Current Summary Of Product Characteristics Research Articles

Information in summaries of product characteristics about use in children is limited and needs standardisation: a systematic analysis in Switzerland

BackgroundA considerable proportion of drugs administered to children are not authorised for this purpose, and consequently off-label use is common in paediatric care. Our aims were to quantify systematically the...

Authorized or Off-Label Use? A Structured Analysis of Summaries of Product Characteristics with Regard to Authorization in Pediatrics.

The Summary of Product Characteristics (SmPC) is required to provide unambiguous information on the authorized use of a medicinal product. Therefore, we performed a structured analysis of the information provided for pediatric patients in current SmPCs. In the German SmPC of the medicinal products of 452 active substances, we analyzed for each of the listed indications whether information on pediatric use was available in Sects. 4.1-4.4 of the SmPC and, if so, whether it was unambiguous. Information was considered unambiguous if it indicated an exact age- or weight-related specification. The analysis also considered the type of marketing authorization and the date of marketing authorization, either before or after the Pediatric Regulation 2007 came into force. Among the 30,354 identified indications in 8464 SmPCs, unambiguous information was found for 72.4% (21,974/30,354) of the indications. Of these, 45.4% (9967/21,974) disclosed a contraindication for the entire population under 18 years of age. The proportion of unambiguous information was higher for medicinal products with centralized marketing authorization (86.5% [1449/1676]) than for those with a national one (71.6% [20,525/28,678]; p<0.001). A higher proportion of unambiguous information was found for the marketing authorization period 2007-2021 compared with 1996-2006 (1996-2006: 63.8% [7466/11,694]; 2007-2021: 82.1% [12,349/15,040]; p<0.001). For about a quarter of all indications, no or only ambiguous information was available for pediatric patients. The measures initiated in recent years to increase pediatric-specific information in SmPCs should be intensified in order to improve drug safety in children and adolescents.

Nirmatrelvir/ritonavir (Paxlovid®): French pharmacovigilance survey 2022

Nirmatrelvir/ritonavir (Paxlovid®) is currently one of the few therapeutic options for coronavirus disease 2019 (COVID-19) curative treatment in non-oxygen-requiring adult patients at-high risk of progressing to severe disease. This recently approved boosted antiviral therapy presents a significant risk of drug-drug interactions (DDI). As part of the enhanced surveillance program in France for COVID-19 drugs and vaccines, the French national pharmacovigilance database (BNPV [base nationale de pharmacovigilance]) was queried in order to better characterize the drug safety profile, with a special focus on DDI. The aim of the study was to describe the adverse drug reactions reported through the BNPV. All nirmatrelvir/ritonavir reports validated in the BNPV from the first authorization in France (January, 20th 2022) to December, 3rd 2022 (date of the query) were considered. An analysis of the scientific literature (PubMed®) and from the WHO pharmacovigilance database (Vigibase) was also performed. Over this period (11 months), 228 reports (40% of serious reports) were registered with a sex ratio of 1.9 female/1 male and a mean age of 66 years old. DDI reports account for more than 13% of reports (n=30) and were mainly related to immunosuppressive drugs overexposure (n=16). A total of 10/228 reports with fatal outcomes were reported in complex clinical settings. The main reported unexpected adverse drug reaction (ADRs) were high blood pressure (n=7), confusion (n=5), acute kidney injuries (AKI, n=7) and various skin reactions (n=22). Apart from situations of disease recurrence (not found in this analysis), data from Pubmed® and Vigibase also reported the above-mentioned events of interest. Overall, this analysis shows that nirmatrelvir/ritonavir safety profile was conform to current summary of product characteristics (SmPC). The main concern was the risk of DDI. Therefore, SmPC and expert recommendations should be systematically consulted before initiation of this antiviral, which is particularly indicated in polypharmacy patients. A case-by-case multidisciplinary approach including a clinical pharmacologist is required in these complex situations. Blood pressure elevation, confusion, cutaneous reactions and AKIs were the main unexpected ADRs of interest to follow, but need to be confirmed with a qualitative approach over time and new reports.

Prospective, Noninterventional Study of Nivolumab in Real-world Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer After Prior Chemotherapy (ENLARGE-Lung).

Nivolumab was the first immune checkpoint inhibitor approved for use in advanced non-small cell lung cancer (NSCLC). This noninterventional, prospective cohort study investigates real-world effectiveness of nivolumab in pretreated NSCLC patients in Germany (Enlarge-Lung/CA209-580). Patients with squamous (SQ) or nonsquamous (NSQ) NSCLC previously treated for locally advanced or metastatic (stage IIIB/IV) disease received nivolumab according to the current Summary of Product Characteristics. Overall survival (OS) was the primary endpoint. Of 907 patients enrolled, 660 patients who were followed for at least 12 months across 79 study centers in Germany, were analyzed. Median OS was 11.2 months [95% confidence interval (CI), 9.1-12.9]; outcomes for the 418 patients with NSQ histology [13.1 mo (95% CI, 10.6-15.6)] were more favorable than outcomes for the 242 patients with SQ histology [8.9 mo (95% CI, 6.4-11.3)]. Patients' age, presence of distant or brain metastases, or line of therapy did not affect outcomes; however, patients with poor performance status (ECOG-PS ≥2, n=80) had shorter median OS [4.7 mo (95% CI, 3.1-5.4)]. This study represents one of the largest real-world cohorts providing outcomes of nivolumab in pretreated NSCLC. The results match well with the published evidence from pivotal clinical trials and demonstrate clinical effectiveness of nivolumab in advanced NSCLC.

PS1407 TWICE WEEKLY CARFILZOMIB IS AN ACCEPTED TREATMENT BY PATIENTS WITH MULTIPLE MYELOMA WHO HAVE RECEIVED AT LEAST ONE PRIOR THERAPY: INTERIM RESULTS OF THE CARO STUDY

Background:Carfilzomib (Kyprolis®) has shown an improved overall survival and a good tolerability in two phase 3 studies (ENDEAVOR, ASPIRE) in patients (pts) with relapsed or refractory multiple myeloma and, thus, received market approval in the combination regimens carfilzomib/lenalidomide/dexamethasone (CAR/LEN/DEX) and carfilzomib/dexamethasone (CAR/DEX). CAR is intended to be given twice weekly in both regimens. In daily practice, poor adherence and persistence to anticancer treatment are serious issues as nonadherence has been shown to lead to higher treatment failure rates, worse outcome and higher total costs of care.Aims:The key objective of the CARO study is to collect real‐world data on the implementation of the recently approved regimens CAR/LEN/DEX and CAR/DEX in routine clinical practice in Germany with a special focus on treatment adherence.Methods:The prospective, multicenter, non‐interventional CARO study was designed to collect data on 300 pts with multiple myeloma from 90 sites across Germany. The primary objective is pts’ adherence to the CAR therapy as prescribed by the treating physician. Secondary objectives are pts’ adherence to LEN and DEX as well as the evaluation of the implementation of the recommended dosing regimens, i.e. a comparison of the actually administered medication versus recommended medication according to current Summary of Product Characteristics (SmPC). Exploratory objectives are effectiveness, safety and health‐related quality of life. The first interim analysis of the CARO study was scheduled 12 months after the recruitment of the first patient.Results:From 10/2016 through 10/2017, 102 pts have been enrolled, thereof 68 pts into the CAR/LEN/DEX cohort and 32 pts into the CAR/DEX cohort. Here, the focus is on the implementation of the recommended dosing regimen in pts who received CAR/LEN/DEX (N = 64). Median age of pts was 72.3 years (range 43.4–84.3), 45.3% were female and 70.3% of pts had a good performance status with a Karnofsky performance score between 80 and 100. The mean relative dose intensity of CAR was 88.1%. 1368 of the scheduled 1591 CAR administrations (86.0%) were given on time. 7.9% (n = 125) of administrations in 43.8% (n = 28) of pts were omitted, 5.0% (n = 80) of administrations in 62.5% (n = 40) of pts were delayed and 1.1% (n = 18) of doses in 18.8% (n = 12) of pts were administered earlier than planned. 1328 of 1466 CAR administrations (90.6%) were given at the recommended dose. 6.2% (n = 91) of doses in 23.4% (n = 15) of pts were reduced, 3.2% (n = 47) of doses in 7.8% (n = 5) of pts were increased. For reasons refer to Figure 1. The mean adherence to the CAR dosing regimen, i.e. the percentage of doses administered as scheduled by the treating physician and not modified for adherence reasons, was 94.8%.Summary/Conclusion:According to our interim results, 86% of CAR administrations were given as scheduled and more than 90% of administrations were given at the recommended dose. Modifications of the recommended CAR regimen were mainly due to safety issues or organizational reasons, but not due to lack of adherence. Though, despite the required twice weekly dosing schedule, the CAR regimen appears to be a well‐accepted treatment by multiple myeloma pts. Results need to be confirmed in the final analysis.image

Interim Results of the Observational Study Caro: Twice Weekly Carfilzomib Is a Convenient Treatment Option for Patients with Multiple Myeloma Who Have Received at Least One Prior Therapy

Introduction:Poor adherence and persistence to anticancer treatment are serious issues in the management of cancer patients since nonadherence has been shown to lead to higher treatment failure rates, worse outcome and higher total costs of care. The combination of the proteasome inhibitor carfilzomib (Kyprolis®) with lenalidomide (Revlimid®) and dexamethasone (CAR/LEN/DEX) or with dexamethasone alone (CAR/DEX) is approved for the treatment of patients with multiple myeloma who have received at least one prior therapy. According to the current approved schedule, carfilzomib has to be given twice weekly in both regimens. Real-world data on the implementation of this treatment recommendation are still limited.Methods:The prospective, multicenter, non-interventional, observational CARO study was designed to collect data on 300 patients with multiple myeloma (CAR/LEN/DEX: 200, CAR/DEX: 100) from 90 sites across Germany. Primary objective is patients' adherence and persistence to carfilzomib therapy as prescribed by the treating physician according to current Summary of Product Characteristics (SmPC). Secondary objectives are patients' adherence and persistence to lenalidomide and dexamethasone as well as the real-world implementation of the recommended CAR/LEN/DEX or CAR/DEX dosing regimen in clinical routine (i.e., the comparison of actually administered medication versus recommended medication according to current SmPC). Exploratory objectives are effectiveness, safety and health-related quality of life. The first interim analysis of the CARO study was scheduled to assess the primary and secondary endpoints 12 months after the recruitment of the first patient.Results:Between October 2016 and October 2017, 102 patients had been enrolled, thereof 68 patients into the CAR/LEN/DEX cohort and 32 patients into the CAR/DEX cohort at the time of the pre-specified interim analysis (database cut: 25 October 2017).Here, the focus is on the adherence of the twice weekly carfilzomib schedule in evaluable patients who received CAR/LEN/DEX (N=64) and on the implementation of the SmPC in terms of timing, dosing and frequency. Median age of patients was 72.3 years (range 43.4-84.3), 45.3% were female and 70.3% of the patients had a good performance status (PS) with a Karnofsky PS score of 80 to 100. The relative mean dose intensity of carfilzomib was 88.1%. 1368 of the scheduled 1591 carfilzomib administrations (86.0%) were given in time. 7.9% (n=125) of administrations were omitted, 5.0% (n=80) of administrations were delayed and 1.1% (n=18) of doses were administered earlier. Carfilzomib was omitted at least once in 43.8% of patients (n=28). 62.5% (n=40) and 18.8% (n=12) of patients, respectively, had a delayed or earlier carfilzomib administration documented at least once during their course of treatment. Reasons for deviations from the recommended carfilzomib dosing schedule concerning timing are depicted in Table 1. 1328 of 1466 carfilzomib administrations (90.6%) were given at the recommended dose. 6.2% (n=91) of doses were reduced. The main reason for dose reduction was the occurrence of adverse events (4.0%, n=58). Other reasons were: nonadherence (1.2%, n=18), organizational reasons (0.1%, n=2) and others (0.9%, n=13). 23.4% (n=15) of patients received at least one reduced carfilzomib dose during their course of treatment.The mean adherence to the carfilzomib dosing regimen (i.e., the percentage of doses administered as scheduled by the treating physician and not modified for adherence reasons) was 94.8%.Conclusion:According to our interim results, 86% of carfilzomib administrations were given in time and more than 90% of administrations were given at the recommended dose. Deviations from the recommended carfilzomib regimen were mainly due to safety issues or organizational reasons, but not due to nonadherence. Carfilzomib treatment adherence was almost 95%. Though, despite the required twice weekly dosing schedule, the carfilzomib regimen seems to be a convenient treatment option for multiple myeloma patients. Results have to be confirmed at final analysis. DisclosuresKnauf:Celgene: Consultancy, Honoraria; Roche: Consultancy; Amgen: Consultancy, Honoraria; Mundipharma: Consultancy; Gilead Sciences: Consultancy; AbbVie: Consultancy; Janssen: Consultancy. Marschner:Amgen: Consultancy, Honoraria; IOMEDICO: Employment, Equity Ownership; Sandoz: Honoraria.

A remarkable response to pazopanib, despite recurrent liver toxicity, in a patient with a high grade endometrial stromal sarcoma, a case report

BackgroundPazopanib is an oral tyrosine kinase inhibitor registered for metastatic renal cell carcinoma and soft tissue sarcoma. Liver toxicity is a common side effect for this class of agents. The current opinion is that in case of severe liver toxicity pazopanib should be interrupted and restarted at a lower dose after returning to Common Terminology Criteria for Adverse Events (CTCAE) grade 1. After recurrence of liver toxicity at the lower dose it is advised to permanently stop pazopanib. We describe a patient with an YWHAE-FAM22 translocated endometrial stromal sarcoma with a remarkable response to pazopanib despite recurrent liver toxicity.Case PresentationA 40 year old woman was diagnosed with metastatic YWHAE-FAM22 translocated endometrial stromal sarcoma. She was treated successively with doxorubicin, megestrol acetate and anastrozole, before pazopanib was initiated. Several dose interruptions and reductions were necessary due to liver toxicity, but nevertheless she had a good partial response. Seven months after the start, pazopanib was permanently stopped because of a bilateral pneumothorax. Nine months later it was reinitiated because of progression and was continued for another 8 months until final disease progression.ConclusionIn contrast to the current summary of product characteristics of pazopanib, the drug was successfully continued despite recurrent liver toxicity, and no further liver function deterioration was found. This case suggests that further dose reductions are good practice when liver toxicity limits treatment in responding patients.Secondly, this patient with rare YWHAE-FAM22 translocated endometrial stromal sarcoma showed a remarkable response to VEGFR/KIT inhibitor pazopanib. Recently, it was reported that this specific subtype of endometrial stromal sarcoma overexpresses CD117, but has no KIT mutations.This case illustrates that (a) pazopanib can be continued in patients with recurrent liver toxicity after dose reductions under strict surveillance and that (b) pazopanib shows good efficacy in YWHAE-FAM22 translocated endometrial stromal sarcoma.

Management of arrhythmia in sepsis and septic shock.

The occurrence of supraventricular arrhythmias is associated with an unfavourable prognosis in septic shock. Available trials are difficult to apply in sepsis and septic shock patients due to included cohorts, control groups and because "one size does not fit all". The priorities in the critically ill are maintenance of the sinus rhythm and diastolic ventricular filling. The rate control modality should be reserved for chronic AF and in situations when the sinus rhythm is difficult to maintain due to extreme stress conditions resulting from a high dosage of vasoactive agents. Electric cardioversion is indicated in unstable patients with an absence of contraindications and is more feasible in combination with an antiarrhythmic agent. Besides amiodarone being preferred for its lower cardiodepressant side effect compared to other agents, drugs with a different degree of betablocking activity are very useful in supraventricular arrhythmias and septic shock, providing echocardiography is routinely used to support their indications within the current summary of product characteristics. A typical patient benefiting from propafenone is without significant structural heart disease, i.e. typically with normal to moderately reduced left ventricular systolic function. Future research should be channelled towards echocardiography-guided prospective controlled trials on antiarrhythmic therapy which may clarify the issue of rhythm versus rate control, the effects of various antiarrhythmic drugs, and a place for electric cardioversion in critically ill patients in septic shock.

Cardiovascular Morbidity and Pure Red Cell Aplasia Associated With Epoetin Theta Therapy in Patients With Chronic Kidney Disease: A Prospective, Noninterventional, Multicenter Cohort Study

PurposeThe European Medicines Agency recommends limiting the hemoglobin (Hb) concentration to 10 to 12 g/dL in adults with chronic kidney disease (CKD) receiving erythropoiesis-stimulating agents such as epoetin theta. This postauthorization study assessed the incidence and intensity of cardiovascular events, including ischemic stroke, in patients receiving epoetin theta for anemia associated with CKD. A secondary end point was adverse drug reactions, including pure red cell aplasia. MethodsIn this prospective, noninterventional, multinational cohort study, consecutive patients with advanced or end-stage renal disease and receiving epoetin theta were followed up for 6 months. Data on reportable adverse events (RAEs) (cardiac disorders, cardiac failure, myocardial infarction, and ischemic stroke and respective subterms), epoetin theta dosage, and Hb concentrations were collected. A post hoc exploratory analysis assessed the incidences of RAEs according to tertiles for individual mean Hb concentration (≤10.7, >10.7–11.47, and >11.47 g/dL for low, intermediate, and high, respectively) and mean weekly epoetin theta dosage (≤62, >62–125, and >125 IU/kg/wk for low, intermediate, and high). FindingsData from 1039 patients were included (577 men, 462 women; mean age, 68.7 years). A total of 101 RAEs were documented in 89 patients (8.6%), for an event rate of 0.1985/person–year. Sixty-four patients (6.1%) died; none of the deaths was considered related to epoetin theta use. The incidence of RAEs was lowest at intermediate Hb concentrations (6.2%) compared with low (11.3%) and high (7.8%) Hb concentrations. The incidence of ischemic stroke was 1.5% at high Hb concentrations versus 0.6% at both the low and intermediate Hb concentrations. The incidence of any RAE was greater in the high-dose group (10.1%) than in the intermediate-dose (8.0%) and low-dose (7.6%) groups. The risk for any cardiovascular RAE or ischemic stroke was greatest in the high-dose/high-Hb group (13.3%), followed by high dose/low Hb (12.6%) and low dose/low Hb (12.1%). The risks for RAEs were lowest at high dose/intermediate Hb (3.8%) and low dose/intermediate Hb (5.3%). The event rate of adverse drug reactions other than the predefined RAEs was 0.0161/person–year. No cases of pure red cell aplasia were reported. ImplicationsThe findings from the present study suggest that, for maintaining the optimal target Hb concentration (10–12 g/dL according to the current summary of product characteristics for epoetin theta; 10–11.5 g/dL according to the current guideline from Kidney Disease Improving Global Outcomes) in anemic adults with CKD, the lowest approved, effective dose epoetin theta should be used.

A Post-Authorisation Safety Survey Evaluating Risperidone Long-Acting Injectable in Romania

Background: The main treatment objectives for schizophrenia, a chronic disease, include clinical response and symptom resolution, relapse prevention, and recovery. Objectives: The primary aim of this prospective survey is to confirm the safety of Risperidone Long-Acting Injectable (RLAI) under marketed conditions. Secondary objectives are to investigate the reasons for the initiation of treatment, effectiveness, and quality of life of patients on RLAI, alongside with compliance, clinical outcome and patients’ and clinicians’ satisfaction with treatment. Methods: In total, 1354 subjects were recruited by 253 investigational sites in Romania. All patients treated with RLAI, as decided after agreement between the physician and the patient, were eligible for inclusion in this survey. Subjects were either patients requiring a switch from previous antipsychotic medication, or patients at onset of schizophrenia. Data was collected at baseline and at one or more data collection moments. The analysis focussed on the 6 and 12 month timepoints. Results: After intake of RLAI, one third of the patients experienced a treatment-emergent AE. The most common reported AEs were psychiatric disorders related to the underlying disease (insomnia, anxiety, depression and psychotic disorder). Other reported AEs included extrapyramidal symptoms, weight gain, and endocrine disorders (amenorrhea, galactorrhea). The frequencies of these AEs were overall in agreement with those described in the current Summary of Product Characteristics. All parameters assessing drug efficacy showed a statistical significant improvement except for the number and the duration of hospitalizations which increased compared to the 6 months pre-study period. Conclusion: Treatment-emergent AEs observed during this study were consistent with the established safety profile of RLAI. In addition, treatment with RLAI resulted in the expected, statistically relevant improvement of psychiatric status in subjects eligible for such treatment, in most cases subjects diagnosed with schizophrenia and schizoaffective disorders.

Fumaderm® in daily practice for psoriasis: dosing, efficacy and quality of life.

Patients with psoriasis suffer from chronic skin disease and impaired quality of life. With a prevalence of 1-3% of the population, psoriasis is one of the most common chronic inflammatory autoimmune diseases. Fumaric acid esters (Fumaderm(®)) are approved for the treatment of psoriasis in Germany, but regular Fumaderm therapy with six tablets per day is often limited due to adverse events. This observational study recorded data on quality of life, treatment efficacy and drug dosing in patients suffering from psoriasis treated with Fumaderm under conditions of daily practice in 78 dermatological centres. In this prospective, multicentre, noninterventional trial we included adult patients with severe plaque psoriasis under outpatient conditions receiving Fumaderm according to the current summary of product characteristics for systemic treatment of psoriasis. At baseline and after 3, 6 and 12 months the dosing regimen under daily conditions, Dermatology Life Quality Index (DLQI) and clinical efficacy with the Psoriasis Area and Severity Index (PASI) were documented. A total of 249 patients were included. The mean DLQI score at study entry was 9·95; the mean PASI was 16·8. The average treatment dose of Fumaderm was 2·8 tablets daily. More than 70% of patients were treated with one to three tablets daily and < 30% were treated with a dose ranging from four to six tablets daily. DLQI and PASI improved in the entire study population by 67·2% and 66·6%, respectively. Specifically, when analysing patients who started Fumaderm within 4 weeks before baseline the mean DLQI score decreased from 11·8 to 2·9 (75% reduction) and the mean PASI score from 19·84 to 7·35 after 12 months (63% improvement). This is the first field study analysing the use of Fumaderm and the improvement of quality of life in patients with psoriasis under daily outpatient conditions. The improvement of DLQI obtained with Fumaderm was comparable with the improvement observed in patients with psoriasis treated with modern biologics. Importantly, in most patients with good clinical response, the treatment dose was one to three tablets daily.

Inconsistencies and misleading information in officially approved prescribing information from three major drug markets.

The summary of product characteristics (SPC) should provide information for the safe prescription and use of a drug. We evaluated the consistency of critical interaction warnings, the quality of presentation of undesirable effects as well as concordance of critical information of representative drugs marketed in the United States, the UK, and Germany. Reciprocal warnings regarding drug-drug interactions that constitute contraindications were frequently missing in the SPCs of the drugs concerned (all countries >40%). Most SPCs did not explicitly exclude adverse reactions considered not reasonably attributable to the use of the drug. Comparing SPCs of different generic brands of the same drug, only 60, 10, and 20% of the US, UK, and German SPCs, respectively, provided identical contraindications. Current SPCs contain inconsistencies and misleading data that are not compatible with the purpose of SPCs, which is to provide a basis for the safe prescription and use of drugs.

E‐SPC – delivering drug information in the 21st century: developing new approaches to deliver drug information to prescribers

e‐SPC – delivering drug information in the 21st century: developing new approaches to deliver drug information to prescribers

Effect of Safety Issues with HIV Drugs on the Approval Process of Other Drugs in the Same Class

Knowledge on the safety of new medicines is limited at the time of market entry. Nearly half of all drugs used to treat HIV registered in the EU required ≥1 Direct Healthcare Professional Communication (DHPC) in the past 10 years for safety issues identified post-approval. The aim was to evaluate the extent to which regulators and industry have addressed the risk of safety issues for HIV drugs based on prior experience with other drugs in the same class and whether doing so impacts development time of these drugs. HIV drugs receiving ≥1 DHPC in the Netherlands between January 1999 and December 2008 were identified. Each drug with a DHPC ('index' drug) was paired with subsequently approved HIV drug(s) in the same class (Anatomical Therapeutic Chemical [ATC] 4th level) ['follow-on' drugs]. Characteristics of safety issues were extracted from the DHPCs of the 'index' drugs. European Public Assessment Reports (EPARs) were reviewed regarding whether the safety issues had been considered during development and approval. Consideration of previously identified safety issues in 'follow-on' drug applications was assessed regarding attention paid to adverse drug reaction (ADR) symptoms in pre-marketing studies, Summary of Product Characteristics (SmPC) and postmarketing commitments, and whether size of the safety population was in accordance with Regulatory guidelines. 'Index' drugs were also paired with drugs in the same class already on the market ('older' drugs). For 'older' drugs, we identified whether the safety issue led to appropriate changes in the current SmPC (January 2011) compared with the SmPC at the time of marketing authorization. Clinical development time was assessed using time from first patent application to market authorization as proxy, and comparison was made between 'index' and 'follow-on' drugs. For 9 (43%) of the 21 centrally authorized HIV drugs, 11 serious safety issues that required a DHPC were identified. Two drugs were excluded from our analysis (DHPCs related to contamination/medication error). Six 'index' drugs were paired, each with one to six 'follow-on' drugs. Three concerned drug-drug interactions (DDIs); the other three were intracranial haemorrhage, neuromuscular weakness and severe skin/hepatic reactions. All but one 'follow-on' drug had information in the EPAR on that specific ADR (i.e. attention was paid to the ADR). The DDIs were addressed in pre-marketing studies and/or the SmPC. Two of the other ADRs were addressed by postmarketing surveillance commitments; intracranial haemorrhage was not addressed. Three safety issues for two 'index' drugs could not be paired with a 'follow-on' drug as no drug in the same class was approved after the corresponding DHPCs were issued. Five of the nine safety issues were added to at least one of the current SmPCs for the 'older' drugs already on the market at the time of DHPC issue. Two safety issues were already in the SmPC of the 'older' drugs at time of market approval and two were not introduced into the SmPC of 'older' drugs. Population size to assess short-term safety complied with the guidelines for four 'index', seven 'follow-on' and three 'older' drugs; population size to assess long-term safety complied for one, three and two drugs, respectively. For five drugs, EPARs did not provide adequate information on population size. No statistically significant difference in development time between 'index' and 'follow-on' drugs was found. Generally, safety issues were taken into account in the approval process of other drugs in the class. The approaches were different and determined by the nature of the ADR. Taking safety issues into account in the approval process did not seem to impact on the time taken to perform the pre-approval clinical programme.

A Feasibility Study Comparing Pharmacist and Physician Recommendations for Sildenafil Treatment

In Europe, pharmacists may be an important first point of contact for men with erectile dysfunction (ED) asking for advice and treatment. To determine if European community pharmacists could appropriately recommend suitability for supply of sildenafil 50 mg for the treatment of ED. For this cross-sectional, observational study, the current Summary of Product Characteristics was adapted to create a study drug information sheet for use in a pharmacy setting in which, for certain patients, supply is not suitable and referral to a physician is recommended. After training and with use of a guidance questionnaire, pharmacists assessed the suitability of supply of sildenafil 50 mg for men presenting to their pharmacy. Men with self-reported ED who were not currently using a phosphodiesterase type 5 inhibitor were recruited. Within 7 days of the pharmacist-patient interaction, a physician with experience in the management of ED telephoned the subject to assess suitability. If there was discordance between the pharmacist and physician recommendations, the case was independently reassessed by a physician specialist in sexual medicine. The primary end point was the concordance rate (with 95% confidence intervals) between pharmacist and physician recommendations. Rates were weighted by country sample sizes. Concordance (95% confidence interval) was 0.70 (0.66-0.74) between pharmacist and physician recommendation, indicating agreement in 70% of cases, and was 0.90 (0.86-0.94) between pharmacist and physician specialist in sexual medicine. Furthermore, if the cases in which the pharmacist did not put subjects at risk (i.e., gave an acceptable recommendation) are assessed, the success rate is 83.5% (79.6-87.4%) and 92.8% (90.1-95.5%), respectively. Pharmacists were accurate in providing suitable treatment recommendation, generally not recommending sildenafil for men without ED and recommending physician assessment when there was any question about cardiovascular health, other comorbidity, or co-medication.

Safety Data and Beneficial Effects of the Combined Oral Contraceptive Ethinylestradiol 0.03 mg/Chlormadinone Acetate 2 mg (Belara®)

The monophasic hormonal combined oral contraceptive (COC) ethinylestradiol (EE) 0.03 mg/chlormadinone acetate (CMA) 2 mg (Belara®) has been shown to have good long-term efficacy and tolerability. The aim of this study was to corroborate the long-term safety of EE 0.03 mg/CMA 2 mg by evaluating the incidence and severity of adverse drug reactions (ADRs) and cycle control over 13 treatment cycles. Additionally, the influence of EE 0.03 mg/CMA 2 mg on dysmenorrhoea, acne and the well-being of subjects was also investigated. This observational study was conducted in Spain, France and Italy from April 2006 to August 2008. Subjects of reproductive age, without contraindications mentioned in the current summary of product characteristics, were prescribed EE 0.03 mg/CMA 2 mg in routine clinical practice. 3771 subjects were analysed and at least one ADR was reported in 833 (22.1%) subjects, with the majority of ADRs (75.6%) being judged as mild or moderate. The most frequently reported ADRs were intermenstrual bleeding (7.7% of all analysed subjects), headache (5.1%) and breast pain (2.7%). Spotting and breakthrough bleeding (defined as slight and heavier intermenstrual bleeding) at baseline were reported by 677 (18.0%) and 268 (7.1%) subjects, but were less frequent in cycles 10-13 (9.6% and 1.7%, respectively). Before study start, 61.8% of subjects suffered from dysmenorrhea, with the intensity being moderate or severe in 66.9% of these subjects. In cycles 10-13, the corresponding values were noted in 15.0% and 25.6% of subjects. The proportion of subjects who suffered from acne decreased from 46.5% at study entry to 14.9% after 13 medication cycles. More than 50% of the subjects who had switched from another oral contraceptive (OC) pill stated that the tolerability of EE 0.03 mg/CMA 2 mg and their health-related well-being were much better or better after two cycles of EE 0.03 mg/CMA 2 mg than when they were taking their previous OC, and about 85% of the subjects assessed the tolerability of EE 0.03 mg/CMA 2 mg as very good or good during the study. These results re-affirmed the favourable ADR profile of the COC EE 0.03 mg/CMA 2 mg, as well as its good cycle control and beneficial effects on dysmenorrhoea, complaints typically occurring during the cycle, acne and well-being.

Topiramate in patients with epilepsy and intellectual disability

This noninterventional single-arm study explored effectiveness and behavioral outcomes in intellectually disabled patients treated with topiramate for epilepsy. Data from 21 patients diagnosed with cerebral palsy were available for evaluation. Behavioral changes were assessed using the validated Aberrant Behavior Checklist and Matson Evaluation of Social Skills for Individuals with Severe Retardation (MESSIER) scales. Some improvement in nearly all behavioral aspects was observed under concomitant topiramate therapy; for example, the Aberrant Behavior Checklist total score changed from 33.7+/-25.8 to 25.3+/-19.1 (P=0.047). In addition, seizure frequency decreased from 16.1+/-22.2/4 weeks to 12.2+/-17.0/4 weeks (N=21, P=0.164). Fifty-two percent of the patients experienced at least 50% seizure reduction during the 24-week treatment period. The safety profile is in accordance with the current Summary of Product Characteristics of Topiramate. Two unexpected deaths were attributed to sudden unexpected death in epilepsy.

Bortezomib Retreatment in Relapsed Multiple Myeloma (MM): Results from a Binational, Multicenter Retrospective Survey

In myeloma therapy retreatment after successful therapy is frequently considered. Here we present pooled data from a German and Swiss multicenter, retrospective survey (26866138MMY4014). The survey started in Germany and was later extended to Switzerland. German data have already been published before. Here we report on the entire cohort of patients for the first time.For inclusion into this analysis, patients with MM had to have had preceding bortezomib treatment, resulting in at least partial remission and a second therapy with Bortezomib on relapse. The intention of this trial was to provide further evidence of the value of a retreatment with bortezomib, description of predisposing factors and comparison of response quality and remission duration in this predefined patient group of bortezomib responders. Data from 36 centers and 94 patients were available for safety analysis. 34 patients had to be excluded from the efficacy analysis due to major deviations from the inclusion criteria, i.e. concomitant antineoplastic treatment, retreatment with bortezomib not being completed, no response during initial bortezomib treatment or missing information about MM-specific interim therapy. Thus 60 patients were left for the per protocol population (PP). Patients had a mean age of 65.5 years (40–89), 56.4% being male. Patients had received a mean of 3.7 prior therapies for multiple myeloma before initial bortezomib therapy, most frequently melphalan-prednisone (44.7%), dexamethasone (38.3%) and/or vincristine-adriamycin-dexamethasone (31.9%). Stem cell transplantation was undertaken in 26.6% of the patients.Mean cycle numbers for initial bortezomib therapy and retreatment were 5.8 and 4.5, respectively. The majority of patients (85.1% and 78.7%, respectively) received a bortezomib dose of 1.3 mg/m2. Concomitant dexamethasone therapy was administered to 43.6% and 62.8% of the patients, respectively. Between the initial bortezomib therapy and bortezomib retreatment 13.8% of the patients received other MM-specific interim therapy.The efficacy analysis was based on the PP population and revealed very encouraging responses. Overall response (OR) was defined as complete response (CR), nearly complete response (nCR) and partial response (PR). With a pre-defined OR of 100% for the initial bortezomib therapy, 63% (49.9–75.4%) responded again to retreatment. Best response is summarized in the table below.Subgroup analyses of the rates of clinical benefit (CR, nCR, PR or SD) were performed by treatment free interval (TFI) after initial bortezomib therapy (<= 6 months versus > 6 months) and by concomitant dexamethasone treatment. In patients with TFI > 6 months a higher rate of clinical benefit (89.7%) could be achieved as compared to TFI <= 6 months (61.9%). Concomitant dexamethasone treatment was associated with a lower rate of clinical benefit (76.5%) than without (84.6%).For 44 patients (46.8%) a total of 125 adverse drug reactions (ADRs) were documented. 21 serious ADRs were documented in 11 (11.7%) patients. 30 patients had died at the time of analysis. 2 patients died due to adverse events (pneumonia and pulmonary oedema) assessed as at least possibly related to bortezomib. For one fatal outcome (pneumonia) causality assessment has not been provided.This binational retrospective survey suggests that the safety profile is in line with the current summary of product characteristics of Velcade and that high remission rates and durable TFIs can be achieved by bortezomib retreatment. A TFI > 6 months could be a good clinical marker for a higher rate of clinical benefit. Results of an ongoing prospective trial on bortezomib retreatment are awaited to confirm these results.Initial bortezomib therapy (N=60)Bortezomib retreatment (N=60)Complete response (CR)12 (20%)8 (13.3%)Nearly complete response (nCR)7 (11.7%)3 (5%)Partial response (PR)41 (68.3%)27 (45%)Stable disease (SD)- (not allowed by selection criteria)10 (16.7%)Progressive disease (PD)- (not allowed by selection criteria)12 (20%)Median time to response3.1 months3.3 months*Median duration of response6.9 months6.1 months*Median treatment free interval8.6 months5.7 months* based on n=47 patients responding to bortezomib retreatment.

Examination of the safety and use of apomorphine prescribed in general practice in England as a treatment for erectile dysfunction

To examine the safety and use of apomorphine as prescribed in general medical practice in England as a treatment for erectile dysfunction (ED). Apomorphine hydrochloride (marketed as Uprima, Abbott Laboratories Ltd, UK) is licensed in the UK as a sublingual therapy for ED. It is the first treatment for ED with a central mode of action. This postmarketing observational cohort study was conducted using prescription-event monitoring (PEM) methods. Exposure information was obtained from dispensed prescription data for patients first prescribed apomorphine between October 2001 and December 2002. Outcome data were derived from Green-Form questionnaires posted to prescribing physicians > or = 6 months after the date of the first apomorphine prescription for each patient. The study cohort comprised 11 185 patients, 99.3% (11,111) of whom were men, with a median (interquartile range) age of 61 (54-68) years. The most frequently reported prescribing indication was ED and the most frequently reported reason for stopping apomorphine was that it was 'not effective'. In addition, the percentage of patients for whom apomorphine was reported to have been effective was relatively low. Headache was the most commonly reported adverse drug reaction, and the most frequently reported clinical condition occurring in the first month of observation. A small number of events (24) were reported that were not listed in the current Summary of Product Characteristics (SPC) and were considered by the prescribing general practitioner (GP) to be associated with apomorphine use. The proportion of patients for whom apomorphine was reported to be effective was low. Also, 'not effective' was the most frequently reported event and a high percentage of patients stopped apomorphine because it was 'not effective'. The most frequently reported clinical adverse events (headache and nausea) were those listed in the SPC. A small number of reports for unlabelled events were thought by prescribers to be related to apomorphine use. The confounding factors of patient age and coexisting disease should be considered when assessing data from this study.

Étude de l'usage de l'acétate de flécaïnide auprès des médecins généralistes et des cardiologues hospitaliers ou libéraux en France. OBEPINE : étude observationnelle des prescriptions de flécaïnide

A pharmacoepidemiological cross-sectional observational study was performed among a representative sample of French general practitioners and cardiologists. The aim of this study was to describe the prescription modalities of flecainide acetate, an Ic class antiarrhythmic, and how these modalities match the marketing authorization and the current summary of product characteristics. A total of 941 physicians participated in the study, 496 GPs and 445 cardiologists, and 1116 patients treated with flecainide for more than one month were included. On average, the patients were 68.7-years-old and 54% of them were women. Most of the initial flecainide prescriptions came from cardiologists (96%) and the check-up included an electrocardiogram (98%), a Holter monitoring (56%) and/or an echocardiography (71%). The preferred indication was supraventricular rhythm disorders (95%) and mostly atrial fibrillation (63%). A small proportion of coronary patients (7%) and of patient suffering from cardiac insufficiency (4%) was found. Flecainide was prescribed with a median posology of 150 mg per day, mostly as LP form (64%). Overall, the indications specified in the summary of product characteristics were respected in 90% of the cases, the contraindications in 91% of the cases and the patient follow-up was appropriate in 99% of the cases. In conclusion, the study showed that the prescription's conditions of flecainide in France complied with the summary of product characteristics data for most of the prescribing physicians with a respect of the indications, contraindications and management recommendations in 84% of the cases.