Colleen M. Culley

Use of an abnormal laboratory value-drug combination alert to detect drug-induced thrombocytopenia in critically Ill patients.

PURPOSE The aim of this study was to assess the performance of a commercially available clinical decision support system (CDSS) drug-laboratory result alert in detecting drug-induced thrombocytopenia in critically ill patients. MATERIALS AND METHODS Adult patients admitted to the medical and cardiac intensive care unit during an 8-week period and identified by 1 of 3 signals in the CDSS, TheraDoc, were eligible. Alerts were generated when the patient had a low platelet count and was ordered a potentially causal drug. Patients were evaluated in real time for the occurrence of an adverse drug reaction using 3 causality instruments. Positive predictive values were calculated for the alert. RESULTS Sixty-four patients with a mean age of 54 years met the inclusion criteria, generating 350 alerts. Positive predictive values were 0.36, 0.83, and 0.40 for signals 1, 2, and 3, respectively. Overall, there were 137 adverse drug reactions identified in the 350 alerts, with heparin, vancomycin, and famotidine as the 3 most common potential causes. CONCLUSIONS A commercial CDSS drug-laboratory alert is effective at identifying drug-induced thrombocytopenia in the intensive care unit and may improve patient safety. Compared with previous studies, the combination alert performs better than alerts based exclusively on laboratory values and should be considered to reduce alert fatigue.

A clinical and pharmacoeconomic justification for intravenous acetylcysteine: a US perspective.

Paracetamol (acetaminophen) poisoning remains the most common exposure reported to US poison information centres and the leading cause of poisoning-related fatalities, despite the availability of an effective antidote, acetylcysteine. Oral acetylcysteine solution has been approved for the management of acetaminophen poisoning in the US for four decades. Until the recent approval of intravenous acetylcysteine in the US, it was necessary to compound the oral solution for intravenous administration. The effectiveness and tolerability of oral and intravenous acetylcysteine for the prevention of hepatotoxicity induced by paracetamol poisoning are well established in the literature. Intravenous acetylcysteine may be preferred over oral administration based on improved tolerability, ease of administration and the shortened course of therapy (20 hours intravenous vs 72 hours oral). The two intravenous acetylcysteine regimens documented in the literature, 48 hours and 20 hours, have similar efficacy when started within 8–10 hours of ingestion. Although there are no legal concerns with continuing the routine compounding of the oral solution to an intravenous product, new standards for pharmacy compounding of sterile preparations set forth by the US Pharmacopoeia highlight that the risk of compounding products for intravenous use must be assessed carefully. Changing the route of administration of a sterile oral solution to an intravenous preparation, when a commercial sterile and pyrogen-free product is available, may not be advisable. The best cost-containment strategies must be used for introduction of the more costly sterile, pyrogen-free intravenous acetylcysteine formulation by hospitals and healthcare systems. The intravenous acetylcysteine product is more cost effective when given for 20 hours than other treatment protocols based on the costs of acetylcysteine and hospitalisation. If used per protocol, the 20-hour intravenous acetylcysteine regimen may decrease hospital length of stay, thereby, offsetting the increased drug cost. Data conflict on the efficacy and administration of intravenous acetylcysteine for off-label uses, such as radiographic contrast media-induced nephropathy prevention and reperfusion in orthotopic liver transplantation. The costs for the intravenous formulation for these indications is significantly higher than use of the oral formulation for oral administration in radiographic contrast media-induced nephropathy prevention and compounded for intravenous use in orthotopic liver transplantation. The oral solution should be retained by healthcare systems for oral and inhalation applications, such as respiratory conditions, oral administration for radiographic contrast media nephropathy prevention, or the use of the 72-hour oral protocol to treat paracetamol poisoning, when the intravenous preparation cannot be used.

Telaprevir: An oral protease inhibitor for hepatitis C virus infection

PURPOSE The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, drug interactions, viral drug resistance, dosage and administration, and place in therapy of telaprevir are reviewed. SUMMARY Telaprevir is an oral NS3/4A protease inhibitor that was recently approved by the Food and Drug Administration for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in adult patients with compensated liver disease, including cirrhosis. In Phase II clinical trials, triple therapy (telaprevir with peginterferon alfa and ribavirin) demonstrated 20-39% higher rates of sustained virological response (SVR) versus standard therapy (peginterferon alfa and ribavirin) in patients with chronic HCV genotype 1. Higher SVR rates were observed in treatment-naive patients or patients who did not respond to prior therapy (did not achieve SVR). Phase III studies also found improved SVR rates in patients treated with triple therapy. Telaprevir is recommended in combination with peginterferon alfa-2a and ribavirin for treatment-naive patients and patients who did not previously respond to peginterferon alfa-2a and ribavirin therapy. Telaprevir is a substrate and inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4 and P-glycoprotein. Drugs that induce or inhibit CYP3A4 may affect concentrations of telaprevir, resulting in reduced efficacy or increased concentrations of telaprevir (and an increased risk for adverse reactions). The most common adverse events reported with telaprevir monotherapy versus placebo were diarrhea, nausea, fatigue, and dry skin. CONCLUSION Telaprevir, an HCV NS3/4A protease inhibitor, has been shown to be effective in increasing SVR rates when used with peginterferon alfa and ribavirin in patients with chronic HCV genotype 1 infection, regardless of treatment history.

Challenge and rechallenge: drotrecogin alfa (activated)-induced prolongation of activated partial thromboplastin time in a patient with severe sepsis.

An 81‐year‐old woman with ischemic bowel underwent laparotomy with small‐bowel resection and developed septic shock. She required broad‐spectrum antibiotics, norepinephrine, and mechanical ventilation. The patient received drotrecogin alfa (activated) 24 μg/kg/hour for a total of 67.5 hours. Coagulation parameters were monitored during her therapy. Significant increases in activated partial thromboplastin time (aPTT) during infusion led to two temporary discontinuations of the drug. Coagulation parameters decreased when the drug was held and increased with each rechallenge. The patient survived the episode and was discharged on postoperative day 27. Medical records of 26 other patients who received drotrecogin alfa (activated) at our institution from November 2001–August 2003 were reviewed retrospectively for coagulation parameters and bleeding rate. Of the 26 patients, nine (35%) were treatment compliant (> 90% of the 96‐hr course). Coagulopathy and bleeding resulted in early discontinuation in four (15%) and six (23%) patients, respectively. An increase in aPTT from baseline to during infusion of drotrecogin alfa (activated) was noted in 14 patients with complete data (p=0.56). A decrease in median platelet count from baseline to during infusion was noted in the six patients who bled during therapy (p=0.01). Two of these patients had platelet counts less than 30 times 103/mm3 during administration. Drotrecogin alfa (activated) should be considered an anticoagulant. In postmarketing reports, clinically significant bleeding occurred more frequently than was noted in a large, randomized, multicenter trial. Patients receiving drotrecogin alfa (activated) should be closely monitored for prolongation of coagulation parameters. Temporary discontinuation of the drug should be considered when international normalized ratio is greater than 3.0, platelet count is less than 15 times 103/mm3, and aPTT is greater than 100 seconds.

Collaboratively designed practice guidelines promote appropriate use of intravenous proton pump inhibitors

Objective To determine the effectiveness of practice guidelines for proton pump inhibitor use at an academic medical center. Methods Patients initiated on intravenous (IV) pantoprazole therapy between July 2001 and May 2002 were evaluated prospectively for appropriateness of therapy. Pharmacists assessed clinical use, dosing strategy, administration route, and prescribing patterns. Results A total of 85 patients were evaluated. Only 25% of the patients were prescribed IV pantoprazole according to established institutional guidelines. The majority of therapy meeting guideline criteria were initiated on pantoprazole by the Gastroenterology service. Due to overuse of pantoprazole, prescribing guidelines were revised to specify indications with proven efficacy (erosive GERD, Zollinger-Ellison or other hypersecretory conditions, and upper gastrointestinal bleeding). Patients who received pantoprazole for stress ulcer prophylaxis, an unapproved indication, had therapy automatically switched to a histamine receptor antagonist. For patients who tolerated oral medications or enteral feedings, therapy was automatically converted to the oral dosage form. Conclusions Evaluation of institutional pantoprazole utilization revealed usage extending beyond indications with proven efficacy. Pharmacists and physicians collaboratively developed evidence-based practice guidelines; adherence to appropriate indications showed a 50% improvement.

Off-Label Use of Agents for Management of Serious or Life-threatening Angiotensin Converting Enzyme Inhibitor–Induced Angioedema

Objective: To evaluate the place in therapy of fresh frozen plasma (FFP), C1 esterase concentrate (C1-INH), ecallantide, and icatibant in the management of angiotensin-converting enzyme inhibitor–induced angioedema (ACEI-IA). Data Sources: A literature search was performed using PubMed (1946 through August 2015) and Embase (<1966 through August 2015). References from identified articles were reviewed. Study Selection and Data Extraction: Consensus papers, practice guidelines, case reports/series, clinical trials, and meeting abstracts published in English and involving humans were included. Data Synthesis: No medications are currently Food and Drug Administration–approved for managing ACEI-IA. Emerging evidence suggests that FFP and medications approved for management of acute attacks of hereditary angioedema, another bradykinin-mediated event, may be effective for use in ACEI-IA. Positive efficacy results were reported with FFP and C1-INH while mixed results have been seen with ecallantide. Off-label icatibant has the most evidence supporting its use in ACEI-IA with rapid symptom resolution (10 minutes to 6 hours) and avoidance of intubation and tracheotomy in several cases. These agents were well-tolerated in ACEI-IA. Conclusion: ACEI-IA is typically a self-limiting event. First-line therapies include ACEI discontinuation, observation, and supportive medications (eg, corticosteroids, antihistamines, and epinephrine). Symptom progression can be life-threatening and may require interventions such as tracheotomy and intubation. Off-label use of FFP and medications approved for hereditary angioedema have resulted in rapid resolution of symptoms and avoidance of intubation. Among these agents, icatibant has the most supporting evidence and has been incorporated into practice guidelines and algorithms as a second-line agent for serious life-threatening ACE-IA.

Coagulation factor VIIa (recombinant) in nonhemophilic patients requiring neurosurgery

PURPOSE The clinical outcomes, safety, and use of resources associated with the administration of factor VIIa (recombinant) to nonhemophilic patients requiring neurosurgery were evaluated. METHODS An interdisciplinary group created guidelines for the pharmacy and therapeutics committee for the unlabeled use of factor VIIa (recombinant). Nonhemophilic patients were eligible to receive the agent without approval from the hematology-coagulation service if they had an intracranial hemorrhage (ICH), were undergoing an emergency neurosurgical procedure, and had coagulopathy. A standard single dose of 40 microg/kg was recommended for these patients. Data were prospectively collected between March 2004 and March 2006 for all neurological surgery patients receiving factor VIIa (recombinant). RESULTS A total of 92 nonhemophilic patients received single doses of factor VIIa (recombinant) under the guidelines during the two-year study period. The majority of patients had a baseline International Normalized Ratio (INR) of >2, underwent emergency neurosurgical procedures, and had an intracranial hemorrhage. All guideline criteria for indication and approval were followed for 48 patients. Eighty-seven patients received concomitant treatment for reversal of anticoagulation. A significant correction in the baseline INR after administration of factor VIIa (recombinant) was noted (p < 0.0001). Five patients experienced adverse events. Implementation of the guidelines decreased the annual cost of factor VIIa (recombinant) by 46%. CONCLUSION A protocol calling for administration of factor VIIa (recombinant) 40 microg/kg in nonhemophilic patients with coagulopathy and ICH led to a rapid and significant decrease in the INR, allowing for emergency surgical intervention. Few adverse events were detected in these patients, and none were deemed to be directly related to factor VIIa (recombinant).

Formulary decisions for pre-1938 medications.

PURPOSE A process is described for formulary revisions consistent with the Food and Drug Administration (FDA)s current initiative to ensure that all drugs marketed in the United States have been approved for safety and efficacy. SUMMARY A list of pre-1938 drugs (i.e., formulations marketed before the Federal Food, Drug, and Cosmetic Act established safety requirements) was compiled from USP DI Volume III and International Journal of Pharmaceutical Compounding lists. Products on the resulting list were reviewed for current marketing and FDA approval status and for availability. The project team recommended formulary addition or retention if a product had been used and been purchased more than once at the hospital in the past year, if no formulary alternative was available, or if the product had been approved by FDA. Nonformulary status was recommended if none of these criteria applied or the product was no longer available. Of 88 pre-1938 formulations of 59 drugs, only 3 had been approved by FDA before 1962 (when evidence of efficacy was first required) and 14 thereafter. Of the 88 formulations, 47 were on the hospitals formulary. The team recommended that 37 formulations be retained on or added to the formulary and that 51 be maintained or designated as nonformulary. The hospitals pharmacy and therapeutics (P&T) committee accepted the recommendations, provided that the 30 nonapproved formulations recommended for formulary status be reviewed as FDA continues its effort to have manufacturers either apply for approval of their products or remove them from the market. The recommendations were also accepted by the health systems P&T committee. CONCLUSION A systematic approach to reviewing pre-1938 medications for the purpose of formulary revision was successful in addressing safety concerns about these older drug formulations.

Using a Clinical Surveillance System to Detect Drug-Associated Hypoglycemia in Nursing Home Residents.

To determine whether a clinical surveillance system could be used to detect drug‐associated hypoglycemia events and determine their incidence in nursing home (NH) residents.