Subcutaneous delivery of biotherapeutics has become a valuable alternative to intravenous administration across many disease areas. Although the pharmacokinetic profiles of subcutaneous and ...intravenous formulations differ, subcutaneous administration has proven effective, safe, well-tolerated, generally preferred by patients and healthcare providers and to result in reduced drug delivery-related healthcare costs and resource use. The aim of this article is to discuss the differences between subcutaneous and intravenous dosing from both health-economic and scientific perspectives. The article covers different indications, treatment settings, administration volumes, and injection devices. We focus on biotherapeutics in rheumatoid arthritis (RA), immunoglobulin-replacement therapy in primary immunodeficiency (PI), beta interferons in multiple sclerosis (MS), and monoclonal antibodies (mAbs) in oncology. While most subcutaneous biotherapeutics in RA, PI, and MS are self-administered at home, mAbs for oncology are still only approved for administration in a healthcare setting. Beside concerns around the safety of biotherapeutics in oncology, a key challenge for self-administration in this area is that doses and dosing volumes can be comparatively large; however, this difficulty has recently been overcome to some extent by the development of high-concentration solutions, the use of infusion pumps, and the coadministration of the dispersion enhancer hyaluronidase. Furthermore, given the increasing number of biotherapeutics being considered for combination therapy and the high dosing complexity associated with these, especially when administered intravenously, subcutaneous delivery of fixed-dose combinations might be an alternative that will diminish these burdens on healthcare systems.
Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative ...effects of these two drugs in patients with multiple sclerosis are not known.
In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.
Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval CI, -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups.
Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.).
Minimizing the pain of local anesthesia injection Strazar, A Robert; Leynes, Peter G; Lalonde, Donald H
Plastic and reconstructive surgery (1963),
2013-September, Letnik:
132, Številka:
3
Journal Article
Recenzirano
Local anesthetic injection is often cited in literature as the most painful part of minor procedures. It is also very possible for all doctors to get better at giving local anesthesia with less pain ...for patients. The purpose of this article is to illustrate and simplify how to inject local anesthesia in an almost pain-free manner.
The information was obtained from reviewing the best evidence, from an extensive review of the literature (from 1950 to August of 2012) and from the experience gained by asking over 500 patients to score injectors by reporting the number of times they felt pain during the injection process.
The results are summarized in a logical stepwise pattern mimicking the procedural steps of an anesthetic injection-beginning with solution selection and preparation, followed by equipment choices, patient education, topical site preparation, and finally procedural techniques.
There are now excellent techniques for minimizing anesthetic injection pain, with supporting evidence varying from anecdotal to systematic reviews. Medical students and residents can easily learn techniques that reliably limit the pain of local anesthetic injection to the minimal discomfort of only the first fine needlestick. By combining many of these conclusions and techniques offered in the literature, tumescent local anesthetic can be administered to a substantial area such as a hand and forearm for tendon transfers or a face for rhytidectomy, with the patient feeling just the initial poke.
Daratumumab is an anti-CD38 monoclonal antibody widely used for treating patients with newly diagnosed or relapsed/refractory multiple myeloma. The subcutaneous formulation of daratumumab was ...developed with the purpose of minimizing the treatment burden (to patients and health care system) associated with intravenous daratumumab. Given its recent approval, there is a knowledge gap regarding the best practices that should be instituted for safe administration of subcutaneous daratumumab.
A retrospective chart review was performed from August 2020 until November 2020 to identify patients either switched to or treated upfront (daratumumab naive) with any subcutaneous daratumumab-based treatment regimen. All patients received appropriate premedications per institutional standards of care. The study end points were to report real-world data regarding administration-related reaction rates (at or following discharge from infusion center), as well as compare their incidence rates to those noted in the COLUMBA study (historical cohort).
The study included 58 patients, of whom 38% (n = 22) were daratumumab naive. The majority (84%, n = 49) received subcutaneous daratumumab in combination with various antimyeloma regimens. There were no cases of administration-related reactions at infusion center or after discharge irrespective of previous exposure to intravenous daratumumab. None of the patients included herein required rescue home medications or visited the emergency department within 24 to 48 hours after subcutaneous daratumumab administration. These translated into a significant difference in incidence of administration-related reactions compared with historical cohort (0% vs. 13%, P = .003).
Subcutaneous daratumumab was extremely well tolerated and could be safely administered without need for monitoring or rescue home medications.
There is a paucity of data regarding the safety of the subcutaneous daratumumab formulation in real-world clinical practice. A retrospective chart review was performed after its addition to institutional formulary. Administration-related reactions were not noted regardless of previous exposure to intravenous daratumumab. Subcutaneous daratumumab could be safely administered without need for monitoring or use of rescue home medications.
Abstract
Background
A number of authors have proposed retrograde arterial embolism as the responsible mechanism for filler-induced blindness. However, no previous human study has substantiated this ...proposed mechanism.
Objectives
The aim of this study was to investigate the pathophysiology of filler-induced blindness using a fresh cadaver perfusion technique.
Methods
A fresh cadaver head perfusion model that simulates both physiologic blood pressure and flow rate of the carotid artery, ophthalmic artery, and supratrochlear artery was used. The common carotid artery was cannulated and the internal jugular vein exposed for open venous drainage. A plasma-based perfusate was circulated through the cadaver head, which was connected to a perfusion system consisting of a roller pump, preload reservoir, and pressure monitor. The hyaluronic acid filler mixed with methylene blue was injected into the cannulated superficial branch of the supratrochlear artery. Cadaver dissection, angiographic study, and histology were used to investigate filler-induced blindness.
Results
Cannulation of the superficial branch of the supratrochlear artery was successful in all six cadavers. Emboli to the ophthalmic artery was successfully demonstrated in the three out of 6 fresh cadaver heads. The C-arm angiogram documented a cut-off sign in the ophthalmic artery due to hyaluronic acid filler emboli. An average intravascular volume of the intraorbital part of the supratrochlear artery was 50.0 µL. The average depth of location of the superficial branch of the supratrochlear artery from the epidermal surface was 1.5 mm.
Conclusions
Our cadaveric study demonstrated that retrograde hyaluronic acid filler emboli to the ophthalmic artery could be produced by the cannulation of the supratrochlear artery. The superficial location of the supratrochlear artery, the rich vasculature surrounding it, and the variability in the anatomy make this possible.
Abstract Aim Injections administered by patients are one of the mainstays of diabetes management. Proper injection technique is vital to avoiding intramuscular injections, ensuring appropriate ...delivery to the subcutaneous tissues and avoiding common complications such as lipohypertrophy. Yet few formal guidelines have been published summarizing all that is known about best practice. We propose new injection guidelines which are thoroughly evidence-based, written and vetted by a large group of international injection experts. Methods A systematic literature study was conducted for all peer-reviewed studies and publications which bear on injections in diabetes. An international group of experts met regularly over a two-year period to review this literature and draft the recommendations. These were then presented for review and revision to 127 experts from 27 countries at the TITAN workshop in September, 2009. Results Of 292 articles reviewed, 157 were found to meet the criteria of relevance to the recommendations. Each recommendation was graded by the weight it should have in daily practice and by its degree of support in the medical literature. The topics covered include The Role of the Professional, Psychological Challenges , Education, Site Care, Storage, Suspension and Priming, Injecting Process, Proper Use of Pens and Syringes, Insulin analogues, Human and Pre-mixed Insulins, GLP-1 analogs, Needle Length, Skin Folds, Lipohypertrophy, Rotation, Bleeding and Bruising, Pregnancy, Safety and Disposal. Conclusion These injecting recommendations provide practical guidance and fill an important gap in diabetes management. If followed, they should help ensure comfortable, effective and largely complication-free injections.
Summary Background Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. We aimed to ...assess the efficacy and safety of benralizumab as add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts. Methods In this randomised, double-blind, parallel-group, placebo-controlled, phase 3 study (CALIMA) undertaken at 303 sites in 11 countries, we enrolled patients aged 12–75 years with severe asthma uncontrolled by medium-dosage to high-dosage inhaled corticosteroids plus long-acting β₂-agonists (ICS plus LABA) and a history of two or more exacerbations in the previous year. Patients were randomly assigned (1:1:1) to receive 56 weeks of benralizumab 30 mg every 4 weeks (Q4W), benralizumab 30 mg every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo (all subcutaneous injection). Patients were stratified (2:1) by baseline blood eosinophil counts 300 cells per μL or greater and less than 300 cells per μL, respectively. Patients and study centre staff were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per μL or greater (intention-to-treat analysis). Key secondary endpoints were pre-bronchodilator forced expiratory volume in 1 s (FEV1 ) and total asthma symptom score. This study is registered with ClinicalTrials.gov , number NCT01914757. Findings Between Aug 21, 2013, and March 16, 2015, 2505 patients were enrolled, of whom 1306 patients were randomised; 425 patients were randomly assigned to and received benralizumab 30 mg Q4W, 441 to benralizumab 30 mg Q8W, and 440 to placebo. 728 patients were included in the primary analysis population. Benralizumab resulted in significantly lower annual exacerbation rates with the Q4W regimen (rate 0·60 95% CI 0·48–0·74, rate ratio 0·64 95% CI 0·49–0·85, p=0·0018, n=241) and Q8W regimen (rate 0·66 95% CI 0·54–0·82, rate ratio 0·72 95% CI 0·54–0·95, p=0·0188, n=239) compared with placebo (rate 0·93 95% CI 0·77–1·12, n=248). Benralizumab also significantly improved pre-bronchodilator FEV1 (Q4W and Q8W) and total asthma symptom score (Q8W only) in these patients. The most common adverse events were nasopharyngitis (90 21% in the Q4W group, 79 18% in the Q8W group, and 92 21% in the placebo group) and worsening asthma (61 14% in the Q4W group, 47 11% in the Q8W group, and 68 15% in the group). Interpretation Benralizumab significantly reduced annual exacerbation rates and was generally well tolerated for patients with severe, uncontrolled asthma with blood eosinophils 300 cells per μL or greater. Our data further refine the patient population likely to receive the greatest benefit from benralizumab treatment. Funding AstraZeneca and Kyowa Hakko Kirin.
Administration into the subcutaneous (SC) tissue is a typical route of delivery for therapeutic proteins, especially for frequent treatments, long-term regimens, or self-administration. It is ...currently believed that the maximum volume for SC injections is approximately 1.5 mL. Larger SC injection volumes are considered to be associated with injection pain and adverse events at the injection site. However, no controlled clinical studies and actual evidence exist to support this assumption. In this review, we discuss current and publically available data related to SC administration volumes. We conclude that injection volumes higher than 3.5 mL are worth exploring if required for the development of efficacious drug treatments. Studying tissue back pressure, injection site leakage, local tolerability, and injection-related adverse events, such as injection pain, should be considered for the development of higher SC injection volumes.
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