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- Post-approval appending of CSARs to drug package inserts: an analysis of the types of adverse reactions and time to addition. [JOURNAL ARTICLE]
- Pharmacoepidemiol Drug Saf 2014 Apr 15.
The aim of this study was to quantitatively analyze clinically significant adverse reactions (CSARs) added to drug package inserts after approval and to investigate the time to these post-approval additions as an indicator of safety-related regulatory actions.Drugs containing new active ingredients that had been approved in Japan from April 2001 to December 2010 were analyzed. We examined CSARs that had been reported in the first version of the package inserts and subsequent additions through notifications from Japan's Ministry of Health, Labour and Welfare until the end of 2011. Relative risks (RRs) for post-approval addition of CSARs were calculated for various categories of disorders. The median lengths of time to post-approval addition of CSARs were compared.A total of 238 drugs were examined. Of the 2487 CSARs associated with these drugs, 737 had been added after approval. The analysis revealed a higher likelihood for post-approval addition of CSARs for "Hepatobiliary disorders" (RR: 1.41; 95% confidence interval [CI]: 1.19-1.68), "Gastrointestinal disorders" (RR: 1.35; 95%CI: 1.10-1.66), and "Musculoskeletal and connective tissue disorders" (RR: 1.52; 95%CI: 1.11-2.07). In contrast, "Cardiac disorders" showed reduced likelihood in comparison with other disorders. For the time until post-approval addition of CSARs, "Skin and subcutaneous tissue disorders" showed the longest durations, with a median of 3020 days.Our quantitative analysis suggests that some CSARs were added more frequently to package inserts after approval and that time to post-approval additions of CSARs varied with the types of adverse drug reactions. These results can support the coherent implementation of pharmacovigilance activities. Copyright © 2014 John Wiley & Sons, Ltd.
- Notoriety bias in a database of spontaneous reports: the example of osteonecrosis of the jaw under bisphosphonate therapy in the French national pharmacovigilance database. [JOURNAL ARTICLE]
- Pharmacoepidemiol Drug Saf 2014 Apr 15.
The purpose of this study was to identify a notoriety bias in a database of spontaneous reports and its consequences on the calculation of the reporting odds ratio (ROR).We used the case/noncase methodology to calculate the ROR for bisphosphonates and osteonecrosis of the jaw (ONJ) in the French national pharmacovigilance database (from 1985 to 2013). To evaluate notoriety bias, drug-related risk factors for ONJ [as specified in the summary of product characteristics (SPC) of bisphosphonates] were systematically scanned for notifications of reports of ONJ occurring under bisphosphonate therapy. When a risk factor was present, the ONJ was considered as not due to bisphosphonates, and a second ROR was calculated under the hypothesis of maximum bias.In total, 148 cases of ONJ were reported (143 with bisphosphonates and five without). The raw ROR was 3448 (95% confidence interval 1413-8417). After analysis of the reports, only 86 had no mention of a risk factor for ONJ. The ROR under the maximum bias hypothesis was 87 (95% confidence interval 63-121). Among ONJ where chemotherapy was being administered simultaneously to bisphosphonates, 27 reports did not consider the chemotherapy to be implicated, despite seven of these occurring in cases where ONJ was mentioned in the summary of product characteristics.The existence of a notoriety bias has an impact on measures of disproportionality. The detection of pharmacovigilance signals might be delayed. It is advisable to list all drugs being taken when an adverse drug reaction occurs, and not only those known to be associated with the observed reaction. Copyright © 2014 John Wiley & Sons, Ltd.
- Normal CYP3A activity during arsenic trioxide therapy. [JOURNAL ARTICLE]
- Ann Hematol 2014 Apr 16.
- Large scale implementation of clinical medication reviews in Dutch community pharmacies: drug-related problems and interventions. [JOURNAL ARTICLE]
- Int J Clin Pharm 2014 Apr 16.
Research on the benefits of clinical medication reviews (CMRs) performed by pharmacists has been conducted mostly in controlled settings and has been widely published. Less is known of the effects after large scale implementation in community pharmacies. An online CMR tool enabled the systematic registration of drug-related problems (DRPs) and implemented interventions derived from CMRs in daily practice.To describe the effects of CMRs on pharmacy practice after large-scale implementation in the Netherlands.268 community pharmacies. Pharmacists were trained on CMRs with a patient centred approach.Retrospective analyses of DRPs, pharmacists' proposals and implemented interventions recorded between January 1st and September 1st 2012.Frequencies of DRPs, intervention proposals, implemented interventions, and drugs involved.4,579 CMRs were analysed. On average 2.9 (SD 2.1) DRPs per review were identified. 4,123 (31 %) of the DRPs led to medication changes. Stopping a drug (16 %) was more frequent than starting a drug (8.1 %). Drugs related to cardiovascular risk management, diabetes and osteoporosis were most frequently involved.This study is the largest analysis of pharmacists-initiated CMRs in the Netherlands to date. The findings demonstrate the potential to reduce medication-related errors through pharmacist involvements in complex pharmacotherapy and the positive impact on the quality of drug therapy through making necessary medication changes. The data also support the need for large-scale implementation of pharmacists-initiated CMRs in the presence of proper training programmes.
- Opioid-related mortality and filled prescriptions for buprenorphine and methadone. [JOURNAL ARTICLE]
- Drug Alcohol Rev 2014 Apr 16.
To assess opioid-related mortality and correlation with filled prescriptions for buprenorphine and methadone.A register study, including data from the Swedish Forensic Pathology and Forensic Toxicology databases 2003-2010, the Prescribed Drug Register and the National Patient Register.A total of 1301 deaths, assessed as related to buprenorphine, methadone or heroin, or a combination of them, were studied. The largest number of fatalities was related to intake of heroin (n = 776), followed by methadone (n = 342) and buprenorphine (n = 168). The total annual number of fatal cases related to the studied drugs more than doubled (116 to 255) during the study period. There were increases in mortality related to both buprenorphine and methadone: from 1 to 49 cases for buprenorphine, and from 19 to 81 cases for methadone. Only one-fifth of the fatal cases had a filled prescription for the maintenance drug assessed as the cause of death.This study showed that most fatalities were not related to filled prescriptions of maintenance drugs, and a substantial illicit use of buprenorphine and methadone resulting in deaths was revealed. To prevent opioid toxicity deaths it is important to make efforts not only to reduce drug diversion from maintenance programs, but also to improve the control of drug trafficking and other illegal sources. [Wikner BN, Öhman I, Seldén T, Druid H, Brandt L, Kieler H. Opioid-related mortality and filled prescriptions for buprenorphine and methadone. Drug Alcohol Rev 2014].
- Chronic opioid use emerging after bariatric surgery. [JOURNAL ARTICLE]
- Pharmacoepidemiol Drug Saf 2014 Apr 14.
Little is known about opioid use after bariatric surgery among patients who did not use opioids chronically before surgery. Our purpose was to determine opioid use the year after bariatric surgery among patients who did not use opioids chronically pre-surgery and to identify pre-surgery characteristics associated with chronic opioid use after surgery.This retrospective cohort study across nine US health systems included 10 643 patients aged 21 years or older who underwent bariatric surgery and who were not chronic opioid users pre-surgery. The main outcome was chronic opioid use the post-surgery year (excluding 30 post-operative days) defined as ≥10 dispensings over ≥90 days or ≥120 total days' supply.Overall, 4.0% (n = 421) of patients became chronic opioid users the post-surgery year. Pre-surgery opioid total days' supply was strongly associated with chronic use post-surgery (1-29 days adjusted odds ratio [OR] 1.89 [95%CI, 1.24-2.88]; 90-119 days OR, 14.29 [95%CI, 6.94-29.42] compared with no days). Other factors associated with increased likelihood of post-surgery chronic use included pre-surgery use of non-narcotic analgesics (OR, 2.22 [95%CI, 1.39-3.54]), antianxiety agents (OR, 1.67 [95%CI, 1.12-2.50]), and tobacco (OR, 1.44 [95%CI, 1.03-2.02]). Older age (OR, 0.84 [95%CI, 0.73-0.97] each decade) and a laparoscopic band procedure (OR, 0.42 [95%CI, 0.25-0.70] vs. laparoscopic bypass) were associated with decreased likelihood of chronic opioid use post-surgery.Most patients who became chronic opioid users the year after bariatric surgery used opioids intermittently before surgery. Copyright © 2014 John Wiley & Sons, Ltd.
- Symptomatic thromboembolic events in patients treated with intravenous-immunoglobulins: Results from a retrospective cohort study. [JOURNAL ARTICLE]
- Thromb Res 2014 Apr 1.
To estimate the incidence and predictors of symptomatic arterial and venous thromboembolic events (TEE) from intravenous immunoglobulin (IVIg) therapy according to its indications.We performed a retrospective cohort study of patients seen at our institution and treated with IVIg over a 36-month period. Indications, comorbility and comedication associated with TEE were identified by a stepwise logistic regression analysis.Of 303 patients included with at least one infusion of IVIg over three years, TEE were identified in a total of 50 patients treated with IVIg, for an incidence of 16.9% (CI 95%: 13.0-21.6); 27 (54%) arterial (9.1%;CI 95%: 6.3-13.0%) and 23 (46%) venous TEE (7.8%; CI95%: 5.2-11.4%), overall mortality was 32%. Per indication there were more patients with autoimmune conditions, secondary immunodeficiency, dysimmune neuropathies, acute rejection of solid organ transplantation and sepsis. Patients with TEE were significantly older, were more likely to be men, they had more comorbid conditions; the doses of IVIg were high (589.4mg/kg/day vs 387.0mg/kg/day, p<0.001) and differences in comedication were found. The stepwise logistic regression analysis retained high doses of IVIg (OR 3.03; CI 95%: 1.49-5.67) and diuretics therapy (OR 1.69; CI 95%: 1.06-3.97) when combined with the usual comorbid confounders.The incidence of TEE from IVIg therapy remains high at one in six patients treated. The most remediable factor is a high daily IVIg load. Decreasing the daily IVIg dose together with carefully weighing diuretics therapy and comorbid risk factors may be the keys to saving lives.
- Anagnostis, S. N. Karras, and D. G. Goulis. Monitoring the efficacy of once-weekly teriparatide. Are bone turnover markers useful in predicting fracture risk?, Curr Med Res Opin. Posted online on 6 Mar 2014. [JOURNAL ARTICLE]
- Curr Med Res Opin 2014 Apr 15.
- The in-vitro effect of complementary and alternative medicines on cytochrome P450 2C9 activity. [JOURNAL ARTICLE]
- J Pharm Pharmacol 2014 Apr 15.
The aim of this study is to establish the inhibitory effects of 14 commonly used complementary and alternative medicines (CAM) on the metabolism of cytochrome P450 2C9 (CYP2C9) substrates 7-methoxy-4-trifluoromethyl coumarine (MFC) and tolbutamide. CYP2C9 is important for the metabolism of numerous drugs and inhibition of this enzyme by CAM could result in elevated plasma levels of drugs that are CYP2C9 substrates. Especially for anticancer drugs, which have a narrow therapeutic window, small changes in their plasma levels could easily result in clinically relevant toxicities.The effects of CAM on CYP2C9-mediated metabolism of MFC were assessed in Supersomes, using the fluorometric CYP2C9 inhibition assay. In human liver microsomes (HLM) the inhibition of CYP2C9-mediated metabolism of tolbutamide was determined, using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).The results indicated milk thistle as the most potent CYP2C9 inhibitor. For milk thistle, silybin (main constituent of milk thistle) was mainly responsible for the inhibition of CY2C9.Milk thistle and green tea were confirmed as potent inhibitors of CYP2C9-mediated metabolism of multiple substrates in vitro. Clinical studies with milk thistle are recommended to establish the clinical relevance of the demonstrated CYP2C9 inhibition.
- Poorly controlled type 2 diabetes mellitus is associated with a decreased risk of incident gout: a population-based case-control study. [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Apr 12.
The aim of this study was to explore the risk of incident gout in patients with type 2 diabetes mellitus (T2DM) in association with diabetes duration, diabetes severity and antidiabetic drug treatment.We conducted a case-control study in patients with T2DM using the UK-based Clinical Practice Research Datalink (CPRD). We identified case patients aged ≥18 years with an incident diagnosis of gout between 1990 and 2012. We matched to each case patient one gout-free control patient. We used conditional logistic regression analysis to calculate adjusted ORs (adj. ORs) with 95% CIs and adjusted our analyses for important potential confounders.The study encompassed 7536 T2DM cases with a first-time diagnosis of gout. Compared to a diabetes duration <1 year, prolonged diabetes duration (1-3, 3-6, 7-9 and ≥10 years) was associated with decreased adj. ORs of 0.91 (95% CI 0.79 to 1.04), 0.76 (95% CI 0.67 to 0.86), 0.70 (95% CI 0.61 to 0.86), and 0.58 (95% CI 0.51 to 0.66), respectively. Compared to a reference A1C level of <7%, the risk estimates of increasing A1C levels (7.0-7.9, 8.0-8.9 and ≥9%) steadily decreased with adj. ORs of 0.79 (95% CI 0.72 to 0.86), 0.63 (95% CI 0.55 to 0.72), and 0.46 (95% CI 0.40 to 0.53), respectively. Neither use of insulin, metformin, nor sulfonylureas was associated with an altered risk of incident gout.Increased A1C levels, but not use of antidiabetic drugs, was associated with a decreased risk of incident gout among patients with T2DM.