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BACKGROUND: TREPROSTINIL IS A PROSTACYCLIN ANALOG USED FOR TREATMENT OF PULMONARY HYPERTENSION (PH) IN ADULTS AND CHILDREN, CURRENTLY AWAITING CLINICAL ASSESSMENT FOR USE IN NEONATES.: OBJECTIVES: WE AIMED TO INVESTIGATE THE USE OF TREPROSTINIL IN NEONATES WITH PH ON EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO) SUPPORT AND MEASURE PLASMA CONCENTRATIONS OF THE DRUG.: METHODS: THIS IS A RETROSPECTIVE CASE-SERIES WITH PROSPECTIVELY COLLECTED BLOOD SAMPLES, CONDUCTED IN A QUATERNARY CARE NEONATAL INTENSIVE CARE UNIT. BRAIN NATRIURETIC PEPTIDE, CARDIAC FUNCTION ON DOPPLER ECHOCARDIOGRAPHY, AND THE OCCURRENCE OF ADVERSE EFFECTS WAS MONITORED. PLASMA CONCENTRATIONS WERE MEASURED USING HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY AND MASS SPECTROMETRY.: RESULTS: FOUR PATIENTS WITH PH REQUIRING ECMO THERAPY WERE STUDIED. TREPROSTINIL DOSES OF 20-58 NG/KG/MIN REACHED CONCENTRATIONS OF 0.99-4.39 NG/ML AND INDUCED CLINICAL IMPROVEMENT. INFUSION OF TREPROSTINIL WAS ASSOCIATED WITH IMPROVED RIGHT VENTRICULAR FUNCTION, REVERSED RIGHT-TO-LEFT SHUNTING THROUGH THE DUCTUS ARTERIOSUS, AND STABLE OR DECREASING NEED FOR VASOPRESSOR SUPPORT. NO ADVERSE EFFECTS WERE OBSERVED: CONCLUSIONS: THIS IS THE FIRST STUDY TO REPORT CLINICALLY THERAPEUTIC TREPROSTINIL CONCENTRATIONS IN CIRCULATING PLASMA AFTER TREPROSTINIL ADMINISTRATION IN NEONATES ON ECMO, WITH ASSOCIATED CLINICAL IMPROVEMENT OF PH AND NO SIGNS OF HEMODYNAMIC INSTABILITY. ispartof: Pharmacotherapy vol:40 issue:10 pages:1054-1060 ispartof: location:United States status: published

Gastrointestinal (GI) malignancies are among the most commonly diagnosed cancers worldwide. Despite the introduction of targeted and immunotherapy agents in the treatment landscape, cytotoxic agents, such as fluoropyrimidines and irinotecan, remain as the cornerstone of chemotherapy for many of these tumors. Pharmacogenetics (PGx) is a rapidly evolving field that accounts for interpatient variability in drug metabolism to predict therapeutic response and toxicity. Given the significant incidence of severe treatment-related adverse events associated with cytotoxic agents, utilizing PGx can allow clinicians to better anticipate drug tolerability while minimizing treatment interruptions or delays. In this review, the PGx profiles of drug-gene pairs with potential impact in GI malignancy therapy - DPYD-5-fluorouracil/capecitabine and UGT1A1-irinotecan - and the available clinical evidence of their roles in reducing severe adverse events are discussed. Considerations for clinical implementation, such as optimal laboratory workflows, electronic health record integration, and stakeholder engagement, as well as provider education, are addressed. Last, exploratory PGx markers in GI malignancy treatment are described. As the PGx knowledge base rapidly evolves, pharmacists will be vital in leveraging their pharmacology knowledge and clinical skills to implement PGx testing in the clinic.

Objective To describe the peramivir (PRV) pharmacokinetics in critically ill children treated for influenza A or B viral infections. Design Retrospective electronic medical record review of prospectively collected data from critically ill children receiving peramivir for influenza A or B viral infections in the pediatric intensive care unit (PICU). Setting A 189-bed, freestanding children's tertiary care teaching hospital in Philadelphia, PA. Patients Critically ill children admitted to the PICU who were infected with influenza between January 1, 2016 and March 31, 2018. Interventions None. Results Eleven patients, two females (18%) and nine males (82%), accounted for 24 peramivir samples for therapeutic drug management. The median age was 5 years (interquartile range 1.5-6.5 yrs) with a median weight of 16.4 kg (interquartile range 14-24 kg). Ten (91%) patients demonstrated a larger volume of distribution, 11 (100%) patients demonstrated an increase in clearance, and 11 (100%) patients demonstrated a shorter half-life estimate as compared with the package insert and previous pediatric trial data for peramivir. Eight (73%) patients tested positive for a strain of influenza A and 3 (27%) patients tested positive for influenza B; 4 of 11 (36%) patients tested positive for multiple viruses. All patients had adjustments made to their dosing interval to a more frequent interval. Ten (91%) patients were adjusted to an every-12-hour regimen and 1 (9%) patient was adjusted to an every-8-hour regimen. No adverse events were associated with peramivir treatment. Conclusion The pharmacokinetics of PRV demonstrated in this PICU cohort differs in comparison to healthy pediatric and adult patients, and alterations to dosing regimens may be needed in PICU patients to achieve pharmacodynamic exposures. Additional investigations in the PICU population are needed to confirm these findings.

Study objectives Continuous intravenous (IV) infusion bumetanide has been associated with severe myalgia in case reports, and the package labeling lists a reported incidence of 0.2% for severe myalgia. The primary objective of this study was to quantify the incidence of bumetanide infusion-induced severe myalgia in patients with acute heart failure (AHF). Secondary objectives were to assess a dose-response relationship between bumetanide infusion rate and occurrence of myalgia and to investigate potential risk factors associated with bumetanide-induced myalgia. Design Retrospective analysis. Setting Large academic medical center. Patients Adults hospitalized with AHF who required bumetanide (≥ 0.5 mg/hr [464 patients]) or furosemide (≥ 20 mg/hr [197 patients]) by continuous IV infusion between September 2015 and May 2017. Measurements and main results The incidence of severe myalgia with IV furosemide infusion was assessed to measure confounding by indication bias. Electronic medical records were used to identify patients exposed to bumetanide 0.25-mg/ml or furosemide 2-mg/ml continuous IV infusions. We defined severe myalgia as a diffuse myalgia with a physician's documented suspicion of bumetanide- or furosemide-induced myalgia unresponsive to electrolyte repletion and necessitating a change to alternative diuretics. The incidence of severe myalgia during bumetanide therapy was 5.8%, with the incidence increasing with higher bumetanide infusion rates: 2.6% for an infusion rate ≤ 1 mg/hour and 10.3% for a rate > 1 mg/hour (p=0.0005). In the multivariate logistic regression analysis, a bumetanide infusion rate > 1 mg/hour was independently associated (odds ratio 4.8, 95% confidence interval 1.94-12.02, p=0.0007) with severe myalgia compared to that with a rate ≤ 1 mg/hour. No patients receiving furosemide continuous IV infusion experienced severe myalgia, although infusion rates were lower in potency than bumetanide infusion rates. Conclusion The incidence of severe myalgia in patients with AHF receiving bumetanide infusion was 5.8%, 29-fold higher than incidence rate listed in the package labeling. Patients receiving infusion rates > 1 mg/hour were 4-fold more likely to experience bumetanide-induced severe myalgia than those receiving rates ≤ 1 mg/hour.

STUDY OBJECTIVE: Numerous medications interact at serotonin (5-hydroxytryptamine [5-HT]) receptors directly or through off-target interactions, causing mild to severe serotonergic adverse drug events (ADEs), particularly among the elderly. Our objective was to develop a novel molecular-based toxicity scoring system to assess serotonergic burden resulting from concurrently administered drugs. Quantitative methods to assess serotonergic burden may provide a useful clinical tool for improving pharmacotherapy. DESIGN: Retrospective cohort study. DATA SOURCES: PharMetrics Legacy health claims database (January 2001–December 2013) and ChEMBL bioactivity database. PATIENTS: A 2–serotonergic drug exposure cohort (78,172 patients) and a 3–serotonergic drug exposure cohort (19,900 patients) were generated, and population-level statistics were collected. Nonexposure cohorts were created for each drug exposure cohort and matched in a 4:1 ratio for age, sex, and length of enrollment. MEASUREMENTS AND MAIN RESULTS: Eight 5-HT medications were screened against multiple bioactivity databases to identify their off-target interactions at 5-HT receptors and serotonin reuptake transporter protein. A computational serotonin burden score (SBS) was derived from the receptor-specific interaction propensities reported from the comprehensive bioactivity screen. Linear regression was used to characterize associations between SBSs and combined total ADE incidence rate detected by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. A significantly greater incidence of 17 potential 5-HT-related ADEs was seen in exposed serotonergic drug cohorts (p

Central nervous system stimulants are a commonly used first-line treatment option for attention-deficit/hyperactivity disorder (ADHD). Stimulants are generally well tolerated, with anorexia and insomnia the most common adverse effects. However, there are some concerns with long-term use of stimulants, such as potential growth delay. Historically, data regarding this long-term adverse effect have been conflicting. In this article, we review the newer data surrounding the effects of central nervous system stimulants on growth parameters in children with ADHD. We conducted a literature search of the PubMed database; only articles using ADHD criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, were included to ensure the most up-to-date review of literature. Nine articles were identified for relevance and quality and are discussed in this review, describing clinical observations of height and weight of adolescent or pediatric patients receiving stimulant medications for ADHD therapy. In summary, this review points toward potential associations between duration of treatment and higher doses of stimulants with decreased weight and body mass index. Furthermore, this review demonstrates that evidence is still conflicting regarding the relationship between stimulant use and significant height decreases. Future studies with higher quality of evidence are needed to observe this potential adverse effect of stimulants in children and adolescents.

STUDY OBJECTIVE: Enzalutamide is an oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC); N-desmethyl enzalutamide is its active metabolite, which has clinically relevant anti-androgen capacities similar to enzalutamide, and carboxylic acid enzalutamide is an inactive metabolite. The aim of our study was to investigate the relationship between enzalutamide and N-desmethyl enzalutamide exposure and treatment response in a real-world cohort of patients with mCRPC. DESIGN: Retrospective, observational, pharmacokinetic study. SETTING: Outpatient clinic at a tertiary cancer center in Amsterdam, the Netherlands. PATIENTS: Sixty-five patients with mCRPC who were treated with enzalutamide 160 mg daily and had at least one steady-state enzalutamide plasma concentration between May 2015 and June 2018; of these patients, 38 were prostate-specific antigen (PSA) responders and 27 were nonresponders. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations, determined by using liquid chromatography with tandem mass spectrometry (LC-MS/MS), were compared between PSA responders and nonresponders. Three clinical end points were evaluated separately in this study: PSA-independent progression-free survival (PFS), time to PSA progression (TTPP), and rate of PSA response (defined as ≥ 50% decrease in PSA level from baseline). Enzalutamide toxicity was defined as discontinuation due to adverse events, dose reductions due to adverse events, or temporary treatment interruption. For these analyses, plasma concentrations of enzalutamide and N-desmethyl enzalutamide were divided into quartiles. Mean ± SD plasma concentrations in the 65 patients were as follows: enzalutamide 11.2 ± 2.8 μg/ml, N-desmethyl enzalutamide 9.9 ± 2.9 μg/ml, and carboxylic acid enzalutamide 6.1 ± 4.3 μg/ml. Plasma concentrations were not significantly different in the PSA responder versus nonresponder groups for enzalutamide (11.5 vs 10.6 μg/ml, p=0.20), N-desmethyl enzalutamide (10.1 vs 9.6 μg/ml, p=0.48), and carboxylic acid enzalutamide (6.5 vs 5.5 μg/ml, p=0.34). Univariate and multivariate analyses did not show a relationship between plasma concentrations and PSA-independent PFS, TTPP, or toxicity. CONCLUSION: This study confirmed that enzalutamide plasma concentrations were not related to PSA-independent PFS, TTPP, or toxicity in patients with mCRPC, and demonstrated that plasma concentrations of its major metabolites were also not associated with treatment response. Based on these findings, there is no role for therapeutic drug monitoring of enzalutamide in patients with mCRPC in daily practice.

Prevalent molecular alterations of the phosphoinositide 3-kinase (PI3K) pathway are found on solid tumors and are expressed in leukocytes, making it a desirable target in both solid and hematologic malignancies. In recent years, two agents targeting this pathway have been approved by the United States Food and Drug Administration, idelalisib and copanlisib, with many others under investigation. Due to the off-target effects seen with these agents, those under development have varying isoform specificity that mitigates toxicity. In this review, we attempt to illustrate the varying differences among these agents, both mechanistically as well as highlight differences in their respective adverse effect profiles.

Tenofovir alafenamide (TAF) is indicated for adult patients with chronic hepatitis B virus (HBV) infection with compensated liver disease at an oral dose of 25 mg/day. TAF is a more stable prodrug in the plasma than tenofovir disoproxil fumarate (TDF), leading to decreased plasma exposure of tenofovir. Decreased exposure is thought to reduce the risk of long-term TDF toxicities, such as nephrotoxicity and decreased bone mineral density (BMD). TAF, a nucleotide reverse transcriptase inhibitor, has the same mechanism of action as TDF. The results of phase III primary trials and extensions showed that TAF is noninferior to TDF at suppressing the HBV viral load in treatment-naive and treatment-experienced HBeAg-negative and HBeAg-positive patients at 48 weeks, 96 weeks, and 144 weeks of therapy. The most commonly reported adverse events were headache, abdominal pain, fatigue, cough, nausea, and back pain. At all evaluated time points (out to 144 wks of treatment), patients who received TAF had less risk of nephrotoxicity and less of a decline in BMD than the patients who received TDF. TAF appears to be safe in patients with a creatinine clearance (Clcr ) above 15 ml/min; however, TAF is not currently recommended in patients with an estimated Clcr below this threshold. TAF is safe in patients with mild hepatic impairment but is not currently recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Intranasal lidocaine has been studied and recommended as an alternative in the management of acute headache. The objective of this systematic review was to evaluate the efficacy and safety of intranasal lidocaine in the acute management of primary headaches. The MEDLINE (1946 to May 2018), EMBASE (1974 to May 2018), Cochrane Central Register of Controlled Trials (2008 to May 2018), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to May 2018), and ClincialTrials.gov online databases were searched. Studies conducted in patients with acute primary headache were included if lidocaine was compared with placebo or alternative treatments, lidocaine dosing was specified, and patients' pain before and after treatment were clearly reported. Six studies met the inclusion criteria. Intranasal lidocaine demonstrated potential benefit over placebo in acute pain reduction and need for rescue medication only in the four studies deemed to be of poor quality, not in the two fair-quality studies. No study reported benefit in preventing headache recurrence or repeat visits to the emergency department. Lidocaine was associated with significantly higher rates of adverse events compared with placebo and may result in lower rates of patient satisfaction. There is insufficient evidence to support the use of intranasal lidocaine in acute management of primary headaches. Further research is warranted to better elucidate whether intranasal lidocaine has a role in the management of specific primary headache subtypes and whether there is an optimal regimen.

OBJECTIVE To examine the association between quinolone use and Achilles tendon injury, comparing well-matched cohorts of users of quinolone and nonquinolone antibiotics, and well-matched cohorts of quinolone users and patients not using any nonquinolone antibiotics. PATIENTS AND METHODS This retrospective cohort study used Clinformatics data from 2008-2014. Using the propensity score, we matched quinolone users with other antibiotic users and quinolone users with nonusers. The primary outcome was Achilles tendon injury within 6 months. Bivariate analyses determined risk factors for Achilles tendon injury, and conditional logistic regression assessed the impact of quinolone use on these injuries. RESULTS A total of 716,522 fluoroquinolone users were matched with other antibiotic users, and 645,034 fluoroquinolone users were matched with nonusers. Rates of Achilles tendon injury were less than 0.5% in all groups. Quinolone use increased the risk of Achilles tendon injury compared with other antibiotic users (odds ratio [OR] 1.24, 95% confidence interval [CI] 1.17-1.31) and nonusers (OR 1.54, 95% CI 1.44-1.64). Interaction with age did not significantly impact the relationship between quinolone use and Achilles injury; however, older quinolone users had a slightly higher relative risk of injury than nonusers versus younger patients. Furthermore, the youngest group of patients had similarly elevated relative risk for injury with quinolone use as did the elderly. CONCLUSION Although quinolone use increases the risk of Achilles tendon injury, the absolute risk increase is minimal, especially when compared with similar morbidity patients taking other nonquinolone antibiotics. In relatively healthy populations, such as the one studied here, quinolone use may not make a clinically significant contribution to risk of Achilles tendon injury, at any age range, among those in need of such drugs.

Study objective Acute kidney injury (AKI) is a common condition associated with both short-term and long-term consequences including dialysis, chronic kidney disease, and mortality. Although the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database is a powerful tool to examine drug-associated events, to our knowledge, no study has analyzed this database to identify the most common drugs reported with AKI. The objective of this study was to analyze AKI reports and associated medications in the FAERS database. Design Retrospective pharmacovigilance disproportionality analysis. Data source Food and Drug Administration Adverse Event Reporting System database. Measurements and main results We queried the FAERS database for reports of AKI from 2004 quarter 1 through 2015 quarter 3. Extracted drugs were assessed using published references and categorized as known, possible, or new potential nephrotoxins. The reporting odds ratio (ROR), a measure of reporting disproportionality, was calculated for the 20 most frequently reported drugs in each category. We retrieved 7,241,385 adverse event reports, of which 193,996 (2.7%) included a report of AKI. Of the AKI reports, 16.5% were known nephrotoxins, 18.6% were possible nephrotoxins, and 64.8% were new potential nephrotoxins. Among the most commonly reported drugs, those with the highest AKI ROR were aprotinin (7614 reports; ROR 115.70, 95% confidence interval [CI] 110.63-121.01), sodium phosphate (1687 reports; ROR 55.81, 95% CI 51.78-60.17), furosemide (1743 reports; ROR 12.61, 95% CI 11.94-13.32), vancomycin (1270 reports, ROR 12.19, 95% CI 11.45-12.99), and metformin (4701 reports; ROR 10.65, 95% CI 10.31-11.00). The combined RORs for the 20 most frequently reported drugs with each nephrotoxin classification were 3.71 (95% CI 3.66-3.76) for known nephrotoxins, 2.09 (95% CI 2.06-2.12) for possible nephrotoxins, and 1.55 (95% CI 1.53-1.57) for new potential nephrotoxins. Conclusion Acute kidney injury was a common reason for adverse event reporting in the FAERS. Most AKI reports were generated for medications not recognized as nephrotoxic according to our classification system. This report provides data on medications needing further research to determine the risk of AKI with these new potential nephrotoxins.

Circulatory shock is a medical emergency that requires rapid intervention to optimize patient outcomes. Although catecholamine vasopressors are considered life-sustaining therapy, they are associated with adverse reactions, and vasopressin and angiotensin II may be used to minimize these adverse effects. However, vasopressin and angiotensin II are also associated with adverse reactions that must be known to the clinician to mitigate risk for patients. This review focuses on the known adverse drug effects of vasopressin and angiotensin II while offering potential solutions to minimize harm with these agents. Future directions with vasoactive medication safety including optimization of the electronic medical record, clinical decision support, prediction analytics, and precision medicine for patients with circulatory shock are also discussed.

Study objective To investigate the efficacy and safety of rituximab in patients with Graves' orbitopathy (GO). Design Systematic review and meta-analysis of four randomized controlled trials. Patients A total of 293 patients with GO who received rituximab or control (either glucocorticoids, the established first-line therapy [three trials], or saline [one trial]). Measurements and results Relevant studies published before February 2018 were identified from the PubMed, EMBASE, Cochrane Library, and Scopus databases and the ClinicalTrials.gov registry. Individual effect sizes were standardized, and a meta-analysis was conducted to calculate the pooled effect size by using a random-effects model. Treatment efficacy was assessed by measuring the following outcomes: clinical activity score (CAS), sight visual acuity reduction (NOSPECS) score, proptosis, diplopia, changes in eye volume, quality of life, and adverse events. In the four included trials, 113 patients in the rituximab group and 108 patients in the control group were evaluated. Compared with the control group, CAS (weighted mean difference 0.57, 95% confidence interval 0.25-0.89) was significantly reduced at 24 weeks in the rituximab group. Compared with the control group, considerable proptosis reduction was also observed in the rituximab group; however, the difference was not significant. The proportion of adverse events in the rituximab group was not significantly higher than that in the glucocorticoid control group, but one of the included trials indicated that the rituximab group had more serious adverse events than the saline control group. Conclusion Rituximab is a relatively safe and viable treatment that is superior to glucocorticoids or saline for patients with moderate to severe GO. However, the incidence of serious adverse events was disparate among the included trials. Additional studies involving a larger sample size and investigating the optimal rituximab dosage, frequency, and method of administration are warranted.

Thiopurine drugs, including azathioprine and 6-mercaptopurine, are used commonly in patients with inflammatory bowel disease for maintenance of remission. Although generally well tolerated, adverse effects lead to discontinuation in a significant minority of patients. Pharmacogenomic studies have suggested that metabolic breakdown of azathioprine in an individual is genetically determined. Coupled with the fact that certain thiopurine metabolites, notably 6-thioguanine nucleotide and 6-methylmercaptopurine, are associated with antiinflammatory effects and adverse effects, respectively, some investigators have examined intentionally shunting the metabolism of azathioprine toward increasing 6-thioguanine nucleotide levels by using low doses of the xanthine oxidoreductase inhibitor allopurinol to improve efficacy and decrease toxicity of azathioprine in patients with inflammatory bowel disease. We performed a search of the MEDLINE and Embase databases for basic and clinical research reports of this modality. Pertinent articles were retrieved, reviewed, and assessed by the authors. Case series, cohort studies, and one randomized trial have investigated adding allopurinol to azathioprine therapy in patients with inflammatory bowel disease. Most reports primarily examined metabolite levels in these patients. In general, the literature suggests that this modality was successful at significantly increasing 6-thioguanine nucleotide levels while decreasing 6-methylmercaptopurine levels. Several small reports have suggested that patients with increased 6-thioguanine nucleotide levels had improved symptoms or symptom remission. Adverse effects and discontinuation rates remained similar or were improved in patients who were taking a thiopurine and started allopurinol. In conclusion, the addition of allopurinol may be an option for optimizing thiopurine metabolite production in select patients with low 6-thioguanine nucleotide levels. Appropriate care and monitoring of these patients are mandatory to prevent neutropenia or other adverse effects.

Lenalidomide is commonly used for multiple myeloma as either induction or maintenance therapy. The agent is associated with a host of adverse effects, but hypoglycemia has only been reported in one phase I trial in patients with solid tumors. We describe a 74-year-old woman who experienced grade 3 hypoglycemia (blood glucose level 35 mg/dl) likely related to lenalidomide. Her medical history was significant for refractory myeloma and type 2 diabetes mellitus. Lenalidomide was started as maintenance therapy following autologous bone marrow transplantation. Approximately 3 years later, she developed refractory hypoglycemia necessitating hospital admission despite stopping antihyperglycemic agents 4 weeks prior to admission. Lenalidomide was withheld during her admission and restarted 2 days prior to discharge. Work-up for causes of persistent hypoglycemia was negative, and her glucose levels improved over her 26-day hospitalization. She was readmitted approximately one month later for hypoglycemia, and lenalidomide was permanently discontinued. Again, work-up for causes of hypoglycemia was negative, and her glucose levels stabilized over her hospitalization. After discontinuation of lenalidomide, hypoglycemia did not recur, and within 1 year the patient required reinitiation of antihyperglycemic medications to control her glucose levels. Given the resolution of hypoglycemia with lenalidomide discontinuation and return of hyperglycemia after restarting the agent, it is likely that lenalidomide was the cause of the patient's hypoglycemia. Use of the Naranjo adverse drug reaction probability scale indicated a definite relationship (score of 9) between the patient's development of grade 3 hypoglycemia and lenalidomide therapy. Although this adverse drug reaction had been previously reported with lenalidomide during phase I trials in patients with solid tumors, only grade 1 or 2 hypoglycemia was reported in three patients. To our knowledge, this is the first reported case of grade 3 hypoglycemia caused by lenalidomide.

Objective Allopurinol is a medication indicated for the treatment and prevention of gout. Through various theorized mechanisms, there has been an observed benefit in reducing aggression in patients with dementia who are refractory to traditional interventions. This case series of eight patients reports the use of allopurinol to treat aggression at the Battle Creek Veterans Affairs Medical Center (BCVAMC). Methods Subjects’ charts were accessed retrospectively to obtain data. Adverse event notes were evaluated to identify the number of aggressive events before the initiation of allopurinol compared to the total number and rates of aggressive events after the initiation of allopurinol. Results A total of eight subjects were included in the case series. Of the subjects started on allopurinol for treating aggression, two cases showed no effect while all other cases responded with a decrease in the number and rate of reported aggressive episodes. Conclusions Allopurinol was observed to decrease the number and rate of aggressive events in patients refractory to other treatments. This article is protected by copyright. All rights reserved.

Omalizumab is recombinant humanized monoclonal antibody to immunoglobulin E. Guidelines for the treatment of chronic idiopathic urticaria (also known as chronic spontaneous urticaria) recommend the use of omalizumab as third-line therapy in addition to high doses of histamine receptor type 1 (H1 ) antihistamines when they are unsuccessful as first- and second-line therapy. We performed a systematic review of the literature to identify studies that evaluated the efficacy of omalizumab for the treatment of chronic idiopathic urticaria, in both controlled and real-world settings, to assess its potential role as a preferred therapy. The PubMed, ScienceDirect, LILACS (Latin American and Caribbean Health Sciences Literature), and Google Scholar databases were searched between January 1, 2000, and November 21, 2016. The search was limited to articles published in peer-reviewed journals in the English language, and 29 studies were included in this review. Omalizumab 300 mg administered every 4 weeks appears to be the most effective and safe dosage, with a rapid response time, for the treatment of chronic idiopathic urticaria, with few minor adverse effects, and appears to be safe in the offspring of pregnant patients who received the drug. However, as published studies of omalizumab are sparse, future studies are warranted. When findings are confirmed in larger studies, due to its efficacy, safety, and increased benefit/cost ratio, omalizumab could become the preferred method of treatment for chronic idiopathic urticaria in patients unresponsive to H1 antihistamines.

Objective Among selective serotonin reuptake inhibitors (SSRIs), paroxetine is strongly anticholinergic and might lead to a higher risk of adverse outcomes such as mortality. This study examined the risk of mortality in depressed elderly nursing home patients using paroxetine and other SSRIs. Methods This study used 2007–2010 Minimum Data Set–linked Medicare data and a propensity score (PS)-matched retrospective cohort study design to achieve the study objective. New users of paroxetine and other SSRIs were followed until they reached the end of the follow-up period (1 year), switched to a different antidepressant class, used psychotherapy, or had a gap of more than 15 days in the use of index antidepressant class, whichever occurred earlier. A robust Cox proportional hazard (PH) model was used to evaluate the risk of mortality associated with the use of paroxetine and other SSRIs in depressed elderly nursing home residents. Results The PS matching yielded 4620 patients each in the two treatment groups. The unadjusted incidence of mortality was 269 (2.9%) for paroxetine and 288 (3.1%) for other SSRIs users in the matched cohort. The robust Cox PH model did not find any significant difference in the risk mortality between the two groups (hazard ratio 1.01; 95% confidence interval 0.86–1.19). Conclusions This study did not find any significant difference in the risk of mortality between users of paroxetine and other SSRIs among elderly nursing home patients with depression. There is a need for further evaluation of other adverse effects of paroxetine due to its anticholinergic effects in the geriatric population.

Idiopathic recurrent pericarditis (IRP) can be challenging to treat. Even after guideline-directed first-line treatment consisting of aspirin (ASA) or a nonsteroidal antiinflammatory drug (NSAID) in combination with colchicine therapy, recurrences still occur in greater than 20% of patients. Many patients then require treatment with long-term corticosteroids, which is not a favorable option due to their short- and long-term adverse effects. Because it is theorized that the pathophysiology of IRP may possess autoimmune sequelae, the use of immunotherapy for the treatment of IRP has emerged. In this review, we describe the literature associated with immunotherapy used to treat IRP in an adult population as well as provide an overview of the safety and monitoring parameters for each agent. The most common immunotherapies used after patients have had multiple recurrences of IRP are anakinra, intravenous immunoglobulin (IVIG), and azathioprine. In most cases, these immunotherapies are adjunctive therapy, with the goal of tapering and discontinuing immunosuppressive corticosteroids. After reviewing the data, anakinra resulted in more patients discontinuing corticosteroids and prevented further recurrences of pericarditis. IVIG resulted in symptom resolution and no further recurrences in most of the patients. Azathioprine was associated with more than half of patients becoming recurrence free; however, many patients required a restart of corticosteroids due to recurrence. Clinicians should be aware of the adverse effects of immunotherapy, ranging from mild gastrointestinal events to risk of infection and serious blood dyscrasias that may require diligent monitoring. The use of immunotherapy for the treatment of adults with IRP should be restricted to patients who have multiple recurrences. Ideally, immunotherapy would be adjunctive to first-line combination therapy with ASA/NSAID plus colchicine, with the goal of tapering and discontinuing immunosuppressive corticosteroids. Furthermore, clinicians should consider cost, drug-drug and drug-disease interactions, and safety, as well as the quality of the retrospective evidence before considering any immunotherapy.

For treatment-naive patients with human immunodeficiency virus infection, efavirenz (EFV), together with tenofovir and emtricitabine, was once widely prescribed given its efficacy and ease of administration in a combination pill. However, the high rate of central nervous system (CNS) toxicities from EFV prompted the U.S. Department of Health and Human Services to move the EFV-based regimen from the recommended to the alternative category. For patients who do meet the criteria for newer recommended antiretroviral treatments, EFV is a viable option and often the mainstay of treatment outside the United States because newer antiretroviral treatments are more expensive. CNS toxicity occurring with the recommended standard dose of EFV remains a challenge and may in part be attributable to polymorphisms in cytochrome P450 (CYP) 2B6, the enzyme involved in the major metabolic pathway for converting EFV to inactive metabolites. Functionally deficient alleles of CYP2B6 such as CYP2B6*6, *18, and *22 may be responsible for significantly higher therapeutic concentrations of EFV at a standard dose of 600 mg/day. We conducted a thorough review of the reported studies to elucidate the relationship between polymorphisms in CYP2B6 with adverse events and treatment response, including virologic suppression, immunologic response, resistance, and discontinuation of treatment. Compelling evidence exists to support the case for CYP2B6 genotype-guided EFV therapy while acknowledging the need for prospective controlled clinical trials to evaluate its clinical utility.

Selection of an appropriate antiretroviral regimen for the patient infected with human immunodeficiency virus can be challenging, as various considerations must be taken into account including viral resistance mutations, patient comorbidities, drug interactions, and the potential for drug-related adverse effects and toxicities. Treatment is further complicated when a clinical scenario arises requiring an alteration in the dosage form. Factors ranging from dysphagia to administration through an enteral feeding tube can affect decisions regarding antiretroviral dosage forms. Limited pharmacokinetic data exist regarding the alteration of antiretroviral medications from their original form. Bioavailability may vary substantially between dosage forms, which can lead to unpredictable drug concentrations. Supratherapeutic or subtherapeutic antiretroviral drug concentrations can result in increased toxicity, virologic failure, or the emergence of drug resistance. We performed a systematic literature search to review the available antiretroviral literature on the modification of solid dosage forms as well as alternative routes of administration of oral antiretroviral agents and their application to clinical practice.

tudy Objective To describe our experience with voriconazole in three patients younger than 2 years using an optimized dosing strategy for voriconazole that incorporates intensive therapeutic drug monitoring (TDM). Design Case series. Setting Large pediatric hospital. Patients Three patients younger than 2 years who received voriconazole therapy and had serum trough concentrations measured between January 1, 2010, and October 31, 2015. Measurements and Main Results A clinical practice guideline developed at our institution was used to standardize initial dosing, appropriate use and timing of TDM, and dosage modifications based on TDM. TDM was used to guide dosing to achieve a target voriconazole serum trough concentration of 2–6 μg/ml. Voriconazole samples were assayed by using a high-performance liquid chromatography analytical method with solid-phase extraction. Initial dosages for the three patients were 9 mg/kg intravenously every 12 hours (one patient) and 9 mg/kg enterally twice/day (two patients). Multiple dose escalations and a more frequent dosing interval were required to achieve trough concentrations within the target range. The final dosages were 12 mg/kg intravenously every 8 hours, 17.7 mg/kg enterally 3 times/day, and 8.5 mg/kg enterally 3 times/day, respectively. In addition to voriconazole trough concentrations, TDM included evaluations for drug toxicities. Visual, neurologic, or hepatic adverse effects were not encountered in the three patients. Conclusion Our data support higher initial doses and perhaps a 3 times/day dosing schedule to achieve voriconazole serum concentrations in the target range for children younger than 2 years. Implementation of a clinical practice guideline with the participation of pharmacists specializing in pharmacokinetics allows for effective use of voriconazole in young children.

Fluoroquinolone antibiotics recently have gained increased national attention due to safety concerns. A well-described and serious adverse event associated with receipt of fluoroquinolones is tendinitis and tendon rupture. These tendon injuries can result in long-term sequelae, including chronic pain and mobility restrictions, and may warrant surgery. Due to the severity of these adverse events, a black box warning is included in the product labeling of all fluoroquinolones. In light of the mounting concerns surrounding fluoroquinolone-associated toxicities, the purpose of this clinical review is to provide a comprehensive summary of the risk of tendinopathy associated with levofloxacin, one of the most widely prescribed antibiotics in the United States, across in vitro, animal, and clinical studies, relative to other antibiotics. As part of this review, clinical presentation and onset, proposed mechanisms, patient-specific risk factors, and management of fluoroquinolone-induced tendon injury are summarized. Data were obtained from a comprehensive PubMed literature search and a review of U.S. Food and Drug Administration documents. Although tendinopathy is considered a fluoroquinolone class-wide toxicity, data from in vitro studies, animal studies, patient-level analyses, and large national and international surveillance reports suggest that levofloxacin, as well as its parent compound ofloxacin, possess higher propensities to cause tendon damage relative to other fluoroquinolones. Risk with ofloxacin and levofloxacin appears to be exposure dependent, with higher doses and longer durations being most commonly associated with tendinopathy. Other well-described patient risk factors for fluoroquinolone-associated tendinopathy include older age (older than 60 yrs), receipt of concomitant corticosteroid therapy, presence of renal dysfunction, and history of solid organ transplantation. Given widespread use of levofloxacin across patient care settings, knowledge of both patient- and drug-specific characteristics associated with increased risk of tendinitis and tendon rupture can promote safe use of levofloxacin and other fluoroquinolones.

BACKGROUND When using area under the concentration-time curve-based strategies for dosing carboplatin, accurate estimation of glomerular filtration rate is required for determining dose. Commonly, the Cockcroft-Gault equation is used, which is dependent on measurement of serum creatinine (SCr). Because analysis of SCr changed to an isotope dilution mass spectrometry (IDMS) standard, we sought to determine the impact of this assay change on carboplatin dosing and related toxicity. METHODS This was a single-center, retrospective chart review of adults treated with carboplatin between April 2008 and April 2010 divided into cohorts that initiated carboplatin before or after IDMS standardization. End points included grade 3 thrombocytopenia, decrease in platelet count, and hospitalization and were evaluated in cohorts based on concomitant chemotherapy. RESULTS The chart review identified 158 patients, with 63 patients in the pre-IDMS group and 95 patients in the post-IDMS group. Average SCr (pre 1.01 mg/dl vs post 0.86 mg/dl, p

Purpose To quantify the risk of glioblastoma (GBM) and its most aggressive form, glioblastoma multiforme (GBM-M), in patients treated with tumor necrosis factor (TNF) inhibitors. Methods Data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and the World Health Organization (WHO) Collaborating Centre for International Drug Monitoring were used to perform a disproportionality analysis. We computed reporting odds ratios (RORs) and corresponding 95% confidence intervals for the association between use of TNF inhibitors (infliximab, adalimumab, etanercept, certolizumab, and golimumab) and GBM or GBM-M compared to all other drugs with adverse events reported in the databases. A harmful signal was deemed for a lower limit of the 95% confidence interval above 1. Results We identified 81 cases of GBM or GBM-M with adalimumab in the U.S. FDA FAERS and 49 cases in the WHO drug monitoring database. For infliximab, 40 and 32 cases were identified in the FAERS and WHO databases, respectfully. Infliximab had the highest association with GBM (WHO: ROR = 7.41 (5.19–10.57), FAERS: ROR = 2.80 [1.89–4.15]). Adalimumab was also highly associated with GBM (WHO: ROR = 3.54 [2.58–4.89], FAERS: ROR = 1.99 [1.41–2.80]). Conclusion Several TNF inhibitors appear to be more strongly associated with GBM compared to other drugs in both the FAERS and WHO databases. Large epidemiologic studies are needed to confirm these findings. Although these results do not demonstrate a cause-and-effect relationship, they warrant further investigation by well-designed epidemiologic studies.

The prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) continues to pose a challenge for clinicians. The development of 5-hydroxytryptamine (serotonin) antagonists and neurokinin-1 receptor antagonists (NK1 -RAs) have demonstrated significant improvements in acute and delayed CINV for highly and moderately emetogenic chemotherapy. Delayed and breakthrough CINV, however, continue to be difficult to manage despite available treatment agents. Randomized clinical trial data suggest that olanzapine, a second-generation thienobenzodiazepine, traditionally used in the treatment of manifestations of psychotic disorders, is an effective agent in these clinical settings. The short-term use of olanzapine has a favorable adverse event profile and was not associated with grade 3 or 4 toxicity in a phase III study. Olanzapine is recommended as an option within first-line prophylaxis for CINV in the National Comprehensive Cancer Network (NCCN) guidelines and is an option for treatment of refractory CINV in the Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology and NCCN guidelines.

Hepatitis C virus (HCV) is the most common blood-borne infection in the United States. The high morbidity and mortality due to untreated infection have prompted updated screening recommendations that now include one-time HCV screening for all patients born between 1945 and 1965, in addition to risk factor-based screening. Current guidelines recommend treatment for all patients with chronic HCV. Treatment for HCV genotype 1 has evolved dramatically since the approval of the direct-acting antivirals. The approval of ledipasvir-sofosbuvir, ombitasvir-paritaprevir-ritonavir and dasabuvir, and simeprevir with sofosbuvir has dramatically altered the treatment landscape. High sustained virologic response (SVR) rates favor treatment, yet access to care poses a challenge for patients and providers. Current and emerging data with new therapies indicate high SVR rates in treatment-naive and treatment-experienced patients, including patients with cirrhosis and in other special populations. Additional data suggest the addition of ribavirin can decrease treatment duration without compromising SVR rates. Resistance is an increasing area of interest in HCV, with baseline mutations identified and the potential for the development of resistance-associate variants in patients undergoing treatment. Due to the rapid evolution of HCV treatment, pharmacists should address challenges and play an integral role in agent selection, dosing, drug interaction screening, adverse effect monitoring, and the coordination of treatment. Clinical application of the latest information will reduce patient risk and improve outcomes.

Amiodarone remains the mostly frequently used antiarrhythmic in clinical practice and is most often used to maintain normal sinus rhythm in patients with atrial fibrillation who have failed a rate control strategy. Amiodarone has superior efficacy over other antiarrhythmics, a lower risk of torsade de pointes, and a better cardiovascular safety profile in patients with structural heart disease. However, amiodarone is associated with notable noncardiac toxicities affecting the thyroid, lungs, eyes, liver, and central nervous system. Since 2000, clinicians have been advised to follow amiodarone monitoring guidelines provided by the Heart Rhythm Society. Adherence to these recommendations in clinical practice, however, is suboptimal. Pharmacists play a major role in ensuring the safe and effective use of medications, particularly high-risk medications such as amiodarone. This qualitative review details the evidence supporting the role of pharmacist-led amiodarone monitoring services (AMS) in improving adherence to amiodarone monitoring guidelines and identifying adverse effects. Five studies were identified, and, overall, these programs had a favorable impact on improving adherence to guideline-recommended monitoring standards for amiodarone. The available evidence is limited by the significant variations in study designs and outcome definitions, lack of patient randomization, and limited generalizability. Nevertheless, available studies suggest that pharmacist-led AMS may improve adherence to recommended monitoring guidelines and identification of amiodarone-related adverse effects. Further study is warranted to demonstrate whether these services impact the overall quality of care provided to patients receiving amiodarone, which may justify broader implementation.

Study Objective To evaluate the safety and tolerability of immunosuppressive drugs used in a planned randomized conversion from a calcineurin inhibitor, tacrolimus, to a mammalian target of rapamycin inhibitor, sirolimus, in de novo kidney transplant recipients. Design Prospective safety analysis of data from a prospective, randomized, open-label, controlled study. Patients A total of 119 adult kidney transplant recipients who received tacrolimus (TAC), mycophenolate sodium (MPS), and prednisone between February 2008 and May 2010; after 3 months of this regimen, 60 of these patients were randomized to conversion from TAC to sirolimus (SRL/MPS group), and 59 patients continued with the TAC regimen (TAC/MPS group). Measurements and Main Results Both groups were followed for 24 months after transplantation for immunosuppressive regimen–associated and time-dependent occurrences of adverse events (AEs) and serious adverse events (SAEs). Before conversion from TAC to SRL, the cumulative incidence of AEs was 98%; 25% were SAEs. Gastrointestinal AEs (66%) and infections (58%) were the most frequent AEs. The incidences of TAC and MPS dose reductions due to AEs were 1.7% and 12%, respectively. After conversion, no significant differences were noted in the SRL/MPS group versus the TAC/MPS group in the cumulative incidences of AEs (100% vs 98%) and SAEs (27% vs 30%). The most common AEs were gastrointestinal (70% vs 54%, p=0.23) and infection (77% vs 73%, p=0.79) in the SRL/MPS versus TAC/MPS groups. The incidence of aphthous ulcer (28% vs 0%, p=< 0.01), sinusitis (10% vs 0%, p=0.01), dermatitis (15% vs 3%, p=0.03), and dyslipidemia (35% vs 14%, p=0.02) were higher in the SRL/MPS group compared with the TAC/MPS group. Cox proportion regression analysis showed a higher relative risk for gastrointestinal (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2–3.01, p

Study Objective Because we previously observed a significant 41% reduction in gemfibrozil exposure after 2 weeks of lopinavir-ritonavir administration, we sought to determine the influence of lopinavir-ritonavir and ritonavir alone on the pharmacokinetics of fenofibric acid, an alternative to gemfibrozil for the treatment of elevated triglyceride levels. Design Open-label, single-sequence pharmacokinetic study. Setting Clinical Research Center at the National Institutes of Health. Subjects Thirteen healthy adult volunteers. Intervention Subjects received a single oral dose of fenofibrate 145 mg during three study phases: before ritonavir administration, after 2 weeks of administration of ritonavir 100 mg twice/day, and after 2 weeks of administration of lopinavir 400 mg–ritonavir 100 mg twice/day. Measurements and Main Results Serial blood samples were collected over 120 hours for determination of fenofibric acid concentrations. Fenofibric acid pharmacokinetic parameter values were compared before and after concomitant ritonavir or lopinavir-ritonavir administration. The geometric mean ratios (90% confidence intervals) for fenofibric acid area under the plasma concentration–time curve were 0.89 (0.77–1.01) after 14 days of ritonavir alone compared with baseline (p>0.05) and 0.87 (0.69–1.05) after 14 days of lopinavir-ritonavir compared with baseline (p>0.05). Study drugs were generally well tolerated; all adverse events were mild or moderate, transient, and resolved without intervention. Conclusion In contrast to a significant interaction between gemfibrozil and lopinavir-ritonavir, neither lopinavir-ritonavir nor ritonavir alone altered the pharmacokinetics of fenofibric acid in healthy volunteers. These data suggest that fenofibrate remains an important option in human immunodeficiency virus–infected patients receiving common ritonavir-boosted therapy.

Antibiotics are often misused, resulting in a high frequency of adverse effects, emergence of drug-resistant organisms, and excessive costs. The high cost of antibiotics is currently receiving the greatest attention. Considerable cost savings can be achieved by appropriate prescribing of antibiotics for patients receiving these drugs prophylactically as well as for those with established infections. This article cites specific examples of how cost-effective antibiotic prescribing practices can realize substantial cost savings without any diminished quality in patient care.

Abnormal uterine bleeding in women with a blood dyscrasia, such as leukemia, or who experience thrombocytopenia secondary to myelosuppressive chemotherapy is a clinical condition associated with significant morbidity. Consequently, effective management is necessary to prevent adverse outcomes. Prevention of menorrhagia, defined as heavy regular menstrual cycles with more than 80 ml of blood loss/cycle or a cycle duration longer than 7 days, in this patient population is the goal of therapy. Gonadotropin-releasing hormone analogs (e.g., leuprolide) are promising therapies that have been shown to decrease vaginal bleeding during periods of thrombocytopenia and to have minimal adverse effects other than those associated with gonadal inhibition. In patients who experience menorrhagia despite preventive therapies, or in patients who have thrombocytopenia and menorrhagia at diagnosis, treatment is indicated. For these women, treatment options may include platelet transfusions, antifibrinolytic therapy (e.g., tranexamic acid), continuous high-dose oral contraceptives, cyclic progestins, or other therapies for more refractory patients such as danazol, desmopressin, and recombinant factor VIIa. Hormonal therapies are often the mainstay of therapy in women with menorrhagia secondary to thrombocytopenia, but data for these agents are sparse. The most robust data for the treatment of menorrhagia are for tranexamic acid. Most women receiving tranexamic acid in randomized trials experienced meaningful reductions in menstrual bleeding, and this translated into improved quality of life; however, these trials were not performed in patients with cancer. Further clinical trials are warranted to evaluate both preventive and therapeutic agents for menorrhagia in premenopausal women with cancer who are receiving myelosuppressive chemotherapy.

Approximately 100,000 patients begin hemodialysis each year in the United States. Although an arteriovenous fistula or graft is the preferred method for long-term vascular access during hemodialysis, as these types of vascular access are the most reliable, approximately 30% of patients require the use of catheters to continue hemodialysis. Tunneled, cuffed hemodialysis catheters are discouraged for permanent vascular access because of their high rates of infection, morbidity and mortality, and thrombotic and technical complications. These catheters have a short functional life span and require medical intervention, often thrombolytic therapy, to treat the catheter malfunction. No thrombolytic agent is specifically indicated for the management of occluded hemodialysis catheters. Thus, we performed a systematic review to critically evaluate all available studies that examined the efficacy, safety, and cost of thrombolytic therapy for the management of dysfunctional hemodialysis catheters. Studies were included if they reported efficacy in a specific proportion of affected dysfunctional hemodialysis catheters; reported the proportion of patients experiencing an adverse outcome (especially bleeding); and described the type of catheter used, dose of thrombolytic agent, administration protocol, dwell time, definition of treatment success, time to follow-up for study end points, and sample size. Eighteen studies met the inclusion criteria. The mean ± SD success rate in clearing dysfunctional hemodialysis catheters was greatest with reteplase at 88 ± 4%, followed by alteplase at 81 ± 37% and tenecteplase at 41 ± 5%. Adverse effects associated with the use of these thrombolytic agents administered at low doses were extremely rare. No serious adverse bleeding events attributed to thrombolytic therapy were reported in any of the trials. Aliquotted reteplase from vials for intravenous use was the least costly thrombolytic agent. Thus, at centers that use high volumes of thrombolytics for dysfunctional hemodialysis catheters, reteplase is the thrombolytic agent of choice.

Study Objective. To assess the effects of the cytochrome P450 (CYP) 3A genotype, CYP3A5, on atorvastatin pharmacokinetics and its interaction with clarithromycin. Design. Prospective, two-phase, randomized-sequence, open-label pharmacokinetic study. Setting. Clinical research center at a teaching hospital. Subjects. Twenty-three healthy volunteers who were screened for genotype: 10 subjects carried the CYP3A5*1 allele (expressors) and 13 subjects did not (nonexpressors). Intervention. In one phase, subjects received a single oral dose of atorvastatin 20 mg. In the other phase, subjects received clarithromycin 500 mg twice/day for 5 days; on day 4 after the morning dose, subjects also received a single oral dose of atorvastatin 20 mg. All subjects participated in both phases of the study, which were separated by at least 14 days. Measurements and Main Results. Pharmacokinetic parameters of both forms of atorvastatin-atorvastatin acid and atorvastatin lactone-were compared between CYP3A5 expressors and nonexpressors, both in the absence and presence of clarithromycin, a strong CYP3A inhibitor. The acid form is pharmacologically active, and the lactone form has been associated with the atorvastatin's muscle-related adverse effects. Atorvastatin acid exposure did not differ significantly between CYP3A5 genotype groups. When subjects had not received clarithromycin pretreatment, the area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-∞)) of atorvastatin lactone was 36% higher in nonexpressors than in expressors (median 47.6 ng•hr/ml [interquartile range (IQR) 37.8-64.3 ng•hr/ml] vs 34.9 ng•hr/ml [IQR 21.6-42.2 ng•hr/ml], p=0.038). After clarithromycin pretreatment, changes in the pharmacokinetic parameters of atorvastatin acid and lactone were not significantly different between the nonexpressors versus the expressors; however, the increase in the AUC(0-∞) of atorvastatin lactone was 37% greater in expressors than in nonexpressors (geometric mean ± SD 3.59 ± 0.57 vs 2.62 ± 0.35, p=0.049). Conclusion. Our data suggest that the CYP3A5 genotype has minimal effects on the pharmacokinetic parameters of atorvastatin and its interaction with clarithromycin; these effects are unlikely to be clinically significant.

Clostridium difficile is an emerging pathogen in certain health care systems and community-based populations that is associated with high rates of morbidity and mortality, as well as increased costs for the health care system. As recurrence rates increase, new pharmacologic agents to treat C. difficile infection are needed. Fidaxomicin, a novel macrocyclic antibiotic, was recently approved by the United States Food and Drug Administration for the treatment of C. difficile-associated diarrhea. Originally isolated from fermentation broth of Dactylosporangium aurantiacum subspecies hamdenensis, the drug has a selective spectrum, distinctive pharmacokinetic and pharmaco-dynamic properties, and a favorable adverse-effect profile. Fidaxomicin has demonstrated similar clinical cure rates (i.e., resolution of diarrhea) compared with vancomycin, with lower recurrence rates and higher global cure rates (i.e., resolution of diarrhea without recurrence) in non-restriction endonuclease analysis type BI, North American Pulsed Field type 1 (NAP1), polymerase chain reaction ribotype 027 (or non-BI/NAP1/027) strains. Overall, fidaxomicin has been generally well tolerated, with the most common adverse effects reported as mild gastrointestinal complaints. Fidaxomicin appears to be a useful agent in the treatment of severe C. difficile infection, demonstrating decreased rates of recurrence.

Study Objective. To assess the drug-related risk of adverse events associated with ziprasidone. Design. Meta-analysis of 19 randomized, placebo-controlled trials. Patients. A total of 4132 adults taking oral ziprasidone who had adverse-event data reported in the studies identified. Measurements and Main Results. A systematic review (January 1996-October 2010) was conducted by using the EMBASE and MEDLINE databases to identify Cochrane reviews, controlled clinical trials, meta-analyses, randomized controlled trials, and systematic reviews; studies were limited to those published in English and those conducted in humans. The www.ClinicalTrials.gov Web site was also searched for ziprasidone studies. A total of 887 citations were reviewed; 31 articles met the criteria for inclusion, of which 19 were included in the final analysis. Data were combined for the meta-analysis by using the Mantel-Haenszel method, random-effects model at 95% confidence. The overall rate of treatment-emergent adverse events for ziprasidone was 73% compared with 60% for patients receiving placebo (p

The United States Food and Drug Administration (FDA) Amendments Act of 2007 mandated that Risk Evaluation and Mitigation Strategies (REMS) be required of manufacturers. These REMS are strategies implemented to manage known or potential risks associated with drugs and to ensure ongoing pharmacovigilance throughout the life of a pharmaceutical product, including once the product becomes available as generic. The elements of an individual REMS program consist of three levels: medication guide or patient package insert, communication plan, and elements to assure safe use (ETASU). A medication guide or patient package insert is used to help prevent serious adverse events, aid in patient decision making, and enhance drug adherence. Communication plans are used to educate health care providers and to encourage their compliance with REMS. The ETASU is a restrictive process that is implemented when it is deemed necessary to ensure that patients have safe access to products with known serious risks that would otherwise be unavailable. To review the components of REMS and specifically assess their impact on health care providers practicing within the organ transplantation arena, a literature search of the MEDLINE database (January 2007-December 2010) was performed, and published materials from the FDA and its Web site were also reviewed. In transplantation, REMS programs exist for both everolimus (medication guide and communication plan) and sirolimus (medication guide). The FDA has stated that all mycophenolic acid derivatives will be subject to a proposed REMS that has not yet been approved; however, both branded mycophenolic acid agents already have approved medication guides. The REMS are a permanent fixture in the development and marketing of pharmaceutical agents, and their further implementation in solid organ transplantation is inevitable. Transplantation providers should take a proactive role in patient education and implementation of REMS within the therapeutic area. It is imperative for health care providers to realize that the ultimate goals of REMS are to reduce the potential for serious risks and to make outcomes from the treatment of disease more predictable.

Study objective To evaluate the clinical response and safety of high-dose daptomycin for treatment of complicated gram-positive infections. Design Multicenter, retrospective, observational, case series analysis. Setting Five academic medical centers in four major United States cities. Patients Two hundred fifty adults, not undergoing dialysis, who received high-dose daptomycin (≥ 8 mg/kg/day) for at least 72 hours for complicated gram-positive infections between January 1, 2005, and March 1, 2010. Measurements and main results Clinical and microbiologic outcomes were assessed at the end of high-dose daptomycin therapy. Safety evaluations were recorded for all patients, and when available, baseline, end-of-therapy, and highest observed serum creatine phosphokinase (CPK) levels were recorded. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) were the primary organisms isolated. The median dose of daptomycin was 8.9 mg/kg/day (interquartile range [IQR] 8.0-10.0 mg/kg/day). The median duration of daptomycin during hospitalization for MRSA and VRE infection was 10 days (IQR 5-16 days) and 13 days (IQR 6-18 days), respectively. Among the 250 patients, high-dose daptomycin was primarily used as salvage therapy after vancomycin treatment (184 patients [73.6%]). Primary infections included complicated bacteremia (119 patients [47.6%]), endocarditis (59 [23.6%]), skin or wound (70 [28.0%]), and bone or joint (67 [26.8%]). Overall, clinical response and microbiologic success were assessed in 83.6% (209/250 patients) and 80.3% (175/218 patients), respectively. Isolates from 13 patients (5.2%) developed nonsusceptibility to daptomycin, with most of these patients having extended vancomycin exposure. Three patients (1.2%) developed an adverse event attributable to high-dose daptomycin therapy, with the event considered either mild or moderate in severity. The median end-of-therapy CPK level was 39 U/L (IQR 26-67 U/L). No significant correlation was found between daptomycin dose and highest observed CPK level. Conclusion Daptomycin dosages of 8 mg/kg/day or greater may be safe and effective in patients with complicated gram-positive infections. Further clinical studies are warranted.

Study Objective. To provide clinicians with an understanding of the comparative occurrence of linezolid and blindness, and to provide any clinically relevant characteristics that may be useful in identifying the patients at risk. Design. Retrospective cohort study. Data Source. Spontaneous reports in the United States Food and Drug Administration Adverse Event Reporting System (AERS) database generated between November 1, 1997, and December 21, 2008. Patients. Twenty-nine patients who experienced blindness while receiving linezolid therapy. Measurements and Main Results. Available information related to each case of linezolid-reported blindness in the AERS database was qualitatively and quantitatively reviewed. Optic nerve disorders, glaucoma, and treatment with linezolid for long durations were common characteristics in patients experiencing blindness. A limitation of AERS is the lack of a quantitative exposure estimate to put rare adverse events of the AERS, such as linezolid-related blindness, into perspective. To overcome this limitation, disproportionality analysis with Bayesian correction methodology was used. Disproportionality analysis uses an adverse event relative reporting ratio (RRR) to compare the occurrence of a specific adverse event with an index drug of interest to the occurrence of the same adverse event with similar agents or with all other FDA-approved prescription drugs. The disproportionality analysis was considered meaningful if the 5th percentile of the distribution of the RRR (RRR05) was 2 or greater. Among the 29 reported cases of linezolid use and blindness, an RRR05 of 2.1 was determined for linezolid-related blindness compared with all other agents listed in the AERS. Also, RRR05 values of 2.7 and 2.2 were found when linezolid was compared with all other systemic antibiotics and a select subgroup of antibiotics, respectively. Conclusion. Although disproportionality analyses suggested a quantitative signal for an association between linezolid use and blindness, causality cannot be inferred from the data. Thus, additional rigorous scientific analyses are warranted to explore these findings.

Study Objective. To determine if the use of acid-suppressing drugs is increased before the occurrence of ischemic events. Design. Population-based, nested case-control analysis. Data Source. Administrative databases in Saskatchewan, Canada. Patients. Cases were 1612 patients (aged ≥ 40 yrs) who started a first-ever antihypertensive drug between January 1, 1994, and December 31, 2003, and were hospitalized for a first ischemic heart event of either myocardial infarction (1002 patients) or unstable angina (610 patients); five control patients were matched to each case patient by age, sex, and year of first antihypertensive prescription (8060 controls). Measurements and Main Results. Within the case and control groups, we calculated exposure to acid-suppressing therapy, defined as proton pump inhibitors (PPIs) or histamine2-receptor antagonists (H2RAs), within 90 days leading up to the event. Exposure to acid-suppressing therapy was higher among cases than controls (15.3% [246/1612] vs 10.4% [837/8060], adjusted odds ratio [AOR] 1.26, 95% confidence interval [CI] 1.06–1.49, p

Study Objective—To evaluate whether the level of systemic exposure to atenolol explains observed interindividual differences in adverse metabolic responses. Design—Open-label, prospective, pharmacokinetic pilot substudy of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. Setting—General clinical research center. Patients—Fifteen hypertensive adults (mean age 46 ± 8.9 yrs) who were enrolled in the PEAR study. Intervention—Patients received atenolol therapy for at least 8 weeks, with 5 of those weeks at a dosage of 100 mg/day, and then underwent a 2-hour oral glucose tolerance test during a pharmacokinetic study visit. Measurements and Main Results—Twenty-hour plasma atenolol concentrations were measured during the pharmacokinetic visit. Glucose and insulin levels were measured during the 2-hour oral glucose tolerance test, and fasting plasma lipid, glucose, and insulin levels were measured at baseline and after 8 weeks of atenolol treatment. A significant association was noted between atenolol area under the concentration-time curve (AUC) and change in fasting glucose level when adjusted for covariates (p=0.0025); the effect was strongest in women. No significant relationship was noted between plasma atenolol concentration and glucose AUC during oral glucose tolerance testing (r=0.08, p=0.78), nor between atenolol AUC and change in triglyceride levels (r=0.13, p=0.63). Conclusion—Higher plasma atenolol exposure may be a risk factor for an increase in fasting plasma glucose level during atenolol treatment. These findings require confirmation in a larger sample.