Lower injection-site reactions and long-term safety, immunogenicity, and efficacy of etanercept biosimilar YLB113: Results from a post-hoc analysis of a double-blind, randomized, phase III comparative study and its open-label extension in patients with rheumatoid arthritis.

AIM: YLB113 biosimilar was evaluated in an open-label extension single-arm study to assess long-term safety, efficacy, and immunogenicity in patients with rheumatoid arthritis (RA). We also report post-hoc results on the incidence of injection-site reactions (ISRs) and injection-site erythema (ISE) from a phase III study. METHOD: Participants from the phase III, double-blind, randomized, 96 week equivalence study who completed the final visit received 50 mg YLB113 subcutaneously every 2 weeks. Key safety end points were assessed through adverse events (AEs), ISRs, ISE, and anti-drug antibody (ADA) incidence. The efficacy end point was change from baseline in Disease Activity Score 28-joint count (DAS28) over time. RESULTS: Of 201 participants, 184 (91.5%) completed the study. Treatment-emergent AEs were experienced by 93.5% and severe AEs by 10.0% of participants. The discontinuation rate due to AEs was 2.0%. Overall, 20.0% of participants reported an incidence of ISRs throughout the open-label extension study. Two participants developed ADAs, and none developed neutralizing ADAs at any time after study drug administration. The overall DAS28 (mean ± SD) change was 2.22 ± 0.95 at the study transition, 2.10 ± 0.91 at week 72, and 2.06 ± 0.89 at the end of the study. In the post-hoc analysis, YLB113 showed a statistically significant lower incidence of ISRs (10 [3.8%], P < 0.0001) and ISE (5 [1.9%], P < 0.0001) compared with the reference product Enbrel®. CONCLUSION: YLB113 demonstrated long-term safety and sustained efficacy for up to 96 weeks. Patients on YLB113 experienced significantly lower ISRs and ISE in a post-hoc analysis of the phase III study when compared with reference product.

COVID Arm After Moderna Booster in Healthcare Worker: A Case Report.

SARS CoV-2 virus has infected more than 200 million people worldwide and more than 4.4 million in Indonesia. The vaccination program has become one of the solutions launched by many countries globally, including Indonesia, to reduce the transmission rate of COVID-19. Various vaccination platforms are produced, such as inactivated, viral vector, mRNA, and protein subunit. The vaccination booster program with mRNA platform (Moderna) was launched by the Indonesian government to give better protection for health care workers, particularly from delta variant. In this case report, we discuss one of the typical side effects of Moderna vaccine, which is referred to as the COVID arm.

Delayed Localized Hypersensitivity Reactions to the Moderna COVID-19 Vaccine: A Case Series.

Importance: In response to the coronavirus disease 2019 (COVID-19) pandemic, 2 mRNA vaccines (Pfizer-BioNTech and Moderna) received emergency use authorization from the US Food and Drug Administration in December 2020. Some patients in the US have developed delayed localized cutaneous vaccine reactions that have been dubbed "COVID arm." Objective: To describe the course of localized cutaneous injection-site reactions to the Moderna COVID-19 vaccine, subsequent reactions to the second vaccine dose, and to characterize the findings of histopathologic examination of the reaction. Design, Setting, and Participants: This retrospective case series study was performed at Yale New Haven Hospital, a tertiary medical center in New Haven, Connecticut, with 16 patients referred with localized cutaneous injection-site reactions from January 20 through February 12, 2021. Main Outcomes and Measures: We collected each patient's demographic information, a brief relevant medical history, clinical course, and treatment (if any); and considered the findings of a histopathologic examination of 1 skin biopsy specimen. Results: Of 16 patients (median [range] age, 38 [25-89] years; 13 [81%] women), 14 patients self-identified as White and 2 as Asian. The delayed localized cutaneous reactions developed in a median (range) of 7 (2-12) days after receiving the Moderna COVID-19 vaccine. These reactions occurred at or near the injection site and were described as pruritic, painful, and edematous pink plaques. None of the participants had received the Pfizer-BioNTech vaccine. Results of a skin biopsy specimen demonstrated a mild predominantly perivascular mixed infiltrate with lymphocytes and eosinophils, consistent with a dermal hypersensitivity reaction. Of participants who had a reaction to first vaccine dose (15 of 16 patients), most (11 patients) developed a similar localized injection-site reaction to the second vaccine dose; most (10 patients) also developed the second reaction sooner as compared with the first-dose reaction. Conclusions and Relevance: Clinical and histopathologic findings of this case series study indicate that the localized injection-site reactions to the Moderna COVID-19 vaccine are a delayed hypersensitivity reaction. These reactions may occur sooner after the second dose, but they are self-limited and not associated with serious vaccine adverse effects. In contrast to immediate hypersensitivity reactions (eg, anaphylaxis, urticaria), these delayed reactions (dubbed "COVID arm") are not a contraindication to subsequent vaccination.

Subcutaneous Injection Site Pain of Formulation Matrices.

PURPOSE: The objective of this work was to systematically evaluate the effects of formulation composition on subcutaneous injection site pain (ISP) using matrices comprising of common pharmaceutical excipients. METHODS: Two randomized, blinded, crossover studies in healthy subjects were conducted at a single site, where subjects received 1 mL SC injections of the buffer matrices. ISP intensity was measured using a 100 mm visual analogue scale (VAS), which was then analyzed via heatmap, categorical grouping, subgroup analysis, and paired delta analysis. RESULTS: Buffer type, buffer concentration and tonicity agent showed a substantial impact on ISP. Citrate buffer demonstrated a higher ISP than acetate buffer or saline). The 20 mM citrate buffer was more painful than 10 or 5 mM citrate buffers. NaCl and propylene glycol were significantly more painful than sugar alcohols (mannitol, sucrose, trehalose or glycerol). Histidine buffers exhibited ISP in the descending order of 150 mM > 75 mM > 25 mM > 0 mM NaCl, while histidine buffers containing Arginine-HCl at 0, 50, or 150 mM all showed very low ISP. Histidine buffer at pH 6.5 showed a lower ISP than pH 5.7. CONCLUSIONS: This systematic study via orthogonal analyses demonstrated that subcutaneous ISP is significantly influenced by solution composition.

Randomized, Open-Label, Single-Dose, Parallel-Group Pharmacokinetic Study of PF-06410293 (adalimumab-afzb), an Adalimumab Biosimilar, by Subcutaneous Dosing Using a Prefilled Syringe or a Prefilled Pen in Healthy Subjects.

This open-label, single-dose, randomized, parallel-group, 2-arm phase 1 bioequivalence (BE) study assessed the pharmacokinetics (PK), safety, and tolerability of PF-06410293 (ADL-PF), an adalimumab (ADL) biosimilar, following administration by prefilled pen (PFP) or prefilled syringe (PFS). A total of 164 healthy adult subjects were randomized (1:1) to receive ADL-PF (40 mg subcutaneously) in the lower abdomen or upper anterior thigh by PFS or PFP; 163 subjects were included in the primary PK analysis. The concentration-time profiles of the ADL-PF PFS and PFP treatment arms were similar. The 90% confidence intervals for the test/reference ratios of the primary end points (area under the serum concentration-time profile from time 0 to 2 weeks after dosing and maximum observed serum concentration) fell within the 80.00%-125.00% prespecified margin for BE. Comparable numbers of subjects experienced adverse events (AEs) between treatment groups, and injection-site pain was similar at all times and for the 2 injection-site locations. This study demonstrated the BE of ADL-PF following subcutaneous administration using either a PFS or PFP device. ADL-PF by PFS or PFP injection was well tolerated, with the distribution of AEs, including injection-site reactions, being similar between treatment arms.

Infections associated with diabetic-care devices.

BACKGROUND AND AIMS: There are more than 463 million people living with diabetes with this number expected to increase to 700 million people by 2045. Diabetes is a risk factor for patients developing various comorbidities including, but not limited to, diabetic neuropathy, retinopathy, chronic kidney disease, vascular impediments, and infections. Due to the continuous invasiveness of monitoring and/or treatment of this disease, site for infections are elevated. METHODS: Information was primarily gathered by employing various PubMed scholarly articles for real-world examples in addition to data extraction from supplementary manuscripts. Key search words employed were: diabetes, insulin site infection, lancing infections, insulin pump associated infections, and continuous glucose monitoring infections. RESULTS: Diabetic care devices used for blood glucose monitoring and insulin administration are an integral part of the disease management and/or treatment in various settings including patient homes, assisted living facilities, community centers, and hospitals. These invasive devices leave a diabetic patient with a small open wound which may get infected or aid in blood borne pathogen transmission. Since diabetes itself has a morbidity and mortality burden, it is important to also study complications arising from the management of diabetes. CONCLUSION: Although cases exist of infections, either by pathogen transmission or direct inoculation of the prick site, these are a very small percentage and thus should not undermine the confidence in diabetes management. This review highlights the instances of these infections and where they most often occur.

Clinical Evaluation of an Investigational 5 mL Wearable Injector in Healthy Human Subjects.

An investigational wearable injector (WI), the BD Libertas Wearable Injector (BD Libertas is a trademark of Becton, Dickinson and Company), was evaluated in an early feasibility clinical study for functional performance, tissue effects, subject tolerability, and acceptability of 5 mL, non-Newtonian ~ 8 cP subcutaneous placebo injections in 52 healthy adult subjects of 2 age groups (18-64 years and ≥ 65 years). Randomized WI subcutaneous injections (n = 208, 4/subject) were delivered to the right and left abdomen and thigh of each subject, 50% (1 thigh and 1 abdomen) with a defined movement sequence during injection. Injector functional performance was documented. Deposition was qualified and quantified with ultrasound. Tissue effects and tolerability (pain) were monitored through 24 hours with corresponding acceptability questionnaires administered through 72 hours. WI (n = 205) automatically inserted the needle, delivered 5 mL ± 5% in 5.42 minutes (SD 0.74) and retracted. Depots were entirely (93.2%) or predominantly (5.4%) localized within the target subcutaneous tissue. Slight to moderate wheals (63.9%) and erythema (75.1%) were observed with ≥ 50% resolution within 30-60 minutes. Subject pain (100 mm Visual Analog Scale) peaked mid-injection (mean 9.1 mm, SD 13.4) and rapidly resolved within 30 minutes (mean 0.4 mm, SD 2.6). Subjects' peak pain (≥ 90.2%), injection site appearance (≥ 92.2%) and injector wear, size, and removal (≥ 92.1%) were acceptable (Likert responses) with 100% likely to use the injector if prescribed. Injection site preference was divided between none (46%), abdomen (25%), or thigh (26.9%). The investigational WI successfully delivered 5 mL viscous subcutaneous injections. Tissue effects and pain were transient, well-tolerated and acceptable. Neither injection site, movement or subject age affected injector functional performance or subject pain and acceptability.

Complication of Soft Tissue Fillers: Prevention and Management Review.

The use of dermal fillers has increased manifold over the past decade, which has been attributed to the ever-increasing need of the population for being young. Fillers have become quite popular both among patients and treating physicians due to their quick and quite predictable results. Filler injection is a safe procedure in the hands of an experienced provider using appropriate technique. Nevertheless, various adverse effects to fillers have been reported that range from mild injection site complications, such as pain and bruising, to severe complications, like tissue necrosis, retinal artery occlusion, and infections. The esthetic provider should be aware of and be able to quickly recognize such complications, and be confident in managing them. In this article we highlight the various adverse effects noted with the use of fillers and discuss prevention and management. J Drugs Dermatol. 2020;19(9):829-832. doi:10.36849/JDD.2020.5084.

Diagnosis and management of hypersensitivity reactions to vaccines.

INTRODUCTION: Many countries in Europe now recommend and enforce mandatory vaccinations to improve vaccination coverage. Thus, the number of adverse events following immunization (AEFI) may show an increase. Among these events, severe hypersensitivity reactions to vaccines are rare. However, it is important that they be identified and recognized so that they may be adequately managed. AREAS COVERED: The literature search was undertaken through PubMed and Embase to identify English-language papers focusing on hypersensitivity to vaccines. EXPERT OPINION: Hypersensitivity reactions following vaccinations are rare and are classified according to their chronology and extension: immediate when they occur within the first 4 hours following administration and non-immediate when they occur later. Local reactions are the most common adverse event following injection of vaccines and generally do not require any allergy workup. Immediate reactions, however, are potentially IgE-mediated and require an allergy workup. In general, a previously known food allergy (i.e., egg or milk) is not a contraindication to immunizations. Patients with a known allergy to gelatin, yeast, latex, antibiotics, or other specific components of vaccines require an allergy workup before administration of the vaccine.

First Clinical Study with AP30663 - a KCa 2 Channel Inhibitor in Development for Conversion of Atrial Fibrillation.

Pharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca2+ activated K+ (KCa 2) channel blocker, prolonged the atrial effective refractory period in preclinical studies and subsequently converted AF into normal sinus rhythm. This first-in-human study evaluated the safety and tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects were explored. Forty-seven healthy male volunteers (23.7 ± 3.0 years) received AP30663 intravenously in ascending doses. Due to infusion site reactions, changes to the formulation and administration were implemented in the latter 24 volunteers. Extractions from a 24-hour continuous electrocardiogram were used to evaluate the PD effect of AP30663. Data were analyzed with a repeated measure analysis of covariance, noncompartmental analysis, and concentration-effect analysis. In total, 33 of 34 adverse events considered related to AP30663 exposure were related to the infusion site, mild in severity, and temporary in nature, although full recovery took up to 110 days. After formulation and administration changes, the local infusion site reaction remained, but the median duration was shorter despite higher dose levels. AP30663 displayed a less than dose proportional increase in peak plasma concentration (Cmax ) and a terminal half-life of around 5 hours. In healthy volunteers, no effect of AP30663 was observed on electrocardiographic parameters, other than a concentration-dependent effect on the corrected QT Fridericia's formula interval (+18.8 ± 4.3 ms for the highest dose level compared with time matched placebo). In conclusion, administration of AP30663, a novel KCa 2 channel inhibitor, was safe and well-tolerated systemically in humans, supporting further development in patients with AF undergoing cardioversion.

Cutaneous adverse events induced by azacitidine in myelodysplastic syndrome patients: Case reports and a lesson from published work review.

Subcutaneous injection of azacitidine (AZA) is an important treatment option for myelodysplastic syndrome (MDS), which improves overall survival. In hematology, the incidence of AZA-induced cutaneous adverse events (AE) has been known to be relatively high, which has not been well recognized by dermatologists. Discontinuation of AZA can result in the deterioration of MDS disease activity. Therefore, on dermatological consultation, precise evaluation of AE severity and careful consideration is required for post-AE medication management. To enhance our understanding of AZA-induced cutaneous AE, we report four cases with two representative cutaneous AE subtypes and summarize the clinicopathological phenotypes and courses of the cases in the published work. Case 1, a 71-year-old man, developed neutrophilic dermatosis involving the dermis and subcutaneous tissue. The other three cases, a 75-year-old man, a 78-year-old woman and a 68-year-old man, presented injection-site erythema associated with flare-up reaction. Discontinuation of AZA was necessary for case 1 alone. The published work review delineated three major subtypes of AZA-induced cutaneous AE: systemic cutaneous reaction, neutrophilic dermatosis type and erythematous type injection-site reaction. Histologically, the first two subtypes are mostly characterized by neutrophil infiltration, while the third subtype presents lymphocytic cell infiltration. Neither AZA discontinuation nor intensive interventions were required for the erythematous type injection-site reaction, while AZA termination or systemic treatments, represented by corticosteroid administration, were preferentially conducted for the systemic cutaneous reaction or the neutrophilic dermatosis type injection-site reaction subgroup. These observations support the necessity of subtype-dependent treatment strategies for the management of AZA-induced cutaneous AE.

Classification and mitigation of negative injection experiences with biologic medications.

Injection site reactions with biologic medications are encountered with variable frequency. Although there is no clear definition, they commonly manifest with pain and irritation at the injection site. Previously proposed reaction classification systems may be impractical or insufficient, and more intuitive nomenclature may benefit clinical dermatologists and patients. Negative injection experiences (NIE) are common reasons for biologic medication nonadherence. Here we provide clinical classifications and recommendations for mitigating these reactions. We categorized NIEs into the following: (a) physical, due to the needle and injection process, (b) irritant, related to properties of the injected solution, and (c) allergic, both immediate and delayed.