Use of four-factor prothrombin complex concentrate (4F-PCC) for management of bleeding not associated with therapeutic anticoagulant use.

INTRODUCTION: Four-factor prothrombin complex concentrate (4F-PCC) may be an option for patients with bleeding unrelated to therapeutic anticoagulation to help with bleeding cessation and reduce blood component requirements. MATERIALS AND METHODS: Retrospective, observational study of adult patients who received 4F-PCC for bleeding not associated with therapeutic anticoagulation between June 2019 and July 2021. Primary outcome was to describe off-label 4F-PCC use in patients not on therapeutic anticoagulation for bleeding management in surgical and non-surgical patients. Additional outcomes evaluated were blood product use, chest tube and drainage output, and coagulation studies before and after 4F-PCC administration as well as other hemostatic agent use and thromboembolic events. RESULTS: Seventy-six patients were included; median age 64 years (IQR 50-69), 66% of bleeding events were associated with surgery, and the majority of 4F-PCC doses ordered by cardiac surgery (68.4%). A total of 110 4F-PCC doses were administered; median 1 dose/patient (IQR 1-2), median total dose 1000 units (IQR 500-1484). Other hemostatic agents commonly administered were protamine (59%), desmopressin (43%), and tranexamic acid (42%). Packed red blood cells, fresh frozen plasma, platelet, and cell saver blood administration and prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time (aPTT) were significantly reduced following 4F-PCC administration. Eight patients (11%) experienced thromboembolic complications. CONCLUSION: Relatively low doses of 4F-PCC (median total dose 1000 units) were associated with decreased blood component requirements and improved PT, INR, and aPTT values in patients with bleeding unrelated to therapeutic anticoagulation. Other hemostatic agent use was common and thromboembolic complications occurred.

Assessment of rabies immune globulin dose rounding at a university health system.

PURPOSE: Describe a dose rounding strategy for rabies immune globulin (RIG) administration. METHODS: Multicenter, retrospective, observational review of patients that received RIG following an exposure from an animal with potential to transmit rabies infection in one health-system from March 2011 through December 2021. The primary outcome was to describe the RIG dose rounding strategy and population of patients that received RIG rounded to the nearest vial size compared to those that did not. Secondary outcomes evaluated additional costs and RIG international units (IU) wasted that could have occurred (rounded group) or did occur (not rounded group), re-presentation to the ED or primary care provider (PCP) within 7 days due to RIG related complaint, and occurrence of rabies infection. Data collection included patient demographics, exposure information, and RIG dose administered. Descriptive data and univariate analyses are reported. Cost and RIG IU wasted were calculated for the dosing strategies. RESULTS: 426 patients were included; 373 (88%) had RIG rounded to the nearest vial size and 53 (12%) did not (mean age 36.1 years ±20.5, 51.6% male, most common exposures were bats [50%], type was bite [58%], and category III exposures [92%]). Those that had RIG rounded were younger and had lower total RIG doses, but similar IU/kg doses to those not rounded. A cost savings of $144,815 and prevention of 40,572 RIG IU wasted was calculated from those patients that had RIG rounded. There was no difference in the rate of re-presentation within 7 days and no cases of human rabies infection in the region during the study period. CONCLUSIONS: RIG dose rounding to the nearest vial size is associated with cost savings and prevention of wasting RIG IU. There was no association with re-presentation to the ED or PCP with RIG related issues within 7 days from administration.

Evaluation of fixed-dose versus variable-dose prothrombin complex concentrate for warfarin reversal.

INTRODUCTION: The purpose was to compare hemostatic efficacy rates for fixed- and variable-dose four-factor prothrombin complex concentrate (4F-PCC) for warfarin reversal. MATERIAL AND METHODS: Retrospective study of patients with non-intracranial major bleeding or undergoing emergent surgery/procedure who received 4F-PCC for warfarin reversal from September 2013 through August 2020. Hemostatic efficacy at 48 h following fixed- or variable-dose 4F-PCC was evaluated using modified International Society on Thrombosis and Hemostasis (ISTH) criteria for major bleeding. Secondary outcomes included occurrence of post-4F-PCC INR ≤ 1.5, in-hospital mortality, time to 4F-PCC administration, and 4F-PCC cost. Univariate analyses were completed and logistic regression used to identify patient-specific factors associated with hemostatic efficacy. RESULTS: A total of 265 patients, 90 (34%) fixed- and 175 (66%) variable-dose 4F-PCC, were included. Hemostatic efficacy was achieved in 34 (37.8%) and 38 (21.7%) in fixed- and variable-dose groups, respectively, p = 0.005. Achievement of INR ≤ 1.5 occurred in 55 (62.5%) in the fixed- and 120 (69.4%) in the variable-dose groups, p = 0.26, and there was no in-hospital mortality difference. Time to administration was a mean 20 min faster and cost was reduced by a mean $1881/dose in the fixed-dose group. The unadjusted odds of achieving hemostatic efficacy was 2.27 among those receiving fixed-dose compared to variable-dose 4F-PCC (95% CI 1.30, 3.98); this was not confounded by initial INR or patient weight. CONCLUSION: Fixed-dose 4F-PCC is associated with a higher likelihood of achieving hemostatic efficacy, quicker time to administration, and reduced cost compared to variable-dose 4F-PCC for warfarin reversal.

Filling the Gaps on the Institute for Safe Medication Practices (ISMP) Do Not Crush List for Immediate-release Products.

The Institute for Safe Medication Practices (ISMP) Do Not Crush List is a common resource for healthcare providers to determine whether an oral solid drug product can be manipulated. However, evidence is weak or missing for a number of immediate-release products. The purpose of this study was to perform an in-depth analysis of these products on the ISMP Do Not Crush List with the goal of removing unnecessary restrictions and providing conditional recommendations if needed. The ISMP Do Not Crush List was reviewed, and the products in question were identified if they were listed with "no reason" provided or "film-coated" as the only reason. A checklist of evaluation criteria was then developed and used for analysis, including special dosage form design, hazardous drug status, and stability and pharmacokinetics concerns. Appropriate references and search strategies were streamlined to perform the evaluation, and manufacturers were also contacted with a standard drug-information inquiry. A total of 20 "film-coated" tablets and 17 "no reason" drug products were identified and evaluated using the above process. The analysis revealed that 9 products are special formulations or high-risk products which indeed should not be crushed. Most of the remaining 28 products presented no risk or a low risk for crushing. Some products may require safety precautions during handling or timely administration of crushed powder to patients with increased monitoring for efficacy and safety. Two summary tables along with the conditional recommendations are provided for pharmacists and other healthcare providers to aid in clinical decision making. A checklist of evaluation criteria was developed and used to perform an in-depth analysis of 37 immediate-release products on the ISMP Do Not Crush List. A significant number of these products were found to be suitable for crushing based on conditional recommendations. Furthermore, the checklist and evaluation strategy present a framework for healthcare providers to assess crushability of any future immediate release oral solid drug products when there are no suitable alternatives.

To crush or not to crush: A brief review of novel tablets and capsules prepared from nanocrystal and amorphous solid dispersion technologies.

PURPOSE: To educate healthcare professionals regarding the risks of manipulating drug products formulated via nanocrystal or amorphous solid dispersion technologies. SUMMARY: Recent pharmaceutics innovations such as nanocrystals and amorphous solid dispersions have been used successfully to improve oral bioavailability of drugs. Over 30 drug products based on these technologies have been approved by the Food and Drug Administration, and more are in the development pipeline. While these products are similar in appearance to traditional tablets or capsules, they should not be crushed or suspended in liquid vehicles. Such manipulations can compromise the integrity of the formulation and subsequently alter the oral bioavailability. It is alarming that the majority of these products are not included in the Institute for Safe Medication Practices (ISMP) "Do Not Crush" list. A summary drug table is presented in this article to provide accurate information for pharmacists and other healthcare providers. CONCLUSION: Novel formulations of tablets and capsules are being used to increase the oral bioavailability of certain drugs. Crushing these products can significantly alter product performance and clinical outcomes. We encourage ISMP to add these drug products to the Do Not Crush list due to wide use of this list throughout healthcare. In the meantime, pharmacists should be mindful of the new formulation technologies and advocate for the proper use of these drug products.