Off-label Group Research Articles

Cannabidiol Treatment for Adult Patients with Drug-Resistant Epilepsies: A Real-World Study in a Tertiary Center.

Around 30% of patients with epilepsy show drug-resistant epilepsy (DRE). While cannabidiol has demonstrated efficacy as an adjunctive treatment in Dravet syndrome (DS), Lennox-Gastaut Syndrome (LGS), and epilepsy related to tuberous sclerosis complex (TSC), its more global effectiveness in adult patients with DRE apart from these three specific contexts needs to be clarified. We conducted a retrospective study at the epilepsy unit of Pitié Salpêtrière Hospital. Patients initiating pharmaceutical cannabidiol treatment and followed for at least 1 year were included. Patients were categorized into "authorized" (LGS, DS, or TSC) and "off-label" groups. Cannabidiol effectiveness and tolerance were compared between groups, and characteristics of responders (patients with >50% reduction in seizure frequency) in the off-label group were examined. Ninety-one patients, followed by a median duration of 24 months, were included. A total of 35.2% of the patients were in the authorized group. No significant differences were observed in responder rates between groups (31.3% vs. 35.6%, p =0.85) and retention rates at 1 year (75.0% vs. 74.6%, p =0.97). Sleepiness was more commonly reported in the authorized group (50.0% vs. 22.0%, p =0.01), with no other significant differences. Among off-label patients (n = 59), clobazam co-prescription was more prevalent in responders (71.4% vs. 28.9%, p =0.002). Our findings suggest that cannabidiol may benefit all adult patients with DRE, particularly those already receiving clobazam. Randomized controlled trials are warranted in off-label patients to validate these observational findings.

Analysis of risk factors for bleeding as a complication of ultrasound-guided percutaneous liver biopsy examination

Objective: To explore the independent risk factors for bleeding in patients following percutaneous liver biopsy examination. Methods: The clinicopathological data of patients who underwent percutaneous liver biopsy examination at Nanjing Second Hospital from January 2012 to December 2021 were retrospectively collected. Univariate and multivariate logistic regression analysis were used to investigate the effect of age, gender, lesion type (diffuse liver parenchymal lesions, focal liver lesions), number of biopsies, tissue length, presence or absence of cirrhosis, presence or absence of portosystemic shunt, erythrocytes, white blood cells, hemoglobin, platelets, prothrombin time, fibrinogen, international normalized ratio, and liver biochemical indicators on bleeding following liver biopsy, as well as to screen independent risk factors. Results: A total of 3 331 patients were examined by percutaneous liver biopsy, and 3 060 cases were actually included by excluding 271 cases who took consultation from other hospitals. The overall postoperative hemorrhagic rate was 1.6% (49/3 060). Of which, forty-four cases (1.4%) had overt bleeding (hemodynamic changes or hemoglobin decreased by more than 20 g/L), five cases (0.2%) had minor bleeding, three cases had subcapsular hepatic hemaotma, and two cases had local bleeding from liver biopsy. Among the overt bleeding cases, two cases were in the off-label group (platelet<50×109/L or international normalized ratio>1.5), and the rest were in the non-off-label group. The results of univariate analysis showed that factors such as focal liver lesions, portosystemic shunt, prolonged prothrombin time, increased international normalized ratio, bilirubin, and alkaline phosphatase were associated with bleeding after liver biopsy in the non-off-label group. The multivariate collinearity diagnosis revealed statistically significant differences for the indicators. Multivariate logistic regression analysis finally included factors such as lesion type, portosystemic shunt, international normalized ratio, total bilirubin, and alkaline phosphatase. The results showed that patients with focal liver lesions were more prone to bleed after surgery than patients with diffuse liver parenchymal lesions (OR=3.396, P=0.002, 95%CI: 1.596-7.228). Patients with portosystemic shunt were more prone to bleed than those without portosystemic shunt (OR=3.301, P=0.018, 95%CI: 1.232-8.845). Patients were more likely to experience bleeding following liver biopsy when their total bilirubin levels were elevated (OR=1.006, P<0.001, 95%CI:1.003-1.008). Conclusion: Focal liver lesions, portosystemic shunts, and elevated total bilirubin are independent risk factors for bleeding after percutaneous liver biopsy.

Financial toxicity of oral chemotherapy in patients with primary brain tumors

Abstract Background Cancer treatment costs continue to rise with the development of new agents. Financial toxicity is defined as the quantifiable costs associated with cancer and cancer treatment in addition to the patient’s associated distress. This study’s rationale is to better understand the financial burden of oral chemotherapies from the perspective of patients with primary brain tumors. Methods After one cycle of oral chemotherapy, we requested patients to complete the financial toxicity-functional assessment of chronic illness therapy (COST-FACIT) survey and additional questions relevant to insurance and cost. We summarized responses with descriptive statistics within strata defined by on-label or off-label oral therapy. Results Sixty surveys were completed, with most patients (n = 53, 88%) receiving on-label therapy; only 7 patients (12%) received off-label oral agents. The mean overall financial toxicity score was 23.1 (SD = 11.3). When asked if their provider discussed treatment cost before initiation, 21 patients (35%) stated that they did, and 39 patients (65%) said they did not discuss cost or did not recall. However, in the off-label cohort, all 7 patients stated that their provider discussed the cost before prescribing. Most patients (70%) had copays. Nine (17%) in the on-label group and 3 (43%) in the off-label group had chemotherapy-associated costs that negatively affected their quality of life. A higher percentage of financial distress occurred in the off-label group. Conclusions Discussing medication costs with patients is an essential part of chemotherapy initiation and may mitigate undue psychosocial and financial distress.

Clinical characteristics of apixaban prescription in AF patients with single dose-reduction criterion: the ASPIRE (efficAcy and safety of aPixaban in rEal-world practice in Korean frail patients with atrial fibrillation) study.

Data on off-label reduced dose risk among patients with atrial fibrillation (AF) who qualify for a single-dose reduction of apixaban is scarce. We prospectively assessed apixaban dosing and clinical characteristics in AF patients meeting a dose reduction criterion. The multicentre, prospective cohort study, the efficAcy and Safety of aPixaban In REal-world practice in Korean frail patients with AF (ASPIRE), encompasses patients with AF who met the criteria for a single-dose reduction of apixaban and were given varying doses of apixaban, either the on-label standard dose or the off-label reduced dose. Of 2,000 patients (mean age 74.3 ± 7.9 years, 55.8% women), 29.7% were ≥80 years, 62.6% weighed ≤60 kg, and 7.8% had serum creatinine ≥1.5 mg/dL. Of these, 51.3% were prescribed an off-label reduced dose of apixaban. The off-label group was characterized with older age, more comorbidities, and antiplatelet agents, while the on-label group had more prior strokes. Physicians preferred off-label reduced dose in the "marginal zone," defined as age 75-80 years, weight 60-65 kg, and creatinine levels 1.2-1.5 mg/dL. In real-world clinical setting of the Korean population, off-label reduced dose apixaban was administered to nearly half of the patients who qualified for a single dose reduction. This reduced dosage was more commonly prescribed to patients with frail characteristics, while patients with a history of stroke were more often given the standard dose as per the label. A future study is planned to contrast the safety and effectiveness of the standard dose against the reduced dose of apixaban in this population.

Safety and efficacy analysis of the off-label use of pipeline embolization devices for intracranial aneurysms: a propensity score matching study.

The safety and efficacy of on-label use of pipeline embolization devices (PEDs) are well established; however, there is much controversy over their off-label use. This study aimed to investigate the safety and efficacy of the off-label use of PEDs for treating intracranial aneurysms. This single-center study retrospectively included patients with digital subtraction angiography, computed tomographic angiography, or magnetic resonance angiography confirmed intracranial aneurysms treated with PEDs who were admitted to our institution between 1 January 2018 and 1 July 2022. Patients were divided into on- and off-label groups according to the Food and Drug Administration criteria published in 2021. Propensity score matching (PSM) was used to balance disparities in baseline information between the two groups. Safety outcomes included postoperative mortality and complication rates, whereas effectiveness outcomes included aneurysm occlusion rate (O'Kelly-Marotta grading system C + D grades), retreatment rate within 12 months, and postoperative functional score [modified Rankin scale (mRS) score]. The study was approved by the Ethics Committee of Scientific Research and Clinical Trial of the First Affiliated Hospital of Zhengzhou University (Ethics number: KY 2018-098-02). All patients provided informed consent. A total of 242 patients with 261 aneurysms (160 on-label and 101 off-label aneurysms) were included in this study. PSM yielded 81 pairs of patients matched for baseline information. Postoperative hemorrhagic, ischemic, and procedure-related complication rates did not reach statistical significance. In addition, no statistically significant differences in the aneurysm occlusion rate, retreatment rate within 12 months, postoperative functional score (mRS score), or mRS score deterioration rate were observed between the two groups. A higher incidence of in-stent stenosis was observed in the off-label (4.9% vs. 21%, p = 0.002) group than in the on-label group; however, all patients were asymptomatic. Compared with on-label use, off-label use of PEDs for treating intracranial aneurysms did not increase the risk of complications, and the occlusion rates were comparable. Therefore, decisions regarding clinical management should not rely solely on on- or off-label indications.

QLTI-05. COST TOXICITY OF ORAL CHEMOTHERAPY IN PRIMARY BRAIN TUMOR PATIENTS

Abstract BACKGROUND Costs associated with cancer treatments in the United States continue to rise as new therapies are approved. Financial toxicity describes both the quantifiable costs associated with cancer as well as the distressful effects related to the costs of treatment. METHODS The goal of this study is to better understand the financial burden of oral chemotherapies on patients with primary brain tumors from their perspective. Following one cycle of oral chemotherapy, we contacted patients per IRB-approved protocol to participate in a 20-question survey (COST-FACIT and other questions relevant to insurance and cost). With descriptive statistics, we summarized survey responses overall and within strata defined by on-label or off-label oral medication use. RESULTS Sixty surveys were completed (58 total patients; 2 completed surveys for a second treatment). Most surveys (n = 53, 88%) reflected on-label therapy use, with only 7 patients (12%) on off-label therapies. The mean overall financial toxicity score was 23.1 (range: 1 – 44); the lower the financial toxicity score, the greater the financial distress of study participants. When asked if their provider discussed treatment cost before initiation, 21 patients (35%) stated that they did, and 39 patients (65%) said they did not discuss cost or did not recall a discussion. However, in the off-label therapies cohort, all 7 patients stated that their provider discussed cost before prescribing. Majority of surveys (70%) noted patient copays associated with these medications. Nine patients (17%) in the on-label group and three patients (43%) in the off-label group had chemotherapy-associated costs that caused negative effects on quality of life. CONCLUSIONS Although the groups are disproportionate, a higher percentage of financial distress occurred in the off-label therapy group. While cost discussions are challenging, they remain an important part of therapy initiation that may decrease undue stress; this will be an area of improvement.

Clinical characteristics of apixaban prescription in AF patients with single dose-reduction criterion: ASPIRE (efficacy and safety of apixaban in real-world practice in Korean frail patients with AF)

Abstract Background/Introduction Previous observational studies reported that off-label underdosed apixaban might be associated with a higher risk of stroke. However, the real-world clinical practice data on the off-label underdosed apixaban in patients with atrial fibrillation (AF) who meet single dose reduction criteria remains scarce. Purpose This study aimed to evaluate the apixaban dosing pattern in patients with AF who met a single dose reduction criterion. The difference in clinical characteristics underlying the on-label and off-label underdose prescription of apixaban was also assessed. Methods The efficAcy and Safety of aPixaban In REal-world practice in Korean frail patients with AF (ASPIRE) study is a multicenter, prospective cohort study. This study included patients with AF having a single dose reduction criterion of apixaban. Study subjects were categorized into two groups according to apixaban dose (on-label 5 mg twice daily [on-label], or off-label underdose 2.5 mg twice daily [off-label]). We evaluated the difference in the clinical characteristics were evaluated. Additionally, the ‘marginal zone’ was defined as age between 75 and 80 years, weight between 60 and 65kg, and creatinine level between 1.2-1.5mg/dL. Results A total of 1997 patients were included in this analysis (mean age 74.3±7.8 years, women 55.8%); 591 (29.7%) patients were 80 years or older, 1250 (62.6%) patients had body weight 60 kg or below, and 156 (7.8%) patients had serum creatinine 1.5mg/dL or higher. Of these patients, 1022 (51.2%) patients were prescribed off-label underdose apixaban. The off-label group was older and had higher mean CHA2DS2-VASC score, Charlson Comorbidity Index, and HAS-BLED scores than the on-label group. Hypertension, heart failure, prior bleeding history, chronic kidney disease, anemia, and concomitant antiplatelet agent usage were more prevalent in the off-label group, but prior stroke history was more common in on-label group. In the age ≥ 80 years group, the marginal zone serum creatinine was more prevalent in off-label group (p=0.011). In the body weight ≤ 60 kg group, the prevalence of marginal zone bodyweight and serum creatinine were higher in off-label group (p&amp;lt;0.001 and p=0.02, respectively). In creatinine ≥ 1.5 mg/dL group, the proportion of marginal zone body weight were more common in off-label underdose group (p=0.001) (Figure). Conclusions Among AF patients with a single dose reduction criterion for apixaban, almost half of the patients were prescribed off-label underdose apixaban. Physicians were more likely to prescribe off-label underdose apixaban in patients with more frail characteristics, whereas on-label apixaban was preferred in patients with prior history of stroke. The clinical outcome of off-label underdose apixaban would be compared with the on-label standard dose in a future study.

(038) Adherence Patterns And Costs For Flibanserin: A Single Practice Experience

Abstract Introduction Flibanserin is a partial serotonin agonist/antagonist and has been approved for use in premenopausal females with hypoactive sexual desire disorder (HSDD). This medication has been used off-label in males and postmenopausal females in the management of low libido. There is a paucity of data on prescribing patterns for both on and off-label use. Objective This study aims to evaluate costs and refill patterns for flibanserin and to determine if adherence was affected by insurance coverage or off-label use. Methods This was a retrospective review of online pharmacy records for patients from one sexual medicine practice that were prescribed flibanserin. De-identified patient information was collected and included age, gender, menopause status, refill information, and out-of-pocket cost. All prescriptions for premenopausal and perimenopausal females met criteria for on-label use and all prescriptions for men and postmenopausal females were considered off-label. Results Data was available from 109 patients. Forty-nine premenopausal/perimenopausal women were included in the on-label group and 60 patients were assigned to the off-label group as they were males (n=31) or postmenopausal females (n=29). Twelve percent of patients never filled their prescription, 28% filled it once, and 60% filled it ≥2 times. There was no significant difference in the percentage of patients with 0, 1 and ≥2 prescriptions filled between the on and off-label groups (12%, 24%, 63% vs. 12%, 32%, 57%). Out-of-pocket cost of flibanserin without insurance coverage was $99 for a 30-day supply or $199 for a 90-day supply. Twenty-one percent of patients had insurance coverage and their cost was $0 or $20 for a 30-day supply. The average out-of-pocket cost was $67 per 30-day supply (SD=$34). There was no significant difference in the percentage of patients with 0, 1 and ≥2 prescriptions filled between patients with and without insurance coverage (0%, 24%, 76% vs. 3%, 34%, 64%). The percentage of patients with insurance coverage did not significantly differ between those with on and off-label prescriptions (25% vs. 19%). Conclusions This study is the first to explore medication adherence and cost of flibanserin. Sixty percent of patients filled ≥2 prescriptions and refill rates were not affected by off-label use or insurance coverage. Only 21% of patients had insurance coverage for the medication. The limitations of the study include a small sample size from one clinic. The results of this study will help clinicians to recognize costs and adherence with on and off-label use of flibanserin. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Sprout Pharmaceuticals, Absorption Pharmaceuticals.

Two Years Follow-Up Outcome of Synergy™ Coronary Stent: Comparison between Case Control Study-Oriented Definition/Criterion and Real-World Results

Objectives: To clarify the 2 years outcome of Bioabsorbable Polymer Everolimus-Eluting Stent (BP-EES) using several criteria/definitions. Previous reports have showed worse outcomes in Real-World (RW) setting than case-Controlled Clinical trials (CC). Methods and Materials: We studied consecutive patients who received BP-EES implantation from October 2017 through January 2018. We adopted the parameters used in previous BP-EES associated CC (SYNERGY, EVOLVE), compared the CC inclusion criteria (on-label) with others (offlabel) at 2 years follow-up. Results: There were 678 BP-EESs inserted in 437 patients (283 male, mean age 72.3±11.2 years). Data from 4 patients lacked, and therefore the follow-up rate was 99.1%. There were 381 patients (87.2%) satisfying the CC criteria. Male gender, ejection fraction &lt;40%, smoker, multiple stenting, total stent length, target vessel failure and all death was higher in the off-label group (P&lt;0.05). Regarding revascularization- related parameters (all target lesion/non-target lesion revascularization), there was no difference between the 2 groups (TLR 6.1% vs 3.6%, non-TL TVR 5.6% vs 10.9%; CC vs off-label, p=ns, respectively). On the other hand, comparison of TLR using the CC definition (ischemia-oriented TLR) and real-world definition (any TLR) showed approximately 2-3 times higher frequency in the real-world basis (1.6% vs 5.8% per patient basis and 2.1%vs 5.8% per stent basis). Conclusions: Different definitions for repeat angioplasty among the reports may be a key cause of the discrepancy in revascularization frequency in dug-eluting stent studies, and it is the different inclusion criteria among studies that are associated with patient vulnerability.

Comparative study of on-label versus off-label treatment of intracranial aneurysms with the Pipeline embolization device.

The Pipeline embolization device (PED) is widely used for the treatment of intracranial aneurysms, including in off-label applications. In this work, the authors compared the real-world efficacy and safety of PED use in on-label and off-label aneurysm treatments. Clinical and angiographic data of patients who underwent PED placement at a high-volume academic medical center were retrospectively obtained. Treatments were classified as on-label if they fell within the applications approved by the United States Food and Drug Administration as of 2021. Recorded outcomes included aneurysm occlusion, procedural complications, ischemic events, in-stent stenosis, intracranial hemorrhage, postprocedural functional status, and death. In total, 416 aneurysms in 330 patients were treated with PED, comprising 256 aneurysms that received on-label treatments and 160 that received off-label treatments. The overall rate of complete aneurysm occlusion was 76.4% for on-label aneurysms and 75.6% for off-label aneurysms (p = 0.898). The risk of ischemic stroke in patients who underwent off-label treatments was 15.2%, which was higher than the 4.2% rate in patients who underwent on-label treatment (p = 0.003). All other clinical complications, procedural complications, and long-term functional status were comparable between the on-label and off-label groups. In real-world practice, off-label use of PED is common and can achieve similar efficacy as on-label use. However, in aggregate, off-label use was found to carry an increased rate of ischemic complications. With judicious attention to safety and individual patient characteristics, these results highlight the scale and general feasibility of off-label PED use by experts.

Four-factor prothrombin complex concentrate use for on-label versus off-label indications: a retrospective cohort study.

This study aimed to characterize the utilization of four-factor prothrombin complex concentrate (4F-PCC) at a tertiary academic medical center and evaluate the incidence of thromboembolic events (TEs) and mortality when used in an on-label versus off-label context. All medical records for consecutive patients having received 4F-PCC over 61-months were retrospectively evaluated. On-label indications for 4F-PCC were defined per FDA guidance, with the remaining indications considered off-label. Three hundred sixty-nine 4F-PCC doses were administered to 355 patients, with 46.6% of administrations classified as off-label. On-label and off-label groups demonstrated similar rates of TEs (16.2% vs. 14%). On-label patients receiving repeated administrations of 4F-PCC or with a post-administration INR ≤ 1.5 had a significantly higher incidence of TE. Off-label patients with a prior history of TE were more likely to develop a TE following 4F-PCC administration. Off-label patients also had a significantly higher 30-day mortality relative to on-label patients (29.1% versus 18.3%). In conclusion, in a large cohort of patients, observed rates of off-label 4F-PCC use were high. Underlying prothrombotic risk factors were predictive of TEs in off-label patients. Moreover, patients receiving off-label 4F-PCC demonstrated higher transfusion rates. Overall, our study findings suggest that the utilization of 4F-PCC in an off-label context may convey a significant risk to patients with uncertain clinical benefits.

Safety and Efficacy of the Off-Label Use of Pipeline Embolization Device Based on the 2018 Food and Drug Administration-Approved Indications for Intracranial Aneurysms: A Single-Center Retrospective Cohort Study.

The pipeline embolization device (PED; ev3/Covidien) has proven safe and effective for treating selected intracranial aneurysms. This device's versatility and popularity have driven increased interest in expanding the latest 2018 Food and Drug Administration-approved indications. To compare "off-label" and "on-label" PED treatment. Retrospective analysis of aneurysms treated with PED at a single center from 2013 to 2019. Comparisons were made based on the 2018 Food and Drug Administration-approved indications. A total of 492 treated aneurysms were included (65.2% on-label and 34.8% off-label). Aneurysm complete and near-complete occlusion rate was nonsignificantly lower in the off-label group (80.9% vs 85.7%; P = .19). Off-label treatment had higher rate of poor functional outcomes (modified Rankin Scale [mRS] >2: 10.3% vs 3.5%; P = .002). Although pretreatment mRS was already higher in the off-label group (5.3% vs 0.3%; P < .001) and there were no differences in mRS worsening during follow-up (5.5% vs 2.9%; P = .15). We also found a trend to a higher rate of intracranial hemorrhagic complications in the off-label group (4.7% vs 1.6%; P = .05), but there were no differences in hemorrhages requiring surgical intervention (1.8% vs 1.3%; P = .65). There were no differences in retreatment, thromboembolic complications, and mortality rates. Off-label PED treatment may be considered for select aneurysms, which are challenging to treat with other techniques. These cases have similar complete and near-complete occlusion rates compared with on-label cases. There are, however, higher risks of poor functional outcomes despite similar rates of thromboembolic and hemorrhagic complications. This is partly explained by the significantly higher pretreatment mRS score in the off-label group.

400 Safety and Efficacy of the Off-label Use of Pipeline Embolization Device Based on the 2018 FDA Approved Indications for Intracranial Aneurysms: A Single Center Retrospective Cohort Study

INTRODUCTION: The Pipeline embolization device (PED) has proven to be safe and effective for treating selected intracranial aneurysms. The versatility and the popularity of this device have driven increased interest in expanding the latest 2018 FDA-approved indications. METHODS: Retrospective analysis of aneurysms treated with PED at a single center from 2013-2019 was performed. Comparisons were made based on the compliance to the 2018 FDA-approved indications. Univariate comparisons and longitudinal analysis were performed. RESULTS: A total of 492 treated aneurysms were included, from which 65.2% were considered on-label and 34.8% off-label. Aneurysm complete and near-complete occlusion rate was non-significantly lower in the off-label group (80.9% vs 85.7%; p=0.19). Off-label treatment had higher rate of poor functional outcomes defined as modified Rankin scale &gt; 2 (10.3% vs 3.5%; p=0.002). Although baseline pre-treatment mRS was already higher in the off-label group (10.3% vs 3.5%; p&lt;0.001). There were no differences in retreatment, thromboembolic complications, intracranial hemorrhagic complications, and mortality rates. CONCLUSION: Off-label treatment with PED may be considered for select aneurysms, which are challenging to treat with other techniques (clipping, coiling, etc.). These cases have similar complete and near-complete occlusion rates compared to on-label cases. There are, however, potential higher risks of poor functional outcomes.

Use of Rituximab as an Off-Label Medication in Glomerular Diseases: Clinical Perspective

Objectives: The aim of this study was to review the use rituximab (RTX) and outcomes in immune-mediated glomerular diseases (glomerulonephritis [GN]) and to compare it to the established literature. Methods: Adult GN patients who received RTX between January 2014 and January 2018 in three public hospitals were reviewed. Membranous nephropathy (MN) and minimal change disease (MCD) were considered diseases with the literature supporting RTX use. Lupus nephritis (LN), primary focal segmental glomerulosclerosis (1^o FSGS), IgA nephropathy, IgG4-related disease (IgG4-RD), and C3GN had insufficient literature support for RTX use. Clinical remission was assessed 6 months after receiving RTX. Results: A total of 61 cases were analyzed. RTX was an add-on therapy in 87%. The remission rate was 95% in the MCD and MN versus 56% in the off-label group (p = 0.002). LN patients had a mean initial estimated glomerular filtration rate (eGFR) of 69 mL/min. All class III LN achieved remission, and 11 of 21 class IV achieved remission. The mean initial eGFR for 1^o FSGS was 33 mL/min, and it did not improve, and only 2 of 5 had partial resolution of proteinuria. Proteinuria improved in 3 of 5 IgG4-RD cases with eGFR stabilization but failed to improve in C3GN cases with eGFR deterioration. Vasculitis cases (6 ANCA-associated vasculitis and 2 IgA vasculitis) were analyzed separately. Remission was achieved in only 2 ANCA-associated vasculitis cases, and none in IgA vasculitis cases. Conclusions: Our data support the use of RTX in resistant MCD and MN. RTX showed success in LN and IgG4-RD but not FSGS or C3GN. The small number of cases of vasculitis does not allow drawing a conclusion on RTX effectiveness.

Off-label direct oral anticoagulants dosing in atrial fibrillation and venous thromboembolism is associated with higher mortality

Background Direct oral anticoagulants (DOAC) are widely used in our practice. Data on inappropriate DOAC dosing in atrial fibrillation (AF), and venous thromboembolism (VTE) treatment is lacking. Our study aimed to assess the frequency, patterns and clinical outcomes in a racially mixed population. Methods We retrospectively evaluated 1,087 DOAC prescriptions for AF or VTE treatment in six months. Prescriptions were classified as either off-label or appropriate following FDA labeling. The off-label group was subclassified as under or overdosing according to the recommended daily dose. Results Most prescriptions (67%) were for AF. African American and Caucasian patients were equally represented (45% each). There were 171 inappropriate prescriptions (16%), with the majority, 106 (62%), being underdosed. There was a significantly higher 30-day readmissions risk (OR=1.69, 95% CI:1.11-2.54, p=0.012) and 1-year all-cause mortality (OR=1.90, 95% CI:1.02-3.37, p=0.032) in the off-label group. There was no significant difference between major bleeding (OR=1.27, 95% CI:0.63-2.37, p=0.480) or new thromboembolic event (OR=1.27, 95% CI:0.73-2.13, p=0.369) based on dose appropriateness. However, underdosing was associated with higher risk of new thromboembolic events (OR=3.15, 95% CI:1.09-9.15, p=0.024). Conclusions One in every six patients received off-label DOACs dosing. Off-label dosing was associated with increased 30-day readmissions and 1-year all-cause mortality.

The genomic landscape of gene fusions across solid tumors and clinical outcome of targeted therapies: A real-world retrospective analysis.

3132 Background: Oncogenic gene fusions can be observed across numerous solid tumor types with therapies targeting fusion events emerging as important treatment modalities. The occurrence of rare fusion events and response to targeted therapy inclusive of off-label drug use has not been fully elucidated. We describe a real-world (RW) landscape of gene fusions in solid tumors and treatment outcomes of targeted therapies. Methods: Patients with solid tumors harboring a gene fusion or rearrangement were retrospectively identified through review of a clinical molecular database housing sequencing data on 6,800 patients from a single-center between 1/1/2015 – 12/31/2019. Patients who received targeted therapy for gene fusions were divided into three arms: off-label, on-label, and clinical trial use. Clinical characteristics were summarized using descriptive statistics. Overall survival (OS) and Progression free survival (PFS) between the three arms were compared using the Kaplan-Meier estimates. Results: A total of 336 (4.9%) patients had a fusion positive solid tumor with 197 (2.9%) having a fusion event predicted to be oncogenic and could be targeted with a drug. Thirty different cancer types had targetable fusions with the three most common types being lung adenocarcinoma (41%), glioblastoma (10.2%), and melanoma (7.1%). The most common observed targetable fusions included ALK (21.3%), RET (11.7%), ROS1 (9.1%), and FGFR2 (8.1%). A total of 71 patients received targeted therapy; 37 (52%) received therapies on-label, 20 (28%) off-label, and 14 (20%) on-trial (Table). The median PFS was 4 months for off-label, 16 months for on-label, and 9 months for on trial-therapy (p=0.02). The median OS was 8 months for off-label, 51 months for on-label, and 11 months for on-trial therapy (p=0.001). Seven out of twenty patients (35%) in the off-label group had PFS for at least 6 months. Three patients had a response for more than one year. However, higher toxicity related discontinuation rate was observed (30%, 8%, 7% for off-label, on-label, and on-trial, p=0.03). Conclusions: Off-label targeted therapy had shorter PFS and OS when compared to on-label therapy. However, 35% patients in the off-label group had at least 6 months PFS. Off-label therapy remained a valuable option for patients who were not candidate for clinical trials or with rare fusions. Further studies are needed to determine which patients are most likely to benefit from targeting gene fusion events.[Table: see text]

High incidence of major bleeding with off-label use of edoxaban.

In clinical practice, edoxaban is sometimes prescribed for off-label use based on the hypothesis that it is as safe and effective as warfarin. However, there is limited safety information on off-label use due to lack of clinical trial. We aimed to analyze the tolerability of off-label use of edoxaban and to identify patient characteristics associated with major bleeding as adverse effects. Patients under edoxaban treatment between January 2017 and December 2017 were enrolled in this retrospective cohort study. The incidence of major bleeding with off-label use compared with on-label use was analyzed using by log-rank test. Univariate and multivariate regression analysis were undertaken to detect independent variables with significant odds ratio that associated with major bleeding. After the exclusion criteria were applied, the patients were divided into two groups: off-label group (n = 30) and on-label group (n = 161). Incidence of major bleeding was found to be higher in the off-label group (13.3%) than in the on-label group (3.7%) (p<0.05). Multivariate adjustment showed that the off-label use or portal vein thrombosis and patients with history of major bleeding has significantly higher incidence of major bleeding. We demonstrated that off-label use of edoxaban may be a significant risk factor for major bleeding.

Safety of enzymatic debridement in extensive burns larger than 15% total body surface area

ObjectivesBromelain-based enzymatic debridement has emerged as an alternative to surgical eschar removal. Indications include partial thickness, mixed pattern, and full-thickness burns. Enzymatic debridement has been approved by the European Medicines Agency for treating burn wounds affecting <15% total body surface area (TBSA). Data and evidence for the treatment of areas >15% TBSA in one session is scarce. The aim of this retrospective study was to retrospectively analyze off-label use of enzymatic debridement in a single burn center for large TBSA burns. MethodsBetween 01/2017 and 12/2018, 59 patients with partial- to full-thickness burns underwent enzymatic debridement in a single center study. Patients were categorized into two groups: the regular use group with a treated area less than 15% TBSA and the off-label group (OG) with larger TBSA debrided in one session. Treatment was evaluated for systemic inflammatory reaction, bleeding, hemodynamic instability and electrolyte shifts. ResultsIn total, 49 patients were treated in the regular use group with a median application area of 6% (IQR 2.5–9.5) and 10 patients were treated in the off-label group with a median application area of 18% (IQR 15–19) TBSA. We found no significant differences regarding blood pressure, body temperature or hemodynamic stability during and after enzymatic debridement. No treatment-related serious adverse events were observed in either group. Catecholamine use was similar in both groups. No differences in leukocyte counts, CRP, PCT and lactate prior to application and during the following three days were observed. Sodium, potassium, chloride and phosphate levels did not differ. We found no evidence of an electrolyte shift. Survival was 49 of 49 patients (100%) in the RG and 7 of 10 patients (70%) in the OG (p = 0.004). ConclusionEnzymatic debridement did not result in any expected or unexpected side effects in the patient groups investigated. These preliminary results indicate the potential safety of bromelain-based enzymatic debridementin the treatment of burns greater than 15% TBSA.

Rehabilitation of severe-to-profound sensorineural hearing loss with an active middle ear implant

Background: Severe-to-profound sensorineural hearing loss (spSNHL) is mostly relying on the use of a cochlear implant (CI).Aims: The present study reports on the auditory outcome from a group of subjects affected by spSNHL who received an AMEI application.Materials and methods: Nine out of 43 subjects who received a fully-implantable AMEI were initially candidated as off-label (primary off-label group or POLG). Twelve subjects showed over time a decrease in bone conduction threshold (BCT) in the operated ear (Secondary Off-Label Group or SOLG): SOLGa with no detectable BCT (9 subjects), SOLGb with residual low-frequency BCT (3 subjects). The auditory assessment included pure tone audiometry and speech audiometry in quiet and noise.Results: A significant PTA5 difference was found at activation in SOLGb group and at the last fitting in SOLGa Group in respect to the label control group. No significant difference was found between POLG group and control group. Speech audiometry in noise revealed a significant lower gain in all three groups in comparison to the control group.Conclusions: The adoption of an AMEI in unconventional indications could be beneficial also for subjects with spSNHL, although this solution can in some cases only be transient before performing CI surgery.

Off-Label Utilization Trend for Recombinant Factor VIIa in Children's Hospitals in the United States

Background: Recombinant FVIIa (rFVIIa) was approved by the Food and Drug Administration (FDA) as a hemostatic agent in 1999 for the treatment of patients with hemophilia and inhibitory antibodies against either factor VIII or IX and subsequently approved for use in patients with congenital factor VII deficiency and Glanzmann Thrombasthenia refractory to platelet transfusions in 2005 and 2014 respectively. These are rare disorders and the use of rFVIIa in these conditions has been found to be effective and safe. Despite this very narrow indication for usage, rFVIIa is being used for a diverse range of off-label indications. Along with uncertainty regarding clinical efficacy, available data suggests that the risk of thromboembolic events is increased when rFVIIa is used in off-label settings. Studies on the off-label use of rFVIIa in children are limited to a few large case series. In a retrospective multicenter cohort study utilizing the Pediatric Health Information System (PHIS) administrative database, Witmer et al demonstrated a 10-fold increase in the annual rate of off-label admissions from 2000 to 2007. The mortality rate in the off-label group was 34% and thrombotic events occurred in 11% of the off-label admissions. We conducted a follow up study to characterize the evolution of the off-label use of rFVIIa in children. Objective: To describe current trends of off-label utilization and adverse effects of rFVIIa in children. Study design: A retrospective multicenter cohort study utilizing the PHIS administrative database was conducted. The PHIS dataset includes 51 children's hospitals in the United States and is representative of tertiary care centers in the nation. In patients, 18 years of age or younger who received rFVIIa between 2012-2018 were included. A label admission was defined as an admission with an International Classification of Diseases (ICD-9 and ICD-10) diagnostic code for hemophilia, Factor VII deficiency or Glanzmann thrombaesthenia; admissions without these codes were classified as off-label. Data were analyzed descriptively. Results: There were 7,738 number of admissions, representing 6,493 unique individual subjects. A total of 78.3 % of the admissions were off-label. The rate of off-label use was stable at approximately 80% of the admissions from 2012-18. The most frequent admitting services for the off-label admissions included cardiology (29.8%), cardiovascular/thoracic surgery (15.7%), critical care (15.0%), neonatal-perinatal medicine (8.7%), and hematology/oncology (6.1%). Over half (54.6%) of off-label administration occurred in children younger than 1 year old. Among the off-label admissions 57 % were male and the median days of use of rFVIIa was 1 day. The mortality rate in the off-label group was 22.3 %. Thrombotic events occurred in 11.4% of the off-label admissions. Among the off-label admissions with thrombotic events, the most common admitting services were cardiology (35.0%) and critical care (21.2%). Conclusion: We have demonstrated that on a per admission basis the predominant use of rFVIIa is off-label. Thrombotic events are common. Although the mortality rate in the pediatric patients who received off-label rFVIIa is high; its lower when compared with the previous review. This may likely reflect, in part, the severity of illness in this patient group. In the absence of clearly supportive data demonstrating safety and efficacy, restraint should be exercised with careful consideration of risk versus benefit for use of rFVIIa in off-label settings. Disclosures Gupta: Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. O'Brien:Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Recombinant FVIIa (rFVIIa) was approved by the Food and Drug Administration (FDA) as a hemostatic agent in 1999 for the treatment of patients with hemophilia and inhibitory antibodies against either factor VIII or IX and subsequently approved for use in patients with congenital factor VII deficiency and Glanzmann Thrombasthenia refractory to platelet transfusions in 2005 and 2014 respectively. These are rare disorders and the use of rFVIIa in these conditions has been found to be effective and safe. Despite this very narrow indication for usage, rFVIIa is being used for a diverse range of off-label indications.