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This research was designed to investigate patient-reported and doctor-reported reasons for the discontinuation of pharmacological treatment in Chinese patients with major depressive disorder (MDD), which was part of the National Survey on Symptomatology of Depression (NSSD) from 2014 to 2015.This cross-sectional study included 649 patients who had discontinued antidepressant medications and 711 patients who had remained on them, selected from a group of 3516 candidates who have had at least one depressive episode. Differences in the two groups' sociodemographic factors, clinical characteristics, medication use, and self-reported reasons for drug discontinuation were compared via Student's t-test or chi-square test. Logistic regression analysis was then used to determine the association of all non-subjective dichotomous and ordinal categorical variables, including the additional 63 items of our physician-evaluated symptomatic assessment, with drug compliance.Compared to the spontaneous drug discontinuation (SDD) group, the drug adherence (DA) group had significantly lower rates of the following: family history of mental disease (9.0% vs 13.6%), highest level of education achieved being post-graduate or above (1.6% vs 4.7%), smoking (5.8% vs 9.7%), and other health problems (33.9% vs 42.4%) (p's 0.05). On the other hand, first-episode depression (48.5% vs 21.9%) and taking of mood stabilizer(s) (8.3% vs 5.6%) were higher in the former group than in the latter (p's 0.05). Logistic Regression Analysis showed that five symptoms, such as depressed mood, were correlated positively with SDD, while another six symptoms, such as psychomotor retardation, were correlated negatively with it. The receiver operating characteristic (ROC) curve of this model yielded an area under the curve (AUC) of 0.701 (95% CI, 0.673-0.729). Notably, there were three main reasons given by patients in the DA group as to why they discontinued their medication(s): (1) concern about long-term side effects (36.1%), (2) no perceived need for taking said medication(s) long-term (34.2%), and (3) believing oneself to have been cured completely (30.0%).The aforementioned factors may affect patient compliance and elicit maladaptive thinking even from patients with good educational backgrounds, increasing the risk of drug discontinuation. Compliance of pharmacological treatment might be improved by increasing clarification and elucidation of different symptom clusters to the patient and combating the main reasons for drug discontinuation.

Aim: Chronic myeloid leukemia (CML) is a BCR-ABL positive myeloproliferative disorder characterized by clonal proliferation of the hematopoietic stem cells. Imatinib mesylate represents the most important agent associated with improved survival in CML that has been introduced for clinical use in 2000s. The original imatinib preparation Glivec ® was subsequently followed by the introduction of biosimilar products containing a variety of excipients. Gastrointestinal side effects represent the major limitation for therapeutic use of imatinib. This study was planned to examine whether excipients in the original and biosimilar imatinib products had any role in the emergence of GIS side effects. Materials and methods: Excipients in imatinib preparations used for the treatment of chronic phase (CP) CML patients followed up and treated at the hematology department of Mersin University between 2000 and 2019 were analyzed with respect to their potential GIS side effects. Results: Totally 42 CML patients included in the study. The median age was 53.2, and female:male ratio was 20:22. They had similar demographic characteristics as compared to previously reported CML populations. No patients had GIS side effect requiring drug discontinuation or switch to another agent. While bovine gelatin and polyvinyl alcohol had no significant effects on GIS side effects, those that contained titanium were found to be associated with a significant increase in the risk of GIS side effects (52%, contained titanium vs 0/2, contained no titanium). These side effects are less frequently in products that have lowest number of excipient types. Conclusion: GIS side effects can be triggered by various excipients in imatinib preparations.

Introduction Continuous usage of direct oral anticoagulants (DOACs) among nonvalvular atrial fibrillation (NVAF) patients is essential to maintain stroke prevention. We examined switching and discontinuation rates for the three most frequently initiated DOACs in NVAF patients in the USA. Methods Patients who initiated apixaban, rivaroxaban, or dabigatran (index event/date) were identified from the Pharmetrics Plus claims database (Jan 1, 2013–Sep 30, 2016, includes patients with commercial and Medicare coverage) and grouped into cohorts by index DOAC. Patients were required to have a diagnosis of NVAF and continuous health plan enrollment for 12 months prior to the index date (baseline period) and at least 3 months during the follow-up period. Drug switching rates to any other DOAC or warfarin and index DOAC discontinuation rate were evaluated separately with descriptive statistics, Kaplan–Meier analysis, and multivariable Cox regression analysis. Results Of the NVAF study population (n = 41,864), 37% initiated apixaban (n = 15,352; mean age 62 years), 51% initiated rivaroxaban (n = 21,250; mean age 61 years), and 13% initiated dabigatran (n = 5262; mean age 61 years). During the follow-up period, the unadjusted drug switching rates of patients treated with apixaban, rivaroxaban, and dabigatran were 3.6%, 6.3%, and 11.1%, respectively (p

Drug metabolism is one of the most important processes involving a drug after administration. Undesirable pharmacokinetic properties may lead to drug discontinuation. In the past several decades, a number of drugs have been withdrawn from the market due to safety issues caused by metabolites, especially reactive metabolites (RMs). Area covered: The focus of this review is on the role that drug metabolites play in drug discovery and developmental stages, with particular emphasis on metabolism-guided lead optimization, safety assessment of drug metabolites, drug-drug interaction potential of metabolites, and RMs safety assessment. In addition, species-related metabolic differences are briefly covered. Expert opinion: For the safety assessment of drug metabolites, a number of factors should be given full consideration, such as dose, in vitro and in vivo correlations, in vivo animal toxicological findings, and the accumulation of metabolites in plasma and/or tissues. Several factors, especially dose and multiple metabolic pathways, can significantly affect the occurrence of idiosyncratic adverse drug reactions (IADRs). Multiple assays should be used to assess RMs and thus avoid false-negative results. There is no clear interplay between the formation of RMs and the occurrence of IADRs. Avoidance of structural alerts and decreasing dose are the most effective strategies in reducing the risk of IADRs.

Introduction and Aim: Previous data have shown the high efficacy of omalizumab in severe asthma. However, factors that may be effective on the response to therapy, relapse rates after drug discontinuation, and efficacy of retreatment remain unclear. This study aimed to evaluate the efficacy of retreatment on relapsed disease. Methods: Patients who were treated with omalizumab at least two years at first treatment and also retreated at least one year were included to study. Patients with adverse effect causing treatment discontinuation at first treatment were excluded. Social demographic data, laboratory findings, pulmonary function tests and adverse effects during retreatment were recorded. Results: 12 patients were included to the study. There was 8 female and mean age of patients was 57,4 ± 11,9 years. Most popular reason to stop omalizumab treatment was patient9s wish (7 patients). Retreatment dosage of omalizumab was found decreased (p>0,05). Mean duration of time from discontinuation of first treatment to retreatment was 12,2±9,7 months. After retreatment asthma control test was improved (p Discussion: Omalizumab retreatment is effective and safe in patients with severe asthma who have benefited from initial omalizumab treatment.

Background Severe hypersensitivity reaction is a dangerous adverse drug reaction in patients receiving cetuximab. It requires drug discontinuation and medical management. Case description A 48-year-old man, previously diagnosed with metastatic colorectal cancer, was admitted for therapy continuation. During the first infusion of cetuximab, the patient experienced acute signs of hypersensitivity reactions. The treatment team decided to administer cetuximab employing the desensitization protocol. Conclusions This study reports a severe hypersensitivity reaction to cetuximab in an adult patient with colorectal cancer. This patient was successfully managed with a new safe and rapid desensitization protocol.

Background The aim of this study was to investigate the drug survival, its efficacy and safety in patients withRA based on the database from the Turkish TURKBIO registry Methods A total of 180 patients were treated with TOFA forRA. Drug survival was assessed. In 118 patients with available data, treatment response was evaluated using thenumber of sensitive and swollen joints, VAS values, DAS28, HAQ and CRPat weeks 12,24,48 and 60 Results At baseline, RA patients had a median(Q1-Q3)disease duration of 14 years.75 patients had used ≥1 biologics previously. The other demographic and clinical features of the patients were shown in table 1. Median(Q1-Q3)followup period was137 weeks. After48 and137 weeks,75% and 48%of the patients respectively, maintained TOFA (figure 1). The most common reason for drug discontinuation was ineffectiveness of treatment(63%), followed by adverse events (23%). After 12 weeks, all disease activity parameters were reduced significantly compared to the baseline and most of them continued to be reduced until week60. No difference was observed in disease activity parameters between the groups with and without previous ≥1biologics at weeks 0,12 and 24 (table 2) Remission rate was(43%)at week 60(observed data) (table 2) A total of 9 adverse events(3infection,3allergic rx,2 rash)were observed during the followup period Conclusions Treatment with TOFA may provide good response rates in RA patients refractory previous biologicals Disclosure of Interest None declared

Background TURKBIO registry is the Turkish version of Danish DANBIO rheumatologic database which has been established in 2011. Demographics and previous or current treatment with conventional (csDMARD) and targeted synthetic (tsDMARD), and biological DMARDs (bDMARDs) were collected. Objectives We aimed to investigate the efficacy and safety status of methotrexate (MTX) vs. leflunomide (LEF) use as a concomitant treatment with bDMARDs and tsDMARD in this registry. Methods Frequencies of achievement of remission or remission +low disease activity (LDA) at the 6th month of bDMARD or tsDMARD treatment were compared between patients who were on these medications with MTX vs. LEF as a concomitant treatment. Drug survival and switch rates of bDMARDs and tsDMARD treatments either with MTX or LEF were compared. The adverse effects with MTX and LEF concomitant use were evaluated as well. Results The study included 725 bDMARD or tsDMARD receiving RA patients from 8 participating centres of the TURKBIO registry. Of these patients, 462 (63.7%) were receiving concomitant MTX and 263 (36.3%) LEF. Demographic findings are given in the table 1. Achievement of remission and remission +LDA at the 6th month of bDMARD or tsDMARD initiation was similar in concomitant MTX vs LEF groups (51.4% vs. 53%, p=0.683). When each bDMARD and tsDMARD was evaluated separately, achievement of remission were again similar in MTX and LEF concomitant users (TNFi: 53% vs. 54%; ABA: 50% vs. 59%; RTX: 53% vs. 61%; TCZ: 42% vs. 35%; p>0.05 for all). For TOFA, although remission +LDA rate was numerically higher in MTX concomitant group than LEF group (42% vs. 21%), the difference was not statistically significant due to the smaller sample size of TOFA (n=33). The results were similar for all DMARD groups when remission was evaluated alone. Drug survival (17±12 vs. 16±11 months, p>0.05) and drug discontinuation (42,2 vs 38, p>0.05) rates of bDMARDs or tsDMARD were also not different in MTX vs. LEF concomitant users. Adverse effects rate (19.5% vs 20.5%, p>0.05) were similar between MTX vs. LEF concomitant users as well. Conclusions Achievement of remission or remission +LDA was not different with the concomitant use of MTX vs. LEF with any bDMARD or tsDMARD treatment in RA patients with a similar safety profile. LEF might be an alternative as a concomitant DMARD in MTX-intolerant RA patients initiating bDMARDs or tsDMARD. Disclosure of Interest None declared

Clinical data of 65 histologically documented ulcerative colitis patients from January 2001 to December 2013 were prospectively recorded till June 2017 and analysed to determine the outcome of long-term maintenance treatment. Drugs used were 5-aminosalicylates, steroids and azathioprine. Primary outcome measure was relapse. Though 73.8% patients relapsed, most occurred within the first five years with mild to moderate severity and were easily controlled with the same medicines. None had progressive disease; drug discontinuation was possible in six cases. Side effects of drugs were negligible. Rates of surgery, colon cancer, complications and disease-related death were very low. Longer disease duration, azathioprine discontinuation and 5-aminosalicylate use in dose

Background: Antiretroviral therapy has led to a substantial reduction in HIV-associated morbidity and mortality. Efficacy of antiretroviral treatment in HIV/AIDS is showing inhibition of viral replication and reduction of viral load to a point where viral particles are undetectable in the blood of infected individuals. This has led to the realization that HIV/AIDS is a chronic illness. Objective: The main objective of this study was to assess drug discontinuation patients who are taking antiretroviral treatment at yeka sub-city woreda 9 and 10 Addis Ababa Ethiopia. Methods: A cross-sectional descriptive study was employed using quantitative approach to assess drug discontinuation among patients who are taking antiretroviral treatment among HIV/AIDS infected persons. Result: At the end of one month study period 219 patients from the total 620 returned to the pharmacy to refill their medication were interviewed and the drug discontinuation to ARV medication was 27 (12.3)% of all prescribed doses. Conclusion and Recommendation: Drug discontinuation to antiretroviral regimen is critical, patient must take 95 percent of the prescribed pills to achieve an 80% of the likelihood of HIV suppression below 50 copies per ml, regarding to the present study the drug discontinuation was 12.3%.

Corneal deposits have been reported with numerous topical medications including fluoroquinolones. However, they have not been documented as a side effect of topical moxifloxacin. In this report, we describe the first case of corneal deposits following the use of preservative-free topical moxifloxacin 0.5% eye drops in a 26-year-old male with keratoconus who underwent a unilateral corneal cross-linking. Increased frequency and prolonged instillation of moxifloxacin eye drops led to corneal precipitation in this patient. Complete resolution of corneal deposits occurred four months after drug discontinuation without sequelae. Keywords: Corneal deposits, Fluoroquinolone, Moxifloxacin

We report a case of a patient with histopathologically diagnosed GIST who had undergone complete tumor resection for primary localized lesion. The patient has received adjuvant imatinib treatment for at least two years. Studies have shown an improvement in RFS with 1 year of adjuvant imatinib, there is no consensus on the appropriate duration of adjuvant. The 2 year RFS rate in ACOSOG Z9000 was 73%, significantly lower than the 1 year RFS rate of 94%. These findings indicate that 1 year of adjuvant is likely to be insufficient, this implies that an extended duration of adjuvant prolongs RFS in patients with high risk of recurrence. The efficacy of re-challenge with imatinib in the subjects who developed recurrence after drug discontinuation indicates that it was probably due to insufficient treatment duration rather than resistence to imatinib. Waiting the results of phase III trial SSGXVIII/AIO about 3 years of treatment with imatinib we conclude that the better choice, for the year 2010, was to treat patient for at least two years.

Background Ticagrelor, a reversible P2Y12 receptor antagonist, is superior to clopidogrel in decreasing major adverse cardiac events in the setting of acute coronary syndrome. However, a high rate of drug discontinuation secondary to ticagrelor-induced dyspnoea has been observed. Clinical details This is a case of persistent and intolerable ticagrelor-induced dyspnoea in a patient requiring drug discontinuation. A review of the literature on the plausible mechanisms is also provided. Conclusion Dyspnoea is a relatively common side effect of ticagrelor, usually mild and not associated with alteration in pulmonary function. However, in cases of persistent and intolerable dyspnoea, drug discontinuation should be considered. It is imperative that healthcare professionals regularly monitor patients receiving ticagrelor therapy with the aims of maintaining medication adherence and providing appropriate alternatives if dyspnoea becomes intolerable.

ResumenDesde la comercialización de fármacos que actúan sobre el remodelado óseo se han registrado numerosos casos de osteonecrosis de los maxilares (ONM), pero hasta hace poco solo se habían descrito casos de ONM asociados a la administración de bifosfonatos. Con la introducción de nuevos agentes antirresortivos han aparecido varios casos de ONM asociados a denosumab. Presentamos el caso de una paciente de 84 años con osteoporosis, que presentó osteonecrosis mandibular tras la colocación de 6 implantes 5 meses después de la administración de denosumab. Una ortopantomografía y una TC mostraron pérdida ósea de la cresta mandibular y exposición ósea periimplantar. Tras el tratamiento conservador con antibióticos y la suspensión de denosumab, se inició el tratamiento con teriparatida reduciéndose la infección del hueso necrótico y se observó nueva remodelación ósea. La patogénesis de la ONM por denosumab no está claramente definida, pero parece que la tasa del éxito de curación es superior a la ONM por bifosfonatos.AbstractSince the introduction of drugs acting on bone remodeling, numerous cases of drug-induced osteonecrosis of the jaw (ONJ) have been reported. Until recently these cases were exclusively associated with the administration of bisphosphonates. With the introduction of new antiresorptive agents such as denosumab, several cases of ONJ associated with its treatment have been recently reported. The case is presented of an 84 year-old osteoporotic female patient who developed mandibular osteochemonecrosis after the placement of 6 implants five months after the administration of denosumab. A panoramic radiograph and CT, showed mandibular crestal bone loss and peri-implant exposure. Conservative treatment with antibiotics and discontinuing denosumab, and starting treatment with teriparatide, decreased the necrotic bone infection and new bone remodeling could be observed. The pathogenesis of denosumab-induced ONJ is not clearly defined, but it seems that the success rate in healing after drug discontinuation is higher than in bisphosphonates-induced ONJ.

Statin-induced musculoskeletal effects account for about two-thirds of all adverse events and are the most common cause for the drug discontinuation. In view of its proven benefit for cardiovascular risk reduction, statins are the most important medications that should not be stopped until absolutely contraindicated. This concept is also endorsed by the recent AHA and NLA recommendations. Various strategies like lowering the daily dose, non-daily dosing, switching therapy, non-statin lipid-lowering drugs, Co-enzyme Q and dietary interventions have been tried with inconsistent results. Newly introduced molecules such as Mipomersen, Evolocumab and Alirocumab may show some promise in management of the statin-intolerant patients in future.

Background: Natalizumab (NTZ) and fingolimod (FGL) are mainly used second line in relapsing–remitting multiple sclerosis (MS), although pivotal trials included mainly treatment-naïve patients. Objective: This study aims to provide real-world data on safety and discontinuation rates. Methods: Using IMSE, a drug monitoring registry for all newer MS drugs in Sweden, we analysed differences in baseline characteristics and 1-year drug survival for patients registered 2011–2013, initiating treatment with NTZ ( n=640) or FGL ( n=876). Among FGL initiators, n=383 (44%) had previously used NTZ (FGLafterNTZ). Results: Compared with NTZ, the FGL cohort was older and more often male (36/38 years, 24%/33% males). Baseline Expanded Disability Status Scale was similar across groups, but MS Severity Score was higher in NTZ patients, and Symbol Digit Modalities Test and MS Impact Scale (MSIS-29) was higher in FGLafterNTZ versus FGLNTZ-naïve patients. Proportion on drug after 1 year was high, NTZ=87%, FGLNTZ-naïve=83% and FGLafterNTZ=76%. Adverse events was the most frequent reason for discontinuing FGL (FGLNTZ-naïve=9%, FGLafterNTZ=12%), and was significantly higher than on NTZ (3%). In contrast, the proportion of patients stopping treatment due to lack of effect was more similar: NTZ=4%, FGLNTZ-naïve=3%, FGLafterNTZ=8%. Conclusion: FGL and NTZ were both well tolerated, but FGL less so than NTZ, especially in patients switching to FGL from NTZ. Group differences were not explained by differences in recorded baseline characteristics.

The different stages of the life cycle of a drug – ‘prenatal' stage, birth of a drug, rapid growth, maturity and stability, decline, and status before ‘death' – are reflected in the three following databases: journal articles (PubMed—www.ncbi.nlm.nih.gov/pubmed); patents (US Patent Office—http://partfl1.uspto.gov/netahtml/PTO/search-adv.htlm); and approved drugs (FDA – www.accessdata.fda.gov/scripts/cder/drugsatfda/index/cfm). These databases are huge, from authoritative sources, correctly classified, and they properly link different datasets. Analysis of such data can uncover hidden patterns important for the assessment of drug status and may also yield some predictions regarding its future prospects. Drug-related, publication-based academic bibliographic records are especially numerous and support the development of various scientometric indices. In combination with information from other types of databases, they can outline various trends in pharmacology. Scientometric indices can be classified into those indicating a change in the status of a drug, and those assessing the chances for success, or even drug discontinuation. Here, we present big data analytics on publication-based academic interest in two segments: (i) description of scientometric indices and (ii) their applications for the assessment of the status of a drug.

Parkinsonism-hyperpyrexia syndrome (PHS), or neuroleptic malignant syndrome (NMS), is a neurophysiologic reaction to the acute withdrawal/decrease of central dopamine levels. It is a severe complication characterized by rigidity, change in consciousness level, fever, hypertension, and autonomic instability, that can be fatal. To the best of our knowledge, PHS following deep brain stimulation (DBS) of subthalamic nucleus (STN) surgery due to anti-Parkinson drug discontinuation has been previously reported only six times. Half of these cases resulted in fatalities. Herein, we report on an early diagnosed case of PHS following bilateral STN-DBS which was successfully treated with the administration of dopamine agonists, fluid replacement, and activation of DBS.

Diagnoses of drug-treatable illnesses has drifted to include milder conditions than in the past. Treating them increases the number of drugs given a person, risking polypharmacy, especially in elderly people with multiple conditions. The adverse consequences of polypharmacy are increased costs, confusion when taking drugs, adverse drug events, intermittent adherence with adverse drug discontinuation effects, and unrecognized delayed adverse effects. Deciding what not to treat helps minimize polypharmacy and its consequences.

We present the case of a 58-year-old woman who developed hypokalaemia and metabolic alkalosis 2 weeks after therapy with colistimethate sodium for the treatment of chronic lower limb ulcer infection by extensively drug-resistant (XDR) Pseudomonas aeruginosa. The metabolic changes observed resembled Bartter syndrome, a group of congenital disorders affecting the distal segments of the renal tubules. The metabolic abnormalities reversed spontaneously 6 days after drug discontinuation. Acquired forms of Bartter syndrome have been reported during courses of antibiotic therapy; however, to our knowledge, this is the first documented case associated with colistimethate therapy in an adult.

The objective in percutaneous coronary intervention (PCI) is to treat flow-limiting atherothrombotic coronary plaques mechanically. Many types of antithrombotic drugs are used to prevent ischemic complications during manipulation of catheters, guidewires, balloons, and stents in coronary arteries while minimizing the risk of bleeding. However, many other types of pharmacologic agents are also used to facilitate PCI. This review focuses on the most commonly used adjunct drugs during PCI. In addition, a recommendation of which drugs should be stopped or interrupted in patients undergoing PCI is provided.

Background JIA is the most common chronic inflammatory rheumatic disease of childhood. TNF inhibitors are used for long-term control of pJIA disease. Objectives To evaluate the 7 year (y) safety of Adalimumab treatment with or without methotrexate (ADA±MTX) when used in current clinical practice for treatment of patients (pts) with active pJIA. Methods This is a 7 y interim analysis of an ongoing, multicenter, non-interventional, observational registry of pts with pJIA with up to10 y safety follow-up. Included pts were treated with ADA±MTX or MTX alone as comparison arm according to routine clinical care in PRINTO/PRCSG centres in EU, USA and Australia. MedDRA observational adverse events (AEs) were recorded from 1st day in the registry through last contact, irrespective of duration of registry treatment. Results In January 2014, enrollment was complete. As of June 1, 2016 cut-off date, 838 pts (301- MTX arm and 537 - ADA±MTX arm) were treated in the registry. There were 39 pts who rolled over from MTX to ADA±MTX arm. At registry entry mean pJIA disease duration was 1.3 y and 3.7 y and mean AJC71 was 5.8 and 5.2 for MTX and ADA±MTX arms, respectively. CHAQ disability index was 0.6 for both arms. Mean duration of study drug exposure in registry was 2.0 y (range: 0.0 – 7.1) and 2.5 y (range: 0.0 – 7.9) for MTX and ADA±MTX arms, respectively. Mean duration of observation in registry was 3.9 y (range: 0.0 – 7.2) and 3.5 y (range: 0.0 – 7.9) for MTX and ADA±MTX arms, respectively. Overall, 213 pts (70.8%) in MTX and 225 pts (41.9%) in ADA±MTX arms discontinued registry drug through 7 y. Main reasons (not exclusively) for registry drug discontinuation for MTX arm: pts required additional therapy (32.6%), other (13.3%), lack of efficacy (11.6%), AEs (9.3%), or pts achieved JIA remission (8.6%); for ADA±MTX arm: lack of efficacy (17.9%), other (7.3%), lost to follow-up (5.6%), AEs (5.4%), or pts achieved JIA remission (5.0%). Frequencies and rates of treatment-emergent AEs (from 1st dose date of registry drug in registry up to last dose + 70 days in registry, excluding AEs occurring during treatment interruption) were similar to those reported for observational AEs (from 1st day in registry up to last contact irrespective of drug treatment duration) (Table). Rate of serious infections was similar between MTX and ADA±MTX arms. One pt (0.2%) reported an event of opportunistic infection (fungal oesophagitis) in ADA±MTX arm. No reports of deaths, malignancies, active tuberculosis, oral candidiasis, demyelination, or congestive heart failure. Conclusions Overall, ADA±MTX was well-tolerated in these pts with pJIA with no new safety signals. The retention rate for registry drug was higher in ADA±MTX arm compared to MTX arm. Acknowledgements AbbVie sponsored the study & contributed with PRINTO & PRCSG to analysis, review, approval of the abstract. X. Leahy & A. Deshmukh (AbbVie) contributed to research. Medical writing: G. Patki (AbbVie). Disclosure of Interest N. Ruperto Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals, Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche, and Wyeth/Pfizer, H. Brunner Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Boehringer-Ingelheim, Pfizer, Regeneron, Hoffman La-Roche, Novartis, Takeda, UCB, and Genentech, Speakers bureau: Genentech Pharmaceuticals, K. Nanda Consultant for: Medac Pharma, Inc., M. Toth: None declared, I. Foeldvari Consultant for: AbbVie and Novartis, J. Bohnsack Consultant for: Novartis, D. Milojevic Consultant for: Genentech and Novartis, C. Rabinovich Grant/research support from: UCB Pharma, Janssen, D. Kingsbury: None declared, K. Marzan Grant/research support from: AbbVie, P. Quartier Grant/research support from: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, and Swedish Orphan Biovitrum, Consultant for: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum, and Sanofi, K. Minden Grant/research support from: Pfizer, AbbVie and Roche/Chugai, Consultant for: Pfizer, Roche, and Pharma-Allergan, Speakers bureau: Pfizer, Roche, and Pharma-Allergan, E. Chalom Speakers bureau: AbbVie, G. Horneff Grant/research support from: AbbVie, Pfizer, Novartis, and Roche, Speakers bureau: AbbVie, Novartis, Sobi, Pfizer, and Roche, R. Kuester Grant/research support from: AbbVie Inc. and Wyeth/Pfizer, J. Dare Grant/research support from: AbbVie, AstraZeneca, Bristol-Myers Squibb, Horizon Pharma, Medac, Pfizer, Roche, and UCB, M. Bereswill Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie, A. Martini Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals, Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, and MedImmune, D. Lovell Consultant for: AstraZeneca, Centocor, Bristol-Myers Squibb, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Xoma, Genentech, Amgen and Forest Research, Speakers bureau: Wyeth Pharmaceuticals

Background There are many biological therapies for Rheumatoid Arthritis (RA) with different mechanisms of action and good efficacy rate; however, up to 40% of patients (pts) fail to respond to the 1st biologic agent, and it is still not clear what strategy to follow after showing inadequate response to tumor necrosis factor α inhibitors (TNF-i) Objectives To assess the clinical response and survival (SVV), in our cohort of RA pts that discontinued the 1st TNF-i, of a 2nd TNF-i vs a nonTNF-i, both in the global cohort and in the subpopulation that dropped out the 1st TNF-I due to inefficacy Methods This observational study included 110 pts in the RA-Paz cohort who previously suspended Ifx (68%) or Ada (32%) between 1999–2016. Two groups were established as they switched to a TNF-i or nonTNF-i. Clinical response was evaluated by DAS28, Delta-DAS28 (ΔDAS28) and EULAR response (E-resp). The assessments were performed at 6 (v-6) and 12 months (v-12) since initiating 2nd biological agent and during the last visit prior to drug discontinuation or ending of the study for those who did not interrupt the drug (v-end). Statistical analysis was performed using SPSS version 20.0 Results Of the 110 pts who had stopped Ifx or Ada as 1st TNF-i, 65% changed to a 2nd TNF-i. The 84% of the overall pts were women. The mean age was 64±14 years and the mean time of 2nd biologic drug was 3.71±3.51 years. 61% associated methotrexate at the beginning of 2nd biologic agent and 56% at the v-end, without differences between those who switched to TNF-i and those who did to nonTNF-i. At v-6 and v-12, there was no difference in ΔDAS28 [at v-6:1.3±1.4 in TNF-i and 1.2±1.2 in nonTNF-i (p=0.919), at v-12: 1.3±1.5 in TNF-I and 1.2±1.1 in nonTNF-i (p=0.852)]. In contrast, at v-end, pts with nonTNF-i showed a higher clinical improvement (ΔDAS28: 0.68±1.7 in TNF-i, 1.8±1.1 in nonTNF-i, p=0.002). At v-6, the TNF-i group achieved higher good E-resp rate (41% vs 18%, p=0.035), but there was no difference at v-12 (36% in TNF-I vs 23% in nonTNF-i, p=0.435). However, at v-end, the nonTNF-I group achieved better E-resp (good resp: 38% in nonTNF-i vs 25% in TNF-I, no resp 18% in nonTNF-i vs 50% in TNF-i, p=0.01). Likewise, 100% (n=7) of the pts that finished 2nd biologic agent by remission, had changed to a nonTNF-i (p Conclusions In our sample of RA patients who suspended Ifx/Ada as 1st TNF-i, switching to a 2nd biologic agent did not show relevant clinical differences between a TNF-i and a nonTNF-i within the 1st year of treatment. However, in the long-term, switching to a nonTNF-i shows enhanced clinical benefits with no impact on survival vis-a-vis a 2nd TNF-i. Despite the efficacy of TNF-i, new therapeutic targets are needed for those who fail to respond to these biological agents Disclosure of Interest None declared

Background The term spondyloarthritis (SpA) encompass a group of crhonic inflammatory disease with predominant axial involvement. Anti-TNF therapy (AT) has stirred up the management of these diseases. Nevertheles, according to nationwide registries of the drug continuation rate in several countries, the rate of treatment failure is considerable. Nowdays there are insufficient data to evaluate the differences between responders (Resp-AT) and non-responders (Nonresp-AT) to anti-TNF therapy. Objectives To compare the main sociodemographic, clinical and analytical features at baseline, after 6 months of treatment and at the end of the first anti-TNF therapy of responders to a first anti-TNF therapy and non-responders to several anti-TNF therapies form our cohort of patients diagnosed with SpA. We also analized the association between drug levels (DL) and antidrug antibody (ADA) in non-responders to several anti-TNF. Methods 181 patients were included, 155 (85%) kept receiving their first AT therapy (responders) and 26 (15%) had discontinued at least two different AT therapies. The main demographic features, disease activity (BASDAI, ASDAS, CRP and ESR) were measured at baseline, after 6 months (v-6) and when the first AT was discontinued. Serum drug levels and/or ADA were measured at drug discontinuation of anti-TNF treatment and last visit in non-responders and responders respectively. Results The mean age was 55.3±15 and 50±10.8 in the resp-AT and nonresp-AT groups, respectively. The demographic and clinical characteristics of both groups are shown in Table 1. At baseline, a lower BMI was observed in the resp-AT group (25.6±5 resp-AT, 28.7±5 nonresp-AT, p=0.013); 59% and 35% were in concomitant treatment with DMARDS at baseline in the resp-AT and nonresp-AT groups respectively (p=0.032); 33% of the resp-AT were in monotherapy in the last visit compared to 62% of the nonresp-AT when discontinued the 1st AT (p=0.008). There were no differences in BASDAI (5.6±2 resp-AT, 6.1±1.9 nonresp-AT, p=0.2) and ASDAS (3.3±1.1 resp-AT, 3.4±1.1 nonresp-AT, p=0.8) at baseline. In v-6, the resp-AT group had a better clinical response in terms of BASDAI (3.2±2.3 in resp-AT, 4.7±2.4 in nonresp-AT, p=0.004) and ASDAS (1.7±0.9 in resp-AT, 2.7±1.2 in nonresp-AT, p=0.00), as well as in the delta-ASDAS (ΔASDAS) (1.56±1.2 resp -AT, 0.7±0.9 nonresp-AT, p=0.04). However, delta-BASDAI (ΔBASDAI) showed no difference between the two groups (2.3±2.3 resp-AT, 1.5±1.6 nonresp-AT, p=0.1). 24% of the nonresp-AT were ADA + at drug discontinuation, while only 0.7% of the AT-resp (AT) were ADA + (p=0.00) at last visit. Conclusions In our cohort of patients with axial SpA, a significant improvement in BASDAI, ASDAS and ΔASDAS after 6 months of treatment is associated with a lower frequency of drop-out of the first AT. Moreover a lower BMI, DMARDS at baseline and absence of ADA determine a better response to AT treatment. Disclosure of Interest None declared

Cutaneous reactions are a common adverse effect of medications. Most are mild but some can be serious and require drug discontinuation.

Background: Although epilepsy surgery is a recognized treatment option for drug-resistant epilepsies since several decades, the management of antiepileptic drugs (AEDs) after successful surgery still remains one of the most difficult and unsolved therapeutic challenges. Indeed, no systematic controlled trials have been specifically conducted so far and no consensus or standardized guidelines regarding postsurgical drug discontinuation policy and procedures are available. Methods: In this paper, we aim to provide an updated overview on the present knowledge on this topic, which is based mainly on retrospective studies reporting practices used in individual centers. Results: Currently available data suggest that: 1) rate of seizure recurrence appears to be higher in patients undergoing early (before 6 months or 9 months according to different studies) AED withdrawal; 2) seizures that recur during AED tapering are easier to control than unprovoked postoperative seizure relapses; 3) there is no evidence to support negative long-term implications on seizure outcomes in patients who attempted AED withdrawal. In the pediatric age group, shorter intervals from surgery to AED reduction and to complete AED discontinuation predict seizure relapse during or after AED reduction/withdrawal. However, this does not correlate with the chances of regaining seizure freedom after drug reintroduction. Conclusion: Carefully conducted prospective longitudinal studies and randomized controlled trials are warranted to establish the correct post-surgical pharmacologic treatment and to identify the best candidates for AEDs discontinuation.

To date, the significance of early intervention with methotrexate and biological disease-modifying anti-rheumatic drugs for rheumatoid arthritis (RA) has not been realized. Longitudinal safety and cost have arisen as new concerns. The concept of a treatment holiday, drug discontinuation after achieving remission, may solve these problems. The authors performed a systematic literature review and identified 13 reports from 10 studies (TNF20, BeSt, OPITMA, HIT-HARD, IMPROVED, PRIZE, IDEA, EMPIRE, tREACH and AVERT) for early RA (≤2 years). Eight out of 13 reports (61.5%) were published in 2013 or 2014, indicating emerging interest in recent years. Also, the authors performed a sub-analysis of the HONOR study (n = 51) to compare early (≤2 years) and established RA. The proportions of remission (REM) and low disease activity were higher in early RA (REM: 63.0 vs 33.3%, p = 0.0346; low disease activity: 77.8 vs 45.8%, p = 0.0185). In conclusion, early intervention is beneficial for successful treatment holiday, which may lead to risk and cost reduction. However, further investigation is required.

IFNβ products and glatiramer acetate are established treatment first-line options in long-term disease-modifying therapy of multiple sclerosis (MS). These self-injectable medications are used once weekly to once daily. Injection-related issues are common patient-cited reasons for nonadherence. Autoinjectors have been shown to support long-term adherence to injectable medications. The ability to self-inject in MS patients has been associated with a reduced risk of missed injections and drug discontinuation, and a beneficial effect on patient independence.The recently introduced easy-to-use prefilled once-weekly pen is a safe and effective device for intramuscular (IM) IFNβ-1a application and provides a convenient method for self-injection. We reviewed the available published evidence on the characteristics of this device. The once-weekly pen facilitates self-injection and was preferred over prefilled syringes by patients in a prospective open-label, multicenter Phase IIIb trial in MS patients who had been using IM IFNβ-1a in prefilled syringes.The simple and safe handling, shielded short needle, single-use disposable design and virtually painless injection by the device may contribute to adherence, quality of life and independence in patients using IM IFNβ-1a.

Background Cases of higher-than-expected disease activity have been reported following fingolimod discontinuation. Objective The objective of this paper is to assess the risk of substantially higher-than-expected disease activity post-study drug discontinuation (SDD) at the individual patient level using data from the Phase III, placebo-controlled FREEDOMS and FREEDOMS II trials. Methods Baseline gadolinium-enhancing T1-lesion volumes were used to statistically model the expected level of MRI disease activity post-SDD. Patients exceeding this level were classed as “MRI outliers.” Patients with an unusually high increase in Expanded Disability Status Scale score, hospitalization for relapse, severe relapse, or relapse with incomplete recovery post-SDD were classed as “clinical outliers.” Results In FREEDOMS, the number of MRI outliers post-SDD was 2/69 (2.9%), 1/65 (1.5%) and 7/83 (8.4%) for the placebo, fingolimod 0.5 mg, and fingolimod 1.25 mg groups, respectively. In FREEDOMS II, the corresponding numbers were 4/72 (5.6%), 6/79 (7.6%) and 3/73 (4.1%). The number of clinical outliers across both trials was low. No consistent evidence of placebo vs fingolimod, dose-related or inter-trial patterns was discernable. Conclusion The low number of clinical and MRI outliers and lack of any discernible pattern within and between trials, including between placebo and fingolimod, argues against a systematic risk of higher-than-expected recurrence of disease activity following discontinuation of fingolimod.

Background The age distribution character makes Multiple myeloma (MM) a geriatric disease. Several geriatric assessment models have built for the identification of the unfit patients and making individual treatments. However, their prediction value on treatment-related toxicities is limited or lacking. It is time to identify the significance of treatment-related toxicities. Methods A total of 119 patients consecutively diagnosed as active MM with previous untreated between 2010 and 2018 in Nanfang Hospital were reviewed. Results Among all 119 patients analyzed, 30 patients exhibited grad 3-4 non-hematologic adverse events (non-HAEs). The MM patients with non-HAEs showed more likely to present geriatric features, such as poor physical status (PS) and renal function, lower hemoglobin (HGB) and albumin (Alb), higher N-terminal B-type natriuretic peptide (NT-proBNP) (P Conclusions Non-hematologic therapy toxicities are correlated with geriatric features, poor survival, high drug discontinuation rate and poor response at 4 months. Disclosures No relevant conflicts of interest to declare.

Background FPA150 is a fully human antibody against B7-H4 (a transmembrane protein of the B7 family) blocking negative regulatory function in T cells. FPA150 additionally exhibits enhanced antibody-dependent cell-mediated cytotoxicity and in vivo synergizes with anti-PD1 agents. We initiated a phase Ia/Ib evaluation of safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and activity in monotherapy (mono) and with anti-PD1 (combo). A current update of this ongoing trial is provided. Methods Trial design (see table).Table1198PTablePhasePatientsDesignDosesObjectiveStatus1aDose EscalationAdvanced solid tumorsAccelerated Titration; 3+3 escalation0.01-0.3mg/kg; 1-20mg/kgSafety, tolerability & PKComplete; recommended dose (RD) identifiedDose ExplorationB7-H4 + solid tumorsPre- and on-treatment biopsies (Bx)3mg/kg; 10mg/kgSafety, tolerability, PK & PDOngoing1a Combo Safety Lead-InB7-H4+ ovarian cancer3+3 De-escalationFPA150 at RD & 200mg pembrolizumab (pembro)Safety, tolerability, PK & RD FPA150Ongoing1b3 Mono cohortsB7-H4+ breast, ovarian & endometrialDose Expansion (Bx)20mg/kgSafety, tolerability, PD & efficacyOngoing1C1 ComboB7-H4+ ovarian cancerDose Expansion (Bx)200mg pembro & RD FPA150Safety, tolerability, PD & efficacyNot yet started Results At 3/15/2019 data snapshot, 29 pts with solid tumors (12 ovarian, 7 GI, 3 GYN, 3 head/neck, 2 GU, and 2 other) received FPA150 in dose escalation (n=21) and dose exploration (n=8). FPA150 demonstrated ∼ dose-proportional exposure at doses ≥0.3mg/kg and half-life of 1-2 weeks. To date, no dose-limiting toxicities, treatment-related serious adverse events or treatment-related adverse events (TRAEs) leading to drug discontinuation have been identified (1 Grade 3 TRAE of decreased lymphocyte count); others were Grade 1-2, with most common being diarrhea (16.7%), and fatigue (13.8%). Enrollment to phase Ib mono and phase Ia combo is ongoing. Expanded safety, PD and activity from phase Ib mono and phase Ia combo will be presented. Conclusions FPA150 RD for phase Ib mono identified as 20mg/kg (Sachdev, ASCO 2019). Mono appears well tolerated during dose escalation/exploration allowing evaluation in combination therapy. Sachdev, J et al. Phase Ia/1b study of first-in-class B7-H4 antibody, FPA150, as monotherapy in patients with advanced solid tumors. Proc Am. Soc. Clin. Oncol 2019. Clinical trial identification NCT03514121. Legal entity responsible for the study Five Prime Therapeutics, Inc. Funding Five Prime Therapeutics, Inc. Disclosure Z.A. Wainberg: Advisory / Consultancy: Bristol Meier Squibb; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bayer. J.C. Sachdev: Honoraria (self): Celgene; Honoraria (self): Novartis; Honoraria (self): Puma Technology; Honoraria (self): Tempus; Honoraria (self): Ipsen; Advisory / Consultancy: Celgene; Research grant / Funding (institution): Celgene; Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy: Five Prime Therapeutics. T. Bauer: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, institution: Ignyta; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Loxo; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Self and institution: Pfizer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Moderna Therapeutics; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Medpacto; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MabVax; Research grant / Funding (institution): Stemline Therapeutics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Glaxo Smith Kline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Immunogen; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Merimack; Research grant / Funding (institution): Immunogen. S. Pant: Advisory / Consultancy: Mirati Therapeutics; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Red hill Biopharma Ltd; Advisory / Consultancy: Xencor; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Novartis; Advisory / Consultancy: Rgenix; Advisory / Consultancy: Sanofi-Aventis; Advisory / Consultancy: Arqule; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Onco Response; Advisory / Consultancy: Sanofi US Services Inc; Advisory / Consultancy: GlaxoSmith Kline; Speaker Bureau / Expert testimony: Tyme, Inc; Speaker Bureau / Expert testimony: 4-D Pharma. S. Chawla: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Threshold Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: CytRx; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Immune Design; Honoraria (self), Speaker Bureau / Expert testimony: TRACON Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Karyopharm Therapeutics; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sarcoma Alliance for REsearch Through Collaboration; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen. N. Marina: Full / Part-time employment: Five Prime Therapeutics. H. Xiang: Full / Part-time employment: Five Prime Therapeutics. W. Deng: Full / Part-time employment: Five Prime Therapeutics. M. Schmidt: Full / Part-time employment: Five Prime Therapeutics. A. Patnaik: Advisory / Consultancy: Bayer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Bristo-Myers Squibb; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Plexxikon; Research grant / Funding (institution): Corvus Pharmaceuticals; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Forty-seven; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Infinity Pharmaceuticals; Research grant / Funding (institution): Proximagen; Research grant / Funding (institution): Pieris; Research grant / Funding (institution): Surface Oncology; Research grant / Funding (institution): Livson; Research grant / Funding (institution): Vigeo Therapeutics; Research grant / Funding (institution): Astella Pharma. P. LoRusso: Advisory / Consultancy: AbbVie; Advisory / Consultancy: Agios; Advisory / Consultancy: Alexion; Advisory / Consultancy: Ariad; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: GenMab; Advisory / Consultancy: Glenmark; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Menarini; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche-Genentech; Advisory / Consultancy: Genentech; Advisory / Consultancy: CytomX; Advisory / Consultancy: Omniox; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Takeda; Advisory / Consultancy: SOTIO; Advisory / Consultancy: Cybrexa; Advisory / Consultancy: Agenus; Advisory / Consultancy: Tyme.

e15007 Background: Afl is one of the antiagiogenic agents used for the treatment for mCRC. Cardiovascular toxicity of Afl is shown to be a main reason of the drug discontinuation but there are no studies on factors associated with nonhem adverse events(AEs). The aim of the study was to define clinical factors associated with the development of Gd.3-4 nonhem AEs. Methods: Pts with mCRC treated with FOLFIRI+Afl were included in a multicenter prospective base from 2016-18. Multivariative regression analysis was performed with Chicago, IL v.22.0. Factors studied included demographic, disease characteristics, data about concomitant diseases(CD) and concomitant medications. Results: 278 pts with mCRC from 18 centers were included. Mean age – 58.7, 48.6% were male, mean number of metastases– 2. ECOG 0-1–97.5%pts. RASm had 133 (47.8%) pts. Afl+FOLFIRI was used as the 2nd line therapy–in 67.6%. CD were in 194 (69.8%), cardiovascular–in 175 (62.9%). ORR(CR+PR)17.3%, SD-43.9%. MedPFS was 6.0 mos. Afl discontinuation due to AEs 11.9%. AE were reported in 201 (72.3%), Gd3-4 – in 69 (24.8%); nonhem AEs – in 178 (64%), Gd3-4–52 (18.8%)pts. Among Gd3-4 nonhem AEs were arterial hypertension Gd1-2–77 (27.7%), Gd3-4-in 36 (12.9%), vomiting Gd1-2–45 (16.2%), diarrhea Gd1-2–in 32 (11.5%), asthenia Gd1-2 –in 29 (10.4%), hepatotoxicity Gd1-2–in 2(5%), thrombosis–in 2 (5%) pts. Multivariate regression analysis showed that among the factors studied number of lines of treatment (OR1.4,95%CI1.1-2.1,p=0.03) and CD requiring medical support (OR 2.0,95%CI1.1-3.7,p=0.03) were found as independent factors of nonhem AE Gd3-4 development. ACE-inhibitors (OR2.2,95%CI1.2-4.3,p=0.02), calcium-channel blockers (CCB)(OR4.1,95%CI1.6-10.4,p=0.003 ) were the medical drugs considered to be significant. Conclusions: Number of lines and CD requiring medical support, especially with ACE-inhibitors or CCB, identifies a significant risk of developing cardiovascular non-hem AEs Gd3-4 with FOLFIRI + Afl.

We compared the risks of switching to another oral anticoagulant (OAC) and discontinuation of direct oral anticoagulants (DOACs) among elderly patients with nonvalvular atrial fibrillation (NVAF) who were prescribed rivaroxaban or dabigatran versus apixaban. Patients (≥65 years of age) with NVAF prescribed DOACs (January 1, 2013 to September 30, 2017) were identified from the Humana research database and grouped into DOAC cohorts. Cox regression analyses were used to evaluate whether the risk for switching to another OAC or discontinuing index DOACs differed among cohorts. Of the study population (N = 38 250), 55.9% were prescribed apixaban (mean age: 78.6 years; 49.8% female), 37.3% rivaroxaban (mean age: 77.4 years; 46.7% female), and 6.8% dabigatran (mean age: 77.0 years; 44.0% female). Compared to patients prescribed apixaban, patients prescribed rivaroxaban (hazard ratio [HR]: 2.08; 95% confidence interval [CI], 1.92-2.25; P < .001) or dabigatran (HR: 3.74; 95% CI, 3.35-4.18, P < .001) had a significantly higher risk of switching to another OAC during the follow-up; compared to patients prescribed apixaban, the risks of discontinuation were also higher for patients treated with rivaroxaban (HR: 1.10; 95% CI, 1.07-1.13, P < .001) or dabigatran (HR: 1.29; 95% CI, 1.23-1.35, P < .001).

The Impact of Drug Discontinuation in Patients Introduction Patients treated with a temporary pacemaker (TPM) due to atrioventricular (AV) block are often monitored after discontinuation of AV node blocking drugs to evaluate the indication for permanent pacing. However, the impact of drug discontinuation is sparsely documented. We investigated to what extent drug discontinuation abolished the need for permanent pacemaker (PPM) implantation. Methods and Results All hospital records of patients who received a TPM at Aalborg Hospital, Denmark, between January 2000 and March 2011 (n = 575) were retrospectively reviewed. Patients with AV block who were treated with a TPM and concomitant cessation of drug therapy were included if there was no other underlying mechanism causing the AV block. AV blocking drugs included antiarrhythmic agents classes II–IV and digoxin. Fifty-five patients fulfilled our inclusion criteria. Forty-seven patients had an indication for a PPM at the initial hospital admission, despite drug discontinuation. Of the remaining 8 patients who were discharged without a PPM, 3 subsequently experienced events: 2 had recurrence of AV block requiring a PPM, and 1 experienced syncope. Thus, in total, 49 (89%) patients had a final indication for a permanent pacemaker (PPM). Of patients receiving beta-blocker monotherapy, 26 (96%) had an indication for a PPM. TPM implantation was complicated by infection or displacement in 11% of cases. Conclusions The vast majority of patients treated with a TPM due to AV block and who receive beta-blockers alone or in combination with digoxin have a final indication for a PPM despite cessation of drug treatment. TPM are frequently associated with complications.

Appropriate periprocedural management of the hematologic parameters in a patient undergoing percutaneous image-guided intervention is highly complex, considering the wide range of procedures and patient demographics. This is further complicated by both the use of short-term and long-term anticoagulants and the increasing use of antiplatelet agents and other medications. Unfortunately, there is currently a general paucity of objective medical data regarding the periprocedural management of patients with abnormal coagulation parameters. In the absence of strong evidence regarding periprocedural management of this patient category, members of the Standards of Practice Committee of the Society of Interventional Radiology (SIR) have proposed general recommendations that may be useful to the practicing interventionalist. The various classes of medications that affect patient coagulation parameters were critically reviewed. When the evidence of literature was weak, conflicting, or contradictory, consensus for the parameter was reached by a minimum of 12 Standards of Practice Committee members by using a modified Delphi consensus method (1). For the purposes of these documents, consensus is defined as 80% Delphi participant agreement on a value or parameter. A time lapse of 5 half-lives of a particular agent (equivalent to about 3% of residual drug activity from the initial dose) is frequently used as a means of normalizing a patient’s bleeding risk (2,3). However, the use of laboratory coagulation thresholds is preferable, as half-lives may vary considerably in individual patients due to factors such as the potential presence of drug-drug interactions, idiosyncratic factors, differences in drug metabolism, or genetic influences. Additionally, the exact time point of drug discontinuation may be uncertain or unreliable. Nevertheless, when appropriate laboratory coagulation parameters are unavailable, disproportionally costly, or logistically cumbersome, the use of 5 halflives to normalize bleeding risk can be adequate. In this table formatted document, we summarize some of the current medications and available literature regarding periprocedural coagulation parameter surveillance and medical management of patients undergoing percutaneous image-guided procedures (Tables 1 and 2). Because of the lack of randomized controlled studies or other high-level evidence on this topic, a Delphi panel of experts constructed

In a research article published in BMC Medicine, Onakpoya and colleagues provide a historical review of withdrawals of medications for safety reasons. However, withdrawn medications are only one part of the picture about how regulatory agencies manage drug risks. Moreover, medications introduced before the increased pre-marketing regulations and post-marketing monitoring systems instituted after the thalidomide tragedy have little relevance when considering the present drug safety picture because the circumstances under which they were introduced were completely different. To more fully understand drug safety management and regulatory agency actions, withdrawals should be evaluated within the setting and timeframe in which the medications are approved, which requires information about approvals and safety warnings. Studies are needed that provide a more comprehensive current picture of the identification and evaluation of drug safety risks as well as how regulatory agencies deal with them. Please see related research article: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0553-2.

Various systemic and even topical drugs were observed to induce acute or chronic pruritus. It is estimated that pruritus may account for about 5 % of all skin adverse reaction after drug intake. It could be localized or generalized. Frequently, the underlying mechanism of drug-induced pruritus is largely unknown. It may start with the first drug administration or may be delayed in time for several weeks or even months. Remarkably, this symptom may also resolve shortly after drug discontinuation or may persist even for several months or years after treatment withdrawal. The current review aims to give a detailed summary about drug-induced pruritus with a special emphasis on systematic grouping of the different forms of drug-induced pruritus and present a therapy of this side effect.

The aim of the study was to compare residue depletion of ractopamine HCl as a β-adrenergic agonist that promotes muscle growth of animals, from internal tissues on days after its repeat administration to animals. The experiment was carried out in 38 albino guinea pigs. Treated animals (n = 30) were orally administered ractopamine HCl in a dose of 3.5 mg/kg body mass per day for 7 consecutive days. On days 1, 10, 20 and 30 of drug discontinuation, animals were randomly sacrificed and the liver, kidney, lung, heart, muscle, spleen and fat samples were collected. In all matrices, ractopamine concentration was determined using validated enzyme-linked immunosorbent assay (ELISA) as a quantitative screening method. The highest ractopamine concentration was recorded on day 1 in the lungs (55.80 ± 15.62 μg/kg), followed by the kidney (21.85 ± 3.91 μg/kg), spleen (12.59 ± 1.95 μg/kg), fat (10.17 ± 5.02 μg/kg), heart (9.73 ± 0.22 μg/kg), liver (5.58 ± 2.09 μg/kg), and lowest in muscle (2.21 ± 1.02 μg/kg). Ractopamine residues were detected in the lungs in the period of 30 days after withdrawal in significantly higher concentrations in comparison to other investigated matrices, suggesting that depletion of ractopamine from the lungs occurs at a much slower rate than its depletion from other internal tissues.

Methotrexate (MTX) is a first-line disease-modifying agent and anchor drug for biologic therapy used in rheumatoid arthritis and other inflammatory rheumatic disorders. Adverse effects are a common cause of drug discontinuation and include preventable serious incidents that may result in patient harm or death.The objective of this study was to audit adherence by health professionals to national and international guidelines for patient education and risk reduction in patients prescribed MTX for inflammatory rheumatic diseases.A combination of interviews, case record reviews, and self-administered patient knowledge questionnaires with individual patient feedback was used. The setting was the rheumatology outpatient department of a district general hospital.Fifty-one patients participated in the audit. The mean age was 58.6 (SD, 13.1) years and median duration of disease was 3.7 years (interquartile range, 1.7-7.6 years). Nurse-led patient education was documented at baseline for 94.1% of participants. Despite this, only 11.8% of participants recognized the potentially lethal drug-drug interaction with trimethoprim/Septrin (co-trimoxazole), and less than 60.8% recognized possible major adverse effects related to MTX. Although lifestyle implications relating to alcohol consumption and pregnancy/breast-feeding were recognized by the majority, only 52.9% of males were aware of recommendations in relation to conception. Univariable and multivariable analyses identified male sex, not speaking English as a first language, and a longer duration of therapy as predictors of lower levels of patient knowledge.Despite consistent baseline patient education, end-user knowledge and awareness pertinent to MTX safety are limited. Good-quality written information in the most appropriate language, patient feedback on educational programs, follow-up testing of patient knowledge, and targeted reeducation are recommended to address individual deficiencies in core knowledge.

Drug-induced liver injury (DILI) represents liver damage from various therapeutic drugs, herbal medicines, plants, or nutritional supplements. DILI is the most frequent reason for drug withdrawal and may lead to acute liver failure, liver transplant, or fatality. Its pathophysiology includes direct hepatotoxicity and idiosyncratic immune reactions. The diagnosis requires serum alanine aminotransferase or alkaline phosphatase elevation > 2-fold above the upper limit of normal, a causality assessment score ≥ 3, and exclusion of other possible causes of liver disease. While early diagnosis and drug discontinuation are imperative to recovery, continued drug exposure may lead to serious undesirable outcomes.

Purpose To assess the impact of perceived palatability of antiretroviral drugs on adherence to therapy of children infected by human immunodeficiency virus and on prescribing patterns by their caring physicians. Methods Design: Two arms—retrospective chart review and a cross-sectional survey. Setting: Tertiary-care pediatric human immunodeficiency virus clinic during a 17-year period. Participants: Children with human immunodeficiency virus infection and physicians actively caring for children with human immunodeficiency virus infection in seven provinces in Canada were surveyed regarding their perception of the palatability of 8-liquid and 15 non-liquid antiretroviral medications and its effect on drug selection. Main Outcome Measure: Effect of taste preferences of antiretroviral drugs on adherence to treatment by infected children and on drug selection by their caring physicians. Results Forty of 119 children (34%) refused at least once to an antiretroviral medication. In 5%, treatment was discontinued because of poor palatability. Ritonavir was the least palatable drug (50% of children; p = 0.01). Ritonavir use (OR 4.80 [95%CI 1.34–17.20]) and male gender (OR 7.25 [95%CI 2.30–22.90]) were independent predictors of drug discontinuation because of poor taste. Physicians also perceived liquid ritonavir as the least palatable (p = 0.01) and the most likely to be discontinued (p = 0.01). However, they commonly prescribed it as first-line therapy (p = 0.06). Conclusions A third of children infected with human immunodeficiency virus fail to adhere to their treatment because of poor drug taste. Physicians are aware of that, but this does not prevent them from selecting the least palatable drugs as first-line therapy. Copyright © 2011 John Wiley & Sons, Ltd.

Pharmaceutical manufacturer labels are an important source of adverse drug event (ADE) information. The study objective was to determine the sufficiency of ADE reporting in US drug labels. A sample of 50 labels was evaluated from the top 200 drugs dispensed in the US. Electronic copies of labels were obtained and reviewed by 2 pharmacists for ADE incidence and discontinuation data. ADE incidence data were provided in 86% of labels. However, discontinuation rates due to ADEs and ADE incidence by dose were only reported in 60%. ADE incidence reporting by age (46%) or gender (18%) was also low. ADEs that occurred in less than 2% of the population were rarely reported. Incidence rates were based on small populations (median of 794) and short term studies (median of 84 days for chronic conditions). Labels for 19 drugs used chronically had no long term study data. Methods for collecting ADE data were stated in only 12% of labels. Adverse drug event and drug discontinuation data is under-reported in US labels. More information on adverse events causing discontinuation (especially serious events) and those related to dose, age, and gender is needed in labels to ensure safe prescribing and dispensing of drugs.