti-anaemic treatment were calculated by conditional logistic regression. RESULTS: Among 69 888 patients receiving first time treatment with epoetin or transfusion, 3316 VTE cases were identified. The aOR for VTE was 1.31 (95% CI 1.03, 1.65) for epoetins, 2.33 (95% CI 2.03, 2.66) for transfusions, and 2.24 (95% CI 1.34, 3.77) for epoetins and transfusions. Sensitivity analyses with a stricter VTE definition or an expanded time window yielded similar results. In the chemotherapy only subcohort the risk difference between epoetins and transfusions could not be verified (aOR 1.48, 95% CI 1.10, 1.98 vs. aOR 1.80, 95% CI 1.49, 2.19). Our study confirmed known VTE risk factors including previous VTE (aOR 14.76, 95% CI 12.79, 17.03) or surgery (aOR 1.83, 95% CI 1.67, 2.01). Epoetin-associated risk decreased after a safety warning by the European Medicines Agency setting maximum haemoglobin target values to 12 g dl(-1) . CONCLUSIONS: Transfusions could be associated with a higher VTE risk than epoetins in cancer patients. Moreover, current prescribing patterns may have decreased the VTE risk for epoetins.

Use of rivaroxaban in Germany: a database drug utilization study of a drug started in hospital.

PURPOSE: The purpose of this drug utilization study was to describe the use of rivaroxaban in Germany during a time period in which approval was limited to the prevention of venous thromboembolism following hip or knee replacement. Additionally, we explored the feasibility of reconstructing inpatient drug use of rivaroxaban in a database where with a few exceptions inpatient prescribing information is not available. METHODS: Source of data was one statutory health insurance providing data on about seven million insurants throughout Germany. Analyses were based on a cohort of rivaroxaban users from launch (October 2008) to December 2009 and encompassed potential indications for rivaroxaban use, treatment duration, and co-prescribing of potentially interacting drugs. Start of rivaroxaban treatment was defined by the date of surgery. RESULTS: During the study period, 425 rivaroxaban users were identified contributing 440 treatment periods. For more than 82% of these episodes labelled indications could be determined. Treatment durations exceeded recommendations in 95% of the episodes following knee replacement whereas rivaroxaban use after elective hip surgery was found to be longer than recommended in 56%. Prescribing of potentially interacting medication was rare except for non-steroidal anti-inflammatory drugs. CONCLUSIONS: Overall, no important off-label use of rivaroxaban was identified. Based on several assumptions that have to be considered in the interpretation of the results our study describes a database approach to reconstruct inpatient drug use for a drug started after a coded hospital procedure, when treatment continues after hospital discharge and no change in drug use is expected in the outpatient setting.

Characteristics and completeness of spontaneous reports by reporter's role in Germany: An analysis of the EudraVigilance database using the example of opioid-associated abuse, dependence, or withdrawal.

Spontaneous reporting is based on the experience of all healthcare professionals (HCPs) but also consumers/non-HCPs and therefore reveals a broad picture of a drug's adverse reactions. Recent studies found substantial differences between reports from these varying sources including the reports' completeness. Using the example of opioid-associated abuse, dependence, or withdrawal, this study analyzed the completeness and characteristics of spontaneous reports from Germany focusing on the reporter. Based on EudraVigilance data, we included all cases of abuse, dependence, or withdrawal associated with opioids indicated for pain therapy and filed from Germany until 2018. Completeness and characteristics were analyzed by a reporter (physician, pharmacist, other HCPs, consumers/non-HCPs) and also by time period to account for other influencing factors. In total, 1721 cases were included, mainly filed by physicians (38.5%) and pharmacists (30.7%). Completeness of demographics varied from 74.5% (other HCPs) to 42.7% (consumers/non-HCPs). Consumers/non-HCPs most often provided any indication/comorbidity (75.2%), whereas this was the case for only 20.2% of pharmacists. Large differences between the reporters were found for almost all characteristics. Other HCPs far more often coded a history of drug abuse, dependence, or withdrawal than other reporters (46.9% vs. 11.6%-24.2%, respectively), and fatal outcomes were also mainly filed by other HCPs (68.1% vs. 14.8%-20.4% by all other reporters). Differences in completeness and characteristics were also observed over time. Studies analyzing spontaneous data should consider potential differences between the various reporting groups in terms of completeness and characteristics. Further, the impact of other influencing factors has to be assessed.

Characteristics and outcomes of cases with methylphenidate abuse, dependence or withdrawal: an analysis of spontaneous reports in EudraVigilance.

Methylphenidate (MPH) is a central nervous stimulant, which is mainly used in attention deficit hyperactivity disorder (ADHD) and narcolepsy. In recent years, rising MPH prescription volumes have drawn attention to possible misuse. We analyzed data on suspected MPH abuse, dependence or withdrawal reported to the EudraVigilance database (1996-2019), comparing case characteristics (e.g. age, indications and outcome). In 1531 cases from 35 countries (median: 29 years, 57.6% male), 42.3% had been diagnosed with ADHD and 8.0% with narcolepsy. Narcolepsy cases were older than ADHD cases (mean age: 47 vs. 22 years), and used co-medications more frequently (79.4 vs. 47.8%). Intravenous MPH administration was most common among individuals not diagnosed with ADHD or narcolepsy. A history of abuse, dependence or withdrawal of any substance was more often documented in fatal than in nonfatal cases (49.0 vs. 22.5%), whereas differences regarding the route of administration were less pronounced. Minors, who presumably received MPH for ADHD treatment, presented less frequently with serious outcomes than older cases or those without an approved indication. Prescribers should exercise caution in adult MPH users and should make a thorough co-medication assessment. Finally, more research on substance abuse in narcolepsy patients is required, which should include comorbidities and co-medication.

Utilisation of transdermal fentanyl in Germany from 2004 to 2006.

PURPOSE: Oral morphine is the first-choice opioid for moderate to severe cancer pain. Transdermal fentanyl is an alternative in patients with stable requirements of high-potency opioids (HPO) or if drugs cannot be taken orally. Drug regulatory authorities have issued several alerts to use transdermal fentanyl only for chronic pain and in HPO-tolerant patients to minimise the risk of severe opioid side effects. The aim of this study was to characterise utilisation of transdermal fentanyl in Germany. METHODS: The analysis was based on data from four German statutory health insurances from the years 2004-2006. Descriptive analyses were performed in new users of transdermal fentanyl to assess HPO-naïvety, potential difficulties with the oral route in HPO-naïve patients and the number of transdermal fentanyl dispensations. The initial dose in new users was assessed in 2005-2006 after marketing of transdermal fentanyl 12.5 µg/hour. RESULTS: Of 35 262 patients with new use of transdermal fentanyl, 29 793 (84.5%) were assessed as HPO-naïve. Of those, 21 596 (72.5%) did not have diagnoses indicating difficulties with the oral route. For 71.2% of the HPO-naïve new users of transdermal fentanyl, the first dose exceeded the recommended dose of 12.5 µg/hour, and 49.3% of them received only one prescription of the drug. CONCLUSIONS: Transdermal fentanyl was used as a first-choice opioid, which may increase the risk of serious opioid side effects, in a substantial number of HPO-naïve patients. Inappropriate prescribing included also high initial doses in HPO-naïve patients and possible prescription for acute pain in a considerable proportion of patients.

3-year prevalence of alcohol-related disorders in German patients treated with high-potency opioids.

PURPOSE: In November 2010, the European Medicines Agency's Committee for Medicinal Products for Human Use completed a review of the safety and effectiveness of modified-release oral high-potency opioids (HPO). The reason for this referral procedure was the concern that some of these controlled-release systems may be unstable when co-ingested with alcohol and that the active substance would be released too quickly. The aim of this study was to estimate the prevalence of alcohol-related disorders (ARD) in German patients treated with HPO approved for pain therapy. METHODS: The source of data was the German Pharmacoepidemiological Research Database including more than 14 million members of four statutory health insurances. The age and sex standardized 3-year prevalence of ARD in patients treated with any type of HPO and in patients receiving modified-release oral HPO was compared with the prevalence of ARD in the general population excluding HPO-treated patients. RESULTS: The age and sex standardized prevalence of ARD was significantly higher in patients treated with any type of HPO (5.5%, 95%confidence interval [CI]: 5.2%-5.9%) or with modified-release HPO (5.4%, 95%CI: 4.8%-5.9%) than in persons belonging to the general population (2.2%, 95%CI: 2.2-2.2%). CONCLUSIONS: Interactions with alcohol in patients receiving modified-release HPO may be of relevance in a substantial number of patients. Physicians should be aware of this potentially dangerous interaction.

Nurse-Filled versus Pharmacy-Filled Medication Organization Devices-Survey on Current Practices and Views of Home Care Nursing Services.

Medication organization devices (MODs) are widely used among home care nursing services. However, current practices such as the responsibility for filling MODs, different MOD types used and requirements of home care nursing services are largely unknown. The study aimed at analyzing home care nursing services' current practices regarding MOD use, investigating their requirements and determining whether different practices met these requirements. A survey was administered online to German home care nursing services in February 2021. The importance of requirements and the extent of satisfaction were measured using a five-point scale. Attitudes towards disposable, pharmacy-filled MODs were recorded as free text. In total, 690 nursing services responded (67.5% privately owned and 34.5% based in large cities), 92.2% filled MODs themselves and used predominantly reusable, rigid MODs. Pharmacies filling MODs used primarily disposable MODs. Satisfaction with current practices was generally high. Respondents filling MODs themselves were more satisfied with nurses' medication knowledge, but less satisfied with cost effectiveness than those who had pharmacies fill MODs. Of all respondents filling MODs themselves who expressed an opinion on disposable, pharmacy-filled MODs, 50.9% were skeptical, primarily due to fear of losing flexibility. However, no difference in satisfaction with flexibility was found between respondents filling MODs themselves and those using pharmacy-filled MODs. In conclusion, employment of MODs in the professional care setting is a complex task with nursing services as key constituents. There is potential for improvement in the inter-professional collaboration between pharmacies and home care nursing services on the use of MODs. Measures for improvement have to address home care nursing services' requirements with respect to flexibility and medication knowledge.

Antidepressant drug use and regional prescribing patterns in Germany: results from a large population-based study.

OBJECTIVE: To consider antidepressant prescribing on a population level with a focus on regional prescribing patterns in Germany. BASIC METHODS: Based on data from about 70 million individuals covered by all statutory health insurance funds in Germany in 2010, the prevalence of antidepressant use (overall, for drug classes and individual drugs) was calculated stratified by age and sex. Regional analyses were performed on a state and also on a district level. MAIN RESULTS: The study population comprised 68 427 464 (female: 53.0%) persons, of which 5 052 293 (7.4%) were prescribed at least one antidepressant. The most frequently prescribed drug class was tricyclic antidepressants whereas on a substance level citalopram was most commonly used. Antidepressant prescribing was lowest in children and adolescents (0.2%) and most common in persons aged 70 years and older (13.4%). Women more often received antidepressants than men (9.7% vs. 4.8%). Prevalence of antidepressant use varied between 8.7% (Saarland) and 6.3% (Saxony-Anhalt) and was generally highest in the southwestern and lowest in the eastern states. Accordingly, districts with the highest prevalence were located in the southwestern states. PRINCIPAL CONCLUSIONS: Antidepressant use in Germany varied considerably by age and sex and also on a state and district level.

Patterns and trends of antibacterial treatment in patients with urinary tract infections, 2015-2019: an analysis of health insurance data.

BACKGROUND: Urinary tract infections are among the most common reason for encounter and subsequent antibiotic prescriptions. Due to the risk of collateral damage and increasing resistance rates, explicit recommendations against the use of fluoroquinolones like ciprofloxacin in uncomplicated urinary tract infections have been issued. However, to what extent these recommendations were followed and if there are relevant differences between the disciplines involved (general practitioners, urologists, paediatricians and gynaecologists) are unknown. METHODS: We used anonymized data from a local statutory health insurance (SHI) company, which covered about 38% of all SHI-insured persons in the federal state of Bremen, Germany between 2015-2019. Data included demographics, outpatient diagnoses and filled prescriptions on an individual level. RESULTS: One-year prevalence of urinary tract infections was 5.8% in 2015 (females: 9.2%, males: 2.5%). Of all 102,715 UTI cases, 78.6% referred to females and 21.4% to males, 6.0% of cases were younger than 18 years. In females, general practitioners were the most common diagnosing speciality (52.2%), followed by urologists (20.0%) and gynaecologists (16.1%). Overall, fluoroquinolones were most often prescribed (26.3%), followed by fosfomycin (16.1%) and the combination of sulfamethoxazole and trimethoprim (14.2%). Fluoroquinolones were most often prescribed by urologists and general practitioners, while gynaecologists preferred fosfomycin. During the study period, shares of fluoroquinolones decreased from 29.4% to 8.7% in females and from 45.9% to 22.3% in males. CONCLUSIONS: Despite a clear trend toward a more guideline adherent prescription pattern, there is still room for improvement regarding the use of second-line antibiotics especially fluoroquinolones. The choice of antibiotics prescribed differs between specialities with higher uptake of guideline-recommended antibiotics by gynaecologists, mainly because of higher prescription shares of fosfomycin.

Drug interactions with phenprocoumon and the risk of serious haemorrhage: a nested case-control study in a large population-based German database.

PURPOSE: Phenprocoumon is the most frequently used vitamin K antagonist in Germany. The aim of this study was to estimate the risk of serious bleeding as a result of the use of drugs with potential interaction with phenprocoumon. METHODS: We conducted a nested case-control study in a cohort of 246,220 phenprocoumon users in the German Pharmacoepidemiological Research Database. Cases were patients hospitalised for haemorrhage of different kinds. Ten controls were matched to each case by health insurance, birth year and sex using incidence density sampling. Odds ratios (OR) with 95% confidence intervals (CI) of the risk of serious bleeding associated with combined use of phenprocoumon and potentially interacting drugs versus phenprocoumon alone were estimated using conditional logistic regression analysis. Our analyses considered multiple risk factors, such as bleeding history, other comorbidities or co-medication. RESULTS: Our study included 2,553 cases and 25,348 matched controls. An increased risk of bleeding was observed for the combined use of phenprocoumon and clopidogrel vs phenprocoumon use alone (OR: 1.83, 95% CI: 1.41-2.36). Antibiotic drugs associated with an increased risk of haemorrhage in the population of phenprocoumon users included the group of quinolones with ORs ranging from 2.74 (95% CI: 1.80-4.18) for ciprofloxacin to 4.40 (95% CI: 2.45-7.89) for levofloxacin, amoxicillin plus clavulanic acid (OR: 2.99, 95% CI: 1.39-6.42) and cotrimoxazole (OR 3.57, 95% CI: 2.36-5.40). Among non-steroidal anti-inflammatory drugs (NSAIDs), ketoprofen and naproxen were associated with the highest risks. CONCLUSION: Significantly elevated risks of major bleeding were mainly observed for drugs with known pharmacodynamic interaction with phenprocoumon, and less for drugs with possible pharmacokinetic interaction.

Tyrosine kinase inhibitors targeting vascular endothelial growth factor and the risk of aortic dissection-A pharmacovigilance analysis.

There are concerns by the United States Food and Drug Administration (FDA) regarding a potential link between tyrosine kinase inhibitors targeting vascular endothelial growth factor (VEGF-TKIs) and the risk of aortic dissection. Elevation of blood pressure induced by VEGF-TKIs has been discussed as part of the pathomechanism. To address this important safety issue, we conducted a large pharmacovigilance study assessing the risk of aortic dissection reporting associated with the use of VEGF-TKIs, thereby exploring the role of blood pressure. We queried the FDA Adverse Event Reporting System from 2004 to 2019 for reports including VEGF-TKIs and aortic dissection and estimated reporting odds ratios (RORs) and 95% confidence intervals (CIs) of aortic dissection associated with the use of VEGF-TKIs. Secondary analyses stratified by the strength of blood pressure elevation (≥10 mmHg vs. <10 mmHg increased systolic or diastolic bloods pressure) and pre-existing arterial hypertension. There were 81 reports of aortic dissection related to VEGF-TKIs during the study period. VEGF-TKIs were associated with an increased risk of aortic dissection reporting (ROR, 4.31; 95% CI, 3.43 to 5.42). The risk was higher among compounds strongly increasing blood pressure (ROR, 5.33; 95% CI, 3.88 to 7.32) than among compounds moderately increasing blood pressure (ROR, 2.79; 95% CI, 1.83 to 4.27). Pre-existing arterial hypertension did not modify the association. Overall, our study showed an increased risk of aortic dissection reporting associated with the use of VEGF-TKIs. Blood pressure elevation seems to play a role in the pathophysiology of this adverse effect.

Regional Differences in Opioid Prescribing in Germany - Results of an Analysis of Health Insurance Data of 57 Million Adult People.

BACKGROUND: Regional variations of opioid use have been reported from many countries. The objective of this study was to examine opioid prescribing patterns in Germany including low- and high-potency opioids (LPO and HPO) focusing on regional differences. METHODS: Data source was the "Information system for health care data" comprising statutory health insurance funds data for about 70 million Germans of all ages. For 2010, we received aggregated data (by age, sex, federal state and district) of Germans (18+) who had been prescribed at least one opioid including the number of prescribed packages. For each stratum, we further received the number of insured persons. We calculated LPO and HPO prevalences and the mean number of prescribed packages. RESULTS: Among 57 million adult Germans (mean age: 50.2 years, 53.8% female), opioid prevalences were 38.7 per 1000 persons for LPOs and 12.8 for HPOs. Prevalences rose with increasing age and were higher in women than in men. On average, LPO users were prescribed fewer packages than HPO users (3.5 vs 7.0). LPO use was highest in the eastern states ranging from 32.9 per 1000 persons (Hamburg) to 47.2 (Saxony-Anhalt). HPOs were most often prescribed in the North and in the East with prevalences varying between 10.6 per 1000 persons (Baden-Württemberg) and 16.9 (Mecklenburg-Western Pomerania). On the district level, prevalences varied by the factors 2.6 and 3.2 for LPOs and HPOs, respectively. CONCLUSION: We found large regional variations in opioid prescribing which probably cannot only be attributed to differences in patient characteristics.