Golimumab: a tumor necrosis factor alpha inhibitor for the treatment of rheumatoid arthritis.

OBJECTIVE: To review the pharmacologic, pharmacokinetic, efficacy, and safety data of golimumab, an anti-tumor necrosis factor alpha (TNF-alpha) monoclonal antibody. DATA SOURCES: A search of MEDLINE (1950-September 2009) was performed to identify any published clinical trials or review articles pertaining to golimumab. Key search terms included golimumab, rheumatoid arthritis, CNTO 148, and anti-TNF-alpha inhibitors. Bibliographies of selected articles were reviewed to identify other relevant citations. Abstracts from national and international meetings and information from the manufacturer were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All available published articles and abstracts describing golimumab's pharmacologic or pharmacokinetic profile, efficacy, and safety were included. DATA SYNTHESIS: Golimumab is a fully humanized TNF-alpha monoclonal antibody that is specific for human TNF-alpha. Trials have investigated the use of golimumab in patients who have rheumatoid arthritis (RA) and are on methotrexate, are methotrexate-naïve, and have previously tried TNF-alpha inhibition therapy. When used in combination with methotrexate or another disease-modifying antirheumatic drug, golimumab therapy results in improvements of clinical outcomes including the American College of Rheumatology parameters in all of the aforementioned populations. Although multiple doses and dosing regimens have been studied, the Food and Drug Administration-approved dose is 50 mg subcutaneously every 4 weeks. The most common adverse effects include injection site erythema, headaches, and nausea. There were a limited number of incidences of serious infection or malignancy. CONCLUSIONS: With 4 TNF-alpha monoclonal antibodies currently on the market, it is unclear what golimumab's place in therapy for RA will be. Some benefits include monthly injections, proven efficacy after previous TNF-alpha inhibitor therapy, and limited antibody development during therapy. However, with a lack of longer-term trials assessing efficacy and safety compared with other TNF-alpha inhibitors, golimumab should be reserved for use after other therapies fail.

Evaluating the Impact of Auto-Calculation Settings on Opioid Prescribing at an Academic Medical Center.

BACKGROUND: Overprescribing of opioids is a key contributor to the opioid epidemic, which has led to a substantial increase in overdose deaths. The purpose of this study was to evaluate the discontinuation of a dispense quantity automatic calculation function on prescribing of as needed (PRN) opioids. METHODS: During the implementation of a new electronic health record (EHR), Vanderbilt University Medical Center discontinued functionality that autocalculated the maximum needed dispense quantity for PRN outpatient prescription opioids. This study analyzed prescribing trends for immediate-release hydrocodone- and oxycodone-containing prescriptions 90 days before and after implementation of the new EHR. RESULTS: A total of 21,323 prescriptions were analyzed in the preintervention group and 22,730 prescriptions in the postintervention group. Discontinuing the autocalculation functionality resulted in a mean decrease of 1.4 dispense units per prescription (58.5 vs. 57.1; p = 0.006) across all patient care areas. The most significant finding was a 10.5% relative decrease in dispense units from inpatient discharge prescriptions (37.2 vs. 33.3; p < 0.001). In the new EHR, PRN oxycodone products defaulted to a dispense quantity of 30, which resulted in a 142.0% (10.0% vs. 24.2%; p < 0.001) increase in oxycodone prescriptions ordered for 30 dispense units but was a net reduction in the doses dispensed per oxycodone prescription. CONCLUSION: This study suggests that removing the autocalculation functionality reduced the number of opioid units ordered. In addition, using a default dispense quantity for PRN opioid prescriptions may decrease the number of opioid dispense units per prescription.

Safety of TNF inhibitors in adolescents and children.

This article describes the use of tumor necrosis factor (TNF) inhibitors in children, reviews the pharmacology of these agents, and reviews and summarizes the current safety information available for etanercept, adalimumab, and infliximab. TNF inhibitors are being used for a variety of indications in children including Crohn's disease and juvenile idiopathic arthritis. However, the full safety profile of these agents is still not known. In adult patients, TNF inhibitors have demonstrated a variety of adverse effects including increased risk of infection, malignancy, demyelinating disorders, and reactivation of latent diseases. In children the rate of adverse effects is harder to elucidate due to the limited number of patients in clinical trials and limited case reports. However, based on the data available, TNF inhibitors have been implicated in increasing the rate of malignancy in children, especially the rate of lymphoma. In addition, similarly with adults the rate of infections is increased and the types of infections are more rare or opportunistic. One of the more common adverse effects continues to be infusion or injection-site reactions, although children tend to have a lower rate of infusion reactions with infliximab compared to adults. Based on the limited safety information and long-term effect data, TNF inhibitors should be reserved in children for patients with refractory disease and the risks need to be understood and assessed prior to initiation.

Interaction between clopidogrel and proton-pump inhibitors.

The American Heart Association/American College of Cardiology guidelines recommend initiating a proton-pump inhibitor (PPI) to prevent gastrointestinal bleeding if patients are receiving concomitant therapy with clopidogrel and aspirin. Recently, concern has been raised regarding the ability of PPIs to decrease the antiplatelet activity of clopidogrel. To date, there are 16 studies that evaluated the outcomes of using clopidogrel with a PPI. One of the studies has shown that adding lansoprazole to clopidogrel has no effect on the concentration of clopidogrel's inactive metabolite. The eight clinical trials that studied the effect of using PPIs and clopidogrel together on platelet function testing have shown differing effects between PPIs. Concurrent omeprazole and clopidogrel use was shown to decrease the antiplatelet effects of clopidogrel in three studies; whereas pantoprazole, lansoprazole and esomeprazole have been shown to have no significant effect on the antiplatelet response to clopidogrel. Six other studies showed that using PPIs and clopidogrel together led to adverse clinical outcomes; however, one study that did a separate analysis on pantoprazole, showed that using pantoprazole with clopidogrel had no significant impact on clinical outcomes. Post hoc analysis from a large randomized trial comparing prasugrel with clopidogrel indicated no clinically significant effects of PPIs in patients treated with either prasugrel or clopidogrel. Preliminary results from a prospective, randomized trial comparing cardiovascular clinical outcomes between omeprazole and placebo in clopidogrel-treated patients have been reported and suggest no interaction. However, the study was stopped prematurely secondary to loss of funding and follow-up limited to a median of 133 days so no firm conclusions were drawn. The data currently available regarding concurrent clopidogrel and PPI use are limited, so further studies are needed to provide a definite conclusion. Until additional prospective studies are available, the use of clopidogrel with a PPI should be avoided, if possible, and a H(2)-receptor antagonist be selected instead. Prasugrel may be administered safely with a PPI as there is currently no evidence of a pharmacokinetic, pharmacodynamic or adverse clinical effects.

Implementation and evaluation of vancomycin nomogram guidelines in a computerized prescriber-order-entry system.

PURPOSE: The implementation and evaluation of vancomycin nomogram guidelines in a computerized prescriber-order-entry (CPOE) system are described. METHODS: Initial vancomycin orders for patients over age 18 years who received vancomycin between August 1 and September 30, 2006 (preimplementation), and between March 1 and April 30, 2007 (postimplementation), were compared with vancomycin nomogram recommendations to determine if the vancomycin regimen ordered coincided with the nomogram recommendation. The numbers of regimen changes and vancomycin serum concentrations measured during the first five days of therapy were also assessed. A multivariate logistic regression model assessed independent predictors of an initial vancomycin order that met the nomogram recommendation RESULTS: A total of 522 vancomycin orders were included in the analysis (279 in the preimplementation group and 243 in the postimplementation group). A significant difference was observed in the percentage of initial vancomycin orders that met nomogram recommendations in the postimplementation group compared with the preimplementation group (36% versus 24%, p = 0.0028). No difference was noted between the two groups in the number of regimen changes or serum vancomycin concentrations measured during the first five days of therapy. In a multivariate analysis, age (p = 0.02) and weight (p < 0.0001) were negatively associated with a vancomycin order that met nomogram recommendations, while the postimplementation group was positively associated with an order that met nomogram recommendations (p = 0.001). CONCLUSION: A vancomycin nomogram implemented into a CPOE system increased the likelihood of patients receiving an initial vancomycin regimen that coincided with the nomogram's recommendations.

Phenytoin toxicity due to genetic polymorphism.

INTRODUCTION: Patients with traumatic brain injury commonly receive phenytoin for seizure prophylaxis. Due to the non-linear pharmacokinetics of phenytoin and narrow therapeutic window, phenytoin concentrations are monitored to ensure efficacy and prevent toxicity. Because phenytoin is hepatically metabolized, polymorphisms within cytochrome P450 enzymes can affect phenytoin concentrations. METHODS: We report a case of a 53-year-old Asian female admitted to the neuroscience intensive care unit after suffering a traumatic brain injury. Phenytoin was subsequently administered for seizure prophylaxis. RESULTS: Four days after being initiated on phenytoin, the patient remained lethargic, and phenytoin toxicity was suspected. Lab values revealed a free phenytoin concentration of 4.4 mg/l, and phenytoin was discontinued. Upon further investigation, it was found that the patient was a cytochrome P450 2C9 poor metabolizer. Causes of the patient's toxic phenytoin concentration such as drug interactions, decreased albumin, and lab error were excluded. The cause of her elevated phenytoin concentration was determined to be hepatic polymorphism. CONCLUSION: This case reveals the clinical significance of genetic polymorphisms and the effect on phenytoin dosage requirements. Because pharmacogenomic testing is expensive and not readily available, routine monitoring of phenytoin concentrations is warranted. Further, established polymorphisms should be documented to prevent toxicity of drugs metabolized by similar pathways.