Factors associated with hematological adverse reactions of drugs authorized via the centralized procedure.

Serious hematological adverse drug reactions (HADRs) may lead to or prolong hospitalization and even cause death. The aim of this study was to determine the regulatory factors associated with HADRs caused by drugs that were authorized up to July 2023 by the European Medicines Agency (EMA) and to evaluate the frequency of HADRs. Using a cross-sectional approach, the type and frequency of HADRs were collected from the Summaries of Product Characteristics of Drugs Authorized by the EMA and analyzed within proprietary, nonproprietary, and biosimilar/biological frameworks. Multivariate statistical analysis was used to investigate the associations of generic status, biosimilar status, conditional approval, exceptional circumstances, accelerated assessment, orphan drug status, years on the market, administration route, and inclusion on the Essential Medicines List (EML) with HADRs. In total, 54.78% of proprietary drugs were associated with HADRs at any frequency, while anemia, leucopenia, and thrombocytopenia were observed in approximately 36% of the patients. The predictors of any HADR, anemia, and thrombocytopenia of any frequency are generic status, biosimilar status, and inclusion on the EML, while the only protective factor is the administration route. Biosimilars and their originator biologicals have similar frequencies of HADRs; the only exception is somatropin. Knowledge of the regulatory factors associated with HADRs could help clinicians address monitoring issues when new drugs are introduced for the treatment of patients.

Pharmacokinetic and pharmacodynamic simulation for the quantitative risk assessment of linezolid-associated thrombocytopenia.

WHAT IS KNOWN AND OBJECTIVE: Linezolid (LZD) may cause thrombocytopenia, which can result in discontinuation of treatment. In this study, the blood LZD trough concentration was estimated based on population pharmacokinetic (PK) parameters derived from two previously published models in the Japanese population to determine the rate of achieving the target trough value when the risk of thrombocytopenia is low and to clarify its relationship with the onset of thrombocytopenia. METHODS: This study included adult patients hospitalized at Shimane University Hospital, who received LZD treatment for at least 4 days from January 2010 to December 2017. Patients whose platelet count fell below 70% before LZD administration were categorized as the thrombocytopenic group. Patient PK parameters were calculated based on the population PK models described by Matsumoto et al. and Sasaki et al., and these parameters were designated A and B, respectively. Based on these parameters, the rate of achieving an LZD trough concentration of less than 8 µg/ml, which is the safety target achievement rate, was calculated using a random simulation for each patient. We further analysed the association between the incidence of thrombocytopenia and patient factors, including safety target achievement rate, through univariate, multivariate, and receiver operating characteristic (ROC) analyses. RESULTS AND DISCUSSION: Patients (n = 77) aged 72 ± 11 years and weighing 56.7 ± 10.9 kg, with a creatinine clearance (CLcr ) of 60.5 ± 47.2 ml/min and a cirrhosis prevalence of 9.1%, were analysed. All patients received LZD at a dose of 600 mg twice daily for a total of 10.9 ± 8.9 days. Univariate analyses revealed significant differences (p < 0.05) in the duration of LZD therapy, serum creatinine, creatinine clearance, LZD clearance, and the safety target achievement rate for parameters A and B between the thrombocytopenic and non-thrombocytopenic groups. A multivariate analysis of these factors stratified with the cutoff values obtained by ROC analysis revealed that the duration of LZD therapy and the safety target achievement rates for parameters A and B were significant factors (odds ratios for duration of LZD therapy: 7.436 [95% confidence interval (CI): 1.918-28.831] and 4.712 [95% CI: 1.567-14.163]; odds ratio for safety target achievement rate: 0.060 [95% CI: 0.016-0.232] and 0.167 [95% CI: 0.056-0.498] for parameters A and B, respectively). When the safety target achievement rates for patients treated with LZD were compared between the thrombocytopenic and non-thrombocytopenic groups, the safety target achievement rate was higher in the non-thrombocytopenic group in both the patients treated with LZD for less than 10 days and those for 10 days or more. Therefore, the safety target achievement rate estimated by the PK/PD simulation may represent to be an important index for risk assessment of LZD-induced thrombocytopenia. WHAT IS NEW AND CONCLUSION: The risk of LZD-induced thrombocytopenia, which increased with the duration of LZD therapy, may be predicted using the safety target achievement rate obtained by the blood concentration simulation.

Anemia requiring transfusion in breast cancer patients on dose-dense chemotherapy: Prevalence, risk factors, cost and effect on disease outcome.

PURPOSE: Dose-dense chemotherapy improves survival but with increased toxicity and treatment-related cost. We report the prevalence of anemia and the possible risk factors associated with chemotherapy-related anemia and determine the cost and time-delay associated with transfusion requirement in Indian patients with non-metastatic breast cancer on dose-dense preoperative chemotherapy. METHODS: In this study, triple-negative breast cancer (TNBC) patients were treated preoperatively with docetaxel and cyclophosphamide alternating with epirubicin and cisplatin every 2 weeks. Patients were evaluated for anemia pre- and post-chemotherapy. We examined trends in the red cell indices, transfusion requirement, time to transfusion, as well as risk factors associated with transfusion during treatment, along with delay in treatment due to anemia and the additional cost incurred. RESULTS: A total of 116 consecutive women with nonmetastatic TNBC were treated with preoperative chemotherapy. The median age was 44.5 years. 56.1% of patients had stage III disease. Anemia was detected at baseline in 54 (46.5%) patients with mild anemia (10-12 g/dl) in 42 (36.2%) patients and moderate anemia (8-10 g/dl) in 12 (10.3%) patients. During the course of treatment, all patients developed anemia. A total of 44 patients (37.9%) required transfusion during chemotherapy, with 55(47.4%) patients developing grade 1-2 anemia and 40 (34.5%) patients developing grade 3 anemia. The factors associated with anemia requiring transfusion were a steeper decline in hemoglobin after two cycles (OR 1.65, p = 0.02), low-grade tumor (OR 2.48, p = 0.03), and thrombocytopenia grade 3 or 4 (OR 4.35, p = 0.034), of which tumor grade and thrombocytopenia remained significant in multivariate analysis. Nearly one-fourth of the study population had a delay between two cycles of chemotherapy due to anemia. A median additional cost of INR 7000 was incurred among those requiring blood transfusion. CONCLUSION: Anemia is a common toxicity associated with dose-dense chemotherapy during curative breast cancer treatment leading to delay in treatment and increased cost. Low-grade tumor, grade 3 or 4 thrombocytopenia, and grade 2 or higher anemia after two cycles of chemotherapy are risk factors for blood transfusions during treatment.

Chemical characterization of anemia-inducing aniline-related substances and their application to the construction of a decision tree-based anemia prediction model.

Anemia is a well-observed toxicity of chemical substances, and aniline is a typical anemia-inducing substance. However, it remains unclear whether all aniline-like substances with various substituents could induce anemia. We thus investigated the physicochemical characteristics of anemia-inducing substances by decision tree analyses. Training and validation substances were selected from a publicly available database of rat repeated-dose toxicity studies, and discrimination models were constructed by decision tree and bootstrapping methods with molecular descriptors as explanatory variables. To improve the accuracy of discrimination, we individually evaluated the explanatory variables to modify them, established "prerules" that were applied before subjecting a substance to a decision tree by considering metabolism, such as azo reduction and N-dealkylation, and introduced the idea of "partly negative" evaluation for substances having multiple aniline-like substructures. The final model obtained showed 79.2% and 77.5% accuracy for the training and validation dataset, respectively. In addition, we identified some chemical properties that reduce the anemia inducibility of aniline-like substances, including the addition of a sulfonate or carboxy functional group and/or a bulky multiring structure to anilines. In conclusion, the present findings will provide a novel insight into the mechanistic understanding of chemically induced anemia and help to develop a prediction system.

Trends in Erythropoiesis-stimulating agent use and blood transfusions for chemotherapy-induced anemia throughout FDA's risk evaluation and mitigation strategy lifecycle.

PURPOSE: Erythropoiesis-stimulating agents (ESAs), indicated for treating some patients with chemotherapy-induced anemia (CIA), may increase the risk of tumor progression and mortality. FDA required a Risk Evaluation and Mitigation Strategy (REMS) to mitigate these risks. We assessed REMS impact on ESA administration and red blood cell (RBC) transfusion as surrogate metrics for REMS effectiveness. METHODS: Retrospective cohort study including data from January 1, 2006 to December 31, 2018 for beneficiaries ≥65 years enrolled in Centers for Medicare & Medicaid Services (CMS) Medicare Parts A/B with a cancer diagnosis; patients with other indications for ESA use were excluded. Study time was divided into five periods demarcated by issuance of CMS National Coverage Determination (NCD) (Pre-NCD, Pre-REMS) and REMS milestones (Grace Period, REMS, post-REMS). Study outcomes were monthly proportion of chemotherapy episodes (CTEs) with concomitant ESA administration, with post-CTE ESA administration, and with RBC transfusions. RESULTS: Of 1 778 855 beneficiaries treated with CT, 308742 received concomitant ESA for CIA. The proportion of CTEs with concomitant and post-CTE ESA administration decreased Pre-REMS (9.0 percentage points [pp] and 3.5 pp, respectively). There were no significant post-REMS changes in the proportion of CTEs with concomitant (0.0 pp) and post-CTE ESA administration (0.1 pp). Fluctuation in RBC transfusions was <4 pp throughout the study period. CONCLUSIONS: Medicare beneficiaries showed a substantive decrease in ESA administration after NCD, with minimal impact by the REMS and its removal. Small changes in RBC transfusion over the study period were likely due to a national secular trend.

The First 2 Years of Biosimilar Epoetin for Cancer and Chemotherapy-Induced Anemia in the U.S.: A Review from the Southern Network on Adverse Reactions.

Biosimilars are biologic drug products that are highly similar to reference products in analytic features, pharmacokinetics and pharmacodynamics, immunogenicity, safety, and efficacy. Biosimilar epoetin received Food and Drug Administration (FDA) approval in 2018. The manufacturer received an FDA nonapproval letter in 2017, despite receiving a favorable review by FDA's Oncologic Drugs Advisory Committee (ODAC) and an FDA nonapproval letter in 2015 for an earlier formulation. We discuss the 2018 FDA approval, the 2017 FDA ODAC Committee review, and the FDA complete response letters in 2015 and 2017; review concepts of litigation, naming, labeling, substitution, interchangeability, and pharmacovigilance; review European and U.S. oncology experiences with biosimilar epoetin; and review the safety of erythropoiesis-stimulating agents. In 2020, policy statements from AETNA, United Health Care, and Humana indicated that new epoetin oncology starts must be for biosimilar epoetin unless medical need for other epoetins is documented. Empirical studies report that as of 2012, reference epoetin use decreased from 40%-60% of all patients with cancer with chemotherapy-induced anemia to <5% of such patients because of safety concerns. Between 2018 and 2020, biosimilar epoetin use varied, increasing to 81% among one private insurer's patients covered by Medicare whose cancer care is administered with Oncology Analytics and to 41% with the same private insurer's patients with cancer covered by commercial health insurance and administered by the private insurer, to 0% in several Veterans Administration Hospitals, increasing to 100% in one large county hospital in California, and with yet-to-be-reported data from most oncology settings. We conclude that biosimilar epoetin appears to have overcome some barriers since 2015, although current uptake in the U.S. is variable. Pricing and safety considerations for all erythropoiesis-stimulating agents are primary determinants of biosimilar epoetin oncology uptake. IMPLICATIONS FOR PRACTICE: Few oncologists understand substitution and interchangeability of biosimilars with reference drugs. Epoetin biosimilar is new to the market, and physician and patient understanding is limited. The development of epoetin biosimilar is not familiar to oncologists.

Outcomes and adverse events of pre- and extensively drug-resistant tuberculosis patients in Kinshasa, Democratique Republic of the Congo: A retrospective cohort study.

BACKGROUND: Extensively drug-resistant tuberculosis (XDR TB) is a very serious form of tuberculosis that is burdened with a heavy mortality toll, especially before the advent of new TB drugs. The Democratic Republic of the Congo (DRC) is among the countries most affected by this new epidemic. METHODS: A retrospective analysis was performed of the records of all patients with pre- and extensively drug-resistant tuberculosis hospitalized from January 1, 2015 to December 31, 2017 and monitored for at least 6 months to one year after the end of their treatment in Kinshasa; an individualized therapeutic regimen with bedaquiline for 20 months was built for each patient. The adverse effects were systematically monitored. RESULTS: Of the 40 laboratory-confirmed patients, 32 (80%) patients started treatment, including 29 preXRB and 3 XDR TB patients. In the eligible group, 3 patients (9.4%) had HIV-TB coinfections. The therapeutic success rate was 53.2%, and the mortality rate was 46.8% (15/32); there were no relapses, failures or losses to follow-up. All coinfected HIV-TB patients died during treatment. The cumulative patient survival rate was 62.5% at 3 months, 53.1% at 6 months and 53.1% at 20 months. The most common adverse events were vomiting, Skin rash, anemia and peripheral neuropathy. CONCLUSION: The new anti-tuberculosis drugs are a real hope for the management of Drug Resistant tuberculosis patient and other new therapeutic combinations may improve favorable outcomes.

Outcomes of treatment with CHOP and EPOCH in patients with HIV associated NHL in a low resource setting.

BACKGROUND: The optimal chemotherapy regimen for treating HIV associated NHL in low resource settings is unknown. We conducted a retrospective study to describe survival rates, treatment response rates and adverse events in patients with HIV associated NHL treated with CHOP and dose adjusted-EPOCH regimens at the Uganda Cancer Institute. METHODS: A retrospective study of patients diagnosed with HIV and lymphoma and treated at the Uganda Cancer Institute from 2016 to 2018 was done. RESULTS: One hundred eight patients treated with CHOP and 12 patients treated with DA-EPOCH were analysed. Patients completing 6 or more cycles of chemotherapy were 51 (47%) in the CHOP group and 8 (67%) in the DA-EPOCH group. One year overall survival (OS) rate in patients treated with CHOP was 54.5% (95% CI, 42.8-64.8) and 80.2% (95% CI, 40.3-94.8) in those treated with DA-EPOCH. Factors associated with favourable survival were BMI 18.5-24.9 kg/m2, (p = 0.03) and completion of 6 or more cycles of chemotherapy, (p < 0.001). The overall response rate was 40% in the CHOP group and 59% in the DA-EPOCH group. Severe adverse events occurred in 19 (18%) patients in the CHOP group and 3 (25%) in the DA-EPOCH group; these were neutropenia (CHOP = 13, 12%; DA-EPOCH = 2, 17%), anaemia (CHOP = 12, 12%; DA-EPOCH = 1, 8%), thrombocytopenia (CHOP = 7, 6%; DA-EPOCH = 0), sepsis (CHOP = 1), treatment related death (DA-EPOCH = 1) and hepatic encephalopathy (CHOP = 1). CONCLUSION: Treatment of HIV associated NHL with curative intent using CHOP and infusional DA-EPOCH is feasible in low resource settings and associated with > 50% 1 year survival.

Use of pre-ART laboratory screening to identify renal, hepatic and haematological abnormalities in Côte d'Ivoire.

BACKGROUND: High demand for HIV-services and extensive clinical guidelines force health systems in low-resource settings to dedicate resources to service delivery at the expense of other priorities. Simplifying services may reduce the burden on health systems and pre-antiretroviral therapy (ART) laboratory screening is among the services under consideration for simplification. METHODS: We assessed the frequencies of conditions linked to ART toxicities among 34,994 adult, ART-naïve patients with specimens referred to the RETRO-CI laboratory in Abidjan, Côte d'Ivoire between 1998 and 2017. Screening included tests for serum creatinine, alanine aminotransferase (ALT) and haemoglobin (Hb) to identify renal dysfunction (estimated glomerular filtration rate < 50 mL/min), hepatic abnormalities (ALT > 5× upper limit of normal) and severe anaemia (Hb < 6.5 g/dL), respectively. We considered screening results across four eras and identified factors associated with the conditions in question. RESULTS: The prevalence of renal dysfunction, hepatic abnormalities and severe anaemia were largely unchanged over time and just 8.4% of patients had any of the three conditions. Key factors associated with renal dysfunction and severe anaemia were age > 50 years (adjusted odds ratio (aOR): 2.53; 95% confidence interval (CI): 2.19-2.92; P < 0.001) and CD4 < 100 cells/µl (aOR: 2.57; 95% CI: 2.30-2.88; P < 0.001). CONCLUSION: The relative infrequency of conditions linked to toxicity in Côte d'Ivoire supports the notion that simplification of pre-ART laboratory screening may be undertaken with limited negative impact on identification of adverse events. Targeted screening may be a feasible strategy to balance detection of conditions associated with ART toxicities with simplification of services.

CONTEXTE: La forte demande de services VIH et les directives cliniques détaillées obligent les systèmes de santé des pays à faibles ressources à consacrer des ressources à la prestation de services au détriment d'autres priorités. La simplification des services peut réduire la charge pesant sur les systèmes de santé et les analyses de laboratoire avant la thérapie antirétrovirale (ART) fait partie des services envisagés pour la simplification. MÉTHODES: Nous avons évalué la fréquence des conditions liées aux toxicités dues à l'ART chez 34.994 patients adultes naïfs pour l'ART avec des échantillons référés au laboratoire RETRO-CI à Abidjan, en Côte d'Ivoire entre 1998 et 2017. Les analyses comprenaient les tests de créatinine sérique, d'alanine aminotransférase (ALT) et d'hémoglobine (Hb) pour identifier respectivement la dysfonction rénale (débit de filtration glomérulaire estimé <50 mL/min), les anomalies hépatiques (ALT >5x la limite supérieure normale) et l'anémie sévère (Hb <6,5 g/dL). Nous avons examiné les résultats des analyses sur quatre époques et identifié les conditions associées aux conditions en question. RÉSULTATS: La prévalence de la dysfonction rénale, des anomalies hépatiques et de l'anémie sévère est restée largement inchangée au fil du temps et seulement 8,4% des patients présentaient l'une des trois conditions. Les facteurs clés associés à la dysfonction rénale et à l'anémie sévère étaient l'âge >50 ans (odds ratio ajusté (aOR): 2,53; intervalle de confiance (IC) à 95%: 2,19 à 2,92; p <0,001) et les CD4 <100 cellules/µl (aOR: 2,57; IC95%: 2,30 à 2,88; P < 0,001). CONCLUSION: La relativement faible fréquence des conditions liées à la toxicité en Côte d'Ivoire soutient la notion selon laquelle une simplification des analyses de laboratoire pré-ART peut être entreprise avec un impact négatif limité sur l'identification des événements adverses. Le ciblage des analyses peut être une stratégie réalisable pour aligner la détection des conditions associées aux toxicités ART à la simplification des services.

Ferric Carboxymaltose in the treatment of chemotherapy-induced anaemia: an effective, safe and cost- sparing alternative to blood transfusion.

Anaemia is highly prevalent in cancer patients, adversely affects quality of life and impacts survival. The pathogenesis is multifactorial, with iron deficiency being a major and potentially treatable contributor. This study aimed to assess the effectiveness and economic impact of ferric carboxymaltose in chemotherapy-induced anaemia. This prospective cohort study between 2015-2016 of chemotherapy-treated patients for solid tumours, grade ≥2 anaemia and iron deficiency evaluated hematopoietic response four weeks after ferric carboxymaltose treatment. Transfusion rate of all cancer patients treated at our ambulatory unit during the two-year study period (2015-2016) was compared to a retrospective cohort (2013-2014) who received blood transfusion only. Between 2015-2016, 99 patients were included and treated with ferric carboxymaltose, the majority of whom (n = 81) had relative iron deficiency. Mean haemoglobin concentrations improved from 9.2 [6.7-10.8] g/dL to 10.6 [7.8-14.2] g/dL four weeks after treatment. A 26% reduction in the transfusion rate was observed from control retrospective to the prospective study group including ferric carboxymaltose treated patients [relative risk 0.74 (95% CI:0.66-0.83)]. The cost analysis showed a benefit for the use of ferric carboxymaltose in chemotherapy-induced anaemia. This study shows that ferric carboxymaltose is an effective, cost-saving support treatment, reducing the need for allogeneic transfusions saving blood units which are a limited resource.

Use and costs of originator and biosimilar erythropoiesis-stimulating agents in the treatment of chemotherapy-induced anemia: real-world evidence from an Italian hospital.

The aim of this retrospective study is to evaluate adherence, switch and costs a year after the start of treatment with different erythropoietin-stimulating agents. There were 277 patients, 200 were originators (72.20%) and 77 (27.80%) were biosimilars. Adherence to treatment for originators is 0.84 ± 0.22 versus 0.76 ± 0.27 for biosimilars (p = 0.3241). Medication adherence was calculated as ratio between received daily dose to prescribed daily dose. The optimum value is 1, values less than 1 indicate loss of adherence.  The cost of treatment per year is €7365 per patient for the use of the originator drug versus €2587 for biosimilars, with a difference of €4777 per patient.

Using PARP Inhibitors in Advanced Ovarian Cancer.

Poly(ADP-ribose) polymerase (PARP) proteins are used by cells in several DNA repair processes. PARP inhibition can result in preferential death of cancer cells when another mechanism for repairing DNA is defective. Two PARP inhibitors, olaparib and rucaparib, have been approved by the US Food and Drug Administration (FDA) for the treatment of recurrent, BRCA-associated ovarian cancer. More recently, these two and a third PARP inhibitor, niraparib, were approved by the FDA as maintenance therapy following platinum-based chemotherapy for recurrent ovarian cancer. This has caused a paradigm shift in disease management and a challenge for clinicians, who must decide how best to use these agents in individualized treatment. The oral formulation is attractive to patients, but adverse effects such as nausea and fatigue can impact quality of life. As clinicians become comfortable selecting PARP inhibitors and managing associated toxicities, future steps will be to investigate how to safely administer them in combination with other therapies.

Cost-Effectiveness of Ibrutinib Compared With Obinutuzumab With Chlorambucil in Untreated Chronic Lymphocytic Leukemia Patients With Comorbidities in the United Kingdom.

BACKGROUND: Ibrutinib shows superiority over obinutuzumab with chlorambucil (G-Clb) in untreated patients with chronic lymphocytic leukemia with comorbidities who cannot tolerate fludarabine-based therapy. However, ibrutinib is relatively more expensive than G-Clb. In this study we evaluated the cost-effectiveness of ibrutinib compared with G-Clb from the United Kingdom (UK) health care perspective. MATERIALS AND METHODS: A 3-state semi-Markov model was parameterized to estimate the lifetime costs and benefits associated with ibrutinib compared with G-Clb as first-line treatment. Idelalisib with rituximab was considered as second-line treatment. Unit costs were derived from standard sources, (dis)utilities from UK elicitation studies, progression-free survival, progression, and death from clinical trials, and postprogression survival and background mortality from published sources. Additional analyses included threshold analyses with ibrutinib and idelalisib at various discount rates, and scenario analysis with ibrutinib as second-line treatment after G-Clb. RESULTS: An average gain of 1.49 quality-adjusted life-years (QALYs) was estimated for ibrutinib compared with G-Clb at an average additional cost of £112,835 per patient. To be cost-effective as per the UK thresholds, ibrutinib needs to be discounted at 30%, 40%, and 50% if idelalisib is discounted at 0%, 25%, and 50% respectively. The incremental cost-effectiveness ratio was £75,648 and £-143,279 per QALY gained for the base-case and scenario analyses, respectively. Sensitivity analyses showed the robustness of the results. CONCLUSION: As per base-case analyses, an adequate discount on ibrutinib is required to make it cost-effective as per the UK thresholds. The scenario analysis substantiates ibrutinib's cost-savings for the UK National Health Services and advocates patient's access to ibrutinib in the UK.

Generic Imatinib Therapy Among Jordanians: An Observational Assessment of Efficacy and Safety in Routine Clinical Practice.

INTRODUCTION: Generic imatinib therapy is being globally considered owing to cost considerations. However, evidence of its efficacy and safety in Middle Eastern clinical settings is scarce. PATIENTS AND METHODS: The efficacy and safety of generic imatinib (Cemivil) were assessed among Jordanian patients diagnosed with chronic myeloid leukemia using an observational, multicenter, prospective study design. Responses were defined using European LeukemiaNet 2009 guidelines and assessed by complete blood counts, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction. RESULTS: All patients (N = 91) were adults with chronic myeloid leukemia treated with generic imatinib 400 mg/day. Thirty-three patients received generic imatinib as first-line therapy, and 58 switched from patented imatinib to generic imatinib after a median of 4.5 years (range, 0.5-13.6 years) of imatinib therapy. The majority (85%; n = 28) of the first-line patients achieved complete hematologic response within 3 months of starting generic imatinib therapy (100% after 6 months [n = 33]). The 12-month major molecular response rate in the intention-to-treat population was 45%. The 12-month major molecular response rate was 88% for patients who switched therapy. The 12-month progression-free and overall survival rates were 92% and 100%, respectively. Most (85%; n = 144) adverse events were mild. Frequencies of drug-related adverse events were similar to patented imatinib. CONCLUSION: This study suggests that the efficacy and safety of generic imatinib in this Middle Eastern population in routine clinical practice are comparable to patented imatinib, and to that of the global population.

Tale of Two Erythropoiesis-Stimulating Agents: Utilization, Dosing, Litigation, and Costs of Darbepoetin and Epoetin Among South Carolina Medicaid-Covered Patients With Cancer and Chemotherapy-Induced Anemia.

PURPOSE: The US Food and Drug Administration (FDA) has approved epoetin and darbepoetin for chemotherapy-induced anemia (CIA). Approved epoetin and darbepoetin dosing schedules were three times per week and weekly, respectively, although off-label, less frequent scheduling was common. In 2004, 2007, and 2008, a US Food and Drug Administration Advisory Committees warned of risks associated with erythropoiesis-stimulating agents. During this period, lawsuits alleging illegal darbepoetin marketing practices have concluded, resulting in $1.1 billion in fines and settlements and one criminal conviction. No prior study, to our knowledge, has reported on the use of darbepoetin versus epoetin for CIA. METHODS: We evaluated the dosing, utilization, and costs of erythropoiesis-stimulating agents among 3,761 South Carolina Medicaid patients with CIA. RESULTS: Epoetin and darbepoetin utilization rates were 22% and 28% in 2003, 10% and 33% in 2007, and 3% and 7% in 2010, respectively. Mean per-patient per-administration epoetin and darbepoetin doses were 40,983 IU and 191 µg, respectively, in 2003 and 47,753 IU and 369 µg, respectively, in 2010. Mean monthly patient costs for epoetin and darbepoetin were $1,030 and $981, respectively, in 2003 and $932 and $1,352, respectively, in 2010. Epoetin use decreased steadily between 2002 and 2010; darbepoetin use increased steadily between 2003 and 2007 and then decreased steadily thereafter. Per-patient dosing of darbepoetin, but not epoetin, increased steadily between 2003 and 2010, and monthly per-patient epoetin costs decreased 3% while the per-patients costs of darbepoetin increased 30% between 2003 and 2010. CONCLUSION: To our knowledge, our findings are the first data reporting on epoetin versus darbepoetin use for CIA and support recently concluded lawsuits involving allegations of illegal marketing practices of the manufacturer of darbepoetin.

Cost-effectiveness analysis of dose-dense versus standard intravenous chemotherapy for ovarian cancer: An economic analysis of results from the Gynecologic Oncology Group protocol 262 randomized controlled trial.

OBJECTIVES: To determine the cost-effectiveness of dose-dense versus standard intravenous adjuvant chemotherapy for ovarian cancer using results from the no-bevacizumab cohort of the Gynecologic Oncology Group protocol 262 (GOG-262) randomized controlled trial, which reported a smaller absolute progression-free survival (PFS) benefit than the prior Japanese trial. METHODS: A three-state Markov decision model from a healthcare system perspective with a 21day cycle length and 28month time-horizon was used to calculate incremental cost-effectiveness ratio (ICER) values per progression-free life-year saved (PFLYS) using results from GOG-262. Costs of chemotherapy, complications, and surveillance were from Medicare or institutional data. PFS, discontinuation, and complication rates were from GOG-262. Time-dependent transition probabilities and within-cycle corrections were used. One-way and probabilistic sensitivity analyses were performed. RESULTS: The model produces standard and dose-dense cohorts with 84.3% and 68.3% progression event proportions at 28months, matching GOG-262 rates at the trial's median follow-up. With a median PFS of 10.3months after standard chemotherapy and a hazard ratio for progression of 0.62 after dose-dense therapy, the ICER for dose-dense chemotherapy is $8074.25 (95% confidence interval: $7615.97-$10,207.16) per PFLYS. ICER estimates are sensitive only to the hazard ratio estimate but do not exceed $100,000 per PFLYS. 99.8% of ICER estimates met a more stringent willingness-to-pay of $50,000 per PFLYS. The willingness-to-pay value at which there is a 90% probability of dose-dense treatment being cost-effective is $12,000 per PFLYS. CONCLUSIONS: Dose-dense adjuvant chemotherapy is robustly cost-effective for advanced ovarian cancer from a healthcare system perspective based on results from GOG-262.

Clinical Assessment of Postoperative Anemia Associated with Edoxaban in Patients Undergoing Total Knee Arthroplasty Compared to Fondaparinux.

Edoxaban, an oral direct factor Xa inhibitor, was developed and approved for anticoagulant thromboprophylaxis after total knee arthroplasty (TKA). We retrospectively investigated the postoperative anemia by oral administration of edoxaban 30 mg compared with fondaparinux 2.5 mg in TKA patients. Two hundred twenty nine patients who underwent TKA in National Hospital Organization Okayama Medical Center from July 2010 to June 2012 were divided into two groups; pre and post approval of edoxaban: fondaparinux-group (F-group) and edoxaban-group (E-group). As the primary endpoint, the frequency of postoperative anemia was evaluated. Blood coagulation values and relations between these parameters and postoperative anemia were also investigated. The frequency of postoperative anemia was significantly higher in E-group than F-group patients (52.7% vs. 37.8%; p<0.05). Hemoglobin (Hgb) levels were decreased with the peak at postoperative day (POD) 3 in both groups, and the change of Hgb values from POD1 (ΔHgb) was significantly increased in the E-group (p=0.04). At each POD, prothrombin time (PT) and international normalized ratio of PT (PT-INR) prolonged from the preoperative day in E-group were significantly higher than F-group. Additionally, PT and PT-INR in the E-group at POD3 were significantly prolonged in patients with postoperative anemia and the sensitivity of cut-off values to predict postoperative anemia was superior to the activated partial thromboplastin time (APTT). Thus, as the frequency of postoperative anemia tended to be higher in E-group, edoxaban 30 mg might require vigilance, and prolonged PT and PT-INR could potentially predict edoxaban-associated postoperative anemia after TKA.

The Impact of the Risk Evaluation Mitigation Strategy for Erythropoiesis-Stimulating Agents on Their Use and the Incidence of Stroke in Medicare Subjects with Chemotherapy-Induced Anemia with Lung and/or Breast Cancers.

Erythropoiesis-stimulating agents (ESAs), found to be effective in reducing anemia in chemotherapy-treated cancer patients, also are associated with an increased risk of cardiovascular events, including stroke. In an attempt to mitigate the risk, the Food and Drug Administration implemented a Risk Evaluation Mitigation Strategy (REMS) in February 2010. The purpose of this study is to evaluate change over time in the incidence of stroke among these patients before and after implementation of REMS. A retrospective data analysis using the Medicare 5% Sample Dataset, 2008-2011, was performed. Patients had to be 65 years of age or older at the start of at least 1 year of continuous enrollment and to have lung and/or breast cancers along with chemotherapy-induced anemia (CIA) in both pre-REMS and post-REMS periods (1Q2008 through 4Q2009 and 1Q2010 through 4Q2011, respectively). Logistic regression was used to evaluate differences in proportions of patients who received ESAs and experienced a stroke pre and post REMS. The pre-REMS cohort included 1252 eligible patients prescribed ESAs; the post-REMS cohort included 949 patients. No statistically significant change in stroke incidence was observed post REMS among patients with CIA who received ESAs. There was a 29.5% decrease in ESA use in patients with lung cancer and a 27.8% decrease in patients with breast cancer. Both were statistically significant. Results adjusted for baseline characteristics and comorbid conditions were similar. There was a statistically significant decrease in ESA use in patients with breast and/or lung cancers post REMS; no statistically significant reduction in the incidence of stroke was observed regardless of cancer type.

Costs and Resource Utilization Associated With Anemia and Rash in Chronic Hepatitis C Patients Treated With Direct-Acting Antiviral Agents in the United States.

PURPOSE: The addition of 2 direct-acting antiviral (DAA) agents, telaprevir and boceprevir, to peginterferon and ribavirin therapy significantly improves sustained virologic response rates in patients treated for chronic hepatitis C virus (CHC) but is associated with a higher risk of adverse events (AEs), including anemia and rash. Using a large administrative claims database, this study compared the health care resource utilization and costs among CHC patients who developed anemia and/or rash while receiving DAA-based therapies (telaprevir and boceprevir) versus those who did not develop anemia or rash. Adjusted costs were compared by using regression analysis. METHODS: Adult patients with ≥1 CHC diagnosis and a prescription for boceprevir or telaprevir were selected from a US-based claims database. The date of the first DAA fill after May 13, 2011, was defined as the index date. Patients were required to have continuous eligibility and no claims for hepatitis B treatment during the 6 months before (baseline) and 12 months after (study period) the index date. Patients were categorized into 4 cohorts based on the development of anemia only, rash only, both anemia and rash (anemia/rash), or neither anemia nor rash (NAR) while receiving DAA-based therapies. Baseline characteristics and study period health care utilization and costs were compared by using univariate statistics between cohorts that developed anemia only, rash only, or anemia/rash and the cohort that did not develop anemia or rash. Adjusted costs were compared by using multivariable regressions. FINDINGS: A total of 2862 patients were identified and categorized into 4 cohorts: 1204 anemia only, 131 rash only, 188 anemia/rash, and 1339 NAR patients. During the study period, patients developing anemia and/or rash incurred significantly more outpatient, dermatologist, and total medical visits compared with the NAR cohort. The anemia-only and anemia/rash cohorts also had significantly more inpatient, emergency department, and hematologist visits, as well as significantly higher adjusted total medical costs ($18,285 and $21,435 vs $11,253), total drug costs ($76,723 and $79,689 vs $63,001), and non-CHC drug costs ($10,391 and $10,475 vs $2437). The rash-only cohort had comparable adjusted total medical and drug costs. IMPLICATIONS: CHC patients who developed anemia while receiving DAA-based therapies incurred significantly higher resource utilization and costs compared with those who did not. The study highlights the need for new CHC treatment regimens that are associated with fewer and less severe AEs, particularly anemia.