Risk of Anaphylaxis Among New Users of GLP-1 Receptor Agonists: A Cohort Study.

OBJECTIVE: To assess risk of anaphylaxis among patients with type 2 diabetes mellitus who are initiating therapy with a glucagon-like peptide 1 receptor agonist (GLP-1 RA), with a focus on those starting lixisenatide therapy. RESEARCH DESIGN AND METHODS: A cohort study was conducted in three large, U.S. claims databases (2017-2021). Adult (aged ≥18 years) new users of a GLP-1 RA who had type 2 diabetes mellitus and ≥6 months enrollment in the database before GLP-1 RA initiation (start of follow-up) were included. GLP-1 RAs evaluated were lixisenatide, an insulin glargine/lixisenatide fixed-ratio combination (FRC), exenatide, liraglutide or insulin degludec/liraglutide FRC, dulaglutide, and semaglutide (injectable and oral). The first anaphylaxis event during follow-up was identified using a validated algorithm. Incidence rates (IRs) and 95% CIs were calculated within each medication cohort. The unadjusted IR ratio (IRR) comparing anaphylaxis rates in the lixisenatide cohort with all other GLP-1 RAs combined was analyzed post hoc. RESULTS: There were 696,089 new users with 456,612 person-years of exposure to GLP-1 RAs. Baseline demographics, comorbidities, and use of other prescription medications in the 6 months before the index date were similar across medication cohorts. IRs (95% CIs) per 10,000 person-years were 1.0 (0.0-5.6) for lixisenatide, 6.0 (3.6-9.4) for exenatide, 5.1 (3.7-7.0) for liraglutide, 3.9 (3.1-4.8) for dulaglutide, and 3.6 (2.6-4.9) for semaglutide. The IRR (95% CI) for the anaphylaxis rate for the lixisenatide cohort compared with the pooled other GLP-1 RA cohort was 0.24 (0.01-1.35). CONCLUSIONS: Anaphylaxis is rare with GLP-1 RAs. Lixisenatide is unlikely to confer higher risk of anaphylaxis than other GLP-1 RAs.

Physician Awareness of the Safe Use of Cyproterone Acetate in Europe: A Survey on the Effectiveness of Additional Risk Minimization Measures.

BACKGROUND: Cyproterone acetate (CPA) is a synthetic progesterone derivative introduced in the 1970s and prescribed as antiandrogenic therapy for inoperable prostate cancer, sexual deviations in men, and signs of androgenization in women. In 2020, the CPA summary of product characteristics (SmPC) was revised to include an updated special warning and precaution about (1) the risk of meningioma with increasing cumulative dose and (2) contraindication in patients with meningioma or history of meningioma. A Direct Healthcare Professional Communication (DHPC) was distributed. The European Medicine Agency's Pharmacovigilance Risk Assessment Committee requested that marketing authorization holders in Europe conduct a survey to assess physicians' knowledge of the updated key safety information. The primary objective of this study was to measure physicians' awareness (i.e., did they receive and review the revised SmPC and DHPC) and level of knowledge and understanding of the key safety information pertaining to the restricted use of CPA monotherapy because of the risk of meningioma. METHODS: This cross-sectional web-based survey was administered to dermatologists, endocrinologists, gynecologists, urologists, oncologists, psychiatrists, and general practitioners in France, Germany, Poland, Spain, and the Netherlands who had prescribed CPA monotherapy in the previous 12 months to assess awareness of the risk of meningioma associated with CPA monotherapy. RESULTS: Of the 613 physicians who participated, 85% correctly indicated that CPA monotherapy should be prescribed with the lowest effective dose, 75% correctly indicated that the risk of meningioma increases with increasing cumulative CPA monotherapy doses, and 73% correctly indicated that treatment with CPA-containing products must be stopped permanently if a patient is diagnosed with meningioma. Overall, 40% of physicians reported having received the DHPC, and 42% reported having received the revised SmPC. CONCLUSIONS: Despite low recall of receipt of the updated SmPC and DHPC, most physicians surveyed are aware of the meningioma risk and actions to mitigate the risk.

Evaluation of Physician Knowledge of Safety and Safe Use Information for Intravitreal Aflibercept Injection in Europe: A Second Survey of Physicians Following Dissemination of Updated Risk-Minimization Materials.

BACKGROUND: Materials have been distributed in the European Union to inform physicians on the safe use of intravitreal aflibercept (IVT-AFL) as part of the risk-minimization plan for IVT-AFL. OBJECTIVE: We aimed to measure physician knowledge and understanding of key safety information for IVT-AFL. METHODS: The current study was a follow-up cross-sectional survey ('wave 2') to an earlier survey ('wave 1') examining the effectiveness of the IVT-AFL educational materials by assessing physician knowledge of the key safety information. Based on wave 1 results, the educational materials were revised to focus more on items of key concern (e.g., use in women of childbearing potential, procedural information); physicians in France, Germany, Italy, Spain, and the UK completed a questionnaire to evaluate their knowledge of key safety information in the revised educational materials. RESULTS: Among 454 physician respondents (of 4715 invited; response rate 9.6%), most reported having received the IVT-AFL Summary of Product Characteristics (SmPC; 89%) and Prescriber Guide (82%). More than half reported receiving the Injection Procedure Video (54%) and Patient Booklet (65%). The highest percentage of correct answers was observed for questions concerning procedural steps, the most important risks, and safe use as emphasized by the educational materials and the SmPC. CONCLUSION: Physician knowledge and understanding of safe use of IVT-AFL, including for questions that prompted revisions to the educational materials, suggests the need to reconsider methods for developing educational materials to follow best practices (e.g., focusing on only key messages and pretesting with end users).

Distribution of gestational age at birth by maternal and infant characteristics in U.S. birth certificate data: Informing gestational age assumptions when clinical estimates are not available.

PURPOSE: We aimed to describe the distribution of gestational age at birth (GAB) to inform the estimation of GAB when clinical or obstetric estimates are not available for perinatal pharmacoepidemiology studies. METHODS: We estimated GAB (median, mode, mean, and standard deviation) and percentage born at each gestational week in groups based on plurality and other variables for live births in CDC's U.S. birth data. RESULTS: In 2020, 3 617 213 newborns had birth certificates with nonmissing GAB. Among singletons (3 501 693), median and mode GAB were both 39 weeks. Births with lower median GAB were from women with eclampsia (37 weeks) or receiving intensive care (37 weeks); newborns receiving intensive care (37 weeks); newborns with birth weight <2500 g (35 weeks), <1500 g (28 weeks), or <1000 g (25 weeks); and newborns not discharged alive (23 weeks). Among twins (112 633), median GAB was 36 weeks (mode, 37 weeks). Additional noteworthy groups were women with 0-6 prenatal visits (median, 34 weeks) or 7-8 prenatal visits (median, 35 weeks) or aged 15-19 years (median, 35 weeks). CONCLUSIONS: Some maternal and infant groups had distinct GAB distributions in the United States. This information can be useful in estimating GAB when individual-level clinical estimates are not available, such as in database studies of medication use during pregnancy.

Post-Authorization Safety Study of Hospitalization for Acute Kidney Injury in Patients with Type 2 Diabetes Exposed to Dapagliflozin in a Real-World Setting.

INTRODUCTION: Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor approved to treat type 2 diabetes mellitus (T2DM), among other conditions. When dapagliflozin was approved in Europe for treating T2DM (2012), potential safety concerns regarding its effect on kidney function resulted in this post-authorization safety study to assess hospitalization for acute kidney injury (hAKI) among dapagliflozin initiators in a real-world setting. OBJECTIVE: The aim of this study was to evaluate the incidence of hAKI in adults with T2DM initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). METHODS: This noninterventional cohort study identified new users of dapagliflozin and comparator GLDs from November 2012 to February 2019 from three longitudinal, population-based data sources: Clinical Practice Research Datalink (CPRD; United Kingdom), the HealthCore Integrated Research Database (HIRD; United States [US]), and Medicare (US). Electronic algorithms identified occurrences of hAKI, from which a sample underwent validation. Incidence rates for hAKI were calculated, and incidence rate ratios (IRRs) compared hAKI in dapagliflozin with comparator GLDs. Propensity score trimming and stratification were conducted for confounding adjustment. RESULTS: In all data sources, dapagliflozin initiators had a lower hAKI incidence rate than comparator GLD initiators (adjusted IRRs: CPRD, 0.44 [95% confidence interval (CI), 0.22-0.86]; HIRD, 0.76 [95% CI, 0.62-0.93]; Medicare, 0.69 [95% CI, 0.59-0.79]). The adjusted IRR pooled across the data sources was 0.70 (95% CI, 0.62-0.78). Results from sensitivity and stratified analyses were consistent with the primary analysis. CONCLUSIONS: This study, with > 34,000 person-years of real-world dapagliflozin exposure, suggests a decreased risk of hAKI in patients with T2DM exposed to dapagliflozin, aligning with results from dapagliflozin clinical trials. STUDY REGISTRATION: European Union Post-Authorisation Studies Register, EUPAS 11684; ClinicalTrials.gov, NCT02695082.

Post-Authorization Safety Studies of Acute Liver Injury and Severe Complications of Urinary Tract Infection in Patients with Type 2 Diabetes Exposed to Dapagliflozin in a Real-World Setting.

INTRODUCTION: At the time of dapagliflozin's approval in Europe (2012) to treat patients with type 2 diabetes mellitus, concerns regarding acute liver injury and severe complications of urinary tract infection (sUTI) led to two post-authorization safety (PAS) studies of these outcomes to monitor the safety of dapagliflozin in real-world use. OBJECTIVE: To investigate the incidence of hospitalization for acute liver injury (hALI) or sUTI (pyelonephritis or urosepsis) among patients initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). METHODS: These two noninterventional cohort studies identified initiators of dapagliflozin and comparator GLDs in November 2012-February 2019 using data from three longitudinal, population-based data sources: Clinical Practice Research Datalink (UK), the HealthCore Integrated Research Database (USA), and the Medicare database (USA). Outcomes (hALI and sUTI) were identified with electronic algorithms. Incidence rates were estimated by exposure group. Incidence rate ratios (IRRs) were calculated comparing dapagliflozin to comparator GLDs, using propensity score trimming and stratification to address confounding. The sUTI analyses were conducted separately by sex. RESULTS: In all data sources, hALI and sUTI incidence rates were generally lower in dapagliflozin initiators than comparator GLD initiators. The adjusted IRR (95% confidence interval) pooled across data sources for hALI was 0.85 (0.59-1.24) and for sUTI was 0.76 (0.60-0.96) in females and 0.74 (0.56-1.00) in males. Findings from sensitivity analyses were largely consistent with the primary analyses. CONCLUSIONS: These real-world studies do not suggest increased risks of hALI or sUTI, and they suggest a potential decreased risk of sUTI with dapagliflozin exposure compared with other GLDs.

The risk of melanoma with rasagiline compared with other antiparkinsonian medications: A retrospective cohort study in the United States medicare database.

PURPOSE: Compare the risk of melanoma between initiators of rasagiline or other antiparkinsonian drugs (APDs) in a Parkinson's disease (PD) population. METHODS: A retrospective cohort study was conducted in the US Medicare claims research database (2006-2015) in adults aged ≥65 years with PD claims. Other APD initiators were randomly matched (4:1) to rasagiline initiators on age, sex, and cohort entry year. Cutaneous melanoma events were identified by a validated claims algorithm. Incidence rates (IRs), incidence rate ratios (IRRs), and Cox-adjusted hazard ratios (HRs) for melanoma comparing rasagiline with other APD initiators were calculated and analyzed by duration of study medication use and cumulative dose of rasagiline. Potential indicators of surveillance bias were explored. RESULTS: Among 23 708 rasagiline initiators and 96 552 matched APD initiators, the crude IR of melanoma/100 000 person-years was 334.3 (95% confidence interval [CI], 291.5-381.6) and 208.2 (95% CI, 190.1-227.5), respectively (crude IRR 1.61; 95% CI, 1.36-1.89). The adjusted HR was 1.37 (95% CI, 1.14-1.65) and increased with longer rasagiline exposure and higher cumulative rasagiline doses. Rasagiline initiators more frequently had dermatologist visits or skin biopsies before cohort entry than APD initiators and had a higher incidence of nonmelanoma skin cancer during follow-up (crude IRR, 1.44; 95% CI, 1.35-1.54). CONCLUSIONS: A small increased incidence of melanoma with exposure to rasagiline compared with other APDs was observed. Although the pattern with dose and duration is consistent with a hypothesized biologic effect, the increased skin cancer surveillance among rasagiline users suggests surveillance bias as a contributing explanation for the observed results.

Evaluating patient and physician knowledge of risks and safe use of rivaroxaban: a survey across four countries.

BACKGROUND: At the request of the European Medicines Agency, a Prescriber Guide and Patient Alert Card were developed to increase awareness and understanding about the initiation of rivaroxaban and potential bleeding risk associated with its use. This study evaluated physician and patient awareness and understanding of key safety messages in these educational materials in three waves. RESEARCH DESIGN AND METHODS: Three cross-sectional surveys were administered to physicians and one survey was administered to patients (wave 1 only) with recent rivaroxaban experience in France, Germany, Spain, and the United Kingdom. RESULTS: Patient and physician knowledge of key safety information in the educational materials was generally high. Patients' knowledge was high for questions related to bleeding risk (80% responded correctly), indication (96%), consulting their doctor (86%-91%), and informing other physicians they are taking rivaroxaban (95%). Physicians' knowledge was particularly high for questions related to bleeding risk (92%-94% across waves), populations at increased risk of serious side effects (76%-94%), contraindications (70%-92%), and invasive procedures (76%-82%). CONCLUSIONS: Among patients and physicians, the highest levels of knowledge were on the most important risks, as expected. The Prescriber Guide and Patient Alert Card were found to be useful sources of information.

Birth prevalence of phenylalanine hydroxylase deficiency: a systematic literature review and meta-analysis.

BACKGROUND: Phenylalanine hydroxylase (PAH) deficiency is an autosomal recessive disorder that results in elevated concentrations of phenylalanine (Phe) in the blood. If left untreated, the accumulation of Phe can result in profound neurocognitive disability. The objective of this systematic literature review and meta-analysis was to estimate the global birth prevalence of PAH deficiency from newborn screening studies and to estimate regional differences, overall and for various clinically relevant Phe cutoff values used in confirmatory testing. METHODS: The protocol for this literature review was registered with PROSPERO (International prospective register of systematic reviews). Pubmed and Embase database searches were used to identify studies that reported the birth prevalence of PAH deficiency. Only studies including numeric birth prevalence reports of confirmed PAH deficiency were included. RESULTS: From the 85 publications included in the review, 238 birth prevalence estimates were extracted. After excluding prevalence estimates that did not meet quality assessment criteria or because of temporal and regional overlap, estimates from 45 publications were included in the meta-analysis. The global birth prevalence of PAH deficiency, estimated by weighting regional birth prevalences relative to their share of the population of all regions included in the study, was 0.64 (95% confidence interval [CI] 0.53-0.75) per 10,000 births and ranged from 0.03 (95% CI 0.02-0.05) per 10,000 births in Southeast Asia to 1.18 (95% CI 0.64-1.87) per 10,000 births in the Middle East/North Africa. Regionally weighted global birth prevalences per 10,000 births by confirmatory test Phe cutoff values were 0.96 (95% CI 0.50-1.42) for the Phe cutoff value of 360 ± 100 µmol/L; 0.50 (95% CI 0.37-0.64) for the Phe cutoff value of 600 ± 100 µmol/L; and 0.30 (95% CI 0.20-0.40) for the Phe cutoff value of 1200 ± 200 µmol/L. CONCLUSIONS: Substantial regional variation in the birth prevalence of PAH deficiency was observed in this systematic literature review and meta-analysis of published evidence from newborn screening. The precision of the prevalence estimates is limited by relatively small sample sizes, despite widespread and longstanding newborn screening in much of the world.

Long-Term Risk of Skin Cancer and Lymphoma in Users of Topical Tacrolimus and Pimecrolimus: Final Results from the Extension of the Cohort Study Protopic Joint European Longitudinal Lymphoma and Skin Cancer Evaluation (JOELLE).

PURPOSE: Evidence is insufficient to infer whether topical calcineurin inhibitors (TCIs; tacrolimus and pimecrolimus) cause malignancy. The study objective was to estimate the long-term risk of skin cancer and lymphoma associated with topical TCI use in adults and children, separately. PATIENTS AND METHODS: A cohort study in Denmark, Sweden, UK, and the Netherlands was conducted. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for nonmelanoma skin cancer (NMSC), melanoma, cutaneous T-cell lymphoma (CTCL), non-Hodgkin lymphoma (NHL) excluding CTCL, and Hodgkin lymphoma (HL) in new users of TCIs versus users of moderate/high-potency topical corticosteroids. RESULTS: The study included 126,908/61,841 adults and 32,605/27,961 children initiating treatment with tacrolimus/pimecrolimus, respectively. Follow-up was ≥10 years for 19% of adults and 32% of children. Incidence rate ratios and (95% confidence intervals) for tacrolimus versus corticosteroid users in adults were <1 for melanoma, non-Hodgkin lymphoma, and Hodgkin lymphoma; and 1.80 (1.25-2.58) for cutaneous T-cell lymphoma. For pimecrolimus, IRRs in adults were <1 for non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and Hodgkin's lymphoma; and 1.21 (1.03-1.41) for melanoma; and 1.28 (1.20-1.35) for nonmelanoma skin cancer. In children, results were inconclusive due to few events. In adults, incidence rate ratios ≥5 years after first topical calcineurin inhibitor exposure were not higher than in overall analyses. CONCLUSION: Overall, we found little evidence associating use of topical calcineurin inhibitors with skin cancer and lymphoma; confounding by indication, surveillance bias, and reverse causation may have influenced these results. Even if causal, the public health impact of these excess risks would be low and confined to the first years of exposure.

Corrigendum to "Incidence of Second Primary Malignancies in Patients with Castration-Resistant Prostate Cancer: An Observational Retrospective Cohort Study in the United States".

[This corrects the article DOI: 10.1155/2019/4387415.].

Virologic Failure Among People Living With HIV Initiating Dolutegravir-Based Versus Other Recommended Regimens in Real-World Clinical Care Settings.

BACKGROUND: Guidelines for initial antiretroviral treatment (ART) regimens have evolved, with integrase strand transfer inhibitors (INSTIs) increasingly prominent. Research on virologic failure (VF) with INSTI therapy is predominantly from clinical trials not care settings, especially for recently approved medications including dolutegravir. We compared outcomes among people living with HIV (PLWH) who initiated recommended regimens in clinical care across the United States. SETTING: We examined 2 groups of PLWH at 8 clinics who initiated ART regimens (August 1, 2013-March 31, 2017): those ART treatment-naive at initiation, and those treatment-experienced. METHODS: The outcome in this longitudinal cohort study was VF, defined as a viral load of ≥400 copies/mL ≥6 months after ART initiation. We examined the proportion of individuals who remained on, switched, or discontinued the regimen. Associations between regimens and outcomes were examined with adjusted Cox proportional hazards models. RESULTS: Among 5177 PLWH, a lower proportion experienced VF on dolutegravir- versus other INSTI- or darunavir-based regimens for previously treatment-naive (7% vs. 12% vs. 28%) and treatment-experienced PLWH (6% vs. 10% vs. 21%). In adjusted analyses, hazard ratios were similar across regimens for the combined outcome of regimen discontinuation or treatment switch. The hazard ratios for VF comparing dolutegravir- to darunavir-based regimens was 0.30 (95% CI: 0.2 to 0.6) among previously treatment-naive PLWH and was 0.60 (95% CI: 0.4 to 0.8) among treatment-experienced PLWH. CONCLUSIONS: The proportion of previously treatment-naive PLWH remaining on recommended ART regimens did not differ by regimen. The likelihood of VF was lower with dolutegravir- than darunavir-based regimens for previously treatment-naive and treatment-experienced PLWH.

Incidence of Second Primary Malignancies in Patients with Castration-Resistant Prostate Cancer: An Observational Retrospective Cohort Study in the United States.

BACKGROUND: New therapies for castration-resistant prostate cancer (CRPC) may be associated with increased risk of second primary malignancies (SPM). We therefore estimated the population-based incidence of SPM among patients with CRPC in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. We also estimated the proportion of men with CRPC with bone metastases and overall survival. METHODS: We conducted a retrospective cohort study of United States (US) men aged ≥ 65 years with CRPC. Cohort entry was from January 1, 2000, to December 31, 2011, with follow-up through December 31, 2013. Castration resistance was defined by treatment with second-line systemic therapy (after surgical or medical castration). SPM were diagnoses of primary cancers (other than prostate) in SEER or Medicare data. RESULTS: Altogether 2,234 patients met eligibility criteria. Most (1,887; 84.5%) had evidence of bone metastases in Medicare claims. SPM occurred in 172 patients (incidence rate 5.9 per 100 person-years; 95% confidence interval [CI], 5.0-6.8; standardized incidence ratio = 3.1, 95% CI, 2.8-3.6, based on SEER incidence rate of all malignancies except prostate cancer among men aged ≥ 65 years). The most common SPM were lung/bronchus (n = 29, 16.9%), urinary bladder (n = 22, 12.8%), and colon/rectum (n = 21, 12.2%). Median survival was 1.2 years (95% CI, 1.1-1.3); 5-year survival was 9% (95% CI, 7-11%). CONCLUSIONS: This study provides the first estimate of SPM risk in older men with CRPC in the US. The incidence rate is approximately threefold higher than the population-based cancer incidence among men without prostate cancer.

Physician and Patient Knowledge of Safety and Safe Use Information for Aflibercept in Europe: Evaluation of Risk-Minimization Measures.

BACKGROUND: As part of the risk-management plan for aflibercept in the European Union, materials have been developed to educate physicians and patients in Europe on the safe use of aflibercept. OBJECTIVES: The objectives of this study were to measure receipt of the educational materials and to evaluate understanding of key safety information for aflibercept. METHODS: An observational cross-sectional study among physicians and patients with recent aflibercept experience in France, Germany, Italy, Spain, and the UK was conducted. Eligible physicians and patients completed a brief questionnaire regarding their knowledge of key safety information. RESULTS: Among the 8424 physicians invited to participate in the survey, 428 physicians were eligible, completed the questionnaire, and were included in this analysis. Most physicians reported having received the aflibercept summary of product characteristics (87%) and prescriber guide (77%); approximately half reported receiving the injection procedure video (50%) and patient booklet (54%). Physician knowledge of the most important topics (i.e., side effects; preparing patients for aflibercept injection) was high. Physician knowledge of dosing was high for neovascular (wet) age-related macular degeneration and lower for less commonly prescribed indications. Most physicians knew the contraindications for aflibercept and recognized possible side effects. Among the 874 patients approached about participation in the study, 773 patients were eligible, completed the questionnaire, and were included in the analysis. Patients' reported receipt was relatively low for the aflibercept patient booklet (38%) and the audio CD (23%). Patient knowledge of the health conditions to discuss with a doctor prior to injection was generally high; knowledge about possible side effects varied. Most patients knew that they should speak to a physician immediately if they experienced a possible side effect of aflibercept. CONCLUSION: Most physicians reported receiving the summary of product characteristics, prescriber guide, and patient booklet; half reported receiving the intravitreal injection procedure video. Patient receipt of the educational material was variable. Observed patterns of knowledge indicated the greatest knowledge of the most important risks emphasized in the educational material and lower knowledge of more complex or less salient aspects of safe use.

Evaluation of Physician Knowledge of the Key Safety Information for Aflibercept in Canada: Evaluation of Risk-Minimization Measures.

BACKGROUND: As part of the risk-management plan (RMP) for aflibercept, materials have been developed to educate physicians in Canada on the key safety information and safe use for aflibercept. OBJECTIVE: The objectives of this study were to assess whether physicians in Canada received and reviewed the aflibercept educational materials (i.e. vial preparation instruction card, intravitreal injection procedure video, and product monograph) and to evaluate their knowledge of key safety information. METHODS: Retinal specialists and ophthalmologists who prescribe and/or administer aflibercept were recruited to complete a survey. Physicians could complete and return a paper questionnaire by mail or complete the questionnaire online via a study website. RESULTS: Of the 308 physicians invited to participate in the survey, 95 (31%) completed the questionnaire. Nearly all physicians (98%) reported receiving at least one of the educational materials. The proportion of correct responses to individual questions on storage and preparation of aflibercept ranged from 54 to 98%. Physician knowledge was high on the recommended dose of aflibercept (91%), dose preparation (91-96% on individual items), and dosing guidelines (75-95% on individual items). Most physicians knew the contraindications for aflibercept (89%) and that aflibercept should not be used in pregnancy unless clearly indicated by medical need in which benefits outweigh risks (60%); 21% responded more conservatively that aflibercept should never be used in pregnancy. Knowledge was high for most questions about injection procedures (91-99% on individual items); however, fewer physicians (24%) correctly reported that the eye should be covered with a sterile drape. Knowledge was high for possible side effects (89-100% on individual items) and actions to take in relation to the potential for increased intraocular pressure (86-93% on individual items). CONCLUSION: Nearly all physicians (98%) reported having received the product monograph, and most (82%) reported having received the vial preparation instruction card; nearly half (46%) reported having received the intravitreal injection procedure video. Physicians' knowledge of the most important topics was high. Knowledge varied for topics that are less frequently encountered (e.g. use in women of childbearing potential) and for recommendations that are not standard medical practice in Canada (e.g. use of sterile drape).

Effectiveness of risk minimization measures for the use of cilostazol in United Kingdom, Spain, Sweden, and Germany.

PURPOSE: The purpose of the study is to evaluate the effectiveness of risk minimization measures-labeling changes and communication to health care professionals-recommended by the European Medicines Agency for use of cilostazol for the treatment of intermittent claudication in Europe. METHODS: Observational study of cilostazol in The Health Improvement Network (United Kingdom), EpiChron Cohort (Spain), SIDIAP (Spain), Swedish National Databases, and GePaRD (Germany). Among new users of cilostazol, we compared the prevalence of conditions targeted by the risk minimization measures in the periods before (2002-2012) and after (2014) implementation. Conditions evaluated were prevalence of smoking, cardiovascular conditions, concurrent use of ≥2 antiplatelet agents, concurrent use of potent CYP3A4/CYP2C19 inhibitors and high-dose cilostazol, early monitoring of all users, and continuous monitoring of users at high cardiovascular risk. RESULTS: We included 22 593 and 1821 new users of cilostazol before and after implementation of risk minimization measures, respectively. After implementation, the frequency of several conditions related to the labeling changes improved in all the study populations: prevalence of use decreased between 13% (EpiChron) and 57% (SIDIAP), frequency of cardiovascular contraindications decreased between 8% (GePaRD) and 84% (EpiChron), and concurrent use of high-dose cilostazol and potent CYP3A4/CYP2C19 inhibitors decreased between 6% (Sweden) and 100% (EpiChron). The frequency of other conditions improved in most study populations, except smoking, which decreased only in EpiChron (48% reduction). CONCLUSIONS: This study indicates that the risk minimization measures implemented by the EMA for the use of cilostazol have been effective in all European countries studied, except for smoking cessation before initiating cilostazol, which remains an area of improvement.

Epidemiology of Adult Soft-Tissue Sarcomas in Germany.

We conducted a retrospective cohort study using data compiled from the regional German cancer registries by the Centre for Cancer Registry Data (ZfKD) at the Robert Koch Institut (RKI) to describe the epidemiology of adult soft-tissue sarcomas (STS) in Germany in 2003-2012, focusing on advanced STS. We identified 33,803 incident adult cases of STS (other than the Kaposi sarcoma and gastrointestinal stromal tumors). The incidence of STS was 6.05 (95% confidence interval (CI), 5.82-6.29) per 100,000 in 2012 (4,079 cases). During 2003-2012, the most common histologic categories were leiomyosarcoma (19%), liposarcoma (16%), and STS not otherwise specified (14%). The overall STS-specific mortality rate in 2012 was 2.31 (95% CI, 2.06-2.57) per 100,000, and the median overall survival from initial diagnosis was 5.83 (95% CI, 5.50-6.08) years. Using STS mortality rates as a proxy for incidence of advanced STS in Germany and applying the age- and sex-specific rates to the corresponding German population, we estimated that 1,581 incident adult advanced STS cases occurred in Germany in 2012. Our findings contribute to a refined understanding of the population burden of STS in Germany, including the number of patients with advanced STS who may be candidates for systemic treatment.

Use of Topical Tacrolimus and Topical Pimecrolimus in Four European Countries: A Multicentre Database Cohort Study.

BACKGROUND: Despite the concerns about a potential increased risk of skin cancer and lymphoma with the use of topical tacrolimus and pimecrolimus, no population-based studies have given an overview of the use of these drugs in Europe. OBJECTIVE: To assess the use of topical tacrolimus and pimecrolimus in children and adults in Europe. METHODS: Multicentre database cohort study comprising data from the Netherlands, Denmark, Sweden and the UK. We analysed users of topical tacrolimus and pimecrolimus starting from the date of first availability (between 2002 and 2003) or start establishment of the prescription database in Sweden (2006) through 2011. Use was assessed separately for children (≤ 18 years) and adults. RESULTS: 32,052 children and 104,902 adults were treated with topical tacrolimus, and 32,125 children and 58,280 adults were treated with topical pimecrolimus. The number of users increased rapidly after first availability, especially for topical tacrolimus. Topical tacrolimus was more frequently used in all countries except Denmark. For both drugs, there was a decrease in users after 2004 in the Netherlands and Denmark and after 2005 in the UK, especially among children. This decrease was largest in Denmark. The decrease in the number of users was temporary for topical tacrolimus, while use remained relatively low for topical pimecrolimus. CONCLUSIONS: The number of topical tacrolimus and pimecrolimus users increased rapidly after regulatory approval. A transient reduction in topical tacrolimus use and a persistent reduction in topical pimecrolimus use was seen after 2004 in the Netherlands and Denmark and after 2005 in the UK.