Sensitivity and specificity of drug interaction databases to detect interactions with recently approved oral antineoplastics.

RATIONALE: Drug-drug interactions (DDIs) with oral antineoplastics (OAs) are of increasing concern given the rapid increase in OA approvals and use in cancer patients. A small pilot study of 20 DDIs with OAs showed significant variability in commonly used DDI screening databases in sensitivity of detecting potentially clinically relevant DDIs. This study builds upon that work by expanding the number of potential DDIs analyzed and including a specificity analysis. METHODS: Newly approved OAs from 2016 to May 2019 (n = 22) were included in this analysis. Prescribing information for each drug was reviewed. A list of explicit and theoretical drug interactions was created for each OA by the two investigators. A board-certified oncology pharmacist adjudicated all DDI pairs for potential clinical significance. In total, 229 DDI pairs were used to analyze sensitivity of 5 DDI databases (Lexicomp®, Micromedex®, Medscape, Eporactes®, & Drugs.com). Additionally, 64 "dummy" or false DDI pairs were created to analyze specificity. Sensitivity and specific were analyzed using Cochran's Qtest, while accuracy was analyzed using chi-square test. RESULTS: There was significant variability among the databases with regards to sensitivity (p < 0.0001), specificity (p < 0.0001), and accuracy (p < 0.0001). In terms of accuracy (max score = 400), Lexicomp®(355), Epocrates® (344), and Drugs.com (352) scored higher than MicroMedex® (270) and Medscape (280). CONCLUSIONS: Considerable variability exists among DDI screening databases with regards to OAs and potential drug interactions. Clinicians should be vigilant in both screening for DDIs with OAs and describing DDIs encountered in clinical practice.

Fibroblast growth factor receptor (FGFR) inhibitors: A review of a novel therapeutic class.

Comprehensive genomic profiling has an emerging role in cancer therapeutics. As treatment options remain needed for advanced cancers, patients are relying increasingly more on tumor genomic alterations as possible targets for cancer treatment. Frequent tumor fibroblast growth factor receptor (FGFR) alterations are seen in many cancers, and include genetic amplifications, mutations, rearrangements and fusions. FGFR inhibitors target these receptor alterations and show promise as a drug class. Currently 2 medications are currently FDA approved: erdafitinib and pemigatinib. Through the FDA accelerated approval process, erdafitinib is indicated to treat metastatic urothelial carcinoma with FGFR2 and FGFR3 alterations, whereas pemigatinib is indicated to treat unresectable cholangiocarcinoma with FGFR2 alterations. Despite growing knowledge about such advanced cancers, treatment is usually palliative. With multiple FGFR inhibitors in the pipeline, further FDA approvals are possible, and it is likely their role in therapy will extend to other cancer types. This review outlines erdafitinib, pemigatinib, their role in cancer, as well as outlining the possible future use of other FGFR inhibitors in urothelial carcinoma, cholangiocarcinoma, and other malignancies.

International usage of an English language oncology pharmacy podcast.

BACKGROUND: Pharmacy-specific podcasts are widely available and appear to be widely consumed. However, little is known about consumption of such podcasts. Objective: To describe the scope of listenership to OncoPharm, an oncology pharmacy podcast, and determine if any episode category is more popular than another. Methods: OncoPharm episodes released from Jan. 1, 2018 to May 10, 2019 were analyzed. The number of downloads or listens (DLs) was extracted from the podcast's hosting platform for evaluation. The number of DLs were tabulated from episode release date through May 31, 2019. The nation of DL was also extracted. Descriptive statistics were used to analyze DL numbers. One-way ANOVA was used to determine if any episode category (Foundational Topic, New Approval, Updates, Landmark Study, or Other) was more popular than another. Student's t-test was used to compare the mean DLs for the first 20 OncoPharm episodes to the last 20 episodes of the evaluation period. Results: Seventy-one podcast episodes were included in the evaluation period. These episodes were downloaded or listened to 17,816 times in 71 nations and territories. The average DLs per episode were 250.9 (SD 87.7). There was no difference in mean DLs by podcast episode category (p = 0.078). The last 20 episodes had more average DLs than the first 20 episodes (p = 0.04). Conclusion: OncoPharm has found a broad and growing audience interested in a variety of oncology pharmacy topics. This expanding and international audience suggests OncoPharm is filling an unmet educational need.

Peripheral neuropathy in non-Hodgkin's lymphoma patients receiving vincristine with and without aprepitant/fosaprepitant.

BACKGROUND: Peripheral neuropathy is a common treatment-related adverse effect associated with vincristine. Vincristine is a major CYP3A4 substrate and is often administered alongside the neurokinin-1 (NK-1) receptor antagonists, aprepitant or fosaprepitant, which are moderate CYP3A4 inhibitors. This inhibition may result in increased concentrations of vincristine and an increased incidence of toxicity. OBJECTIVE: The primary objective of this study was to investigate if there is a clinically significant drug interaction between vincristine and aprepitant or fosaprepitant resulting in early-onset peripheral neuropathy. The secondary objective of this study was to investigate the cumulative rate of chemotherapy-induced peripheral neuropathy (CIPN). METHODOLOGY: This was a single-centered, retrospective, cohort chart review. Patients receiving vincristine-based chemotherapy between 1 July 2010 through 30 June 2018 were identified and reviewed for concomitant use of aprepitant or fosaprepitant and incidence of neuropathy. Early-onset CIPN was defined as neuropathy onset during the first cycle of chemotherapy. RESULTS: A total of 115 subjects were retrospectively reviewed over the study period, of whom 71 were included in the aprepitant/fosaprepitant group and 44 were included in the group without a NK-1 receptor antagonist. Of the subjects who received aprepitant/fosaprepitant, 26.7% experienced early-onset peripheral neuropathy as compared to 22.7% in the group without a NK-1 receptor antagonist (P = 0.627). Overall, CIPN was higher in the group who received aprepitant/fosaprepitant compared to the group without (56% vs. 36%, P = 0.036). CONCLUSION: There appears to be an increased risk of CIPN with the concomitant use of vincristine and aprepitant or fosaprepitant.

Direct oral anticoagulants in patients with cancer.

PURPOSE: This review summarizes the available evidence concerning direct oral anticoagulant (DOAC) use to treat venous thromboembolism (VTE) in patients with cancer as well as pertinent safety data on the use of DOACs in patients with both cancer and atrial fibrillation. SUMMARY: The introduction of DOACs into clinical practice changed the way thrombotic complications are managed and prevented in diverse patient populations, including VTE and atrial fibrillation. Low-molecular-weight heparins have been the standard of care for treating VTE in cancer patients due to superiority over vitamin K antagonists in preventing recurrent VTE. Therefore, widespread DOAC use for VTE in patients with active cancer has not been adopted. CONCLUSION: Recent randomized clinical trials (SELECT-D, Hokusai VTE Cancer) have provided evidence that DOACs may have a role in treating VTE in cancer patients.

Severe sunitinib-induced myelosuppression in a patient with a CYP 3A4 polymorphism.

Sunitinib, an oral vascular endothelial growth factor receptor, is a first-line option for metastatic renal cell carcinoma and widely used in clinical practice. Despite the proven benefit of sunitnib in metastatic renal cell carcinoma, patients may suffer from a variety of adverse events including hypertension, fatigue, hypothyroidism, hand-foot skin reactions, rash, depigmentation, and myelosuppression. Myelosuppression is usually mild, transient and resolves during the two weeks at the end of each cycle where no drug is taken. We present a case of severe and early grade 3 neutropenia and thrombocytopenia occurring two weeks into a six-week cycle. Because of the extreme nature of the toxicity, CYP 3A4 polymorphisms were explored. The patient was found to be heterozygous for CYP 3A4*22, at least partially explaining the early-onset and severity of myelosuppression. This pharmacogenetics information resulted in a rechallenge of dose-reduced sunitinib, which was well tolerated by the patient. The current state of pharmacogenomics concerning sunitinb is also presented, and the need for greater research in this area is highlighted.

Mannitol Prescribing Practices With Cisplatin Before and After an Educational Newsletter Intervention.

Background: Mannitol has been used in the past for the prevention of cisplatin-induced nephrotoxicity. Studies on its efficacy have conflicting results. An educational newsletter was designed for local oncologists on the conflicting data of mannitol use in preventing cisplatin-induced nephrotoxicity. Purpose: The purpose of this study was to determine whether a pharmacist-created newsletter intervention led to changes in the mannitol prescribing practices of local oncologists. Methods: A newsletter describing the paucity of evidence to support mannitol use to prevent cisplatin-induced nephrotoxicity was distributed via e-mail to local oncologists in October 2010. Mannitol prescribing rates were retrospectively evaluated before and after newsletter distribution. The Mann-Whitney U test was used to compare nonparametric continuous data. The chi-square test was used for nominal data. Descriptive statistics were performed for baseline demographics, and odds ratios were calculated for possible risk factors for acute kidney injury (AKI). The primary endpoint was a change in mean mannitol dose before and after the newsletter intervention. The secondary endpoint was the difference in the rate of AKI before and after the intervention. Data were collected for 67 patients with various malignancies. Results: There was a difference in the average mannitol dose before and after newsletter intervention (P = .02). The rates of AKI before and after newsletter were similar. Conclusion: A pharmacist-led newsletter intervention was associated with significantly decreased rates of mannitol usage after intervention.

Drug Interaction Database Sensitivity With Oral Antineoplastics: An Exploratory Analysis.

PURPOSE: Drug interactions are a concern in oncology with the shift toward oral antineoplastics (OAs). Using electronic databases to screen for drug interactions with OAs is a common practice. There is little literature to guide clinicians on the reliability of these systems with OAs. The primary objective of this study was to explore the sensitivity of commonly available drug interaction databases in detecting drug interactions with OAs. METHODS: A list of 20 drug interactions with OAs was developed by two Board-certified oncology pharmacists. The list included multiple types of drug interactions. The sensitivity in detecting these interactions by MicroMedex, Facts & Comparisons, Lexi-Interact, and Epocrates were evaluated. These databases were chosen based on their local availability and widespread use in practice. Drugs.com was evaluated as a surrogate for a patient-accessible drug interaction database. The Cochran Q test was used to assess the sensitivity distribution across the five groups. RESULTS: Lexi-Interact and Drugs.com had a sensitivity of 95% for the 20 tested drug interaction pairs. Epocrates had a sensitivity of 90%, and both Micromedex and Facts & Comparisons had a sensitivity of 70%. There was a statistically significant difference ( P = .016) in the distribution across the databases in detecting clinically significant drug interactions. CONCLUSION: Commonly used databases for identifying drug interactions with oral antineoplastics vary significantly in their sensitivity. Clinicians should not rely on a single database and should consider using multiple resources as well as sound clinical judgment. Further work is needed in this area.

Drug interaction between idelalisib and diazepam resulting in altered mental status and respiratory failure.

In recent years, several new oral anticancer drugs have been approved, many via an accelerated approval process. These new agents have the potential for drug interactions, but lack of familiarity with these drugs by clinicians may increase the risk for drug interactions. We describe an interaction between the new anticancer agent idelalisib (CYP 3A4 inhibitor) and diazepam (CYP 3A4 substrate) that resulted in altered mental status and type II respiratory failure resulting in hospitalization. After discontinuation of both agents, the patient recovered quickly. Idelalisib was reinitiated after discharge. Lorazepam was substituted for diazepam since it is not metabolized via CYP 3A4. Both agents were tolerated well thereafter. This interaction was only flagged by two of four commonly used drug interaction databases. Clinicians should exercise caution with initiating new oral anticancer agents and consider the potential for drug interactions without solely relying on drug interaction databases.

Cardiovascular Toxicity and Management of Targeted Cancer Therapy.

The advent of effective oral, molecular-targeted drugs in oncology has changed many incurable malignancies such as chronic myeloid leukemia into chronic diseases similar to coronary artery disease and diabetes mellitus. Oral agents including monoclonal antibodies, kinase inhibitors and hormone receptor blockers offer patients with cancer incremental improvements in both overall survival and quality of life. As it is imperative to recognize and manage side effects of platelet inhibitors, beta blockers, statins, human immunodeficiency virus drugs and fluoroquinolones by all healthcare providers, the same holds true for these newer targeted therapies; patients may present to their generalist or other subspecialist with drug-related symptoms. Cardiovascular adverse events are among the most frequent, and potentially serious, health issues in outpatient clinics, and among the most frequent side effects of targeted chemotherapy. Data support improved patient outcomes and satisfaction when primary care and other providers are cognizant of chemotherapy side effects, allowing for earlier intervention and reduction in morbidity and healthcare costs. With the implementation of accountable care and pay for performance, improved communication between generalists and subspecialists is essential to deliver cost-effective patient care.

Student Performance in a Pharmacotherapy Oncology Module Before and After Flipping the Classroom.

Objective. To determine if a flipped classroom improved student examination performance in a pharmacotherapy oncology module. Design. Third-year pharmacy students in 2012 experienced the oncology module as interactive lectures with optional case studies as supplemental homework. In 2013, students experienced the same content in a primarily flipped classroom. Students were instructed to watch vodcasts (video podcasts) before in-class case studies but were not held accountable (ie, quizzed) for preclass preparation. Examination questions were identical in both cohorts. Performance on examination questions was compared between the two cohorts using analysis of covariance (ANCOVA), with prior academic performance variables (grade point average [GPA]) as covariates. Assessment. The students who experienced the flipped classroom approach performed poorer on examination questions than the cohort who experienced interactive lecture, with previous GPA used as a covariate. Conclusion. A flipped classroom does not necessarily improve student performance. Further research is needed to determine optimal classroom flipping techniques.

Low rate of cetuximab hypersensitivity reactions in Northeast Tennessee: An Appalachian effect?

PURPOSE: Cetuximab is a monoclonal antibody with a known risk of hypersensitivity reactions. Early studies showed hypersensitivity reaction rates of 3%, but there appears to be a higher incidence in the southeastern United States. To confirm the findings from nearby institutions that cetuximab-associated hypersensitivity reactions occur in approximately 20% of patients in the southeastern United States. METHODS: A retrospective chart review was conducted at Johnson City Medical Center in Johnson City, Tennessee. Each patient's first infusion was analyzed for hypersensitivity reaction, as well as for demographic information such as allergy and smoking history, pre-medications, and malignancy type. RESULTS: Data from the first infusion of cetuximab were collected for a total of 71 patients with various malignancies. The overall rate of grade 3 or higher hypersensitivity reaction was 1.4%, and total rate of hypersensitivity reaction was 8.5%. These findings more closely correlate to the early clinical trials and package insert. Both severe (p = 0.001) and any-grade (p = 0.002) hypersensitivity reaction occurred less frequently in one Southeastern Appalachian medical center compared to academic medical centers directly to the east and west. CONCLUSIONS: Patients in southern Appalachia may be less likely to develop cetuximab hypersensitivity reactions compared to surrounding areas in the Southeastern U.S. These results lend support to the theory that exposure to lonestar ticks (Amblyomma americanum) may be responsible for the development of IgE antibodies to cetuximab that cause hypersensitivity reactions. The development of quick and reliable bedside predictors of cetuximab hypersensitivity reactions may aid clinicians considering the use of cetuximab.

Soft tissue calcification secondary to imatinib mesylate in a patient with gastrointestinal stromal tumor.

Imatinib mesylate has been associated with the changes in bone turnover. We report a case of the development of tissue calcification in a patient on long-term therapy with this drug. A 48-year-old male patient with gastrointestinal stromal tumor and liver metastasis complained of abdominal pain. His treatment included hepatic artery chemoembolization and partial hepatectomy in addition to chronic imatinib mesylate for 4 years. On physical examination, he had a peritoneal mass just beneath the laparotomy incision scar that, after resection, was found to be dystrophic bone formation. Based on the previous studies suggesting bone changes due to chronic therapy with imatinib mesylate, we believe that the patient's new bone formation was causally related to the use of this drug. To our knowledge, there are no similar reported cases in the literature.

Probable etoposide interaction with Echinacea.

Echinacea is an herbal supplement commonly used as an immune system stimulant to prevent infections, such as the common cold or flu. Echinacea has been documented as a cyctochrome P450 (CYP) 3A4 inhibitor in vitro, but no formal studies have been conducted in humans. Etoposide is a cytotoxic, topoisomerase II inhibitor, chemotherapeutic agent used in the treatment of lung cancer. Etoposide is primarily metabolized by CYP 3A4. We report the first possible drug-herbal interaction between Echinacea and etoposide. A 61-year-old gentleman newly diagnosed with nonsmall cell lung cancer began concurrent chemoradiation with cisplatin and etoposide. He was admitted to the hospital on day 8 of his first cycle and found to be thrombocytopenic. His platelet count eventually reached a nadir of 16 × 10(3)/L, requiring platelet transfusion support. Upon admission, it was discovered he was taking Echinacea, which was discontinued. He received his next cycle of chemotherapy without taking Echinacea. His platelet count decreased to a nadir of 44 × 10(3)/L, but he did not require platelet transfusions. Echinacea likely contributed to this patient's profound thrombocytopenia and should be avoided in patients receiving etoposide and possibly other chemotherapeutic drugs that are CYP 3A4 substrates.

Incidence of vancomycin-resistant enterococci (VRE) infection in high-risk febrile neutropenic patients colonized with VRE.

PURPOSE: This study seeks to determine the incidence of vancomycin-resistant enterococci (VRE) infection in high-risk neutropenic fever patients colonized with VRE and to determine patient characteristics associated with VRE infection. METHODS: We conducted a retrospective, single-center, unmatched case-control study. Fifty-three VRE-colonized, high-risk patients with neutropenic fever were identified between January 2006 and February 2009. The two most common diagnoses/conditions included acute myeloid leukemia and hematopoietic stem cell transplantation. Data collected included days of neutropenia, days of fever, demographic data, culture results, and antimicrobial therapy. RESULTS: Twenty of the 53 patients (38%) with VRE colonization developed a VRE infection. The most common VRE infections were bacteremias (26%). The presence of neutropenia lasting longer than 7 days was associated with the development of VRE infection in this high-risk population colonized with VRE. The timeframe to develop VRE infection varied from 1 day to 2 weeks. CONCLUSION: For patients colonized with VRE, approximately 38% of high-risk neutropenic patients developed a VRE infection. This is the first study to specifically evaluate the incidence of VRE infections in febrile neutropenic patients colonized with VRE. Future research into the use and efficacy of empiric VRE coverage is needed.