Correction to: In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study.

An amendment to this paper has been published and can be accessed via the original article.

Real-world use of biological drugs in patients with psoriasis/psoriatic arthritis: a retrospective, population-based study of years 2010-2014 from Southern Italy.

BACKGROUND: Biological drugs, such as infliximab, etanercept, adalimumab, ustekinumab, golimumab and certolizumab are third-line therapy for psoriasis (PsO) and psoriatic arthritis (PsA), but they may be used at earlier stage in severe forms. This study investigated the pattern of use and costs of biological drugs for PsO/PsA in a large population from Southern Italy during the years 2010-2014. METHODS: This was a retrospective, population-based, drug-utilization study, using healthcare administrative databases of the ASL (Local Health Unit) and two hospitals of Messina Province (Sicily) in the years 2010-2014. Incident users of adalimumab, ustekinumab, infliximab, etanercept and golimumab for PsO/PsA were characterized. Yearly prevalence of use and costs, as well as time to treatment discontinuation and switch were assessed. RESULTS: During the study period, 517 patients received at least one study drugs prescription for PsO/PsA and 304 (58.8%) were incident users, mostly treated with adalimumab (33.6%). Incident users were mostly males (59.8%), with a median age of 49 years. The prevalence of biological drugs users in PsO/PsA increased from 4.3 to 6.9 per 10,000 inhabitants from 2011 to 2014. Pharmaceutical expenditure of the study drugs almost doubled (from 2.6 to 4.7 million euros over 5 years of observation). During the first year of treatment, discontinuation occurred in 31.8% of incident users and switch was not infrequent (7.4%). CONCLUSIONS: Prevalence of use and costs of biological drugs for PsO/PsA substantially increased in recent years in a large population of Southern Italy. Larger uptake of lowest cost biological drugs, and biosimilars whenever available, may help access to the most innovative drugs.

In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study.

BACKGROUND: Evidences show that around 20% of biosimilar or originator erythropoiesis-stimulating agents (ESAs) users are hyporesponsive. Controversial post-marketing data exist on the predictors of ESA hyporesponsiveness. The aim of this study was to identify predictors of ESA hyporesponsiveness in patients with chronic kidney disease (CKD) or cancer in clinical practice. METHODS: During the years 2009-2015, a multi-center, population-based, cohort study was conducted using claims databases of Treviso and Caserta Local Health Units (LHUs). All incident ESA users were characterized at baseline and the differences between the baseline hemoglobin (Hb) value, that is the Hb registered within 30 days prior to the first ESA dispensing (index date, ID) and each outcome Hb value (registered between 30 and 180 days after ID) were calculated and defined as delta Hb (ΔHb). Incident ESA users were defined as hyporesponsive if, during follow-up, they registered at least one ΔHb < 0 g/dL. Including all potential predictors of ESA hyporesponsiveness and stratifying by indication for use, univariate and multivariate binary logistic regression models and Receiver Operating Characteristic (ROC) curves were carried out. RESULTS: In general, 1080 incident ESA users (CKD: 57.0%; cancer: 43.0%) were identified. In CKD, predictors of ESA hyporesponsiveness were C-reactive protein (OR = 1.2, 95% CI: 1.0-1.5; P-value = 0.060) and high levels of baseline Hb (OR = 1.7, 95% CI: 1.2-2.2; P-value< 0,001), the latter being also predictor of ESA hyporesponsiveness in cancer (OR = 1.7, 95% CI: 1.1-2.4; P-value = 0.007). Both in CKD and in cancer, the type of ESA, biosimilar or originator, was not a predictor of ESA hyporesponsiveness. In CKD, concomitant use of iron preparations (OR = 0.3, 95% CI: 0.2-0.7; P-value = 0.002) and of high dosage of angiotensin-converting enzyme inhibitors/angiotensin II-receptor blockers (OR = 0.5, 95% CI: 0.3-0.9; P-value = 0.022) were protective factors against ESA hyporesponsiveness. CONCLUSIONS: The study confirmed traditional potential predictors of hyporesponsiveness to ESA. The use of biosimilar or originator ESA was not a predictor of hyporesponsiveness in an outpatient setting from two large Italian areas. A better knowledge of the predictors of ESA response would allow a better anemia management to improve patients' quality of life.

Pharmacokinetics of new oral anticoagulants: implications for use in routine care.

INTRODUCTION: Since 2008, new oral anticoagulants (NOACs) have been approved for the prevention of venous thromboembolism (VTE) in patients receiving hip or knee replacement surgery, prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), treatment of deep vein thrombosis (DVT), and pulmonary embolism (PE). Premarketing randomized clinical trials (RCTs) of NOACs demonstrated their non-inferiority in terms of efficacy vs. warfarin (traditional oral anticoagulant - TOA), with lower risk of serious adverse drug reactions, especially cerebral hemorrhages. In clinical practice, pharmacokinetic aspects of NOACs have to be carefully taken into account to optimize the benefit-risk profile of these drugs. Areas covered: An overview of major issues related to pharmacokinetics of NOACs, such as drug-drug interactions, over- and underdosage in special populations (e.g. elderly, underweight, and chronic kidney disease patients), and impact on adherence and persistence to NOACs therapy and ultimately clinical outcomes in real-world setting, is provided. Expert opinion: NOACs have been proven to be a better option than traditional anticoagulants due to better tolerability and ease of use. However, given specific pharmacokinetic characteristics, NOAC therapy has to be carefully tailored and monitored in relation to patient characteristics with the final goal of maximizing benefits and minimizing risks.

Long-Term Intravitreal Ranibizumab as a Potential Additional Risk Factor for Neurodegeneration in Parkinson's Disease: A Case Report.

In November 2012, a 72-year old patient was diagnosed with left eye wet age-related macular degeneration. The patient received three monthly intravitreal injections of ranibizumab, with complete resolution of retinal hemorrhage and edema and reinstatement of visual acuity. In May 2015, symptomatic relapse was detected. The patient was again treated with intravitreal ranibizumab, with overall six injections till the end of February 2016. In May 2016, the patient complained of left hand resting tremor, bradykinesia, and postural rigidity of head and trunk. A diagnosis of clinically established PD was made based on new criteria of the Movement Disorders Society. Single Photon Emission Computerized Tomography of the Dopamine Transporter with (123I) ioflupane documented a low Dopamine Transporter (DAT) uptake mostly in the right striatum. Due to the documented protective role of vascular endothelial growth factor (VEGF) on the dopaminergic neurons, intensive intravitreal injections of the anti-VEGF agent ranibizumab may have played as an additional risk factor accelerating the neurodegeneration process related to PD and the onset of the related clinical signs and symptoms.

Safety of Biologics, Including Biosimilars: Perspectives on Current Status and Future Direction.

In recent years, marketing of highly innovative and costly biologics improved the management of high-burden diseases such as autoimmune diseases, cancers, and chronic renal failure. Several widely prescribed biologics have recently lost or will shortly lose their patents, thus opening avenues to the marketing of a growing number of biosimilars worldwide, which are products similar in terms of quality, safety, and efficacy to already licensed reference products, thus allowing for potential savings in pharmaceutical expenditure. Numerous debates about the interchangeability between biosimilars and reference products are still ongoing, owing to concerns about potential immunogenicity raised by switching, which may cause a lack of effect and toxicity. Patients successfully treated with biologic therapy may theoretically receive biosimilars to contain costs, if reference product and related biosimilar are judged as interchangeable. However, the positions of regulatory agencies on the interchangeability and automatic substitution of biologics with biosimilars are very different. The benefit-risk profile of biosimilars has been often questioned by clinicians owing to the limited amount of pre-marketing information on clinical efficacy and safety, despite biosimilarity being based on a comparability exercise with the reference product to gain the biosimilar approval. Nevertheless, after more than 10 years of marketing from the first biosimilar approval in Europe, no proof of differences in terms of the safety profile of biosimilars and originators has been reported. In this context, post-marketing evaluation of both biologics and biosimilars safety profiles through analyses from spontaneous reporting databases and claims databases is crucial. An important issue for the pharmacovigilance of biologics concerns the traceability, indicating the brand name and batch number in spontaneous adverse drug reaction reports, but this requirement is not frequently addressed. This review aims to provide an overview of the characteristics and potential challenges in the safety profile assessment of biologics with a focus on the post-marketing setting.

Pattern of Use of Biosimilar and Originator Somatropin in Italy: A Population-Based Multiple Databases Study During the Years 2009-2014.

PURPOSE: Somatropin [recombinant growth hormone (rGH)] is approved in children and adults for several conditions involving growth disturbances and the corresponding biosimilar is available in Italy since 2006. No population-based data are available on the pattern of rGH use in Italian clinical practice. This study aimed at exploring the pattern of biosimilar and originator rGH use in six Italian centers, where different policy interventions promoted biosimilar use. METHODS: This population-based, drug-utilization study was conducted in the years 2009-2014, using administrative databases of Umbria, Tuscany, and Lazio Regions and Local Health Units of Caserta, Treviso, and Palermo. Naïve rGH users were characterized, and prevalence of use and discontinuation were assessed over time. RESULTS: Among 6,785 patients treated with rGH during the study years, 4,493 (66.2%) were naïve users (males/females = 1.3), mostly affected by GH deficiency. The prevalence of rGH use increased from 2009 to 2010, remaining stable thereafter, but it was heterogeneous across centers (twofold higher prevalence of use in center n.2 than centers n.4 and 1 in 2014). Biosimilar rGH uptake increased over time but was low (7.8% in 2014) and heterogeneous as well. Discontinuation of rGH therapy occurred in 54.0% of naïve users, more frequently in females than males (58.1 vs. 50.9%). During the first year of treatment, discontinuation was frequent (39.9%), but no statistically significant differences were observed in treatment persistence for biosimilar vs. originator rGH (p > 0.05). CONCLUSION: Geographical heterogeneity in the prevalence of rGH use was observed. Similarly, the biosimilar rGH uptake was low and variable across centers. Post-marketing monitoring is required to continuously monitor the benefit-risk profile of rGH, thus guaranteeing greater savings than only promoting lowest cost rGH.

Author Correction to: Prevalence of Use and Cost of Biological Drugs for Cancer Treatment: A 5-Year Picture from Southern Italy.

Unfortunately, many errors were identified in the published article. The original article was corrected.

Treatment of Medication-Related Osteonecrosis of the Jaw and its Impact on a Patient's Quality of Life: A Single-Center, 10-Year Experience from Southern Italy.

INTRODUCTION: No official guidelines are available for the management of medication-related osteonecrosis of the jaw (MR-ONJ). The additional benefit of surgery after pharmacological treatment is debated by both clinicians and patients. OBJECTIVE: The aim of this study was to evaluate the changes in patients' MR-ONJ-related quality of life (QoL) after pharmacological treatment with or without surgery in a large cohort affected by MR-ONJ. METHODS: Anonymized data on patients diagnosed with MR-ONJ were extracted from the database of the Osteonecrosis of the Jaw Treatment Center (University of Messina, Italy) in the years 2005-2015. QoL was evaluated at the moment of MR-ONJ diagnoses (T0), after pharmacological treatment with or without surgery (T1 and T2, respectively), based on scores from the European Organisation for Research and Treatment of Cancer (EORTC) QOL Module for Head and Neck Cancer (global oral health status [GOHS]) and a visual analog scale (VAS), stratified by indication for use. RESULTS: Among 100 patients, 36% were affected by osteoporosis (OSTEO group) and 64% were affected by cancer (ONC group). Considering T0, QoL scores were higher in the OSTEO group then in the ONC group. At T1, GOHS and VAS increased in both groups (OSTEO group: +9.9% and +39.9%; ONC group: +35.4 and +97.2%, respectively). Pharmacological treatment was effective in reducing pain (OSTEO group: -22.0%; ONC group: -44.8%), and social contact troubles (OSTEO group: -40.3%; ONC group: -26.7%). At T2, GOHS and VAS further increased. Scores related to 'pain' and the troubles related to the 'social dimension' also decreased (OSTEO group: -91.3% and -72.0%; ONC group: 50.8% and -16.4%, respectively). CONCLUSIONS: MR-ONJ-related QoL increased after pharmacological treatment and, more notably, after surgery, which may offer benefits to selected patients. QoL data may help clinicians in promoting tailored management of MR-ONJ.

Prevalence of Use and Cost of Biological and Non-Biological Targeted Therapies for Cancer Treatment: A 5-Year Picture from Southern Italy.

BACKGROUND AND OBJECTIVES: Considering the clinical and economic burden of biological and non-biological targeted therapies in cancer treatment, it is necessary to explore how these drugs are used in routine care in Italy and how they affect the sustainability of the National Health Services. This study aimed to investigate the prevalence of use and costs of biological and non-biological targeted therapies for cancer treatment in a general population of Southern Italy in the years 2010­2014. METHODS: This was a retrospective, observational study using data from the healthcare administrative databases of Messina Province for the years 2010-2014. In this study, users of biological and non-biological targeted therapies for cancer treatment were characterized and the prevalence of use and costs were calculated over time. The potential impact of biosimilars on the expenditure was also estimated. RESULTS: Of a population of 653,810 residents in the Messina area during the study years, 2491 (0.4%) patients received at least one study drug. The most frequently used were monoclonal antibodies (mAbs) (n = 1607; 64.5%) and tyrosine kinase inhibitors (TKIs) (n = 609; 24.4%). mAbs were mainly used by females (60.3%) for metastasis due to an unspecified primary tumor, lymphomas, or breast cancer (24.2, 16.7, and 13.7%, respectively). Most users of small molecules were males (56.3%) being treated for multiple myeloma, metastasis due to unspecified primary tumor, leukemia, and lung cancer (13.1, 12.6, 9.5, and 8.9%, respectively). During the study years, the prevalence of use doubled from 0.9 to 1.8 per 1000 inhabitants; likewise, the related expenditure grew from €6.6 to €13.6 million. Based on our forecasts, this expenditure will grow to €25 million in 2020. Assuming a 50% biosimilar uptake (trastuzumab and rituximab), a potential yearly saving of almost €1 million may be achieved. CONCLUSIONS: In recent years, the use and costs of biological and non-biological targeted therapies in cancer patients dramatically increased in a large population from Southern Italy. This trend may be counterbalanced by adopting biosimilars once they are available. Claims databases represent a valid tool to monitor the uptake of newly marketed biological drugs and biosimilars as well as other non-biological targeted therapies.

Interchangeability of biosimilar and biological reference product: updated regulatory positions and pre- and post-marketing evidence.

INTRODUCTION: Since 2006, biosimilars have been available in several countries worldwide, thus allowing for potential savings in pharmaceutical expenditure. However, there have been numerous debates about the interchangeability of biosimilars and reference products based on concerns of immunogenicity by switching between biological products, which may cause lack of effect and toxicity. AREAS COVERED: The authors provide the reader with an overview of the different positions of regulatory authorities on the interchangeability and automatic substitution of biosimilars and reference products. Presently, the FDA allows automatic substitution without prescriber intervention if the biosimilar is interchangeable with reference products, while the European Medicines Agency delegate to each single EU member state. EXPERT OPINION: Different approaches in defining interchangeability and automatic substitution call for harmonization to increase confidence of healthcare professionals and patients about the clinical impact of switching. Networks of electronic healthcare records and administrative databases, potentially linkable to clinical charts and registries may rapidly assess frequency and benefit-risk profile of different switching patterns in routine care at different levels, thus integrating and strengthening pre-marketing evidence.

How did the Introduction of Biosimilar Filgrastim Influence the Prescribing Pattern of Granulocyte Colony-Stimulating Factors? Results from a Multicentre, Population-Based Study, from Five Italian Centres in the Years 2009-2014.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs) are biological products for which the main indication of use is chemotherapy-induced neutropenia. Biosimilars of G-CSFs have been available in Europe since 2007. OBJECTIVE: The objective of this study was to investigate the prescribing pattern of G-CSFs in five Italian centres using different healthcare policy interventions to promote the use of biosimilars in routine care. METHODS: This retrospective, population-based drug utilization study was conducted during the years 2009-2014 using the administrative databases of the Caserta, Treviso and Palermo Local Health Units (LHUs) and the Tuscany and Umbria regions. G-CSF users were characterized and the prevalence of use, proportion of biosimilar users and switching pattern of different G-CSFs were evaluated over time and across centres. RESULTS: Overall, 30,247 patients were treated with G-CSFs in the years 2009-2014, of which 29,083 (96.2 %) were naïve users. The overall prevalence of G-CSF use increased from 0.8 per 1000 inhabitants in 2009 to 1.1 per 1000 in 2014. An increase in the proportion of the use of the biosimilar filgrastim by the total G-CSF users was observed in all centres: from 0.2 % (2009) to 66.2 % (2014). However, heterogeneity across different centres was reported, with the largest increase in Treviso LHU (from 0 to 89.1 % from 2009 to 2014). During the first year of treatment, switching between different G-CSFs was frequent (20.3 %). CONCLUSIONS: Heterogeneity in the use of G-CSF and, in particular, biosimilar filgrastim across different Italian centres was observed, probably due to different regional healthcare policy interventions. During the first year of treatment, switching between different G-CSFs was frequent. Considering the impact of biological drugs on pharmaceutical expenses, it is necessary to harmonize healthcare policies promoting the use of biological drugs with the lowest cost.

Comparative Effectiveness of Biosimilar, Reference Product and Other Erythropoiesis-Stimulating Agents (ESAs) Still Covered by Patent in Chronic Kidney Disease and Cancer Patients: An Italian Population-Based Study.

BACKGROUND: Since 2007 biosimilars of erythropoiesis-stimulating agents (ESAs) are available on the Italian market. Very limited post-marketing data exist on the comparative effectiveness of biosimilar and originator ESAs. AIM: This population-based study was aimed to compare the effects of biosimilars, reference product and other ESAs still covered by patent on hemoglobinemia in chronic kidney disease (CKD) and cancer patients in a Local Health Unit (LHU) from Northern Italy. METHODS: A retrospective cohort study was conducted during the years 2009-2014 using data from Treviso LHU administrative database. Incident ESA users (no ESA dispensing within 6 months prior to treatment start, i.e. index date (ID)) with at least one hemoglobin measurement within one month prior to ID (baseline Hb value) and another measurement between 2nd and 3rd month after ID (follow-up Hb value) were identified. The strength of the consumption (as total number of defined daily dose (DDD) dispensed during the follow-up divided by days of follow-up) and the difference between follow-up and baseline Hb values [delta Hb (ΔHb)] were evaluated. Based on Hb changes, ESA users were classified as non-responders (ΔHb≤0 g/dl), responders (0<ΔHb≤2 g/dl), and highly responders (ΔHb>2 g/dl). A multivariate ordinal logistic regression model to identify predictors for responsiveness to treatment was performed. All analyses were stratified by indication for use and type of dispensed ESA at ID. RESULTS: Overall, 1,003 incident ESA users (reference product: 252, 25.1%; other ESAs covered by patent: 303, 30.2%; biosimilars: 448, 44.7%) with CKD or cancer were eligible for the study. No statistically significant difference in the amount of dose dispensed during the follow-up among biosimilars, reference product and other ESAs covered by patent was found in both CKD and cancer. After three months from treatment start, all ESAs increased Hb values on average by 2g/dl. No differences in ΔHb as well as in frequency of non-responders, responders and highly responders among different types of ESAs were observed in both indications of use. Overall, around 15-20% of ESA users were non-responders. Strength of treatment, but no type of dispensed ESAs was found to be predictor of responsiveness to treatment. CONCLUSIONS: No difference on the effects on hemoglobinemia among users of either biosimilars or reference product or ESAs covered by patent was observed in a general population from Northern Italy, despite a comparable dispensed dose of the different ESAs during the first three months of treatment.