Christine M. Cheng

Bevacizumab for Neovascular Ocular Diseases

Objective: To review the efficacy and safety of off-label use of bevacizumab for neovascular ocular diseases. Data Sources: A PubMed (1966–January 2007) search was conducted using the terms human, intravitreal, bevacizumab, macular, and retinopathy. Meeting abstracts from the American Academy of Ophthalmology, Retina Society, Macula Society, and Association for Research in Vision and Ophthalmology were reviewed. Study Selection and Data Extraction: Controlled studies, unpublished reports involving 100 or more subjects, and published reports describing 5 or more subjects were reviewed. Only English-language articles were considered. Data Synthesis: Intravitreal bevacizumab has been evaluated in 133 patients in unpublished controlled studies. Over 3500 patients have been evaluated in open-label studies with duration of follow-up ranging from 3 months to 1 year. The most common use was neovascular age-related macular degeneration (AMD). Other conditions studied included diabetic retinopathy, pathological myopia, neovascular glaucoma, and macular edema due to diabetes, retinal vein occlusion, or uveitis. Statistically significant improvements in visual acuity, as well as decreases in retinal thickness and the extent of choroidal neovascularization, were noted. Intravitreal bevacizumab was well tolerated over the short term. In a registry compiling adverse experiences of 7113 intravitreal injections, rates of adverse events were less than or equal to 0.21%. Conclusions: Uncontrolled studies support a benefit of intravitreal bevacizumab in neovascular AMD for 3 months to 1 year. Low cost is a significant advantage of bevacizumab. Patients should discuss the potential risks and benefits of intravitreal bevacizumab and other available therapies with their physicians before receiving treatment. Controlled trials are needed to characterize the safely and efficacy of intravitreal bevacizumab and determine the optimal treatment regimen.

The FDA extended warning for intravenous haloperidol and torsades de pointes: How should institutions respond?†

BACKGROUND In September 2007, the Food and Drug Administration (FDA) strengthened label warnings for intravenous (IV) haloperidol regarding QT prolongation (QTP) and torsades de pointes (TdP) in response to adverse event reports. Considering the widespread use of IV haloperidol in the management of acute delirium, the specific FDA recommendation of continuous electrocardiogram (ECG) monitoring in this setting has been associated with some controversy. We reviewed the evidence for the FDA warning and provide a potential medical center response to this warning. METHODS Cases of intravenous haloperidol-related QTP/TdP were identified by searching PubMed, EMBASE, and Scopus databases (January 1823 to April 2009) and all FDA MedWatch reports of haloperidol-associated adverse events (November 1997 to April 2008). RESULTS A total of 70 of IV haloperidol-associated QTP and/or TdP were identified. There were 54 reports of TdP; 42 of these events were reportedly preceded by QTP. When post-event QTc data were reported, QTc was prolonged >450 msec in 96% of cases. Three patients experienced sudden cardiac arrest. Sixty-eight patients (97%) had additional risk factors for TdP/prolonged QT, most commonly receipt of concomitant proarrhythmic agents. Patients experiencing TdP received a cumulative dose of 5 mg to 645 mg, patients with QTP alone received a cumulative dose of 2 mg to 1540 mg. CONCLUSIONS While administration of IV haloperidol can be associated with QTP/TdP, this complication most often took place in the setting of concomitant risk factors. Importantly, the available data suggest that a total cumulative dose of IV haloperidol of <2 mg can safely be administered without ongoing electrocardiographic monitoring in patients without concomitant risk factors.

Systematic review of medication safety assessment methods.

PURPOSE The accuracy, efficiency, and efficacy of four commonly recommended medication safety assessment methodologies were systematically reviewed. METHODS Medical literature databases were systematically searched for any comparative study conducted between January 2000 and October 2009 in which at least two of the four methodologies-incident report review, direct observation, chart review, and trigger tool-were compared with one another. Any study that compared two or more methodologies for quantitative accuracy (adequacy of the assessment of medication errors and adverse drug events) efficiency (effort and cost), and efficacy and that provided numerical data was included in the analysis. RESULTS Twenty-eight studies were included in this review. Of these, 22 compared two of the methodologies, and 6 compared three methods. Direct observation identified the greatest number of reports of drug-related problems (DRPs), while incident report review identified the fewest. However, incident report review generally showed a higher specificity compared to the other methods and most effectively captured severe DRPs. In contrast, the sensitivity of incident report review was lower when compared with trigger tool. While trigger tool was the least labor-intensive of the four methodologies, incident report review appeared to be the least expensive, but only when linked with concomitant automated reporting systems and targeted follow-up. CONCLUSION All four medication safety assessment techniques-incident report review, chart review, direct observation, and trigger tool-have different strengths and weaknesses. Overlap between different methods in identifying DRPs is minimal. While trigger tool appeared to be the most effective and labor-efficient method, incident report review best identified high-severity DRPs.

Unlabeled uses of botulinum toxins: A review, part 1

PURPOSE Efficacy and safety data regarding the unlabeled uses of botulinum toxins are reviewed, and the pharmacology, adverse effects, and characteristics of commercially available botulinum toxins are discussed. SUMMARY More than 300 articles have been published on the use of botulinum toxins, particularly botulinum toxin type A, to treat conditions characterized by excessive smooth or skeletal muscle spasticity. Botulinum toxins are synthesized by Clostridium botulinum and cause temporary local paralysis of the injected muscle by inhibiting acetylcholine release at the neuromuscular junction. While botulinum toxins have Food and Drug Administration-approved labeling to treat a limited number of spasticity disorders, including cervical dystonia and blepharospasm, the toxins have more than 50 reported therapeutic uses. Among these uses, the most rigorously studied indications include achalasia, essential tremors, palmar hyperhidrosis, chronic anal fissures, headache prophylaxis, and limb spasticity. The main adverse effects of the toxins are pain and erythema at the injection site, although unintended paralysis of muscles adjacent to the site of toxin injection may also occur. CONCLUSION Clinical studies support the use of botulinum toxins for certain conditions, although more studies are needed to establish the role of the drug relative to conventional therapies and to determine patient predictors of response. Although botulinum toxins are generally well tolerated, a patient-specific risk-benefit assessment should precede any decision to use them for unlabeled indications.

Black Box Warning Contraindicated Comedications: Concordance Among Three Major Drug Interaction Screening Programs

BACKGROUND Black box warnings represent the strongest safety warning that the Food and Drug Administration can issue for a marketed prescription drug. Some black box warnings recommend against coadministration of specific medications due to an increased risk for serious, perhaps life-threatening, effects. OBJECTIVE To determine the level of agreement in presence, clinical severity scores level of documentation ratings, and alert content among 3 leading drug interaction screening programs with regard to contraindicated comedications that are mentioned in black box warnings. METHODS We reviewed the prescribing information for currently marketed prescription drugs with a black box warning that mentioned a contraindicated drug combination. We selected the drug interaction databases Facts & Comparisons 4.0, MICROMEDEX DRUG-REAX, and Lexi-Comp Lexi-Interact to evaluate the interactions. Discrepancies in the inclusion of interactions and level of agreement in clinical severity scores and level of documentation ratings for each interaction were assessed, using descriptive statistics, Spearmans correlation coefficient, Kendall-Stuart Ö-c, and Cronbachs α. RESULTS We identified 11 drugs with black box warnings that contained information on 59 unique contraindicated drug combinations, only 68% of which were covered by any source. Lexi-Comp detected the most interactions (n = 29) and DRUG-REAX the least (n = 18). Only 3 drug combinations were detected and rated as contraindicated or potentially life-threatening in all 3 databases. The severity scores and level of documentation ratings varied widely. CONCLUSIONS There are discrepancies among major drug interaction screening programs in the inclusion, severity, and level of documentation of contraindicated drug combinations mentioned in black box warnings. Further studies could explore the implications of these inconsistencies, particularly with regard to the integration of black box warning information in clinical practice. Clinicians should consult multiple drug resources to maximize the potential for detecting a potentially severe drug interaction.

A review of three stand-alone topical thrombins for surgical hemostasis

BACKGROUND Topical thrombins are active hemostatic agents that can be used to minimize blood loss during surgery. Before 2007, the only topical thrombins available were derived from bovine plasma. Antibody formation to bovine thrombin and/or factor V, with subsequent risk of cross-reactivity with human factor V, and hemorrhagic complications associated with human factor-V deficiencies have been described in case reports of surgeries in which bovine thrombins were used. This risk is now included in the boxed warning section of the bovine thrombin prescribing information. In 2007 and 2008, 2 new topical thrombins from nonbovine sources received approval for use from the US Food and Drug Administration. The 3 active topical thrombins that are currently marketed are bovine plasma-derived thrombin, human plasma-derived thrombin, and human recombinant thrombin. OBJECTIVE The purpose of this review was to evaluate the literature on the efficacy and safety of topical thrombins and discuss the pharmacoeconomic considerations associated with their use. METHODS PubMed, EMBASE, and International Pharmaceutical Abstracts were searched for relevant papers published in English through October 10,2008, using the terms thrombin, human recombinant thrombin, bovine thrombin, plasma derived thrombin, and topical thrombin. Manufacturer-provided materials were also reviewed. Abstracts and unpublished data, as well as evaluations of sealants, adhesives, glues, and other hemostats that contain thrombin mixed with fibrinogen and other clotting factors, were excluded. RESULTS Four randomized, double-blind studies involving the active, stand-alone topical thrombins were found. The bovine thrombin involved in these studies was the predecessor to the currently marketed, highly purified bovine formulation. No studies comparing the human products, studies involving the highly purified bovine preparation, or placebo-controlled studies involving bovine thrombin were found. In a Phase III comparison of human recombinant thrombin and bovine thrombin, the percentages of patients who achieved hemostasis within 10 minutes of topical thrombin application were 95.4% and 95.1%, respectively (95% CI, -3.7 to 5.0). The incidence of hemostasis within 10 minutes was also similar in a Phase III comparison of human plasma-derived thrombin and bovine thrombin (both, 97.4% [95% CI, 0.96 to 1.05]). In the study that compared human recombinant and bovine thrombin, the incidence of antiproduct antibody formation was 21.5% (43/200) in the bovine thrombin group and 1.5% (3/198) in the human recombinant thrombin group (P < 0.001); patients with antibodies to bovine thrombin had numerically higher incidences of bleeding or thromboembolic events than did patients without these antibodies (19% vs 13%; P value not reported). Human plasma-derived thrombin is available as a frozen sterile solution that must be thawed before application, whereas the human recombinant and bovine plasma-derived products are supplied as unrefrigerated sterile powders that must be reconstituted before use. The human thrombins are more costly than bovine thrombin on a per-vial basis. The average wholesale prices (US

Intrathecal Ziconotide for Refractory Chronic Pain

, 2008) for 5000-IU vials of bovine thrombin and human recombinant thrombin were

Potential roles for pharmacists in pharmacogenetics

87.85 and

Trends in Boxed Warnings and Withdrawals for Novel Therapeutic Drugs, 1996 Through 2012

103.20, respectively; the average wholesale price for a 4000- to 6000-IU vial of human plasma-derived thrombin was

Expression Quantitative Trait Loci and Receptor Pharmacology Implicate Arg1 and the GABA-A Receptor as Therapeutic Targets in Neuroblastoma

96.00. CONCLUSIONS Topical thrombins vary in the ways in which they are manufactured and their safety profiles, storage requirements, and costs. Human recombinant thrombin and human plasma-derived thrombin have each been shown to have hemostatic efficacy comparable to that of bovine thrombin. Bovine thrombin carries the risk of formation of cross-reactive antibodies to bovine thrombin, factor V, and other impurities that may be present in these formulations. Immunogenicity data for the currently marketed, highly purified bovine thrombin relative to older formulations of bovine thrombin could not be found. Whether the potential safety advantage justifies the added cost of the human products remains to be established.