A case series analysis of serious exacerbations of viral hepatitis and non-viral hepatic injuries in tocilizumab-treated patients.

BACKGROUND AND AIMS: Reports of moderate to severe liver injury associated with tocilizumab, an interleukin-6 (IL-6) receptor antagonist, have been reported in the post-marketing setting. This case series aims to characterize cases of tocilizumab-associated clinically significant hepatic injury. METHODS: We analysed cases of severe acute liver injury associated with tocilizumab reported in the FDA Adverse Event Reporting System and the medical literature. RESULTS: We identified 12 cases in which tocilizumab was a suspected primary cause of liver injury and eight cases in which serious sequelae of underlying or coincident viral hepatitis were temporally associated with its use. Using the Drug-Induced Liver Injury Network (DILIN) severity scale, five of 12 cases were Grade 5 (two liver transplants, three deaths), one was Grade 4 (liver failure) and six were Grade 3 (serious events with elevated bilirubin). Two cases reported liver atrophy with low hepatocellular expression of Ki-67, a marker of cellular proliferation. Among the eight cases of tocilizumab-associated viral hepatitis exacerbation, three were scored as DILIN severity Grade 5 (one liver transplant, two deaths), one was Grade 4 (liver failure), and four were Grade 3. The reported viral hepatitis events were hepatitis B virus (HBV) reactivation (n = 3), hepatitis C virus (HCV) flare (n = 1), cytomegalovirus (CMV)-induced liver failure (n = 1), Epstein-Barr virus hepatitis (n = 1), acute hepatitis E (HEV, n = 1) and HEV-induced macrophage activation syndrome (n = 1). CONCLUSION: Tocilizumab may be a primary cause of severe liver injury, as well as exacerbate underlying viral hepatitis. The disruption by tocilizumab of IL-6-mediated immune protection and hepatocyte regeneration may aggravate clinical outcomes in some cases.

Drug Interaction Between Febuxostat and Thiopurine Antimetabolites: A Review of the FDA Adverse Event Reporting System and Medical Literature.

BACKGROUND: There is a known drug interaction (DI) between xanthine oxidase (XO) inhibitors and the thiopurine immunosuppressants, azathioprine (AZA) and mercaptopurine (6-MP). Xanthine oxidase inhibition increases concentrations of AZA and 6-MP active metabolites, possibly resulting in myelosuppression. When allopurinol is used with AZA or 6-MP, dose reduction of AZA or 6-MP is recommended. Febuxostat is a newer XO inhibitor approved for the treatment of gout. OBJECTIVE: To determine the clinical impact of the febuxostat-thiopurine DI. DESIGN AND SETTING: Case series derived from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and published medical literature. PATIENTS: Nineteen patients who received concomitant febuxostat and either AZA or 6-MP. MEASUREMENTS: Laboratory and clinical data. RESULTS: Nineteen cases reporting myelosuppressive events were identified in patients receiving febuxostat with AZA or 6-MP. Eighteen cases were treated with the combination of AZA and febuxostat. A median of 1.6 months elapsed from initiation of the drug combination until discovery of the event. Sixteen cases required hospitalization; 15 reported administration of blood products. Thirteen cases reported resolution of the event with discontinuation of both drugs, two reported discontinuation of the thiopurine only, and one reported discontinuation of febuxostat only. LIMITATIONS: Thiopurine monotherapy may cause myelosuppression. Complications of immunosuppression that may contribute to the real-world morbidity and mortality associated with the febuxostat-thiopurine DI were not examined. Finally, FAERS data are limited by the voluntary nature of reporting. CONCLUSION: Current febuxostat labeling contraindicates concomitant administration of febuxostat with either AZA or 6-MP. This case series demonstrates that the DI can result in clinically significant adverse events and is supportive of current febuxostat labeling.

Pruritus after discontinuation of cetirizine.

BACKGROUND: Intense pruritus or itching emerging after discontinuation of cetirizine has been the subject of postmarketing reports submitted to the U.S. Food and Drug Administration (FDA), published in the medical literature, and discussed on the internet. To better understand and further investigate this adverse event, we analyzed cases of pruritus occurring after discontinuation of cetirizine in the FDA Adverse Event Reporting System (FAERS) database and medical literature. METHODS: We conducted a retrospective study to identify and describe cases of pruritus occurring after discontinuation of cetirizine in the FAERS database and medical literature through April 24, 2017. Data collected from the reports included demographic information, reason for use, serious outcome, report source, duration of cetirizine use, time to onset of pruritus after cetirizine discontinuation, presence of associated urticaria, treatment for pruritus, concomitant comorbidities and medications associated with pruritus, rechallenge information, and patient outcome information. RESULTS: We identified 146 cases of pruritus after discontinuation of cetirizine. Reporting frequency increased starting in 2008. The median patient age was 38 years (n = 141), ranging from 6 to 71 years, and cases were predominantly reported in females (n = 110). Most cases (n = 115) were submitted directly to the FDA from consumers or healthcare providers. The median duration of use of cetirizine prior to discontinuation was 24 months (n = 130), ranging from 0.3 to 172.2 months. The median time to onset of pruritus from discontinuation was 2 days (n = 91), ranging from 0.5 to 5 days. Of the 55 cases that reported discontinuation of cetirizine again after restarting, 54 reported pruritus recurrence. CONCLUSIONS: Our case series provided evidence of an association between the discontinuation of cetirizine and the development of pruritus. The mechanism by which cetirizine causes pruritus upon discontinuation is unknown. Patients and prescribers should have knowledge of this adverse event, given the widespread use and availability of cetirizine, and potential impact on patient quality of life.

Evaluation of Postmarketing Reports from Industry-Sponsored Programs in Drug Safety Surveillance.

INTRODUCTION AND OBJECTIVE: Adverse event reports from industry-sponsored programs, such as patient support programs, have contributed to a rise in the number of individual case safety reports in the US Food and Drug Administration Adverse Event Reporting System database. This study aimed to characterize individual case safety reports from industry-sponsored program and non-industry-sponsored program sources and compare their usefulness in safety signal detection. METHODS: Individual case safety reports of six drug and biological products were identified in the Food and Drug Administration Adverse Event Reporting System database between the date of Food and Drug Administration product approval and the first quarter of 2017. A random subset of industry-sponsored program and non-industry-sponsored program individual case safety reports were then compared to identify differences in reporters, outcomes, data completeness, and usefulness. The 'usefulness' of individual case safety reports was assessed by manually reviewing the availability of key information in the narrative (e.g., temporality, comorbidities). RESULTS: Compared with non-industry-sponsored program reports, more industry-sponsored program reports were associated with a serious outcome (51.4% vs. 58.8%, p = 0.02) and were reported by consumers (35.5% vs. 50.4%, p < 0.01). Industry-sponsored program reports tended to contain more data elements than non-industry-sponsored program reports (i.e., age, sex, indication for use), but completeness was variable across products. No significant difference in usefulness was identified between non-industry-sponsored program and industry-sponsored program individual case safety reports (30.6% vs. 28.5%, p = 0.42). Useful reports that contained at least one serious, unlabeled adverse event represented only 4% and 6.2% of the non-industry-sponsored program and industry-sponsored program report cohorts, respectively. CONCLUSIONS: Our study suggests that reports obtained from industry-sponsored programs in the Food and Drug Administration Adverse Event Reporting System database contain more data elements but are similar to non-industry-sponsored program reports with regard to 'usefulness' in signal detection.

Antimicrobial Monotherapy versus Combination Therapy for the Treatment of Complicated Intra-Abdominal Infections.

STUDY OBJECTIVE: It is unknown if ß-lactam monotherapy is sufficient for complicated intra-abdominal infections or if broader coverage is required, such as with vancomycin. This study sought to determine the clinical outcomes of piperacillin/tazobactam (PIP/TAZ) monotherapy compared to combination therapy with vancomycin and PIP/TAZ for complicated intra-abdominal infections among patients within a surgical intensive care unit (ICU). DESIGN: Retrospective cohort study. SETTING: Three surgical ICUs at a tertiary academic medical center. PATIENTS: Four hundred seventeen patients with a secondary peritonitis identified by International Classification of Diseases, Ninth Revision codes who received either PIP/TAZ monotherapy (228 patients) or PIP/TAZ and vancomycin combination therapy (189 patients). MEASUREMENTS AND MAIN RESULTS: The primary outcome was day 28 clinical cure; secondary outcomes included day 7 clinical cure, length of stay (LOS), and mortality. There were no statistically significant differences between the monotherapy and combination therapy groups with respect to day 28 clinical cure (33.9% vs 25.5%, p=0.064), day 7 clinical cure (23.6% vs 17.6%, p=0.14), or 28-day mortality (7% vs 7.9%, p=0.72). LOS in the ICU was significantly shorter in the monotherapy group (6 days) compared with the combination therapy group (7 days; p=0.04); however, hospital LOS was not significantly different. CONCLUSIONS: No difference was observed in clinical cure rates at day 28 or day 7 between those who received PIP/TAZ monotherapy compared to PIP/TAZ and vancomycin combination therapy.

Compliance With Institutional Antimicrobial Dosing Guidelines in Patients Receiving Continuous Venovenous Hemodialysis.

OBJECTIVE: Describe the rate of compliance with institutional antimicrobial dosing guidelines in patients on concomitant continuous venovenous hemodialysis (CVVHD). METHODS: This single-center retrospective chart review evaluated adult patients receiving concomitant intravenous antimicrobials and CVVHD for at least 24 hours over a 2-month period. RESULTS: A total of 42 patients, 76 antimicrobial courses, and 208 study days (24 hours of concomitant therapy) were evaluated. Overall, antimicrobials were dosed according to the institutional guidelines on 162 (78%) of 208 study days. All nonconcordant doses were below recommendations. The recommended dose was never received prior to antibiotic or CVVHD discontinuation in 22% of the cases. In cases where antimicrobials were initiated when the patient was already on CVVHD, 74% of the initial doses met guideline criteria. Pharmacist recommendation was associated with increased dosing compliance (94% vs 73% of study days, P = .001). During transition from CVVHD to intermittent hemodialysis (IHD), only 62% of antimicrobial doses were decreased by the first IHD day. CONCLUSIONS: Antimicrobial dosing in patients on CVVHD was below institutional guideline recommendations in many cases. Pharmacist recommendation was associated with compliance. Centers should evaluate their own compliance rate with institutional guideline recommendations for CVVHD and implement initiatives to improve dosing practices.

Postoperative adverse effects after recent or remote lithium therapy.

Patients receiving preoperative lithium therapy for bipolar disorder may present unique challenges in the perioperative period and during critical illness. Two cases of critically ill patients who developed lithium-induced adverse reactions in the perioperative period due to the low therapeutic index are reported.

Impact of a clinical pharmacy admission medication reconciliation program on medication errors in "high-risk" patients.

BACKGROUND: Medication errors are common upon hospital admission. Clinical pharmacist involvement in medication reconciliation is effective in identifying and rectifying medication errors. However, data is lacking on the economic impact, time requirements, and severity of errors resolved by clinical pharmacists. OBJECTIVE: To determine the incidence of unintended admission medication discrepancies resolved by clinical pharmacists. Secondary objectives were to determine the type of discrepancies, potential severity, proximal cause, and economic impact of this clinical pharmacy program. METHODS: This was a single-center, prospective, observational study conducted at a major teaching medical institution. Following institutional review board approval, data collection was conducted over a 4-week period (August 22, 2011, to September 16, 2011). Descriptive statistical methods were performed for all data analyses. RESULTS: A total of 517 patients involving 5006 medications were included in this study. More than 25% (n = 132) of patients had at least 1 error associated with a medication ordered on hospital admission. Pharmacists resolved a total of 467 admission medication errors (3.5 ± 2.3 errors/patient). The most common type of medication error resolved was medication omission (79.6%). In regard to severity, 46% of medication errors were considered significant or serious. Overall, the mean total time was 44.4 ± 21.8 minutes per medication reconciliation. This clinical pharmacy program was estimated to carry a net present value of $5.7 million over 5 years. CONCLUSION: Clinical pharmacist involvement within a multidisciplinary health care team during the admission medication reconciliation process demonstrated a significant improvement in patient safety and an economic benefit.

Improving adverse drug event detection in critically ill patients through screening intensive care unit transfer summaries.

PURPOSE: This study aimed to determine the frequency and type of adverse drug events (ADEs) identified in intensive care unit (ICU) transfer summaries and in the hospital discharge summaries to demonstrate the effectiveness of ICU transfer summary surveillance in the identification of ADEs. METHODS: A retrospective electronic medical record review was conducted for medical ICU patients admitted between January 2009 and April 2009 to a large, academic medical center. The Harvard Practice Scale and the modified Leonard Assessment Scale were used to evaluate the presence of an ADE from the ICU transfer and hospital discharge summaries. RESULTS: Two hundred and fifty-four patients were identified for inclusion with a median medical ICU length of stay of 4.5 days and hospital length of stay of 13 days. The ICU transfer summary review revealed 173 ADEs among 124 unique patients with a rate of 33.9 ADEs per 1000 hospital patient days. Sixty-nine ADEs among 63 unique patients were identified through the hospital discharge summary with a rate of 13.5 ADEs per 1000 hospital patient days. Only 23.1% of ADEs discussed in the ICU transfer summary were also discussed in the hospital discharge summary. CONCLUSIONS: The use of ICU transfer summaries is an effective tool to increase ADE detection. The use of an ICU transfer summary should be considered as an adjunct method to an existing ADE surveillance system for heightened pharmacovigilance.

Treatment of dabigatran-associated bleeding: case report and review of the literature.

Dabigatran etexilate is a competitive, direct thrombin inhibitor that works in the coagulation cascade to ultimately prevent thrombus formation. It is recommended by the 2012 American College of Chest Physicians evidence-based clinical practice guidelines as first-line therapy over vitamin k antagonists for long-term antithrombotic therapy in patients with paroxysmal or persistent nonrheumatic atrial fibrillation who are at intermediate to high risk of stroke and systemic embolism (grade 2B). However, serious postmarketing events involving life-threatening bleeding are emerging with no antidote for reversal of the anticoagulant effect being available for use. Potential reversal agents are being used in clinical practice with questionable efficacy and safety profiles. We report a case involving an 84-year-old male with acute kidney injury who developed life-threatening gastrointestinal and surgical site bleeding secondary to dabigatran accumulation. Use of the Naranjo probability scale indicated a probable cause between the bleeding event and dabigatran use. After discontinuation of drug therapy, fresh frozen plasma, recombinant coagulation factor VIIa, and cryoprecipitate were administered as potential reversal agents with negligible benefit. However, this patient appeared to slowly benefit with administration of continuous venovenous hemodialysis. Based upon our experience with this patient and literature review, the most effective treatment algorithm for dabigatran-associated bleeding may be to utilize hemodialysis initially.

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.

Importance of direct patient care in advanced pharmacy practice experiences.

The Accreditation Council for Pharmacy Education issued revised standards (Standards 2007) for professional programs leading to the Doctor of Pharmacy degree in July 2007. The new standards require colleges and schools of pharmacy to provide pharmacy practice experiences that include direct interaction with diverse patient populations. These experiences are to take place in multiple practice environments (e.g., community, ambulatory care, acute care medicine, specialized practice areas) and must include face-to-face interactions between students and patients, and students and health care providers. In 2009, the American College of Clinical Pharmacy (ACCP) identified concerns among their members that training for some students during the fourth year of pharmacy curriculums are essentially observational experiences rather than encounters where students actively participate in direct patient care activities. These ACCP members also stated that there is a need to identify effective mechanisms for preceptors to balance patient care responsibilities with students' educational needs in order to fully prepare graduates for contemporary, patient-centered practice. The 2010 ACCP Educational Affairs Committee was charged to provide recommendations to more effectively foster the integration of pharmacy students into direct patient care activities during advanced pharmacy practice experiences (APPEs). In this commentary, the benefits to key stakeholders (pharmacy students, APPE preceptors, clerkship sites, health care institutions, academic pharmacy programs) of this approach are reviewed. Recommendations for implementation of direct patient care experiences are also provided, together with discussion of the practical issues associated with delivery of effective APPE. Examples of ambulatory care and acute care APPE models that successfully integrate pharmacy students into the delivery of direct patient care are described. Enabling students to engage in high-quality patient care experiences and to assume responsibility for drug therapy outcomes is achievable in a variety of practice settings. In our opinion, such an approach is mandatory if contemporary pharmacy education is to be successful in producing a skilled workforce capable of affecting drug therapy outcomes.

Extracellular signal-regulated kinase activation by parathyroid hormone in distal tubule cells.

The PTH receptor (PTH1R) activates multiple signaling pathways, including extracellular signal-regulated kinases 1 and 2 (ERK1/2). The role of epidermal growth factor receptor (EGFR) transactivation in ERK1/2 activation by PTH in distal kidney cells, a primary site of PTH action, was characterized. ERK1/2 phosphorylation was stimulated by PTH and blocked by the EGFR inhibitor, AG1478. Upon PTH stimulation, metalloprotease cleavage of membrane-bound heparin-binding fragment (HB-EGF) induced EGFR transactivation of ERK. Conditioned media from PTH-treated distal kidney cells activated ERK in HEK-293 cells. AG1478 added to HEK-293 cells ablated transactivation by conditioned media. HB-EGF directly activated ERK1/2 in HEK-293 cells. Pretreatment of distal kidney cells with the metalloprotease inhibitor GM-6001 abolished transactivation of ERK1/2 by PTH. The role of the PTH1R COOH terminus in PTX-sensitive ERK1/2 activation was characterized in HEK-293 cells transfected with wild-type PTH1R, with a PTH1R mutated at its COOH terminus, or with PTH1R truncated at position 480. PTH stimulated ERK by wild-type, mutated and truncated PTH1Rs 21-, 27- and 57-fold, respectively. Thus, the PTH1R COOH terminus exerts an inhibitory effect on ERK activation. EBP50, a scaffolding protein that binds to the PDZ recognition domain of the PTH1R, impaired PTH but not isoproterenol or calcitonin-induced ERK activation. Pertussis toxin inhibited PTH-stimulated ERK1/2 by mutated and truncated PTH1Rs and abolished ERK1/2 activation by wild-type PTH1R. We conclude that ERK phosphorylation in distal kidney cells by PTH requires PTH1R activation of G(i), which leads to stimulation of metalloprotease-mediated cleavage of HB-EGF and transactivation of the EGFR and is regulated by EBP50.