Post-marketing Experience Research Articles

Evaluating Real-World Experience With Maribavir for Treatment of Refractory/Resistant Cytomegalovirus in Renal Transplant Recipients.

Maribavir was recently approved by the FDA, expanding treatment options for post-solid-organ transplant refractory/resistant CMV. We sought to describe the post-marketing experience with maribavir at a large academic transplant center. This was a retrospective observational study of all renal transplant recipients treated with maribavir for refractory/resistant CMV DNAemia/disease. CMV viral loads, immunosuppression regimens and management, resistance testing, and antiviral therapy durations were reviewed. Outcomes of interest included treatment success, defined as undetectable CMV DNAemia for two consecutive weeks or detected but unquantifiable DNAemia for five consecutive weeks, as well as the emergence of antiviral resistance, and recurrent DNAemia. From 2021 to 2023, 5/10 (50%) patients achieved durable virologic suppression with maribavir (classified as responders). Among responders, 2/5 (40%) experienced low-level CMV DNAemia recurrence (defined as a viral load less than 1000 IU/mL) within 8 weeks of antiviral discontinuation. Among nonresponders, 2/3 (66.7%) were found to have UL97 protein mutations associated with maribavir resistance identified 85 and 75 days after initiation of maribavir. Two patients are currently on maribavir with clinical outcomes that are yet to be determined. Responders had a mean reduction of 200mg (SD-274mg) in mycophenolate dosing with nonresponders having a mean increase of 167mg (SD-764mg). Maribavir, often in conjunction with mycophenolate dose reduction, was effective for many patients with refractory/resistant CMV DNAemia at our transplant center, though several experienced recurrent DNAemia. In patients who did not respond to therapy, resistance to maribavir was frequently detected. Clinicians treating these patients should remain vigilant for rebound CMV DNAemia and consider repeat antiviral resistance testing.

Safety Profile of Paxlovid in the Treatment of COVID-19.

With the urgent and widespread application of Paxlovid, a novel antiviral drug for Coronavirus Disease 2019 (COVID-19) in clinical practice, concerns regarding its actual efficacy and safety have emerged. In order to provide more evidence to support its clinical application, we sought to perform a descriptive analysis of cases who experienced at least one Paxlovid-related adverse event (AEs) and reported to the FDA Adverse Event Reporting System (FAERS) in the post-marketing period. Individual adverse event reports between January 1, 2022 and September 30, 2022, were downloaded from the FAERS website. We completed a descriptive study about the safety of Paxlovid in the treatment of COVID-19. Further, we also analyzed the onset time of Paxlovid-related AEs. As of 30 September 2022, 16,529 de-duplicated cases were submitted to the FDA, and 5,860 (35.45%) were female. The average age was 58.38 years (S.D. 15.50). Most reports (12,390, 74.96%) were submitted by consumers and 1,436 (8.68%) concerned serious outcomes. The most frequently reported AEs were disease recurrence (7,724, 16.23%), dysgeusia (2,877, 6.05%), and diarrhoea (1,448, 3.04%). The median onset time of Paxlovid-related AEs was 8 days (interquartile range,1-10 days), and most of the cases (2,629, 19.12%) occurred on the day after Paxlovid initiation. This study indicates that the most common AEs reported with Paxlovid in post-marketing experience are consistent with the safety assessment of antiviral drugs. Even without emerging apparent safety concerns, the incidence of serious outcomes was unexpectedly high, and a few cases of potential new AEs occurred.

Vonoprazan: A Review in Helicobacter pylori Infection.

Treatment for the eradication of Helicobacter pylori infection, a leading cause of peptic ulcer disease and an important risk factor for gastric cancer and mucosa-associated lymphoid tissue lymphoma, is indicated whenever infection is identified. However, treatment success rates with current guideline-recommended proton-pump inhibitor (PPI)-based regimens remain suboptimal, with one potential factor associated with treatment failure being inadequate acid suppression. Vonoprazan (Voquezna®) is a first-in-class potassium-competitive acid blocker with the potential to provide potent and sustained acid suppression. Following clinical trials conducted mainly in Asia (supported by post-marketing experience from Asia) and the phaseIII PHALCON-HP trial conducted in the USA and Europe, vonoprazan is now approved in the USA for use in combination with amoxicillin (dual therapy) or amoxicillin and clarithromycin (triple therapy) for the treatment of H.pylori infection in adults. The vonoprazan-based dual and triple therapy regimens were generally well tolerated in PHALCON-HP. In addition, vonoprazan has advantages including a rapid onset of action and no food effect, making vonoprazan-based dual and triple therapy regimens valuable alternatives to standard PPI-based triple therapy in the treatment of H.pylori infection.

Abstract 15265: Rilonacept for Refractory Pericarditis Following Immune Checkpoint Inhibitor Therapy: A Case Report

Background: Immune checkpoint inhibitor (ICI)-mediated cardiotoxicities are rare but potentially fatal. Myocarditis, with clinical presentations ranging from asymptomatic to cardiogenic shock, and pericarditis, have been reported in clinical trials and as post-marketing experience with immunotherapy. It is estimated to occur in less than 1% of individuals receiving single immune checkpoint inhibitor therapy, with a median time to onset of 30 days. Herein, we report a case of late-onset ICI-mediated myopericarditis presenting with cardiogenic shock, followed by recurrent pericarditis refractory to steroid taper. Case Presentation: A 44-year-old woman with triple-negative breast cancer underwent chemotherapy, immune checkpoint inhibitor therapy with Pembrolizumab, lumpectomy, and radiation therapy. After the treatment, the patient developed symptoms consistent with myopericarditis, complicated by pericardial effusion with tamponade and cardiogenic shock. The patient underwent emergent pericardiocentesis and, due to refractory shock, was initiated on high-dose steroid therapy with complete resolution. However, during the tapering of steroids, the patient experienced a recurrence of pericarditis, characterized by chest pain, recurrent pericardial effusion, and elevated inflammatory markers. NSAIDs and colchicine were initiated early in the management but failed to achieve symptom control. Given the refractory nature of the recurrent pericarditis, the decision was made to reintroduce prednisone therapy, which led to substantial symptomatic improvement. To avoid further flares with steroid taper, the patient was started on rilonacept. It led to sustained pain control, and steroids were successfully tapered. Conclusion: Pericarditis is a rare complication of pembrolizumab. There are no specific guidelines on the management of ICI-related recurrent pericarditis. Rilonacept was added due to the refractory nature of her symptoms with steroid taper. It led to sustained improvement in pain, and steroids were successfully tapered.

Immune Checkpoint Inhibitors in Patients with Pre-existing Neurologic Autoimmune Disorders.

The use of immune checkpoint inhibitors (ICIs) for oncologic indications is associated with immune-related adverse events (irAEs). Patients with pre-existing autoimmune diseases are at increased risk of irAEs and have largely been excluded from clinical trials of ICIs. Therefore, there is limited data on the safety of safety of ICIs in patients with pre-existing neurologic autoimmune diseases (nAIDs) such as myasthenia gravis and multiple sclerosis. This review aims to synthesize the literature on the post-marketing experience with ICI in patients with pre-existing nAID and to discuss possible strategies for mitigating the risk of post-ICI nAID relapses. Patients with pre-existing myasthenia gravis (MG), myositis, and paraneoplastic encephalitis appear highly susceptible to neurologic relapses of their underlying neurologic disorder following ICI initiation; these relapses can cause considerable morbidity and mortality. In patients with multiple sclerosis (MS), the risk and severity of MS relapses following ICI appears to be relatively lower compared to MG. Preliminary evidence suggests that older MS patients with no recent focal neuroinflammatory activity may be safely treated with ICI. Among the several case reports of ICI in patients with a history of Guillain-Barre syndrome (GBS), neurologic worsening was only recorded in one patient who was in the acute phase of GBS at the time of ICI start. Initiating an ICI in a patient with pre-existing nAID involves a complex risk-benefit discussion between the patient, their oncologist, and neurologist. Relevant issues to consider before ICI include the choice of disease-modifying therapy for nAID (if any) and strategies for promptly identifying and managing nAID relapses should they occur. Currently, the literature consists mainly of case reports and case series, subject to publication bias. Prospective studies of ICI in patients with nAID are needed to improve the level of evidence.

Thrombosis with thrombocytopenia syndrome: A database review of clinical trial and post-marketing experience with Ad26.COV2.S

BackgroundThrombosis with thrombocytopenia syndrome (TTS) is a very rare disorder described after vaccination with adenoviral vector-based COVID-19 vaccines. Co-occurring thrombosis with thrombocytopenia reported after vaccination can be a proxy for identification of TTS. MethodsDescriptive database review of all cases of co-occurring (within 42 days) thrombosis with thrombocytopenia in participants in Ad26.COV2.S clinical trials or recipients of Ad26.COV2.S in real-world clinical practice. Cases were retrieved from Janssens’ clinical trial and Global Medical Safety databases. ResultsThere were 34 cases of co-occurring thrombosis with thrombocytopenia in Ad26.COV2.S recipients (46 per 100,000 person-years) and 15 after placebo (75 per 100,000 person-years) in clinical trials. Among Ad26.COV2.S recipients, mean age at the time of the event was 63 years (range 25–85), 82 % were male, mean time-to-onset 112 days (range 8–339) post-last Ad26.COV2.S dose, 26 events occurred post-dose-1, and 7 within a 28-day risk window post-vaccination. Diagnostic certainty was evaluated using Brighton Collaboration, US Centers for Disease Control and Prevention, and European Medicines Agency Pharmacovigilance Risk Assessment Committee case definitions. One case met the highest level of diagnostic certainty for all 3 definitions. There were 355 spontaneous reports of co-occurring thrombosis with thrombocytopenia in the Global Medical Safety database, 47 % males, 85 % within 28-days after vaccination. Twenty-seven cases met the highest level of diagnostic certainty for all definitions, 21 female, 19 with cerebral venous sinus thrombosis, age-range 18–68 years. Time-to-onset was 7–14 days post-vaccination in 20 cases. There were 8 fatalities. ConclusionTTS induced by Ad26.COV2.S is very rare. Most co-occurring thrombosis with thrombocytopenia does not constitute TTS.

Safety of opicapone after 5 years of post-marketing experience worldwide (P14-11.013)

<h3>Objective:</h3> Review the safety data of opicapone (OPC) after five years of marketing experience worldwide. <h3>Background:</h3> OPC is a once-daily catechol-O-methyltransferase (COMT) inhibitor proven to be effective in PD patients with motor fluctuations. OPC marketing authorisation was first granted on 24 June 2016 (EU). It was launched in October 2016 and is currently marketed in over 18 countries worldwide (including the US since September 2020). <h3>Design/Methods:</h3> Patient exposure to marketed OPC was estimated based on worldwide ex-factory sales cumulatively until 30 September 2021 (assuming the ex-factory amounts delivered were entirely dispensed and administered, and were used at the dosage of 1 hard capsule/day). From the first marketing authorisation until 30 September 2021, safety data was pooled and analysed from global post-marketing sources, including spontaneous, health authorities, literature reports, and non-interventional studies. Cumulative summary tabulations of adverse events arranged by primary System Organ Class (SOC) and preferred terms within each SOC were retrieved and sorted. <h3>Results:</h3> The estimated patient exposure was 1 413 624 patient-months during the period, corresponding to 117 802 patient-years. In the 5-year period, 4035 events were reported, 545 (13.5%) serious and 3490 (86.5%) non-serious. This corresponds to an incidence of 34.3 reports per 1000 patient-years. The 5 SOCs with the highest number of events were “Nervous system disorders”, “General disorders and administration site conditions”, “Psychiatric disorders”, “Gastrointestinal disorders” and “Surgical and medical procedures”. The 10 most frequently reported adverse events were “Dyskinesia”, “Muscle rigidity”, “Hallucination”, “Bradykinesia”, “Constipation”, “Tremor”, “Gait disturbance”, “Freezing phenomenon”, “Sleep disorder” and “Reduced facial expression”. <h3>Conclusions:</h3> Safety reports during 5 years of post-marketing experience with OPC were uncommon, and mostly refer to non-serious adverse events. Motor-symptoms of PD were among the most frequently reported adverse events. No new relevant safety concern was identified. OPC continues to have an adequate safety and tolerability profile with a favourable benefit-risk ratio. <b>Disclosure:</b> Mr. Guedes has received personal compensation for serving as an employee of BIAL - Portela &amp; C.ª, S.A.. Joana Graça has received personal compensation for serving as an employee of BIAL - Portela &amp; C.ª, S.A.. Ms. Sampaio has nothing to disclose. Mariana Vieira has received personal compensation for serving as an employee of Bial - Portela &amp; Cª, S.A.. Francisco Rocha has received personal compensation for serving as an employee of BIAL - Portela. Helena Gama has received personal compensation for serving as an employee of Bial-Portela &amp; Cª S.A..

A Brighton Collaboration standardized template with key considerations for a benefit/risk assessment for the Medigen COVID-19 protein vaccine

The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group has prepared standardized templates to describe the key considerations for the benefit-risk assessment of several vaccine platform technologies, including protein subunit vaccines. This article uses the BRAVATO template to review the features of the MVC-COV1901 vaccine, a recombinant protein subunit vaccine based on the stabilized pre-fusion SARS-CoV-2 spike protein S-2P, adjuvanted with CpG 1018 and aluminum hydroxide, manufactured by Medigen Vaccine Biologics Corporation in Taiwan. MVC-COV1901 vaccine is indicated for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 12 years of age and older. The template offers details on basic vaccine information, target pathogen and population, characteristics of antigen and adjuvant, preclinical data, human safety and efficacy data, and overall benefit-risk assessment.The clinical development program began in September 2020 and based on demonstration of favorable safety and immunogenicity profiles in 11 clinical trials in over 5,000 participants, it has been approved for emergency use based on immunobridging results for adults in Taiwan, Estwatini, Somaliland, and Paraguay. The main clinical trials include placebo-controlled phase 2 studies in healthy adults (CT-COV-21), adolescents (CT-COV-22), and elderly population (CT-COV-23) as well as 3 immunobridging phase 3 trials (CT-COV-31, CT-COV-32, and CT-COV-34) in which MVC-COV1901 was compared to AZD1222. There are also clinical trials studying MVC-COV1901 as homologous and heterologous boosters (CT-COV-24 and CT-COV-25).The totality of evidence based on ∼3 million vaccinees to date includes a mostly clean safety profile, with adverse events mostly being mild and self-limiting in both clinical development and post-marketing experience, proven immunogenic response, and real-world effectiveness data. The immunogenic profile demonstrates that MVC-COV1901 induces high levels of neutralizing and binding antibodies against SARS-CoV-2. There is a dose-dependent response and a significant correlation between binding and neutralizing antibody activity. Antigen-specific T-cell responses, particularly a Th1-biased immune response characterized by high levels of interferon gamma and IL-2 cytokines, have also been observed. Coupled with this, MVC-COV1901 has favorable thermostability and better safety profiles when compared to other authorized vaccines from different platforms, which make it potentially a good candidate for vaccine supply chains in global markets.

Repurposing MS immunotherapies for CIDP and other autoimmune neuropathies: unfulfilled promise or efficient strategy?

Despite advances in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and other common autoimmune neuropathies (AN), still-many patients with these diseases do not respond satisfactorily to the available treatments. Repurposing of disease-modifying therapies (DMTs) from other autoimmune conditions, particularly multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), is a promising strategy that may accelerate the establishment of novel treatment choices for AN. This approach appears attractive due to homologies in the pathogenesis of these diseases and the extensive post-marketing experience that has been gathered from treating MS and NMOSD patients. The idea is also strengthened by a number of studies that explored the efficacy of DMTs in animal models of AN but also in some CIDP patients. We here review the available preclinical and clinical data of approved MS therapeutics in terms of their applicability to AN, especially CIDP. Promising therapeutic approaches appear to be B cell-directed and complement-targeting strategies, such as anti-CD20/anti-CD19 agents, Bruton's tyrosine kinase inhibitors and anti-C5 agents, as they exert their effects in the periphery. This is a major advantage because, in contrast to MS, their action in the periphery is sufficient to exert significant immunomodulation.

Reported Rates of Intraocular Inflammation with Intravitreal Aflibercept Administered via Pre-Filled Syringe or from Vials in Clinical Practice Between 2012 and 2022.

To determine the reported rates of intraocular inflammation (IOI) in patients treated with intravitreal aflibercept (IVT-AFL) 2 mg in routine clinical practice (ie, outside interventional studies), across all indications and within all countries (excluding the United States), with access to either the vial presentation or pre-filled syringe (PFS). A search was conducted using the Bayer EYLEA® Global Safety Pharmacovigilance Database for reported cases of IOI and IVT-AFL use between October 2012 and March 31, 2022. With more than 10 years of post-marketing experience with the IVT-AFL vial presentation (>25 million sold units), and over 2 years of experience with the PFS of IVT-AFL (>6.7 million sold units) the rate of any IOI, including endophthalmitis, outside the United States was 0.3 events per 10,000 units for the PFS and 1.2 events per 10,000 units for the vial presentation. The event rates specifically for endophthalmitis were 0.1 per 10,000 units for the IVT-AFL PFS and 0.6 per10,000 units for the IVT-AFL vial presentation. In patients with retinal diseases treated in routine clinical practice with IVT-AFL either from a vial or the PFS, medically important adverse events of IOI, and in particular, endophthalmitis, are infrequently reported events. Numerically, reported rates of IOI and endophthalmitis are low for the vial presentation and even lower for the PFS.

Safety Profile of Molnupiravir in the Treatment of COVID-19: A Descriptive Study Based on FAERS Data

Concerns have been raised about the actual benefit and safety of molnupiravir, a new antiviral treatment for coronavirus disease 2019 (COVID-19). In order to provide additional evidence to support its use, we aimed to evaluate the real safety profile based on post-marketing pharmacovigilance data. Molnupiravir safety data were captured from the FDA Adverse Event Reporting System (FAERS). We performed a descriptive analysis of the baseline demographic characteristics of patients who experienced at least one adverse drug reaction (ADRs) related to molnupiravir, and then evaluated those most frequently reported. As of 31 March 2022, 612 reports of ADRs related to molnupiravir were submitted to the FDA, 301 (49.18%) were related to females and 281 (45.92%) to males. Most reports (524; 85.62%) were submitted by healthcare professionals and 345 (56.37%) concerned serious outcomes. The most common reported ADRs were diarrhoea (57; 4.51%), rash (36; 2.85), nausea (29; 2.30%), and COVID-19 pneumonia (22; 1.74%). The most frequent adverse reactions reported with molnupiravir in the U.S. post-marketing experience are consistent with the safety evaluation of the antiviral medicine. Even if no evident safety concerns emerged, an unexpectedly high rate of serious adverse reactions together with a few cases of potential new adverse reactions occurred.

Ruxolitinib for Myelofibrosis in Resource Limited Settings : A Slip between the Cup and the Lip

Background and Objective:Ruxolitnib, an orally bioavailable non-specific JAK inhibitor is a novel drug used for treating myelofibrosis by targeting the unique disease biology and has significantly reduced symptomatic burden in these patients. In resource limited countries, the data on post marketing experience with this relatively novel agent is limited. The major objectives of this study was to examine the challenges encountered with the use of Ruxolitinib in our resource limited setting. Methods:Patients with confirmed diagnosis of myelofibrosis and initiated on ruxolitinib therapy consecutively during the time period between December 2013 to March 2019 at our institute were included in the study. The data was collected from electronic medical records over a period of 12 months from March 2020 to March 2021. Results:This retrospective analysis included forty six patients and their baseline characteristics are summarized in Table 1. Twenty five (54.3%) patients received lower than the recommended dose for the corresponding platelet count. On response assessment, the mean MPN SAF ISS score showed reduction from 30 (6-64) to 15 (2-38).Among the 36 patients with splenomegaly documented in records, a spleen response below costal margin of <5cm was seen in 2 (5.5%), 5 - 10cm in 9 (25%) and >10cm in 22 (61.1%) patients. . The patients were followed up for a median of 29.5 months (0-76 months) after Ruxolitinib initiation.At the time of data locking, 12 (26%) patients were still on ruxolitinib, 13 (28.2%) patients were lost to follow up and 7 (15.2%) patients died. Rest of the fourteen (30.4%) patients discontinued ruxolitinib, the reasons being financial constraints in 7 (50%), disease progression in 3 (21.4%), haematological toxicity in 2 (14.2%) and intolerance due to non-haematological causes in 2 (14.2%). Haematological adverse events that necessitated dose reduction or cessation of drug were anemia and thrombocytopenia. The serious non-hematological adverse events were renal dysfunction, pancreatitis, COVID infection, DIC and pulmonary alveolar haemorrhage in one patient each and two cases of active tuberculosis. Seven (15.2%) patients died while on therapy or shortly after discontinuing ruxolitinib. The causes of death were pulmonary alveolar haemorrhage, disease progression, disseminated intravascular coagulation post cardiac valve surgery, pneumonia complicated by sepsis/ hemophagocytic lymphohistiocytosis (HLH) and COVID infection. Among these, 2 patients died within one month of stopping ruxolitinib. The possibility of ruxolitinib discontinuation syndrome (RDS) was considered retrospectively in these patients. The overall mean survival time was 145.4 ±16 months (95% CI: 114 - 176.8months). Discussion:At the time of last follow-up, more than half of the patients in our study group had either discontinued therapy or were lost to follow up. The most common reason for discontinuation was financial burden, the other reasons being disease progression and intolerance. In our setting, the patients entail an annual cost of approximately 2560 USD, 4530 USD and 4770 USD for 5mg BD, 15mg BD and 20mg BD respectively within patient assisted programs and much higher outside these programs. In a country like India with a nominal Gross Domestic Product (GDP) per capita of around 2191 USD, this not only reflects the high cost of the drug but also the discordant pricing of the different doses resulting in opting for lower doses. The financial burden of the drug is also reflected in the NICE Appraisal Committee recommendation that though ruxolitinib is clinically effective, it is not cost effective for symptomatic therapy CONCLUSION In spite of having a good symptom response, many of our patients discontinued the drug because of its "financial toxicity". In developing economies, better access to the drug and doing away with suboptimal doses need to be addressed so that the target population can reap its therapeutic effect in entirety. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

REAL-WORLD UTILIZATION OF IMMUNE GLOBULIN INTRAVENOUS 10% AT PHYSICIAN OFFICE INFUSION CENTERS

<h3>Introduction</h3> Immune Globulin Intravenous (human) 10% liquid (IGIV 10%) was FDA-approved in 2012, voluntarily withdrawn in 2016, and reintroduced in 2019 by a new manufacturer with an optimized manufacturing process. Given the manufacturing process changes and utilization of the product in the US, the assessment of post-marketing clinical experience is warranted. The objective of this study is to evaluate post-marketing tolerability of IVIG 10% in a real-world setting. <h3>Methods</h3> We conducted a retrospective observational review of a random sample of patients who received IGIV 10% from 8/2021-5/2022 at physician office infusion centers (OICs) throughout the US. Study data from electronic medical records included demographics, therapy details, and infusion-related adverse events (AEs). <h3>Results</h3> Twenty-three of 96 IGIV 10% patients were randomly-selected from 9 OICs. The mean age was 74±5.3 years with 78% female. Common comorbidities included hypertension (74%) and gastroesophageal reflux disease (61%). One patient was immune globulin (IG) naïve, and 22 patients (96%) were IG-treatment experienced. Most (91%) had primary immunodeficiencies, with one chronic lymphocytic leukemia and one dermatomyositis. The mean IGIV 10% dose was 432±129.2 infused every three or four weeks. IGIV 10% infusions were titrated over an average of 78±28.8 minutes with an average maximum infusion rate of 154±18.8 mL/hr. During the study, patients received a mean of 7±2 infusions. Of 155 infusions, five AEs were reported (fatigue, headache, nausea, dizziness) during 4 infusions (17%) for an overall AE rate per infusion of 3%. <h3>Conclusions</h3> IGIV 10% was successfully administered to patients in OICs and was well-tolerated over multiple infusions.

Pimavanserin and Parkinson's Disease Psychosis: A Narrative Review.

Pimavanserin (PMV) is the first approved drug for treating hallucinations and delusions in Parkinson’s disease (PD) psychosis. Psychosis is one of the leading causes of nursing home placement in people with PD. Furthermore, hallucinations are a more frequent cause of institutionalization than motor disability or dementia related to PD. The management of PD psychosis involves antipsychotic medications. Most of the drugs in this class directly block dopamine D2 receptors, leading to significantly worsening motor symptoms in patients with PD. The most commonly used medications for managing PD psychosis are quetiapine, clozapine, and PMV. This literature review aims to study pimavanserin’s history, mechanism, clinical trials, and post-marketing experience. PMV is a potent 5-HT2A receptor antagonist/inverse agonist. Moreover, this drug can interact with 5-HT2C receptors. We calculated some physicochemical descriptors and pharmacokinetic properties of PMV. Eight clinical trials of PMV and PD psychosis are registered on ClinicalTrials.gov. Only four of them have complete results already published. Meta-analytic results showed that PMV efficacy is inferior to clozapine. However, PMV has a significantly lower number of side-effects for managing psychosis in PD. Medicare database assessment revealed 35% lower mortality with PMV compared to other atypical antipsychotics. Moreover, sensitive statistical analysis demonstrated that PMV is a protective factor for the risk of falls in individuals with PD.

Evaluating the Use of Dalbavancin for Off-Label Indications.

(1) Background: Dalbavancin is a long-acting lipoglycopeptide antibiotic approved for skin and soft-tissue infections. Post-marketing experience suggests dalbavancin is being used for off-label indications that normally require long-term intravenous (IV) antibiotics; however, data assessing this off-label usage are limited. The purpose of this study was to evaluate the real-world efficacy, safety, and financial impact of off-label dalbavancin use. (2) Methods: This is a retrospective, observational study conducted within a 4-hospital health system. Adult patients who received dalbavancin from January 2018 to January 2021 for an off-label indication were included. The primary outcome was clinical success at 90 days. Secondary outcomes included safety (nephrotoxicity and hepatotoxicity). A pharmacoeconomic analysis was performed by comparing the cost of dalbavancin to the anticipated cost of patient stay if standard IV therapy was given. (3) Results: Forty-eight patients met study criteria. Indications included osteomyelitis (54%), endocarditis (23%), bacteremia (15%), and prosthetic joint infection (8%). The predominant organism was S. aureus (60%), with 42% caused by methicillin-resistant S. aureus. Overall, 41 (85%) patients achieved clinical success at 90 days, including 85% with osteomyelitis, 82% with endocarditis, and 86% with bacteremia. There were no instances of nephrotoxicity or hepatotoxicity. Estimated cost avoidance per patient was USD 5313 and USD 1683 if traditional IV therapy would have been completed in the hospital and skilled nursing facility, respectively. (4) Conclusion: Dalbavancin was associated with a relatively high success rate for the treatment of off-label indications and may be a cost-effective alternative to traditional IV antibiotic therapy.

Safety and tolerability of preventive treatment options for chronic migraine

Introduction: Relative to migraine generally, chronic migraine (CM) imposes greater disability, healthcare utilization and socioeconomic burden. Six therapies currently possess a credible evidence base for prevention/suppression of CM. This review is intended to provide an assessment of their relative utility, defined as a blend of safety, tolerability and efficacy, focusing in particular on their safety and tolerability. Areas Covered: We discuss all six medications currently FDA-approved for migraine prevention which also specifically possess credible evidence of efficacy in treating CM. While we do address the efficacy of each, our primary emphasis involves assessment of safety and tolerability data derived from clinical trials and post-marketing experience. Expert Opinion: Recent research involving CM has led to the identification of highly targeted and typically well-tolerated therapies. For patients who experience obstacles to accessing these newer therapies, topiramate is available as an evidence-based alternative, but contraindications, drug-drug interactions and poor tolerability may limit or prevent its use. Although data to support such intervention presently is limited, clinically challenging CM cases may benefit from combination therapy. “Real world” studies are needed to evaluate such polytherapy, along with studies intended to assess the long-term safety of the individual therapies and their use during pregnancy and breast-feeding.

Safety of Eslicarbazepine Acetate in Elderly Versus Non-Elderly Patients with Focal Seizures: From Pooled Data of Clinical Studies to 8 Years of Post-Marketing Experience.

IntroductionThe prevalence of epilepsy increases in elderly patients aged > 65 years, and treatment is challenging because clinical data are limited.ObjectiveOur objective was to evaluate the safety of eslicarbazepine acetate (ESL) in patients aged ≥ 65 years versus non-elderly patients with focal seizures.MethodsThe safety data of seven phase II and III, double-blind, open-label, randomized clinical studies of ESL in adults were pooled. At least possibly related treatmentemergent adverse events (TEAEs) and ESL post-marketing adverse drug reactions (ADRs) were analyzed separately by age categories.ResultsThe most frequently reported at least possibly related TEAEs in elderly (N = 120) versus non-elderly patients (N = 1863) were dizziness (10.8 vs. 20.3%), somnolence (9.2 vs. 12.6%), and hyponatremia (6.7 vs. 1.5%). Elderly patients presented a higher incidence of serious TEAEs (22.5 vs. 7.6%) and at least possibly related serious TEAEs (6.7 vs. 2.5%), probably because treatment was complicated by comorbidities and comedications. After an estimated cumulative exposure of over 2 million patient-months worldwide and 8 years of post-marketing surveillance, hyponatremia was the most frequently reported ADR (n = 232), accounting for 14.6% and 6.8% of the ADRs reported in elderly (n = 473) and non-elderly patients (n = 2406), respectively. This was followed by ADR/safety information such as drug–dose titration not performed (7.0 vs. 5.4%), product use in unapproved indication (4.9 vs. 1.9%), off-label use (3.4 vs. 2.2%), dizziness (3.4 vs. 3.5%), and seizure (2.1 vs. 5.8%).ConclusionNo specific safety issue was identified from the pooled studies for elderly compared with non-elderly patients. After 8 years of post-marketing surveillance, the qualitative safety of ESL remains similar to that observed in the clinical studies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-021-01097-5.

Long-Term Efficacy Outcomes of Natalizumab vs. Fingolimod in Patients With Highly Active Relapsing-Remitting Multiple Sclerosis: Real-World Data From a Multiple Sclerosis Reference Center.

Background: Natalizumab (NTZ) and fingolimod (FTY) are second-line disease modifying treatments (DMTs) approved for Relapsing – Remitting Multiple Sclerosis (RRMS). Few studies are available on a direct comparison between NTZ and FTY, based on post-marketing experience, with conflicting results and reporting relatively short follow-up period.Aim: We hereby report real-world experience of a MS Center with respect to NTZ vs. FTY comparison in terms of efficacy and safety, referencing long-term follow-up.Methods: We used retrospective data for all patients that received 2nd-line treatment NTZ (since May 2007) or FTY (since September 2011). Primary endpoints were, among others, annual EDSS score (mean change from baseline), time to disability worsening or improvement, Annualized Relapse Rate (ARR) after 12 and 24 months and upon total treatment duration, time to first relapse and time to radiological progression.Results: A total of 138 unmatched patients, 84 treated with NTZ and 54 treated with FTY were included. Following Propensity Score (PS) matching, 31 patients in each group were retained. Mean follow-up period for NTZ- and FTY-treated patients was 4.43 ± 0.29 and 3.59 ± 0.32 years (p = 0.057), respectively. In the matched analysis, time to disability improvement and time to disability worsening was comparable between groups. A higher proportion of patients remained free of relapse under NTZ, compared to FTY (Log Rank test p = 0.021, HR: 0.25, 95% CI: 0.08–0.8), as well as free of MRI activity (Log Rank test p = 0.006, HR: 0.26, 95% CI: 0.08–0.6). Treatment discontinuation due to MRI activity was significantly higher for FTY-treated patients compared to NTZ (Log Rank test p = 0.019, HR: 0.12, 95% CI: 0.05–0.76).Conclusion: Our results indicate toward NTZ superiority with respect to relapse and MRI activity outcomes. The fact that NTZ-treated patients may achieve long-standing clinical and radiological remission points toward the need for long follow-up data.

German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - Part 2: Treatment monitoring and specific clinical or comorbid situations.

German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - Part 2: Treatment monitoring and specific clinical or comorbid situations.

Evaluation of the Safety and Tolerability of Rapid Infusion of Biosimilar Rituximab Truxima® — the University College London Hospitals (UCLH) Experience

▪Rituximab is a chimeric anti-CD20 monoclonal antibody approved in the EU (MabThera®; Roche) and US (Rituxan®; Genentech) to treat non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL).In April 2017 the first biosimilar rituximab (Truxima®; NAPP) was approved in the UK for all indications of the reference biologic. Its adoption is expected to deliver a significant reduction in treatment costs.Administration of rituximab is associated with infusion-related reactions (IRRs). The incidence of IRRs is greatest with the first infusion and decreases significantly with subsequent infusions.To reduce the risk of IRRs, manufacturers recommend that the first dose is gradually increased every 30 minutes in 50mg/hour increments to a maximum of 400mg/hour. For subsequent infusions gradually increase every 30 minutes in 100mg/hour increments to a maximum of 400mg/hour, known as standard subsequent rate infusion. This means a typical rituximab infusion can take 4-6 hours.If the first infusion is well-tolerated, it is now widespread practice to administer subsequent MabThera® doses as a rapid infusion over 90 minutes, whereby 20% of the dose is given over the first 30 minutes, with the remaining 80% over the following 60 minutes (Sehn et al, Blood 2007).Reverting to slower infusion rates with the introduction of biosimilar rituximab could adversely impact daycare unit capacity, nursing resource, appointment length, and patient satisfaction.AimThe aim of our study was to assess the safety of rapid infusion of Truxima® by reviewing infusion related adverse events in patients 1) switching from MabThera® 2) with previous exposure to MabThera® but last dose received over 6 months ago and 3) rituximab naïve patients.MethodIn May 2017 all patients were switched from MabThera® to Truxima® at UCLH, London. Truxima® doses given between 22nd May and 26th July 2017 were identified from the electronic prescribing system (Chemocare®). Infusion-related reactions were noted from nursing infusion records and graded using Common Terminology Criteria for Adverse Events version 4.03.Patients who had been receiving MabThera® as a rapid infusion continued at this rate with Truxima®. Those patients who had received only one prior dose of MabThera® at the standard first dose infusion rate received their first Truxima® dose as a rapid infusion.Patients who had not received MabThera® for over 6 months or were MabThera® naïve, received their first Truxima® dose at the standard first dose infusion rate. If well-tolerated, subsequent doses were given as a rapid infusion.All patients received premedication with paracetamol (acetaminophen) and antihistamine.ResultsTable 1 shows the patient characteristics, MabThera® and Truxima® infusion rates and infusion-related reactions.DiscussionThe results showed that rapid infusion of Truxima® was well-tolerated in all three groups of patients. Additionally, patients switching from MabThera® safely received their first Truxima® dose as a rapid infusion. One patient switching from MabThera® developed tachycardia during their first Truxima® dose at rapid infusion rate; however this patient was able to receive subsequent Truxima® doses with additional glucocorticoid pre-medication without IRRs.Grade 2 or 3 IRRs were observed with 8 first rate infusions (12%) and 4 of the patients have received further Truxima® doses so far. These patients received their next dose at standard subsequent infusion rate with glucocorticoid pre-medication without incident, and 2 of the patients have had further doses as a rapid infusion without an IRR. Updated results will be presented at the ASH meeting 2017.ConclusionThis study is the first reported post-marketing experience of rapid infusion of biosimilar rituximab and showed that patients can be safely switched from MabThera® to Truxima® without reverting to slower infusion rates. In addition patients who tolerated their first infusion rate of Truxima® were able to tolerate a rapid infusion rate with subsequent doses.These findings will facilitate the introduction of Truxima® at centres prescribing rituximab without adversely impacting resource utilisation or patient experience. [Display omitted] DisclosuresCheesman:Roche: Consultancy; Novartis: Consultancy; Napp: Consultancy; Amgen: Consultancy. Ardeshna:ADC Therapeutics: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses. Townsend:Roche: Consultancy.