Comparative Safety of Originator and Biosimilar Epoetin Alfa Drugs: An Observational Prospective Multicenter Study

Background: Erythropoiesis-stimulating agents (ESAs) are biological molecules approved for the treatment of anemia associated with chronic renal failure. Biosimilars were licensed for use in Europe in 2007. Aim: This study aimed to compare the safety profile of biosimilars with respect to the reference product in a nephrology setting. Methods: A prospective study was conducted in four Italian regions between 1 October 2013 and 30 June 2015. The study population included patients aged 65 18 years undergoing hemodialysis and treated with epoetins as per the clinical practice of the participating centers. The two comparison cohorts included patients treated with either an originator or a biosimilar epoetin alfa. Each patient was followed up until occurrence of any safety outcome of interest (grouped into three major categories), switch to a different ESA product, transplant or peritoneal dialysis, death, or end of the study period, whichever came first. Results: Overall, 867 subjects were included in the study (originator: N = 423; biosimilar: N = 444). Biosimilar users were older than originator users (median age of 76 vs 64 years, respectively), more frequently affected by arrhythmia (29.3 vs 22.5%), and less frequently candidates for transplantation (3.8 vs 18.2%). Cox-regression analysis showed no increase in risk of safety outcomes in biosimilar users, even after adjusting for confounding factors: 1.0 (95% confidence interval [CI] 0.7\u20131.3) for any outcomes; 1.1 (95% CI 0.7\u20131.8) for problems related to dialysis device; 0.9 (95% CI 0.6\u20131.5) for cardio- and cerebro-vascular conditions; 0.9 (95% CI 0.6\u20131.5) for infections. Conclusion: This study confirms the comparable safety profiles of originator and biosimilar epoetin alfa drugs when used in patients receiving dialysis

Farmacosorveglianza

Il capitolo fornisce gli elementi essenziali riguardanti la farmacosorveglianza. Dopo brevi cenni storici vengono definiti gli obiettivi della farmacosorveglianza, classificate e descritte le principali reazioni avverse da farmaci, illustrati i sistemi di sorveglianza con particolare riferimento alla segnalazione delle reazioni avverse

La strana caduta a terra di Teresa: caso clinico

Si tratta di una caso clinico di rabdomiolisi da farmac

Bisphosphonate-Associated Cardiac Adverse Reactions: Reports from the Italian Database of Spontaneous Reporting of Adverse Drug Reactions

Background: Oral and intravenous bisphosphonates (alendronate, clodronate, risedronate, pamidronate, ibandronate, and zoledronic acid) are front-line agents in the management of osteoporosis, malignant skeletal disease, and Paget’s disease. In the USA, in 2006, there were more than 30 million prescriptions for oral bisphosphonates alone and in Italy, in 2011, bisphosphonates have been the third class of drugs most prescribed by physicians. Different kinds of adverse drug reactions (ADRs), such as upper GI adverse events, renal toxicity, influenza-like illness, musculoskeletal pain, osteonecrosis of the jaw, and ocular events have been associated to bisphosphonates. The association with cardiac side effects are limited in the literature and particularly focalized on the atrial fibrillation.[1,2] The Italian Summary Products Characteristics of clodronate, zolendronate, ibandronate, pamidronate lists some cardiac ADRs, only the SPC of zoledronic acid reports atrial fibrillation. Aim: To describe and discuss the spontaneous reports of cardiac disorders associated to bisphosphonates from the Italian ADR database. Methods: The Italian database on spontaneous reporting (IDvigilance) holds reports of suspected ADRs submitted since 1988. Every 6 months the database is analysed to filter out potential signals. Signal detection is done by qualitative case-by-case analysis and by using as quantitative methodology the Proportional Reporting Rate. Results: Up to December 31st 2011, IDvigilance held 161 474 reports: 84% of them coming from physicians, 6% from pharmacists, 2% from nurses, and only 1% from consumers. In 1799 reports, one or more adverse reactions associated with bisphosphonate therapy were referred. Among these, 36 (2%) reported cardiac disorders as the preferred term. The percentage of female was 86%, the percentage of serious reports was 22% and the median age was 67 years. The drug more frequently reported was clodronate alone or in association with lidocaine (12 out of 36) followed by alendronate (8 out of 36) and zoledronic acid (7 out of 36). The most frequently reported bisphosphonates- related cardiac ADRs included hypertension (10 cases), tachycardia (7) and atrial fibrillation (4), most of them related to clodronate + lidocaine. Conclusions: Some reports, in the Italian database, indicate possible cardiac ADRs in association with bisphosphonates. Physicians and patients who use bisphosphonates should remain vigilant for cardiac side effects and in particular for atrial fibrillation. References 1. John Camm A. Review of the cardiovascular safety of zoledronic acid and other bisphosphonates for the treatment of osteoporosis. Clin Ther 2010; 32 (3): 426-36 2. Loke YK, Jeevantham V, Singh S. Bisphosphonates and atrial fibrillation: systematic review and meta-analysis

Slow subcutaneous infusion of flumazenil for the treatment of long-term, high-dose benzodiazepine users: a review of 214 cases

Despite the first reports concerning benzodiazepine dependence being published in the early 1960s literature, the risk of benzodiazepine addiction is still greatly debated. The severe discomfort and life threatening complications usually experienced by long-term benzodiazepine users who suddenly interrupt benzodiazepine intake have led to the development of several detoxification protocols. A successful strategy used by our Addiction Unit is abrupt benzodiazepine cessation by administering flumazenil slow subcutaneous infusion (FLU-SSI) with an elastomeric pump. Although some studies proved the efficacy of flumazenil infusion more than 20 years ago, only a few centres in the world offer this method to their patients. This paper reports the data related to 214 subjects addicted to high doses of benzodiazepine and treated with the FLU-SSI method between 2012 and 2014. This technique is less invasive and requires less nursing intervention than intravenous infusion. Our data support FLU-SSI as a possible efficient strategy for the treatment of patients with long-term, high-dose benzodiazepine addiction, and could become a routine therapy as long as the necessary further studies on dose, duration of infusion and safety issues are carried out

The Role of the Cortex in Absence Epilepsy: Focal or generalized Epilepsy?

Classical theories on absence epilepsy suggest that the bilateral generalized spike-wave discharges (SWDs) characterizing absence epilepsy, are caused by thalamo-cortical oscillations, resulting in a condition in which an abnormally excitable cortex interacts with thalamus and brain stem reticular. Recently, a new theory based on experimental findings in the WAG/Rij rat, a genetic model of absence epilepsy, suggests instead that somatosensory cortex contains a focus that initiates a cascade of events that ultimately leads to the occurrence of the bilateral and generalized SWDs if the state of the thalamo-cortical circuitry is favorable. In this case, the cortical focus could be the dominant factor in initiating paroxysmal oscillations within the corticothalamic loops.In order to confirm these hypothesis, we decided to perform in four different cerebral areas (peri-oral cortex, visual cortex, lateral and ventral thalamus) gene-array analysis for cell signaling pathways involved in spindles generation and propagation, validated subsequently by immunohistochemical procedures. The Oligo GEArray® Rat Signal Transduction Pathway Finder™ Gene-array profiles the expression of 113 genes representative of the 18 signal transduction pathways, such as immediate early genes (egr-1, c-fos, c-jun), genes involved in the cell stress pathway (tcf5, hsp27, hspca, p53) or in NFĸB pathway (icam-1, il1, il2, pecam, vcam1). Although preliminary, these data suggest different genes modulations in the cerebral areas and may provide further evidence of a cortical focus in absence epilepsy