Expert opinion on drug safety
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Expert Opin Drug Saf · Mar 2015
ReviewA safety assessment of crizotinib in the treatment of ALK-positive NSCLC patients.
In the past decade, the treatment of NSCLC has been revolutionized by the discovery of key oncogenic driver mutations and the therapies that specifically target these mutations. Crizotinib has been shown to be an inhibitor of MET, anaplastic lymphoma kinase (ALK) and ROS1 receptor tyrosine kinases, and is FDA approved for ALK inhibition. Crizotinib is effective in NSCLC that harbors ALK translocations resulting in overexpression of oncogenic ALK fusion proteins. ⋯ Compared to standard chemotherapy, crizotinib shows improved progression-free survival in ALK-positive NSCLC, with patient's reporting improved quality of life. However, certain adverse events are more frequent with crizotinib versus standard chemotherapy and must be monitored for closely. The most common adverse events include ocular and gastrointestinal disturbances, cardiac and endocrine abnormalities, and peripheral edema. Many, though not all, of these side effects are likely due to the multiple tyrosine kinases inhibited by crizotinib, and will likely improve with second- and third-generation inhibitors that inhibit ALK more specifically.
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Expert Opin Drug Saf · Feb 2015
ReviewCardiac risks associated with antibiotics: azithromycin and levofloxacin.
Azithromycin and levofloxacin have been shown to be efficacious in treating infections. The adverse drug events associated with azithromycin and levofloxacin were considered rare. However, the US FDA released warnings regarding the possible risk of QT prolongation with azithromycin and levofloxacin. ⋯ Results are discordant. Two retrospective studies utilizing large databases demonstrated an increased risk of cardiovascular death with azithromycin, when azithromycin was compared with amoxicillin. Two other retrospective studies found no difference in cardiovascular death associated with azithromycin and other antibiotics. For levofloxacin, the increased risk of cardiovascular death was only found in one retrospective study. Therefore, the risks and benefits of antibacterial therapies should be considered when making prescription decisions. This study should not preclude clinicians from avoiding azithromycin and levofloxacin. If a patient has an indication to receive an antibiotic and if azithromycin or levofloxacin is needed, it may be used, but the potential risks must be understood.
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Outcomes of two large double-blind placebo-controlled studies of oral dimethyl fumarate (DMF) in multiple sclerosis (MS) provided the basis for its marketing approval as Tecfidera® by the US FDA in early 2013 and the European Medicines Agency in February 2014. The safety of DMF is complemented by experience in the use of an oral mixture of fumaric acid esters, including DMF for psoriasis (Fumaderm®; DMF and monoethyl fumarate [DMF-MEF]) licensed in Germany in 1994. ⋯ DMF is generally safe and well tolerated. Flushing and gastrointestinal side effects are relatively common for the approved DMF dose but are ordinarily mild and self-limited. No increase in malignancies has been reported despite theoretical concerns. Although progressive multifocal encephalopathy has been reported anecdotally in 5 of > 196,000 patient-years of experience with fumaric acid esters, none of the 65,000 DMF MS patients treated in the first year has been affected. Appendix to the abstract: Subsequent to the acceptance of this article for publication, the manufacturer has notified physicians of the death of one patient from PML complicating use of DMF in the DEFINE study extension (ENDORSE). This does not alter the expert opinion rendered regarding the safety of DMF. We await the outcomes and recommendations from the ongoing investigation into this case.
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Expert Opin Drug Saf · Jan 2015
Review Comparative StudyWarfarin versus dabigatran etexilate: an assessment of efficacy and safety in patients with atrial fibrillation.
Oral anticoagulation is the mainstay for stroke and thromboembolic event prevention in patients with atrial fibrillation (AF). Given limitations of warfarin therapy, non-vitamin K oral anticoagulants have been developed including direct thrombin inhibitors (i.e., dabigatran etexilate). Dabigatran etexilate has been tested thoroughly in terms of efficacy and safety in clinical trials and studies, involving 'real-world' cohorts. In this review, currently available evidence in patients with non-valvular AF is discussed. ⋯ Dabigatran etexilate appeared to have several pharmacokinetic and pharmacodynamic advantages over warfarin, as well as a favorable efficacy and safety profile being at least noninferior and often superior to warfarin in patients with non-valvular AF. The latter was shown in the clinical trials, meta-analyses and studies with 'real-world' data. Currently ongoing trials will expand the body of evidence on warfarin and will aid decision making in currently controversial areas. Important limitations of dabigatran etexilate include contraindications for its use in patients with prosthetic heart valves and end-stage chronic kidney disease.