Sarah A. Nisly

Canagliflozin, a new sodium–glucose cotransporter 2 inhibitor, in the treatment of diabetes

PURPOSE The published evidence on the pharmacology, pharmacodynamics, pharmacokinetics, safety, and efficacy of a promising investigational agent for managing type 2 diabetes is evaluated. SUMMARY Canagliflozin belongs to a class of agents-the sodium-glucose co-transporter 2 (SGLT2) inhibitors-whose novel mechanism of action offers potential advantages over other antihyperglycemic agents, including a relatively low hypoglycemia risk and weight loss-promoting effects. Canagliflozin has dose-dependent pharmacokinetics, and research in laboratory animals demonstrated high oral bioavailability (85%) and rapid effects in lowering glycosylated hemoglobin (HbA(1c)) values. In four early-stage clinical trials involving a total of over 500 patients, the use of canagliflozin for varying periods was associated with significant mean reductions in HbA(1c) (absolute reductions of 0.45-0.92%) and fasting plasma glucose (decreases ranged from 16.2% to 42.4%) and weight loss ranging from 0.7 to 3.5 kg. More than a dozen Phase II or III clinical trials of canagliflozin in adults are ongoing or were recently completed, but the final results of most of those studies have not been published. Adverse effects reported in clinical trials of canagliflozin include urinary tract and genital infections, occurring in about 10% of patients. Additional and larger Phase III clinical trials to delineate the potential role of canagliflozin and other SGLT2 inhibitors in the management of diabetes (including studies involving the elderly, children, and patients with renal or hepatic dysfunction) are planned or currently underway. CONCLUSION Canagliflozin and other investigational SGLT2 inhibitors have a novel mechanism of action that may offer a future alternative treatment pathway for managing type 2 diabetes.

GLP-1 Agonists in Type 1 Diabetes Mellitus.

Objective: To review the use of GLP-1 agonists in patients with type 1 diabetes mellitus (T1DM). Data Sources: A search using the MEDLINE database, EMBASE, and Cochrane Database was performed through March 2016 using the search terms glucagon-like peptide 1 (GLP-1) agonists, incretin, liraglutide, exenatide, albiglutide, dulaglutide, type 1 diabetes mellitus. Study Selection and Data Extraction: All English-language trials that examined glycemic end points using GLP-1 agonists in humans with T1DM were included. Data Synthesis: A total of 9 clinical trials examining the use of GLP-1 agonists in T1DM were identified. On average, hemoglobin A1C (A1C) was lower than baseline, with a maximal lowering of 0.6%. This effect was not significant when tested against a control group, with a relative decrease in A1C of 0.1% to 0.2%. In all trials examined, reported hypoglycemia was low, demonstrating no difference when compared with insulin monotherapy. Weight loss was seen in all trials, with a maximum weight loss of 6.4 kg over 24 weeks. Gastrointestinal adverse effects are potentially limiting, with a significant number of patients in trials reporting nausea. Conclusion: The use of GLP-1 agonists should be considered in T1DM patients who are overweight or obese and not at glycemic goals despite aggressive insulin therapy; however, tolerability of these agents is a potential concern. Liraglutide has the strongest evidence for use and would be the agent of choice for use in overweight or obese adult patients with uncontrolled T1DM.

Tobramycin-Induced Hepatotoxicity

Objective: To report a case of tobramycin-induced hepatotoxicity. Case Summary: A 20-year-old female was hospitalized for treatment of Pseudomonas aeruginosa bacteremia and osteomyelitis. Empiric intravenous antibiotic therapy with piperacillin/tazobactam, vancomycin, and ciprofloxacin was started, and based on the results of culture and sensitivity testing, was changed to intravenous ceftazidime and tobramycin 70 mg every 8 hours on hospital day 3. Liver enzyme levels then increased over days 3–6. Tests for hepatitis A, B, and C were all nonreactive, and HIV testing was negative. On day 8, therapy was changed from ceftazidime to piperacillin/tazobactam and the tobramycin dose was increased to 100 mg every 8 hours. Due to a continued increase in total bilirubin, aspartate aminotransferase, and alanine aminotransferase, piperacillin/tazobactam was discontinued and aztreonam was started on day 10. All antibiotics were stopped on day 12 and the elevated liver parameters began to decrease. Aztreonam and ciprofloxacin were restarted on day 16, and most laboratory test results returned to baseline levels by day 19; total bilirubin and alkaline phosphatase decreased to lower than baseline values. Discussion: This case illustrates a possible occurrence of tobramycin-induced hepatotoxicity. Liver enzymes rose when tobramycin therapy was initiated, markedly increased when the tobramycin dose was increased, then resolved upon discontinuation of therapy. Other medication-related causes were ruled out by temporal relationship or rechallenge (aztreonam). Use of the Naranjo probability scale indicated a possible relationship between hepatotoxicity and tobramycin therapy. Other adverse reaction scales specific for evaluation of drug-induced liver disease were also used. Both the Council for International Organizations of Medical Sciences and Maria and Victorino scales indicated a probable likelihood of tobramycin-induced hepatotoxicity. This patient was not rechallenged with tobramycin due to the highly suggestive timeline present, lack of specific symptoms, and unnecessary risk to the patient. Conclusions: Although no other case reports on this interaction have been published through October 9, 2007, historical data from tertiary sources reveal the possibility of aminoglycoside-induced hepatotoxicity; therefore, tobramycin-induced hepatotoxicity cannot be ruled out in this patient. Clinicians should be aware of this adverse event.

Strategies for the Management of Postoperative Anemia in Elective Orthopedic Surgery.

Objective: To assess the use of oral iron, intravenous (IV) iron, and erythropoiesis-stimulating agents (ESAs) for the prevention and management of perioperative anemia in elective orthopedic surgery patients, and to provide a clinical algorithm for use. Data Sources: A PubMed and MEDLINE search was conducted from 1964 through March 2016 using the following search terms alone or in combination: orthopedic, surgery, elective, anemia, blood transfusion, iron, erythropoiesis-stimulating agents, and erythropoietin. Study Selection and Data Extraction: All English-language prospective and retrospective human studies and meta-analyses evaluating oral iron, IV iron, or ESA alone or in combination in elective orthopedic surgery patients were evaluated, provided they reported blood transfusion outcomes. Data Synthesis: A total of 9 prospective and retrospective studies and 1 meta-analysis were identified and included. In the preoperative setting, administration of oral iron, IV iron, or ESA alone or in combination to correct underlying anemia led to significantly reduced transfusion rates. Transfusion requirements were generally less with combination therapy (ESA + oral or IV iron). In the short-term perioperative or postoperative period, use of oral or IV iron led to conflicting results, with some reporting a statistically significant reduction in blood transfusions, whereas others reported none. Conclusions: In elective orthopedic surgery, IV or oral iron with or without an ESA may provide benefit in prevention of postoperative anemia and results in blood transfusion reduction without significantly increasing the risk of adverse events. These agents should be considered at the lowest effective dose with emphasis on administration prior to planned surgery.

Association between application scores and positive onsite interviews of pharmacy residency applicants

Application to pharmacy residency programs has become increasingly competitive over the past several years. Although successful candidates must excel in the various stages of the application process, preparing written applications and securing onsite interviews are early and arguably the most

Implementation of an Order Set to Adhere to National Patient Safety Goals for Warfarin Therapy

Background In 2009, The Joint Commission mandated full compliance with National Patient Safety Goal (NPSG) 03.05.01 to reduce the likelihood of patient harm associated with anticoagulant therapy. Methods We conducted a retrospective chart review of inpatients receiving warfarin at Methodist Hospital pre and post implementation of a warfarin order set between January 2008 and July 2011. The primary endpoint of this study was overall adherence to laboratory monitoring. Secondary endpoints included compliance with individual laboratory parameters, percentage of patient educational sessions completed prior to discharge, and percentage of appropriate follow-up arrangements documented on discharge. Results A total of 707 patients were assessed. Overall adherence to laboratory monitoring parameters significantly improved from 71.8% to 87.5% (odds ratio [OR], 2.76; 95% CI, 1.87- 4.07; P < .001). Additional improvements were seen in patient education prior to discharge, and appropriate follow-up arrangements were documented at discharge. Conclusions This analysis demonstrates that implementation of an order set assists in adherence to policies and procedures designed to address the NPSG 03.05.01. Additionally, pharmacy involvement in monitoring, educating, and arranging for follow-up may lead to successful completion of these parameters.

Simvastatin: A Risk Factor for Angioedema?:

Objective: To report a case of simvastatin-induced angioedema in a patient with near nightly episodes of orofacial angioedema. Case Summary: A 75-year-old African American female presented to the emergency department with recurrent face, lip, and tongue swelling. The patient described frequent episodes of orofacial edema, with 4 emergency department visits over the previous 6 months. Her home medications were reviewed and simvastatin was identified as a possible contributing medication. Simvastatin was discontinued with resolution of the symptoms during hospitalization and a significant reduction in episodes. Discussion: Drug-induced angioedema has been documented with several agents, most commonly angiotensin-converting enzyme inhibitors. The association with different drug classes has led to several postulated pathways for the development of angioedema. Notable mechanisms include mediation by bradykinin, inhibition of arachidonic acid metabolism, and complement activation. Each pathway culminates in increasing vascular permeability causing fluid accumulation in subcutaneous tissues. While statin use has been associated with drug-induced angioedema in postmarketing reports, there are no published cases involving simvastatin. Use of the Naranjo probability scale demonstrated a probable relationship between simvastatin use and the patients recurrent angioedema. Conclusions: While statin use is not commonly associated with angioedema, clinicians must be aware of this possible adverse reaction. Consideration must also be given to potential drug interactions, increasing the risk of this adverse event.

Pharmacy residents as primary educators within a professional pharmacy elective

BACKGROUND AND PURPOSE The purpose of this study was to evaluate the impact of a course change from a faculty-led professional pharmacy elective to a primarily pharmacy resident-led course on student satisfaction and learning. EDUCATIONAL ACTIVITY AND SETTING In 2014, pharmacy residents were transitioned into primary teaching roles in a drug-induced diseases elective to increase student exposure to residents and different teaching styles. Student learning roles did not change. Course evaluations and grades were compared between the resident-led year and prior year. FINDINGS There was no significant difference between overall course grades during the resident-led year (94.2 ± 36.6 in 2014 vs. 94.1 ± 2.7 in 2013; p=0.975). Course evaluations were similar to the previous year and students provided favorable feedback. DISCUSSION AND SUMMARY This pharmacy resident-led elective allowed for resident integration in to an interactive professional elective. Student satisfaction with the course remained similar to the previous year and overall course grades did not differ.

Continuous Infusion Ketorolac for Postoperative Analgesia Following Unilateral Total Knee Arthroplasty

Background: Previous clinical trials have demonstrated benefit with the addition of continuous infusion (CI) ketorolac to a multimodal pain regimen in surgical patients. Data following major orthopedic surgery are minimal and conflicting. Objectives: To evaluate CI ketorolac use following unilateral total knee arthroplasty (TKA) through assessment of patient-reported pain scores, opioid consumption, and safety outcomes. Methods: This was a retrospective, open-label cohort study that included patients undergoing unilateral TKA at a single-center teaching hospital. Participants were categorized into 2 study groups based on postoperative management: CI ketorolac or opioid protocol (OP). The first group received a ketorolac 30-mg bolus followed by CI 3.6 mg/h plus as-needed (PRN) opioids. The OP group received PRN narcotics in a tiered protocol. The primary end point was comparison of median pain scores. Secondary end points included opioid consumption (morphine equivalent units [MEUs]) in the first 48 hours postoperatively, length of stay, and adverse effects. Results: Of 447 patients screened, 191 were analyzed (CI ketorolac, n = 116; OP, n = 75). Median pain scores were significantly lower in the CI ketorolac group at 48 hours postoperatively (3 [2-4] vs 3.5 [2.5-5], P = 0.033). Cumulative MEUs at 48 hours were significantly lower in the CI ketorolac group (33.9 ± 38.5 mg vs 301.6 ± 36.6 mg, P < 0.001). Patients in the CI ketorolac group experienced less respiratory depression (5.2% vs 25.3%, P < 0.001) and less naloxone administration (0% vs 8%, P = 0.002) compared with the OP group. Other adverse effects were similar among groups. Conclusions: Postoperative CI ketorolac improved pain control while reducing opioid consumption and adverse effects.

Medication utilization evaluation of dabigatran and rivaroxaban within a large, multi-center health system

OBJECTIVE The objective of this medication utilization evaluation (MUE) was to determine the appropriateness of dabigatran and rivaroxaban while also reviewing outcomes for safety and effectiveness within a large, multi-center health system. METHODS A retrospective chart review was performed using the systems electronic medical record. A data inquiry was requested and generated for dabigatran usage from July 28, 2011 through July 28, 2012 and for rivaroxaban from March 1, 2012 to July 31, 2012 at eight health system hospitals. All patients receiving at least one dose were eligible for inclusion in the MUE. RESULTS For dabigatran, 78 of 390 unique patient encounters were analyzed (20%). All 62 rivaroxaban encounters were included in the analysis. Dabigatran was used for appropriate indications in 94% of encounters and 82% for rivaroxaban. Based on indication and renal function, 87% of dabigatran patients and 92% of rivaroxaban patients received correct dosing. For patients transitioning to or from another anticoagulant, appropriate transitions occurred in 44% of dabigatran transitions and 48% of rivaroxaban transitions. At discharge, 83% of dabigatran and 86% of rivaroxaban therapy was continued. There were no reported strokes or systemic embolism with dabigatran, but one reported deep vein thrombosis occurred during hospitalization with rivaroxaban therapy. Documented bleeds in 5% of dabigatran and 3% of rivaroxaban patients. Patient education was documented for 37% of dabigatran and 26% of rivaroxaban patients receiving therapeutic anticoagulation. CONCLUSION This MUE revealed the appropriate use of dabigatran and rivaroxaban therapy with few safety outcomes within a large, multi-center health system.