Post-authorization Safety Study Research Articles

Hydroxyethyl starch 130/0.42/6:1 for perioperative plasma volume replacement in 1130 children: results of an European prospective multicenter observational postauthorization safety study (PASS)

Third-generation hydroxyethyl starch (HES) is now approved also for the use in children, but safety studies including large numbers of pediatric patients are still missing. Therefore, we performed an European multicentric prospective observational postauthorization safety study (PASS) to evaluate the use of HES 130/0.42/6:1 in normal saline (ns-HES) or a balanced electrolyte solution (bal-HES) in children undergoing surgery. Children aged up to 12 years with ASA risk scores of I-III receiving ns-HES (Venofundin 6%; Braun) or bal-HES (Tetraspan 6%; Braun) were followed perioperatively. Demographic data, surgical procedures performed, anesthesia, hemodynamic and laboratory data, adverse events (AE), and adverse drug reactions (ADR) were documented using a standardized case report form. Of 1130 children studied at 11 European pediatric centers from 2006 to 2009 (ns-HES, 629 children; bal-HES, 475 children; mean age, 3.6 ± 3.8 [range, day of birth-12 years]; and body weight, 15.4 ± 13 [0.9-90 kg]), 1104 were included for analysis. The mean infused HES volume was 10.6 ± 5.8 (0.83-50) ml·kg(-1). In the 399 (36.1%) cases with blood gas analysis before and after HES infusion, hemoglobin and strong ion difference decreased significantly in both groups, whereas bicarbonate and base excess (BE before infusion: ns-HES -1.8 ± 3.1, bal-HES -1.2 ± 3.3 mm; after infusion: ns-HES -2.5 ± 2.8; bal-HES -1.1 ± 3.2 mm, P < 0.05) decreased only with ns-HES but remained stable with bal-HES. Chloride concentrations increased in both groups and were significantly higher with ns-HES (Cl before infusion: ns-HES 105.5 ± 3.6, bal-HES 104.9 ± 2.9 mm; Cl after infusion: ns-HES 107.6 ± 3.4, bal-HES 106.3 ± 2.9 mm, P < 0.05). For the AE/ADR rates, dose-response but no age relationships could be demonstrated. No serious and no severe ADR directly related to HES (i.e. anaphylactoid reaction, clotting disorders, renal failure) were observed. Moderate doses of HES 130/0.42/6:1 for perioperative plasma volume replacement seem to be safe even in neonates and small infants. The probability of serious ADR is lower than 0.3%. Changes in acid-base balance may be decreased when HES is used in an acetate-containing balanced electrolyte solution instead of normal saline. Caution should be exercised in patients with renal function disturbances and those with an increased bleeding risk.

Post-Approval Safety Study (PASS) of Lenalidomide Compared with Other Treatments in Patients with Relapsed or Refractory Multiple Myeloma

Abstract 1867 Background:In recent years, there have been major advances in the treatment of multiple myeloma (MM) as patients now have treatment options that greatly improve clinical outcomes. Many publications have described the safety of anti-myeloma drugs in the clinical trial setting. However, very few have addressed the issue of tolerability of these agents in a real-world clinical setting. Lenalidomide is an effective treatment option for MM and is currently approved by the EMA and US FDA for the treatment of MM patients who have received at least 1 prior therapy. Here we analyze the tolerability of 3 common novel agent-based anti-myeloma therapies in daily clinical practice. Methods:This observational post-authorization safety study was designed to characterize the safety profile of lenalidomide and to compare the incidence of adverse events (AE) with those occurring in patients receiving other anti-myeloma treatments. Patients entering the study had previously received at least 1 prior therapy and were commencing a new treatment for their relapsed/refractory MM (RRMM). Patients were enrolled into the Lenalidomide Cohort (lenalidomide plus dexamethasone) or the Background Cohort (all other treatments) based on investigator's discretion. Thromboprophylaxis was allowed, but not required. Results:As of July 2011, 2201 RRMM patients in 265 institutions in 17 European countries were enrolled. 1500 received lenalidomide, 538 bortezomib, 90 thalidomide, and 73 received other therapies or had missing data. 75 patients from the Background Cohort crossed over to receive lenalidomide. Median follow-up was 20.7 weeks (range, 0.1–125.7 weeks). Overall, the median age was 69 years (range, 29–92) and 55% were male. Most patients had a good performance status (ECOG 0–1) but 18% had an ECOG score of 2–4. The median number of previous treatment lines was 2 (1–6), 51.5% had 2 previous lines and 24% had 3 or more. Baseline characteristics across treatment groups were similar. Patients receiving lenalidomide had a median treatment duration of 4.4 months; patients receiving bortezomib and thalidomide had 3.4 months and 3.7 months, respectively. NCI grade 3/4, serious and life threatening AEs are presented in the table. Venous thromboembolism was experienced in 5% of lenalidomide-treated patients (3% had grade 3/4); 0.7% of bortezomib-treated patients (0.6% had grade 3/4); 1 (1%) thalidomide-treated patient had grade 3/4. Peripheral neuropathy was observed in 10% of lenalidomide-treated patients (1% had grade 3/4); 28% of bortezomib-treated patients (4% had grade 3/4); and 21% of thalidomide-treated patients (2% had grade 3/4). Ten (0.5%) invasive second primary malignancies (SPM) were reported across all treatment groups; 5/1500 (0.3%) patients treated with lenalidomide, 4/538 (0.7%) with bortezomib, and 1/90 (1%) with thalidomide. Three cases of second primary hematologic malignancies (lenalidomide, 2; bortezomib, 1; thalidomide, none) and 7 cases of second primary solid tumors (lenalidomide, 3; bortezomib, 3; thalidomide, 1) were observed. Additionally in the lenalidomide group, 1 patient each developed a non-invasive basal cell carcinoma and a non-invasive fibrous histiocytoma. All of these patients were heavily pre-treated and most had received autologous stem cell transplantation to support high-dose melphalan during the course of their disease. 51% of patients in the lenalidomide group discontinued therapy while 65% and 71% discontinued bortezomib and thalidomide treatments, respectively. Primary reasons for discontinuation were adverse events (lenalidomide, 13%; bortezomib, 14%; thalidomide, 18%) and disease progression (lenalidomide, 15%; bortezomib, 13%; thalidomide, 17%). Overall, 1% of patients died due to an adverse event suspected to be related to drug (lenalidomide, 1%; bortezomib, 0%; thalidomide, 1%). Conclusion:Consistent with previous reports, lenalidomide is generally well tolerated. With the exception of peripheral neuropathy, adverse events in this group of patients treated in daily clinical practice appeared similar across treatment groups.Table 1:Adverse events according to NCI (version 3) gradingEvents (NCI grades)LenalidomideBortezomibThalidomide(At least one event occurred)(N = 1500)(N = 538)(N = 90)Any grade 3–4 event38%36%38%Drug-related grade 3–4 event25%22%19%Drug-related serious event11%8%11% Disclosures:Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Symeonidis:Novartis Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Genzyme: Research Funding; Pfizer: Research Funding; Gilead: Consultancy, Research Funding. Bird:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Genzyme: Membership on an entity's Board of Directors or advisory committees. Bacon:Celgene Corporation: Employment. Rosettani:Celgene Corporation: Employment. Kueenburg:Celgene Corporation: Employment. Minton:Celgene Corporation: Employment, Equity Ownership.

Prospective, observational registry of branded imatinib and nilotinib exposure in pregnant women: Voluntary postauthorization safety study.

TPS205 Background: Family planning decisions for patients of child-bearing age are impacted by their cancer diagnosis. Imatinib and nilotinib are category D drugs (ie, demonstrated risk to the fetus; however, the benefits of therapy may outweigh the potential risk to the fetus). Limited data exist concerning the safety of these drugs during pregnancy and the consequences of interrupting treatment. The Registry does not recommend patients receiving imatinib or nilotinib become pregnant, but serves only to document exposures that occur, and to collect information on the pregnancy outcome, maternal course of disease, and infant follow-up. Methods: The registry intends to enroll 225 women (≥18 years) treated with branded-only imatinib and nilotinib within 6 months prior to or during pregnancy (generic imatinib and nilotinib reports are excluded). The schedule of visits and treatment are according to local standard of care. Women are divided into two cohorts: 1) pregnancy/fetal: received tyrosine kinase inhibitors (TKIs) within 14 days of conception or at any time during pregnancy; 2) interrupted TKI: received TKIs within 6 months prior to conception but interrupted TKIs in preparation for/as a result of pregnancy. To identify signals of teratogenicity, the registry uses a general population baseline rate of birth defects, and the prevalence of defects in cohorts 1 and 2 may be compared. Cases will be quantitatively analyzed for the emergence of unique or patterns of defects. The primary objective is to monitor TKI-exposed pregnancies to estimate the prevalence of birth defects (calculated by dividing number of birth defects by total number of exposed live births from cohort 1. The secondary objectives are to: 1) determine the impact of treatment interruption on maternal disease status; 2) to assess and estimate the prevalence of serious adverse pregnancy outcomes; 3) and to assess and estimate the prevalence of developmental delays and functional deficits among infants during the first year of life. Maternal disease status is analyzed comparing disease status at registration, pregnancy outcome, and 1-year after birth, stratified by length of TKI interruption.

Pregnancy and safety outcomes in women vaccinated with an AS03-adjuvanted split virion H1N1 (2009) pandemic influenza vaccine during pregnancy: A prospective cohort study

Infection with influenza virus during pregnancy poses a significant risk of complications for both mother and fetus. During the H1N1 2009 pandemic, pregnant women constituted one of the priority groups for vaccination in many countries, creating a need for close monitoring of the safety of the vaccine in pregnant women. We present findings from an analysis of a cohort of pregnant women (N=267) from a prospective, observational, post-authorization safety study of the AS03-adjuvanted split virion H1N1 (2009) pandemic vaccine. There were 265 known pregnancy outcomes with 261 live births, four spontaneous abortions with no congenital anomalies, and no stillbirths. There were six live births with congenital anomalies, of which one was diagnosed before vaccination. A total of 247 women (94.6%), of whom four had twin pregnancies, delivered at term, and 14 women (5.4%), of whom two had twin pregnancies, delivered preterm (between Weeks 24 and 36 of gestation), with three of them (1.1%) occurring before 32 weeks (very preterm). Twenty-one neonates (8.1%) had a low birth weight (<2.5kg), of whom nine (3.5%) were term neonates. The prevalence of all outcomes was in line with the expected rates. The adverse events reported were consistent with the events anticipated to be reported by this study population. No adverse events of special interest were reported.The results of this analysis suggest that exposure to the AS03 adjuvanted H1N1 (2009) vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes including spontaneous abortion, congenital anomalies, preterm delivery, low birth weight neonates, or maternal complications. Although limited in size, the fully prospective nature of the safety follow-up of these women vaccinated during pregnancy is unique and offers an important degree of reassurance for the use of the AS03 adjuvanted H1N1 (2009) vaccine in this high risk group for H1N1 infection.

A novel isotonic balanced electrolyte solution with 1% glucose for intraoperative fluid therapy in neonates: results of a prospective multicentre observational postauthorisation safety study (PASS)

Neonates have a higher metabolic rate and an increased risk of perioperative hypoglycemia and lipolysis, but during anesthesia, both oxygen consumption and metabolic rate are decreased, and this may lead to reduced intraoperative glucose requirements. The objective of this prospective multicentre observational postauthorisation safety study was to evaluate the intraoperative use of a novel isotonic balanced electrolyte solution with a low glucose concentration of 1% (BS-G1) in neonates with a particular focus on changes in acid-base, electrolyte, and glucose concentrations. Following the local ethics committee approval, neonates with a postmenstrual age under 45 weeks and an ASA risk score of I-IV undergoing intraoperative administration of BS-G1 were enrolled. Patient demographics, the performed procedure, adverse drug reactions, hemodynamic data, and the results of blood gas analysis before and after infusion were documented with a focus on changes in acid-base, electrolyte, and glucose concentrations. In 66 neonates (ASA I-IV; postmenstrual age 38 ± 4, range 25-45 weeks; body weight 2.9 ± 0.9, range 0.65-4.6 kg), the mean infusion rate was 10.4 ± 3.2 (range 4.5-19.6) ml·kg(-1) ·h(-1) BS-G1. During the infusion, hemoglobin, hematocrit, bicarbonate, base excess, anion gap, strong ion difference, and calcium decreased, and chloride and glucose increased significantly within the physiological range. All other measured parameters including sodium and lactate remained stable. Neither hypoglycemia (glucose < 3 mm) nor hyperglycemia (glucose > 10 mm) was documented after BS-G1 infusion. No adverse drug reactions were reported. The study shows that the intraoperative use of an isotonic balanced electrolyte solution with 1% glucose and a mean infusion rate of 10 ml·kg(-1) ·h(-1) helps to avoid acid-base dysbalance, hyponatraemia, hypoglycemia, ketoacidosis, and hyperglycemia in surgical neonates. A careful intraoperative monitoring and adaptation of the infusion rate as needed is crucial because the glucose and fluid requirements may vary widely between subjects.

A 2-year post-authorization safety study of high-strength pancreatic enzyme replacement therapy (pancreatin 40,000) in cystic fibrosis

Objective: At the request of the Medicines and Healthcare Regulatory Agency and in agreement with the appropriate authorities, an observational, multi-center, non-interventional, post-authorization safety study of high-strength pancreatic enzymes was conducted.Research design and methods: Patients with exocrine pancreatic insufficiency due to cystic fibrosis (CF) who had previously taken high doses of pancreatic enzymes received pancreatin 40,000 capsules (Creon 40,000 Minimicrospheres, Abbott GmbH, Hanover, Germany) as part of their normal treatment for up to 2 years. Initial doses were calculated to match previous established doses in lipase units, with adjustment if required.Main outcome measures: Safety focused on serious suspected adverse drug reactions. Maldigestion symptoms and body weight were also monitored. Patients were managed according to general guidelines common to all major CF units in the UK, although minor variations were expected. The coefficient of fat absorption was not assessed as this was a safety rather than an efficacy study.Results: Sixty-four patients were enrolled at nine UK centers. Two deaths occurred during the study, which were considered unrelated to therapy by investigators. There were no further serious suspected adverse drug reactions related to pancreatin 40,000 and no cases of fibrosing colonopathy. Daily lipase doses were reduced by 11% after switching to pancreatin 40,000. Maldigestion symptoms improved and mean body weight increased from baseline to last observation (mean + 6.1 kg in patients < 18 years old).Conclusions: No safety concerns were identified with pancreatin 40,000 therapy for up to 2 years. Daily lipase doses were not increased when switching to pancreatin 40,000.

A novel isotonic-balanced electrolyte solution with 1% glucose for intraoperative fluid therapy in children: results of a prospective multicentre observational post-authorization safety study (PASS)

The recommendations for intraoperative fluid therapy in children have been adapted from hypotonic to isotonic electrolyte solutions with lower glucose concentrations (1-2.5% instead of 5%) to avoid hyponatremia and hyperglycemia. The objective of this prospective multicentre observational post-authorization safety study was to evaluate the intraoperative use of a novel isotonic-balanced electrolyte solution with 1% glucose (BS-G1) with a particular focus on changes in acid-base status, electrolyte and glucose concentrations. Following local ethics committee approval, pediatric patients aged up to 4 years with an ASA risk score of I-III undergoing intraoperative administration of BS-G1 were enrolled. Patient demographics, the performed procedure, adverse drug reactions, hemodynamic data, and the results of blood gas analysis before and after infusion were documented with a focus on changes in acid-base status, electrolyte and glucose concentrations. In 107 patients (ASA I-III; age 16.2 ± 15.4, range day of birth to 47.7 months; body weight 8.8 ± 4.8, range 1.6-18.8 kg), the mean volume infused was 20 ± 12.6 (range 3.6-83.3) ml·kg(-1) BS-G1. During the infusion, hemoglobin, hematocrit, anion gap, strong ion difference, and calcium decreased and chloride and glucose increased significantly within the physiologic range. All other measured parameters including sodium, bicarbonate, base excess, and lactate remained stable. Neither hypoglycemia (glucose <2.5 mmol·l(-1) ) nor hyperglycemia (glucose >10 mmol·l(-1) ) was documented after BS-G1 infusion. No adverse drug reactions were reported. The studied isotonic-balanced electrolyte solution with 1% glucose helps to avoid perioperative acid-base imbalance, hyponatremia, hyperglycemia, and ketoacidosis in infants and toddlers and may therefore enhance patient safety.

A new, safe and convenient 5-L dual-chamber container for automated peritoneal dialysis

Automated peritoneal dialysis (APD) provides the opportunity for home-based dialysis, enabling the patient to optimize their lifestyle by maintaining their normal daily routine. Use of a larger bag size and biocompatible solution is desirable. In an effort to further improve patient convenience and reduce the probability of infusing only the buffer contents from the outflow chamber, we designed a 5-L dual-chamber container system with a dual-seal system consisting of a long seal between the dextrose chamber and buffer chambers and a short SafetyMoon™ seal between the buffer chamber and container outflow connector. The safety and effectiveness of this new container system was assessed in a non-interventional, prospective, open-label, multi-centre, uncontrolled, Baxter-sponsored post-authorization safety study in 249 patients from 7 countries in Europe. No mis-infusion events were noted throughout the study where 68 519 Physioneal™ 5-L bags in Clear-Flex™ were used for an average (SD) of 4.3 (1.9) months per patient. Overall, the percentage of patients and/or care providers rating the 5-L bag preparation as very easy or easy at baseline (0-8 weeks), 9-16, 17-24 and 25-32 weeks ranged from 94 to 97%. Assuming a Poisson distribution for the bag count data, the estimated change in number of bicarbonate/lactate dialysis fluid bags (5 or 2.5 L) as a percent of prior bag use was -36%, while the estimated change in number of bags for ALL solutions as a percent of prior bag use was -31%. The predominant reasons given by the investigators for prescribing 5-L PD solutions at study onset were biocompatibility, easier and convenient for their patients to use, physiological pH and less bag connections. None of the 92 serious adverse events were suspected to be related to the Physioneal 5-L PD solution. Use of a larger, Physioneal 5-L bag mitigates the concern regarding the possibility of mis-infusing the buffer chamber solution, is convenient to use by the patient/health care provider and is associated with more than a 30% reduction in the weekly number of dialysis solution bags required per patient for their APD therapy.

Safety and efficacy of long-acting injectable risperidone in daily practice: an open-label, noninterventional, prospective study in schizophrenia and related disorders

This postauthorization safety study evaluated the long-term safety, tolerability, and efficacy of risperidone long-acting injectable (RLAI) in routine clinical practice. In this 6-month, multicenter, European, naturalistic study, patients were included if, during routine clinical practice, long-term antipsychotic therapy with RLAI was deemed necessary by the treating physician. Efficacy measures included Clinical Global Impression-Severity and Global Assessment of Functioning. Safety was evaluated by recording treatment-emergent adverse events (AE). RLAI was initiated in 5134 patients (aged 14-94 years); predominantly male (58.6%) with paranoid schizophrenia (69.8%). RLAI initial doses were 25 mg every 2 weeks (37.0% patients), 37.5 mg (18.0%), and 50 mg (44.4%). Treatment was completed by 4314 patients (84.0%). RLAI was discontinued on account of loss to follow-up (n=346; 6.7%), insufficient response (n=116; 2.3%), and AEs (n=106; 2.1%). Clinical Global Impression-Severity significantly improved from baseline to endpoint (P<0.001). Patient functioning on the Global Assessment of Functioning scale also significantly improved from baseline to endpoint (45.4 + or - 16.0 vs. 62.4 + or - 17.7, respectively, P<0.001). Treatment-emergent AEs were recorded by 1018 (20%) of patients. AEs occurring in > or = 5% of patients were akathisia, extrapyramidal disorders, depression, psychotic disorder, anxiety, and weight gain. Serious AEs were reported by 384 (8%) patients. This study confirms good safety, tolerability, and efficacy with RLAI in routine clinical practice.

Safety and tolerability of Esberitox® tablets in children with viral cold diseases: a post-authorisation safety study (PASS)

Aim: Documentation on safety and tolerability of Esberitox® tablets (Thujae occidentalis herba, Echinaceae radix, Baptisiae tinctoriae radix; formerly Esberitox® N) in a group of children from 4–11 years of age treated for viral cold diseases.

Hydroxyethyl starch 130/0.42/6:1 for perioperative plasma volume replacement in children: preliminary results of a European prospective multicenter observational postauthorization safety study (PASS)

Several clinical studies have shown that hydroxyethyl starch (HES) may be as effective and safe as, but less expensive than, albumin when used for perioperative plasma volume replacement (PVR) in children. The new third generation HES 130/0.42 solution was designed to reduce adverse drug reactions (ADRs) and improve safety while maintaining efficacy. Therefore, the objective of this prospective multicenter observational postauthorization safety study (PASS) was to evaluate the perioperative use of HES 130/0.42 in 1000 children with a particular focus on possible ADRs. Approximately 300 of 1000 pediatric patients aged up to 12 years with ASA risk scores of I-III receiving perioperative HES 130/0.42 (Venofundin 6%; Braun, Melsungen, Germany) should be enrolled for interims analysis in the first year. The statistical sample size calculation showed that this number of patients would be sufficient to detect a 1% incidence of ADRs. Following approval by local ethics committee, patient demographics, data relating to HES 130/0.42 use, the procedures performed, anesthesia, and ADRs were documented with a particular focus on cardiovascular stability, hemodilution, acid-base balance, renal function, blood coagulation, and hypersensitivity. Three hundred and sixteen children (ASA I-III, age 3 +/- 3.4 [range, day of birth-12 years], body weight 13 +/- 10.5 [range, 1.1-60 kg]) were studied at five centers in Germany, Austria, and Italy from May 2006 until August 2007. Forty-five percent of the patients underwent abdominal surgery, 12.4% urologic procedures, 11.4% thoracic surgery, 7.6% orthopedic procedures, and 7% cardiovascular surgery. The mean volume of infused HES 130/0.42 was 11 +/- 4.8 ml x kg(-1) (range, 5-42). Cardiovascular stability was maintained in all cases. After HES infusion, hemoglobin (11.5 vs 10.25 g x dl(-1)), base excess (-2 vs -2.7 mmol x l(-1)), anion gap (12.9 vs 11.2 mmol x l(-1)), and strong ion difference (34.3 vs 31.4 mmol x L(-1)) decreased, and chloride (105.7 vs 107.8 mmol x l(-1)) increased significantly (P < 0.05). No serious ADRs (i.e., anaphylactoid reaction, renal failure, clotting disorders) were observed. Moderate doses of HES 130/0.42 help to maintain cardiovascular stability and lead to only moderate changes in hemoglobin concentration and acid-base balance in children. The probability of serious ADRs is lower than 1%. Therefore, HES 130/0.42 for PVR seems to be safe and effective even in neonates and small infants with normal renal function and coagulation.

C.24.02 Preclinical profiling of antipsychotics – new data and implication on clinical outcome

A post-authorisation safety study was carried out as part of the EU Risk Management Plan to examine the long-term (up to 12 months) use of quetiapine XL as prescribed in general practice in England.To present a description of the drug utilisation characteristics of quetiapine XL.An observational, population-based cohort design using the technique of Modified Prescription-Event Monitoring (M-PEM). Patients were identified from dispensed prescriptions issued by general practitioners (GPs) for quetiapine XL between September 2008 and February 2013. Questionnaires were sent to GPs 12 months following the 1st prescription for each individual patient, requesting drug utilisation information. Cohort accrual was extended to recruit additional elderly patients (special population of interest). Summary descriptive statistics were calculated.The final M-PEM cohort consisted of 13,276 patients; median age 43 years (IQR: 33, 55) and 59.0% females. Indications for prescribing included bipolar disorder (n = 3820), MDD (n = 2844), schizophrenia (n = 2373) and other (non-licensed) indications (n = 3750). Where specified, 59.3% (7869/13,276) were reported to have used quetiapine IR (immediate release formulation) previously at any time. The median start dose was highest for patients with schizophrenia (300 mg/day [IQR 150, 450]). The final elderly cohort consisted of 3127 patients and 28.5% had indications associated with dementia. The median start dose for elderly patients was highest for patients with schizophrenia or BD (both 100 mg/day [IQR 50, 300]).The prevalence of off-label prescribing in terms of indication and high doses was common, as was use in special populations such as the very elderly. Whilst off-label use may be unavoidable in certain situations, GPs may need to re-evaluate prescribing in circumstances where there may be safety concerns. This study demonstrates the ongoing importance of observational studies such as M-PEM to gather real-world clinical data to support the post-marketing benefit:risk management of new medications, or existing medications for which license extensions have been approved.

Hydroxyethyl starch 130/0.42/6:1 for perioperative plasma volume replacement is safe and effective in children

In several clinical studies it has been shown that hydroxyethyl starch (HES) may be as effective and safe but less expensive as albumin when used for perioperative plasma volume replacement in children. The new third-generation HES 130/0.42 solution was designed to reduce adverse drug reactions (ADR) and improve safety while maintaining efficacy. In this prospective multicentric observational postauthorization safety study, therefore, the perioperative application of HES 130/0.42 was examined in children with a focus on possible ADR.