Post-marketing Experience Research Articles

Herpes zoster vaccine live: A 10 year review of post-marketing safety experience

BackgroundZoster vaccine is a single dose live, attenuated vaccine (ZVL) indicated for individuals ≥50 years-old for the prevention of herpes zoster (HZ). Safety data from clinical trials and post-licensure studies provided reassurance that ZVL is generally safe and well tolerated. The objective of this review was to provide worldwide post-marketing safety information following 10 years of use and >34 million doses distributed. MethodsAll post-marketing adverse experience (AE) reports received worldwide between 02-May-2006 and 01-May-2016 from healthcare professionals following vaccination with ZVL and submitted to the MSD AE global safety database, were analyzed. ResultsA total of 23,556 AE reports, 93% non-serious, were reported. Local injection site reactions (ISRs), with a median time-to-onset of 2 days, were the most frequently reported AEs followed by HZ. The majority of HZ reports were reported within 2 weeks of vaccination and considered, based on time-to-onset, pathogenesis of HZ, and data from clinical trials, to be caused by wild-type varicella-zoster virus (VZV). HZ confirmed by PCR analysis to be VZV Oka/Merck vaccine-strain was identified in an immunocompetent individual 8 months postvaccination and in 4 immunocompromised individuals. Disseminated HZ was reported very rarely (<1%) with 38% occurring in immunocompromised individuals. All reports of disseminated HZ confirmed by PCR as VZV Oka/Merck vaccine-strain were in individuals with immunosuppressive conditions and/or therapy at the time of vaccination. ConclusionsThe safety profile of ZVL, following 10 years of post-marketing use, was favorable and consistent with that observed in clinical trials and post-licensure studies.

Safety Profile of Eslicarbazepine Acetate as Add-On Therapy in Adults with Refractory Focal-Onset Seizures: From Clinical Studies to 6 Years of Post-Marketing Experience.

IntroductionEslicarbazepine acetate was first approved in the European Union in 2009 as adjunctive therapy in adults with partial-onset seizures with or without secondary generalization.ObjectiveThe objective of this study was to review the safety profile of eslicarbazepine acetate analyzing the data from several clinical studies to 6 years of post-marketing surveillance.MethodsWe used a post-hoc pooled safety analysis of four phase III, double-blind, randomized, placebo-controlled studies (BIA-2093-301, -302, -303, -304) of eslicarbazepine acetate as add-on therapy in adults. Safety data of eslicarbazepine acetate in special populations of patients aged ≥65 years with partial-onset seizures (BIA-2093-401) and subjects with moderate hepatic impairment (BIA-2093-111) and renal impairment (BIA-2093-112) are also considered. The incidences of treatment-emergent adverse events, treatment-emergent adverse events leading to discontinuation, and serious adverse events were analyzed. The global safety database of eslicarbazepine acetate was analyzed for all cases from post-marketing surveillance from 1 October, 2009 to 21 October, 2015.ResultsFrom a pooled analysis of four phase III studies, it was concluded that the incidence of treatment-emergent adverse events, treatment-emergent adverse events leading to discontinuation, and adverse drug reactions were dose dependent. Dizziness, somnolence, headache, and nausea were the most common treatment-emergent adverse events (≥10% of patients) and the majority were of mild-to-moderate intensity. No dose-dependent trend was observed for serious adverse events and individual serious adverse events were reported in less than 1% of patients. Hyponatremia was classified as a possibly related treatment-emergent adverse event in phase III studies (1.2%); however, after 6 years of post-marketing surveillance it represents the most frequently (10.2%) reported adverse drug reaction, with more than half of these cases occurring with eslicarbazepine acetate at daily doses of 1200 mg. Other adverse drug reactions reported in post-marketing surveillance are seizure (5.8%), dizziness (4.1%), rash (2.6%), and fatigue (2.1%). The safety profile of eslicarbazepine acetate in renal and hepatic impairment subjects (phase I studies) and in elderly patients (phase III study) did not raise any specific concern.ConclusionAfter 6 years of post-marketing surveillance, eslicarbazepine acetate maintains a similar safety profile to that observed in pivotal clinical studies.

The role of natalizumab in the treatment of multiple sclerosis: benefits and risks.

Natalizumab, a monoclonal antibody that blocks lymphocyte infiltration in the central nervous system, is a valuable tool in the treatment of relapsing forms of multiple sclerosis (MS). In a phase III clinical trial comparing natalizumab with placebo over 2 years, natalizumab reduced annualized relapse rate by 68%, 12-week confirmed disability progression by 42%, and reduced contrast-enhancing lesions by 92%. In post hoc analyses, natalizumab treatment was associated with 37% of patients achieving no evidence of disease activity (versus 7% on placebo) and 30% achieving sustained disability improvement (versus 19% on placebo). Natalizumab did not achieve a statistically significant primary composite disability outcome in a trial of 887 patients with secondary progressive MS, but it did demonstrate a benefit on a prespecified component of the 9-Hole Peg Test. The greatest risk of natalizumab treatment is progressive multifocal leukoencephalopathy (PML), with a 23% mortality rate. Risk stratification on the basis of immunosuppressant exposure, natalizumab treatment duration and anti-John Cunningham virus (JCV) antibody status and index has greatly improved clinical decision making. Other potential serious natalizumab-associated risks reported in clinical trials and postmarketing settings include infusion reactions, hepatotoxicity and rare, serious opportunistic infections. With more than a decade of continuous postmarketing experience, natalizumab remains a very effective option for patients with relapsing forms of MS. To optimize appropriate selection of natalizumab for patients with relapsing MS, however, a thorough understanding of individual patient risk factors for PML or other adverse events is also required.

P-134 Vedolizumab Use in Patients with IBD Undergoing Surgery: A Summary from Clinical Trials and Post-marketing Experience

P-134 Vedolizumab Use in Patients with IBD Undergoing Surgery: A Summary from Clinical Trials and Post-marketing Experience

P-135 A Description of Joint-Related Events in Patients Receiving Vedolizumab from Clinical and Post-marketing Safety Experience

P-135 A Description of Joint-Related Events in Patients Receiving Vedolizumab from Clinical and Post-marketing Safety Experience

DOP024 Vedolizumab clinical and post-marketing safety experience of opportunistic infections

DOP024 Vedolizumab clinical and post-marketing safety experience of opportunistic infections

P668 Post-marketing experience of vedolizumab in inflammatory bowel disease: analysis of pneumonia and other respiratory tract infections

Background: The annual incidence of pneumonia has been reported as 13.8/1000 in patients with IBD versus 7.6/1000 in healthy subjects (IRR 1.82; 95% CI: 1.75–1.88) [1]. Vedolizumab (VDZ) is a humanised monoclonal antibody that binds to α4β7 integrin, selectively blocking gut-specific lymphocyte trafficking. Gut selectivity may reduce the infection risk compared with anti-tumour necrosis factor-alpha [anti-TNFα] agents, which cause systemic immunosuppression. Here we describe pneumonia and other respiratory tract infections reported after initiation of VDZ therapy in the post-marketing (PM) setting. Methods: PM VDZ safety data from the Global Safety Database (May 2014–May 2016) were reviewed to identify reports of lower respiratory tract infections (LRTIs) and upper respiratory tract infections (URTIs) using the following MedDRA v19.0 High Level Terms: “LRT and lung infections”, “LRTIs not elsewhere classified (NEC)”, “URTIs”, and “URTIs (NEC)”. Results: During almost 50,000 (∼46,978) patient-years of VDZ therapy, 40 serious and 68 non-serious LRTI events were reported in 106 patients; 54 events were pneumonia (n=34 serious; n=20 non-serious; ∼1 event/1000 patient-years of therapy). Regarding potential risk factors for pneumonia, 2 patients had undergone surgery ≤30 days prior to the event; 2 were current/former smokers (smoking history and prior surgery information not provided in 51/54 and 16/54 patients, respectively). Other LRTI events were: bronchitis (n=1 serious; n=26 non-serious); LRTIs (not otherwise specified; n=2 serious; n=20 non-serious); lung infection (n=2 serious; n=2 non-serious); lung abscess (n=1 serious; n=0 non-serious). Most LRTIs occurred ≥2 months after first VDZ infusion (n=32/108 events; not reported [NR] n=64/108 events). There were 4 serious and 313 non-serious URTIs in 300 patients, with nasopharyngitis the most frequently reported (n=201/317 events). Most URTIs occurred ≥2 months after first VDZ infusion (n=77/317 events; NR n=182/317 events). Patient demographics/clinical characteristics are shown (Table 1). Table 1. Patient demographics and clinical characteristics Conclusions: From almost 50,000 patient-years of VDZ therapy, RTIs (including pneumonia) were infrequent and most patients continued VDZ. These data represent experience of VDZ in a “real-world” setting and complement existing data from clinical trials. Limitations associated with PM safety reporting (incomplete data, voluntary reporting and difficulty establishing a causal relationship between drug and event) must be considered when interpreting these results.

Two-year postmarketing safety experience with oral eliglustat in adults with type 1 Gaucher disease

Two-year postmarketing safety experience with oral eliglustat in adults with type 1 Gaucher disease

Biosimilars in inflammatory bowel disease: A review of post-marketing experience.

Biologic compounds are obtained from living organisms or cell cultures by means of biotechnology methods. A similar biologic drug, commonly called biosimilar, is a product copied by a native approved biologic drug whose license has expired. Biosimilar drugs usually are marketed at a lower price and provide important financial savings for public healthcare systems. Some differences between biosimilars and original biologic drugs might exist but they are acceptable if they fall within defined “boundaries of tolerance”: differences in some features between the two molecules are considered important only if clinical relevant. Considering that the efficacy of the innovator biologic drug has already been established, the clinical studies required for approval of a biosimilar could be reduced compared with those required for the approval of the originator. In this review, real life data available in inflammatory bowel disease patients treated with biosimilars are reported, documenting in general satisfactory outcomes, sustained efficacy and no sign of increased immunogenicity, although, further controlled data are awaited.

Management and Outcomes of Atrial Fibrillation in Patients Receiving Ibrutinib for Hematologic Malignancies at a Single Center

▪BackgroundIbrutinib (IB) is Food and Drug Administration approved for chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström’s macroglobulinemia (WM). High overall response rates, extended progression free survival, and an acceptable adverse event profile make IB an impactful therapy for these malignancies. Atrial fibrillation (AF) has been identified as a less common but serious adverse effect of IB with reported incidence ranging from 2-16% in clinical trials and post-marketing experience. AF can be associated with significant morbidity and mortality, including congestive heart failure and embolic events such as stroke. Data regarding the management of AF in this patient population is thus far limited. Embolic stroke prevention poses a particular clinical challenge as IB carries an inherent bleeding risk that may be increased by antiplatelet therapy and therapeutic anticoagulation. We report the management and outcomes of a large cohort of patients who developed AF while on IB therapy.MethodsPatients with hematological malignancies and incident or recurrent AF while on IB therapy at the Ohio State University were identified retrospectively. Incident AF was defined as new onset AF in patients without a history AF and recurrent AF as an AF event requiring new intervention in patients with a prior history of AF. Data pertaining to patient demographics, comorbid conditions, AF events, AF management, stroke prevention strategies, and complications of AF therapy were collected. AF events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 andcongestive heart failure, hypertension, age, diabetes mellitus, stroke (CHADs2) scores were calculated. Major bleeding was defined as a decrease in hemoglobin of 2g/dL or more, requiring a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site, or contributing to death. Clinically relevant non-major bleeding events were graded according to CTCAE criteria. Management strategies and outcomes are summarized.ResultsSeventy-two patients with incident or recurrent AF were identified. Fifty-nine patients developed incident AF while 13 patients developed recurrent AF while on IB. Baseline characteristics are presented in Table 1.Patients with recurrent AF were older, had worse baseline ECOG performance status, and longer baseline PR interval on electrocardiogram assessment.Patients were followed for a median of 4.3 years from the start of ibrutinib and 1.7 years from AF event.Ninety-three percent of the AF events were grade 1-2 and 7% were grade 3. First-line therapy forAF included rate-control for 54 (75%) patients, interventional procedural strategies for 8 (11.1%), and rhythm-control for 3 (4.2%). Seven (9.7%) patients required no intervention. Twenty-two patients (30.5%) required a second and 4 (5.5%) required third-line AF management intervention. Among those with a secondary AF management strategy, rhythm control was the most frequently utilized (n=10, 45.5%). During the AF events, 31 (43.1%) patients continued IB, 35 (48.6%) temporarily held IB, 5 (6.9%) discontinued IB, and one patient had the dose reduced. Stroke prevention strategies are described in Table 2. Patients with recurrent AF were less likely to be treated with anticoagulation when compared to patients with incident AF. Six (8.3%) patients had a major bleeding event and 2 of these patients went on to have a second major bleed. Of the 8 major bleeding events, 3 occurred with concomitant antiplatelet therapy and no patients were on anticoagulation therapy at the time of bleeding. Eighteen (25%) patients developed a total of 25 clinically relevant non-major bleeding events (9 grade 1 events, 13 grade 2 events, 2 grade 3 events, and 1 could not be graded). Only one potential embolic event occurred in a patient with a CHADs2 score of 1 on aspirin 325mg who developed symptoms consistent with stroke.ConclusionsAF events in patients being treated with IB are generally manageable and in the majority of cases did not result in IB discontinuation. Clinically relevant bleeding events are common, and caution must be exercised when initiating routine antiplatelet therapy and/or anticoagulation in patients with IB. Risk of ischemic stroke was low in our patient population, though follow up was limited. The optimum strategy for stroke prophylaxis in patients with concurrent IB is unclear. [Display omitted] DisclosuresChristian:Pharmacyclics: Research Funding; Janssen: Research Funding. Porcu:miRagen: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial. Woyach:Morphosys: Research Funding; Karyopharm: Research Funding; Acerta: Research Funding. Jones:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Innate Pharma: Research Funding; Novartis Oncology: Consultancy; Pharmacyclics: Consultancy.

P061 Post-marketing safety experience with 300IR 5-grass pollen tablet for allergic rhinoconjunctivitis

P061 Post-marketing safety experience with 300IR 5-grass pollen tablet for allergic rhinoconjunctivitis

Update on clinical evidence (Part II): A summary of the main post market studies.

Bioresorbable vascular scaffolds (BVS, Absorb, Abbott Vascular, Santa Clara, CA) received the CE mark in October 2011, and were approved by the Food and Drug Administration in July 2016. After their introduction in clinical practice a broad amount of post-marketing clinical experience with BVS has been generated so far in Europe and outside the United States. The available BVS registries differ in many aspects, including their being single-center or multicenter, single-arm or controlled, sponsored or investigator-initiated, published or presented at a large-scale international meeting. This article provides an overview of clinical results of the main post-marketing studies of BVS available. © 2016 Wiley Periodicals, Inc.

Post-marketing Safety Experience with Vedolizumab: Skin Reactions (Psoriasiform and Eczematous)

Post-marketing Safety Experience with Vedolizumab: Skin Reactions (Psoriasiform and Eczematous)

Post-marketing Safety Experience with Vedolizumab: Malignancy

Post-marketing Safety Experience with Vedolizumab: Malignancy

PTU-062 Vedolizumab: Early Experience and Medium-Term Follow up Data from Two UK Tertiary IBD Centres

Introduction Vedolizumab was recently granted NICE approval for moderate-to-severe Crohn’s disease (CD) and ulcerative colitis (UC). Novel pathways agreed by our CCG meant that patients at Guy’s & St. Thomas’ and King’s College Hospitals had early access to vedolizumab. Methods Records of patients commencing vedolizumab between Nov 2014–15 were screened. Those completing at least 14 weeks of treatment were included. Clinical activity was assessed using Harvey-Bradshaw Index (HBI) or Simple Clinical Colitis Activity Index (SCCAI) at baseline, 14 and 30 weeks. Response: HBI/SCCAI reduction ≥3. Remission: HBI Results 60 patients (CD: 32, 53%, UC 25, 42%, IBD-U 3, 5%) commenced vedolizumab (m:f 29:31, age: 39 (18–74), follow-up: 5 months (1–13)). 19 were excluded from our analysis (3 IBD-U, 5 stomas, 11 treated for Of 32 patients with active disease at baseline, 17 (53%) responded and 11 (34%) achieved remission by week 14. The response and remission rates for CD were 8/15 (53%) and 6/15 (40%). In UC they were 9/17 (53%) and 5/17 (29%). Response and remission rates in anti-TNF experienced patients were 12/26 (46%) and 6/36 (35%) compared to 5/6 (83%) and 5/6 (83%) in anti-TNF naive patients, respectively. 7/11 (64%) with active disease at baseline who completed 30 weeks of treatment responded and achieved remission. Faecal calprotectin fell significantly (pre-induction: 1076 (90–4800), post-induction: 478 (10–3184), p = 0.029 for n = 14) and CRP remained stable (pre-induction: 4 (1–70), post-induction: 4 (1–72), p = 0.28 for n = 40). Rates of steroid use at each time point: 19/41 (46%) at baseline, 11/41 (21%) at week 14 and 3/15 (20%) at week 30. Surgery was required in 4/41 (10%, CD:3 and UC:1). Conclusion Our experience mirrors a previously reported real-world cohort 1 and demonstrates similar efficacy to the GEMINI trials. This data demonstrates a meaningful reduction in clinical and biochemical disease activity as well as a steroid-sparing effect in patients with complex and previously refractory disease. We did not see a significant difference in efficacy between patients with UC and CD. Reference 1 Christensen B. et al . Post-marketing experience of vedolizumab for IBD: The University of Chicago experience . ECCO; Barcelona, 2015. Disclosure of Interest None Declared

Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus.

SummaryNitazoxanide is a broad-spectrum antiviral agent undergoing clinical development for treatment of influenza and other viral respiratory infections. Nitazoxanide exhibits in vitro activity against Middle East respiratory syndrome coronavirus (MERS-CoV) and other coronaviruses, inhibiting expression of the viral N protein. Nitazoxanide also suppresses production of pro-inflammatory cytokines in peripheral blood mononuclear cells and suppresses interleukin 6 production in mice. Having been used extensively in clinical trials and in post-marketing experience, nitazoxanide is an attractive drug candidate for treatment of Middle East respiratory syndrome. Future research should include in vitro mechanism studies, animal models of MERS-CoV infection, clinical trials, including dose-ranging trials, and evaluation of combination therapy with other potential MERS-CoV antivirals.

Risk Mitigation Strategies for Adverse Reactions Associated with the Disease-Modifying Drugs in Multiple Sclerosis.

Over the past several years, the number of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) has doubled in number. The 13 approved agents have shown a wide range of efficacy and safety in their clinical trials and post-marketing experience. While the availability of the newer agents allows for a wider selection of therapy for clinicians and patients, there is a need for careful understanding of the benefits and risks of each agent. Several factors such as the medication efficacy, side-effect profile, patient's preference, and co-morbidities need to be considered. An individualized treatment approach is thus imperative. In this review, risk stratification and mitigation strategies of the various disease-modifying agents are discussed.

Direct-acting oral anticoagulants: pharmacology, indications, management, and future perspectives.

In recent years, several direct-acting oral anticoagulants (DOAC) have become available for use in Europe and other regions in indications related to prophylaxis and treatment of venous and arterial thromboembolism. They include the oral direct thrombin inhibitor dabigatran etexilate (Pradaxa, Boehringer Ingelheim) and the oral direct FXa inhibitors rivaroxaban (Xarelto, Bayer HealthCare), apixaban (Eliquis, Bristol-Myers Squibb), and edoxaban (Lixiana/Savaysa, Daiichi-Sankyo). The new compounds have a predictable dose response and few drug-drug interactions (unlike vitamin k antagonists), and they do not require parenteral administration (unlike heparins). However, they accumulate in patients with renal impairment, lack widely available monitoring tests for measuring its anticoagulant activity, and no specific antidotes for neutralization in case of overdose and/or severe bleeding are currently available. In this review, we describe the pharmacology of the DOAC, the efficacy, and safety data from pivotal studies that support their currently approved indications and discuss the postmarketing experience available. We also summarize practical recommendations to ensure an appropriate use of the DOAC according to existing data. Finally, we discuss relevant ongoing studies and future perspectives.

Sphingosine 1-phosphate receptor modulators in multiple sclerosis.

Sphingosine 1-phosphate (S1P) receptor modulators possess a unique mechanism of action as disease-modifying therapy for multiple sclerosis (MS). Subtype 1 S1P receptors are expressed on the surfaces of lymphocytes and are important in regulating egression from lymph nodes. The S1P receptor modulators indirectly antagonize the receptor's function and sequester lymphocytes in lymph nodes. Fingolimod was the first S1P agent approved in the USA in 2010 for relapsing MS after two phase III trials (FREEDOMS and TRANSFORMS) demonstrated potent efficacy, and good safety and tolerability. Post-marketing experience, as well as a third phase III trial (FREEDOMS II), also showed favorable results. More selective S1P receptor agents-ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303-are still in relatively early stages of development, but phase I and II trials showed promising efficacy and safety. However, these observations have yet to be reproduced in phase III clinical trials.

The PANGAEA study design - a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice.

BackgroundFingolimod (Gilenya®) is an oral medication for patients with highly active relapsing-remitting Multiple Sclerosis (RRMS). Clinical trials and post-marketing experience on more than 114,000 patients have established a detailed safety profile. Total patient exposure now exceeds 195,000 patient-years as stated in the last financial report (Dec 2014) of the Novartis Pharma AG, Basel, Switzerland. However, less is known about the safety of long-term fingolimod use in daily practice. Here, we describe the study design of PANGAEA (Post-Authorization Non-interventional German sAfety of GilEnyA in RRMS patients), a prospective, multicenter, non-interventional, long-term study to collect safety, efficacy, and pharmacoeconomic data on RRMS patients treated with fingolimod (0.5 mg/daily) under real-world conditions in Germany.MethodsPANGAEA is striving to assess a real-world safety and efficacy profile of fingolimod, based on data from 4,000 RRMS patients, obtained during a 60-month observational phase. A pharmacoeconomic sub-study of 800 RRMS patients further collects patient-reported outcome measures of disability, quality of life, compliance, treatment satisfaction, and usage of resources during a 24-month observational phase. Descriptive statistical analyses of the safety set as well as of stratified subgroups such as patients with concomitant diabetes mellitus and pretreated patients (e.g., natalizumab) will be conducted.DiscussionPANGAEA seeks to confirm the current safety profile of fingolimod obtained in phase I-III clinical trials. The study design presented here will additionally provide guidance on the therapeutic use of fingolimod in clinical practice and possibly assists physicians in making evidence-based decisions.