Unexpected drug-induced Raynaud phenomenon: Analysis from the French national pharmacovigilance database.

Therapie. 2017 Oct;72(5):547-554

Authors: Bouquet É, Urbanski G, Lavigne C, Lainé-Cessac P

Abstract
OBJECTIVE: To estimate the association between exposure to medicinal products and Raynaud phenomenon.
METHODS: The study used the data of all adverse drug reactions notified to the French national pharmacovigilance database. All cases reported between 1st January 1995 and 10th December 2012 were selected. A case/non-case method was used to measure disproportionality of the association between drug exposure and Raynaud phenomenon. The cases concerned all observations involving Raynaud phenomenon. Non-cases comprised all other reports of adverse drug reactions over the same period.
RESULTS/DISCUSSION: Among the 307,128 adverse drug reaction reports selected from the French national pharmacovigilance database, 175 involved Raynaud phenomenon, most of them affecting women (61.1%). The mean age was 50.1 years, and 8% had a past medical history of Raynaud phenomenon. According to the summaries of product characteristics, 42.3% of these cases were exposed to drugs known to induce Raynaud phenomenon. Unexpected Raynaud phenomenons (unlisted in the summaries of product characteristics) were associated with exposure to drugs for which Raynaud phenomenons are published (interferons, ribavirin, gemcitabine) or for which Raynaud phenomenons are not published (hepatitis B vaccine, isotretinoin, leflunomide, hydroxycarbamide, rofecoxib, telmisartan, zolmitriptan).
CONCLUSION: The case/non-case method is usually used to generate signals. Further epidemiological studies are now necessary to confirm these findings.

PMID: 28336160 [PubMed - indexed for MEDLINE]

Personalized Medicine in the Paediatric Population: The Balance Between Pharmacogenetic Progress and Bioethics.

Curr Pharm Biotechnol. 2017;18(3):253-262

Authors: Schiavone S, Neri M, Pomara C, Riezzo I, Trabace L, Turillazzi E

Abstract
Personalized medicine (PM) is becoming increasingly important in contemporary clinical and research scenarios. In the context of PM, pharmacogenomics and pharmacogenetics are aimed at the genetic personalization of drug response. Extrinsic and intrinsic factors may explain interindividual variability in drug response. Among such factors, age seems to specifically intervene to modulate drug response since normal developmental changes may influence the exposure-response relation. Consequently, the potential benefit of pharmacogenomics (PGx) in the paediatric population is considerable. However, many challenges still exist in incorporating PGx into clinical practice. In fact, drug prescribing in the paediatric population is often based on extrapolation from clinical trials conducted on adults as there is often a lack of paediatric data. Children are not just 'small adults', as they have their own pharmacological characteristics in terms of drug metabolism and efficacy, adverse drug reactions and toxicity. Although children might potentially benefit from such research, many ethical concerns arise at the intersection of the spheres of drug development and genetic testing. Children require particular attention because of their vulnerability both in research and the clinical applications of PGx; furthermore, children range from preterm newborns and neonates to infants and toddlers and to adolescents, thus forming a further heterogeneous target group. In this paper, we focus on some ethically relevant concerns (i.e., informed consent, stigmatization, ancillary information) that might arise as a result of the possible application of PGx tests in both paediatric practice and research.

PMID: 28176639 [PubMed - indexed for MEDLINE]

Personalized Medicine and Adverse Drug Reactions: The Experience of An Italian Teaching Hospital.

Curr Pharm Biotechnol. 2017;18(3):274-281

Authors: La Russa R, Finesch V, Di Sanzo M, Gatto V, Santurro A, Martini G, Scopetti M, Frati P

Abstract
BACKGROUND: The personalized medicine is a model of medicine based on inherent difference given by the genetic heritage that characterizes us, diversity that can affect also our response to administered therapy. Nowadays, the term "adverse drug reaction" is identified with any harmful effect involuntary resulting from the use of a medicinal product; pharmacogenomics, in this field, has the aim to improve the drug response and to reduce the adverse reaction.
METHODS: We analyzed all reports of adverse reaction collected in the Pharmacovigilance Centre database of an Italian University Hospital, at the Sant'Andrea Hospital Sapienza University of Rome, in a period of two years.
RESULTS: Comparing the data result from our analysis with several studies found in literature, it is evident that adverse drug reactions represent an important problem in the management of a health care system. However, the development of pharmacogenetics and pharmacogenomics, allowing a personalized treatment, can improve clinical practice.
CONCLUSION: This study highlights the great potential of pharmacogenomics in reducing adverse reactions and suggests the need for further pharmacogenomic clinical trials to better personalize drug treatment and to refine the current pharmacovigilance strategies.

PMID: 28176638 [PubMed - indexed for MEDLINE]

FDA drug labeling: rich resources to facilitate precision medicine, drug safety, and regulatory science.

Drug Discov Today. 2016 Oct;21(10):1566-1570

Authors: Fang H, Harris SC, Liu Z, Zhou G, Zhang G, Xu J, Rosario L, Howard PC, Tong W

Abstract
Here, we provide a concise overview of US Food and Drug Administration (FDA) drug labeling, which details drug products, drug-drug interactions, adverse drug reactions (ADRs), and more. Labeling data have been collected over several decades by the FDA and are an important resource for regulatory research and decision making. However, navigating through this data is challenging. To aid such navigation, the FDALabel database was developed, which contains a set of approximately 80000 labeling data. The full-text searching capability of FDALabel and querying based on any combination of specific sections, document types, market categories, market date, and other labeling information makes it a powerful and attractive tool for a variety of applications. Here, we illustrate the utility of FDALabel using case scenarios in pharmacogenomics biomarkers and ADR studies.

PMID: 27319291 [PubMed - indexed for MEDLINE]

A narrative review of the safety concerns of deprescribing in older adults and strategies to mitigate potential harms.

Expert Opin Drug Saf. 2018 Jan;17(1):39-49

Authors: Reeve E, Moriarty F, Nahas R, Turner JP, Kouladjian O'Donnell L, Hilmer SN

Abstract
INTRODUCTION: As with prescribing or continuing medications, deprescribing brings with it the potential for harm as well as benefit. Uncertainty and avoidance of harm has been reported as a barrier to deprescribing in practice and may contribute to continuation of inappropriate medications. Areas covered: This narrative review covers four main safety concerns/potential harms of deprescribing in older adults: adverse drug withdrawal events, return of medical condition(s), reversal of drug-drug interactions and damage to the doctor-patient relationship. These are discussed in relation to medications in general, with some examples of medication classes used to illustrate the potential safety concerns. The majority of these harms can be minimized or even prevented by using a patient-centered, structured deprescribing process with planning, tapering and close monitoring during, and after medication withdrawal. Expert opinion: More research is needed into the safety concerns of deprescribing, however, avenues exist during drug development and post-marketing surveillance to gain knowledge on this topic. Questions remain about when it is suitable to discontinue certain medications/medication classes and there is uncertainty about the harms and benefits of both medication continuation and discontinuation in complex older adults.

PMID: 29072544 [PubMed - indexed for MEDLINE]

Non-Health Care Facility Cardiovascular Medication Errors in the United States.

Ann Pharmacother. 2017 Oct;51(10):825-833

Authors: Kamboj AK, Spiller HA, Casavant MJ, Hodges NL, Chounthirath T, Smith GA

Abstract
BACKGROUND: Prior studies have not examined national trends and characteristics of unintentional non-health care facility (HCF) medication errors associated with cardiovascular drugs.
OBJECTIVE: To investigate non-HCF medication errors associated with cardiovascular drugs reported to poison control centers in the United States.
METHODS: A retrospective analysis of non-HCF medication errors associated with cardiovascular drugs from 2000 to 2012 was conducted using the National Poison Data System database.
RESULTS: There were 278 444 medication errors associated with cardiovascular drugs reported to US poison control centers during the study period, averaging 21 419 exposures annually. The overall rate of cardiovascular medication errors per 100 000 population increased 104.6% from 2000 to 2012 ( P < 0.001) and the highest rates were among older adults. Most cases (83.6%) did not require treatment at a HCF. Serious medical outcomes were reported in 4.0% of exposures. The cardiovascular drugs most commonly implicated in medication errors were β-blockers (28.2%), calcium antagonists (17.7%), and angiotensin-converting enzyme inhibitors (15.9%). Most of the 114 deaths were associated with cardiac glycosides (47.4%) or calcium antagonists (29.8%). Most medication errors involved taking or being given a medication twice (52.6%).
CONCLUSIONS: This study describes characteristics and trends of non-HCF cardiovascular medication errors over a 13-year period in the United States. The number and rate of cardiovascular medication errors increased steadily from 2000 to 2012, with the highest error rates among older adults. Further research is needed to identify prevention strategies for these errors, with a particular focus on the older adult population.

PMID: 28608723 [PubMed - indexed for MEDLINE]

Dysregulation of cytokine mediated chemotherapy induced cognitive impairment.

Pharmacol Res. 2017 Mar;117:267-273

Authors: Ren X, St Clair DK, Butterfield DA

Abstract
One of the major complaints patients who survive cancer often make is chemotherapy induced cognitive impairment (CICI), which survivors often call "chemo brain." CICI is a side effect of chemotherapy due to the cytotoxicity and neurotoxicity of anti-cancer drugs causing structural and functional changes in brain, even when drugs that do not cross the blood brain barrier (BBB) are used. Diminished cognitive functions including diminution of learning and memory, concentration and attention, processing speed and executive functions that reduce quality of life and ability to work are common signs and symptoms of CICI. There still is not a clarified and complete mechanism for CICI, but researchers have pointed to several biochemical candidates. Chemotherapy-induced, cytokine-mediated involvement in CICI will be mainly discussed in this review paper with emphasis on different types of cytokines, correlated with BBB and epigenetic changes. Mechanisms of ROS-generating, anti-cancer drugs and their relation to cytokine-mediated CICI will be emphasized.

PMID: 28063894 [PubMed - indexed for MEDLINE]

Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer.

Ann Oncol. 2016 Jul;27(7):1291-8

Authors: Chatterjee M, Turner DC, Felip E, Lena H, Cappuzzo F, Horn L, Garon EB, Hui R, Arkenau HT, Gubens MA, Hellmann MD, Dong D, Li C, Mayawala K, Freshwater T, Ahamadi M, Stone J, Lubiniecki GM, Zhang J, Im E, De Alwis DP, Kondic AG, Fløtten Ø

Abstract
BACKGROUND: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients.
PATIENTS AND METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10 mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and non-linear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events (AEs) of interest based on their immune etiology.
RESULTS: Overall response rates were 15% [95% confidence interval (CI) 7%-28%] at 2 mg/kg Q3W, 25% (18%-33%) at 10 mg/kg Q3W, and 21% (95% CI 14%-30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6weeks indicated a flat relationship (regression slope P > 0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the AE incidence to be similar among the clinically tested doses.
CONCLUSIONS: No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.
CLINICALTRIALSGOV REGISTRY: NCT01295827.

PMID: 27117531 [PubMed - indexed for MEDLINE]

Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study.

Ann Oncol. 2016 Jul;27(7):1273-9

Authors: Folprecht G, Pericay C, Saunders MP, Thomas A, Lopez Lopez R, Roh JK, Chistyakov V, Höhler T, Kim JS, Hofheinz RD, Ackland SP, Swinson D, Kopp M, Udovitsa D, Hall M, Iveson T, Vogel A, Zalcberg JR

Abstract
BACKGROUND: The combination of aflibercept with FOLFIRI has been shown to significantly prolong overall survival in patients with metastatic colorectal cancer (mCRC) after progression on oxaliplatin-based therapy. This trial evaluated the addition of aflibercept to oxaliplatin-based first-line treatment of patients with mCRC.
PATIENTS AND METHODS: Patients with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus aflibercept (4 mg/kg) or mFOLFOX6 alone. The primary end point of this phase II study was the progression-free survival (PFS) rate at 12 months in each arm. The analysis of efficacy between the arms was a pre-planned secondary analysis.
RESULTS: Of 236 randomized patients, 227 and 235 patients were evaluable for the primary efficacy analysis and safety, respectively. The probabilities of being progression-free at 12 months were 25.8% [95% confidence interval (CI) 17.2-34.4] for the aflibercept/mFOLFOX6 arm and 21.2% (95% CI 12.2-30.3) for the mFOLFOX6 arm. The median PFS was 8.48 months (95% CI 7.89-9.92) for the aflibercept/mFOLFOX6 arm and 8.77 months (95% CI 7.62-9.27) for the mFOLFOX6 arm; the hazard ratio of aflibercept/mFOLFOX6 versus mFOLFOX6 was 1.00 (95% CI 0.74-1.36). The response rates were 49.1% (95% CI 39.7-58.6) and 45.9% (95% CI 36.4-55.7) for patients treated with and without aflibercept, respectively. The most frequent treatment-emergent grade 3/4 adverse events (AEs) excluding laboratory abnormalities reported for aflibercept/mFOLFOX6 versus mFOLFOX6 were neuropathy (16.8% versus 17.2%) and diarrhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endothelial growth factor inhibition class-effect grade 3/4 AEs for aflibercept/mFOLFOX6 versus mFOLFOX6 were hypertension (35.3% versus 1.7%), proteinuria (9.2% versus 0%), deep vein thrombosis (5.9% versus 0.9%) and pulmonary embolism (5.9% versus 5.2%).
CONCLUSION: No difference in PFS rate was observed between treatment groups. Adding aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated with higher toxicity.
CLINICAL TRIAL NUMBER: NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41.

PMID: 27091810 [PubMed - indexed for MEDLINE]

A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC).

Ann Oncol. 2016 Jul;27(7):1266-72

Authors: Oki E, Murata A, Yoshida K, Maeda K, Ikejiri K, Munemoto Y, Sasaki K, Matsuda C, Kotake M, Suenaga T, Matsuda H, Emi Y, Kakeji Y, Baba H, Hamada C, Saji S, Maehara Y

Abstract
BACKGROUNDS: Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur-uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer.
PATIENTS AND METHODS: The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20-80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500-600 mg/day on days 1-5, followed by 2 days rest) or S-1 (80-120 mg/day on days 1-28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events.
RESULTS: In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63-0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm.
CONCLUSION: One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection.

PMID: 27056996 [PubMed - indexed for MEDLINE]

Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas.

Ann Oncol. 2016 Jul;27(7):1226-34

Authors: Ruan J, Shah B, Martin P, Schuster SJ

Abstract
Lenalidomide is an oral immunomodulatory drug with significant activity in indolent B-cell and mantle cell lymphomas. Lenalidomide has a manageable safety profile whether administered as a single agent or in combination with rituximab. The combination of lenalidomide with rituximab, known as the 'R(2)' regimen, enhances efficacy over what has been shown with monotherapy and has demonstrated activity in patients considered resistant to rituximab. Tolerability of these regimens has been consistent among studies. Asymptomatic neutropenia is the most common grade 3/4 adverse event, typically managed by dose interruption, followed by dose reduction once neutrophils have recovered. Nonhematologic toxicities (e.g. fatigue) are generally low-grade, manageable with concomitant treatment, and/or lenalidomide dose modification. More frequent with R(2), immune-related symptoms such as rash and tumor flare are important to recognize as lenalidomide-associated treatment effects in patients with lymphoma who require supportive care and potential dose modifications. Severe tumor flare reactions with painful lymphadenopathy are not typically observed outside of chronic lymphocytic leukemia/small lymphocytic lymphoma. Venous thromboembolism is uncommon in lymphomas, though prophylaxis is recommended. The general safety profile, differences between lenalidomide monotherapy and R(2) treatment, and optimal strategies for managing adverse events are discussed here.

PMID: 27052651 [PubMed - indexed for MEDLINE]

Impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients: a randomized phase III study.

Ann Oncol. 2016 Jul;27(7):1235-41

Authors: Jacot W, Firmin N, Roca L, Topart D, Gallet S, Durigova A, Mirr S, Abach L, Pouderoux S, D'Hondt V, Bleuse JP, Lamy PJ, Romieu G

Abstract
BACKGROUND: A minority of early breast cancer (EBC) patients treated with adjuvant or neoadjuvant chemotherapy have sufficient baseline vitamin D (vitD) level. This randomized phase III study assessed the safety and efficacy of a tailored, high-dose, oral vitD supplementation in restoring a normal 25-hydroxy vitD (25OHD) level in this population.
PATIENTS AND METHODS: Participants received a 6-month conventional (C) vitD and calcium supplementation or a 6-month high-dose oral vitD regimen tailored on the deficiency (T) and a conventional calcium supplementation. The primary end point was the 6-month percentage of 25OHD serum level normalization.
RESULTS: A total of 215 patients including 197 patients with vitD deficiency were recruited, and 195 patients were randomized (T, 100; C, 95). Compliance to the daily oral supplementation was 68.4% and 67% in the C and T arms, respectively. Discontinuous high-dose vitD compliance appeared higher in the T arm (77%). At 6 months, more patients presented with a normalized vitD level in the T arm (30% versus 12.6%; P = 0.003). Supplementation was well tolerated, and no significant difference in the treatment-related toxicity between the two arms was reported. Fifty-two patients without vitD normalization from the C arm switched to the T arm after 6 months. At 12 months, 44% of these patients achieved vitD normalization.
CONCLUSION: A tailored high-dose oral vitD supplementation safely allows a higher percentage of the serum 25OHD level normalization compared with a conventional regimen in chemotherapy-treated EBC patients. As compliance to a daily oral supplementation remains poor in this setting, an adaptation of the treatment schedule is warranted.
CLINICAL TRIAL NUMBER: NCT01480869.

PMID: 27029707 [PubMed - indexed for MEDLINE]

25 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

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25 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

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Understanding Potential Drug Side Effects: Can We Translate Molecular Mechanisms to Clinical Applications?

Anesthesiology. 2017 07;127(1):6-8

Authors: Koster A, Levy JH

PMID: 28475557 [PubMed - indexed for MEDLINE]

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13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

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13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

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("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

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("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

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