Expert Opinion on Drug Safety

Description

  • Impact factor
    2.74
  • 5-year impact
    2.43
  • Cited half-life
    4.10
  • Immediacy index
    0.66
  • Eigenfactor
    0.00
  • Article influence
    0.74
  • ISSN
    1744-764X

Publications in this journal

  • Carlo Selmi, Angela Ceribelli, Stanley M Naguwa, Luca Cantarini, Yehuda Shoenfeld
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    ABSTRACT: Introduction: The development of biologic therapies has been an enormous leap in the management of patients with rheumatoid and psoriatic arthritis. Since the first anti-TNF-α therapies, numerous molecules have been identified as targets of immunomodulatory therapies, such as IL-1 (anakinra, canakinumab), IL-6 (tocilizumab), CD20(+) B cells (rituximab), CTLA4 (abatacept) and two additional anti-TNF-α therapies (certolizumab pegol, golimumab). Areas covered: In the present review, we will describe the safety issues related to the immunosuppressive action of these biologic drugs that are mainly represented by infection and malignancy. The risk of infection should be identified before initiating a biologic treatment and markers checked over time, in particular for tuberculosis and hepatitis B and C viruses. Other infections (bacterial, viral, parasitic; opportunistic; surgery-related) and safety issues may require temporary interruption of the treatment until complete resolution. No significantly increased risk of malignancy, both hematological and solid, has been associated with the use of biologic agents. In all cases, it is difficult to dissect the risks related to biologics from those related to baseline treatments. Expert opinion: Detailed medical history and laboratory screening should be performed before starting biologic therapies. Clinicians should be aware of the different safety profiles associated with different molecules and they should follow up data coming out of the existing registries for biologics in regard to new or old side effects.
    Expert Opinion on Drug Safety 12/2014;
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    ABSTRACT: Introduction: Glucagon-like peptide 1 receptor (GLP-1Rx) agonists might elicit unwelcome side effects and concerns have recently been raised about their safety.Areas covered: Available evidence about safety, tolerability and potential adverse events relative to GLP-1Rx agonists presently used. We searched the MEDLINE database using the terms: ‘GLP-1 receptor agonists’, ‘Incretin therapy side effects’, ‘exenatide’, ‘ liraglutide’, ‘exenatide long-acting release’, ‘lixisenatide’. Articles were selected on the basis of the study design and importance, in the light of authors’ clinical experience and personal judgment. The main safety concern about GLP-1Rx agonists use is the possible association with increased risk of pancreatitis and/or tumors. This concern stems mainly from limited observations in animal models not confirmed in similar studies. Furthermore, clinical studies reporting association between GLP-1Rx agonist use and pancreatitis/cancer are marred by several biases and both clinical trials and post-marketing analyses failed to demonstrate a significant association.Expert opinion: As stated by both FDA and EMA, the safety concerns emerged so far about GLP-1RX agonists should not affect present prescribing habits. Thus, although a strict data monitoring must be encouraged, they should not prevent access to the benefits of an innovative treatment, such as GLP-1Rx agonists use, to a large diabetic population still confronted with unmet needs.
    Expert Opinion on Drug Safety 12/2014;
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    ABSTRACT: Introduction: 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. Areas covered: Case reports/case series, observational studies and clinical trials assessing cardiovascular risks associated with azithromycin and levofloxacin were critically reviewed, including 15 case reports/series, 5 observational studies and 5 clinical trials that investigated the cardiac risks associated azithromycin and levofloxacin. Expert opinion: 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.
    Expert Opinion on Drug Safety 12/2014;
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    ABSTRACT: Introduction: VEGF is a mediator of angiogenesis. Thus, concerns have been expressed following the use of VEGF inhibitors for the treatment of neovascular age-related macular degeneration (nAMD). Ranibizumab, and more recently aflibercept, are VEGF inhibitors licensed for the treatment of nAMD. Bevacizumab is also used but unlicensed for this application.Areas covered: A non-systematic review of nAMD trials was undertaken to investigate four outcomes: all-cause mortality, all systemic serious adverse events (SSAEs), arteriothrombotic events (ATEs) and gastrointestinal (GI) complications. Differences in event rates with injections of ranibizumab compared to bevacizumab, aflibercept, photodynamic therapy (PDT) and sham were explored and quantified using fixed-effect meta-analyses.Expert opinion: Anti-VEGF agents can influence vascular health; however, the data suggest no difference in the risk of an ATE or death between anti-VEGF agents. Clinical trials are limited in their size and eligibility criteria and databases of patients treated in routine practice should also be scrutinized.
    Expert Opinion on Drug Safety 12/2014;
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    ABSTRACT: Introduction: Dipeptidyl peptidase inhibitors (DPP-4-i) are highly selective inhibitors of the enzyme DPP-4. They act by increasing levels of incretin hormones, which have potent effects on insulin and glucagon release, gastric emptying, and satiety. Our goal is to review the safety issues related to DPP-4-i. Areas covered: This review is based upon a PubMed search of the literature using keywords alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin, DPP-4-i, glucagon-like polypeptide-1 agonists, as well as extensive personal clinical trial experience with each of these agents. The current DPP-4-i have very different chemical structures. Saxagliptin has significant cytochrome P450 metabolism and carries a risk of drug interactions. Linagliptin has primarily entero-hepatic excretion, a benefit in renally impaired patients. A concern arose related to congestive heart failure in the SAVOR TIMI trial of saxagliptin. Several major cardiac studies are underway, with two concluded. Despite lingering uncertainty related to pancreatitis and pancreatic cancer, large randomized trials have not shown an increased risk with DPP-4-i treatment. Cutaneous adverse effects occur with a low frequency with some of these agents. Expert opinion: DPP-4-i are an additional choice in the group of anti-hyperglycemics. Their principal advantage is a low incidence of hypoglycemia, making these agents desirable in patients such as the elderly and those with cardiac disease. Several large trials have hinted at less cardiac risk with DPP-4-i than with sulfonylureas. The CAROLINA Trial comparing linagliptin and glimepiride may provide a conclusive answer to this question.
    Expert Opinion on Drug Safety 12/2014;
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    ABSTRACT: Introduction: The approval of belimumab and other advances in the field have narrowed the window for off-label use of biologicals in systemic lupus erythematosus (SLE). For consideration in severe and refractory disease, safety will play a major role. Areas covered: We reviewed the literature on safety aspects of off-label biological use in SLE. Significant evidence is available for rituximab, whereas data on the off-label SLE therapy with other biologicals are much more limited. Published trials and open-label experience in SLE allow for some conclusions on abatacept, and on approaches targeting TNF, IL-1 and IL-6 receptors. Expert opinion: Anti-TNF antibodies apparently are the only ones inducing SLE-specific autoantibodies, but even these were not associated with flares. Risks for severe infections certainly remain a major serious concern, particularly in combinations with glucocorticoids and/or immunosuppressants. These findings reiterate that experience with both the disease and the drugs will be essential for keeping patients safe. The available data suggest a manageable adverse event profile for rituximab and do not prove unacceptable risks for other biologicals. Reports frequently only include very few patients, with the inherent danger of bias due to lacking reports on failed treatment attempts.
    Expert Opinion on Drug Safety 12/2014;
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    ABSTRACT: Introduction: Chronic treatment with levodopa is associated with the development of motor fluctuations and dyskinesias particularly in young Parkinson patients. In some cases, dyskinesias become so severe that they interfere with normal movement and negatively impact quality of life. Areas covered: In this review, we discuss benefits and limits of available therapeutic approaches aimed at delaying or managing dyskinesias as well as new strategies that are currently under investigation. Expert opinion: Among available treatments, monotherapy with dopamine agonists in the early phases of the disease reduces the risk for dyskinesias compared with levodopa. Nevertheless, dopamine agonists are unable to prevent dyskinesias once levodopa is added, which is always required once disease severity progresses. Convincing evidence of dyskinesia improvement has been shown only for deep brain stimulation and to some extent also for duodenal levodopa infusion and subcutaneous apomorphine. These approaches are expensive, have restrictive inclusion criteria and can cause potentially serious side effects. Alternative therapies include drugs targeting nondopaminergic neurotransmitter systems. Amantadine improves dyskinesias but its long-term effect is often unsatisfactory. Glutamatergic and gabaergic compounds have been tested in clinical trials, with promising results. By contrast, adrenergic drugs, fipamezole and idazoxan, did not show antidyskinetic effect.
    Expert Opinion on Drug Safety 12/2014;
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    ABSTRACT: Introduction: Glucose dysregulation and type 2 diabetes mellitus (T2DM) are feared antipsychotic drug adverse effects. Despite increasing utilization, data about antipsychotic risk of T2DM in youth are scarce. Areas covered: We conducted a systematic PubMed/MEDLINE search until 15 May 2014 focusing on studies with ≥ 20 youths aged ≤ 24 years, reporting quantitative data on: i) change in fasting glucose, hemoglobin A1c, insulin or insulin resistance after antipsychotic initiation (studies = 19, n = 2123,age = 13.3 years, follow up = 28.8 weeks); or ii) prevalence (studies = 4) or incidence (studies = 8, follow up = 1.57 years) of T2DM in antipsychotic-exposed youth (studies = 10, n = 65,486, age = 14.2 years) versus healthy controls (studies = 4, n = 246,828), psychiatric controls (studies = 5, n = 61,784) or without control groups (studies = 2). Expert opinion: Antipsychotics are associated with early adverse changes in glucose metabolism that are greater with all analyzable antipsychotics compared to controls, being highest with olanzapine, followed by quetiapine, aripiprazole and risperidone; but data were scarce. Although T2DM is fortunately rare in antipsychotic-treated youth, its prevalence (odds ratio [OR] = 8.176, 95% CI = 7.139 - 9.362) and incidence (OR = 1.450, 95% CI = 1.101 - 1.911, p = 0.006) were higher than in healthy controls. Similarly, T2DM prevalence (OR = 3.475, 95% CI = 3.019 - 4.001, p < 0.0001) and incidence (OR = 5.376, 95% CI = 4.004 - 7.233, p < 0.0001, excluding one outlying study) were higher than in psychiatric controls. Antipsychotics should only be used after lower-risk interventions failed, and inappropriately low clinical metabolic monitoring must be remedied.
    Expert Opinion on Drug Safety 12/2014;
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    ABSTRACT: Objective: Histamine H1 receptor (H1R) antagonists often have sedative side effects, which are caused by the blockade of the neural transmission of the histaminergic neurons. We examined the brain H1R occupancy (H1RO) and the subjective sleepiness of levocetirizine, a new second-generation antihistamine, comparing fexofenadine, another non-sedating antihistamine, as a negative active control. Methods: Eight healthy volunteers underwent positron emission tomography (PET) imaging with [(11)C]doxepin, a PET tracer that specifically binds to H1Rs, after a single oral administration of levocetirizine (5 mg), fexofenadine (60 mg) or placebo in a double-blind crossover study. Binding potential ratios and H1ROs in the cerebral cortices regions were calculated using placebo. Subjective sleepiness was assessed with the Line Analogue Rating Scale and the Stanford Sleepiness Scale. Results: There was no significant difference between the mean brain H1RO after levocetirizine administration (8.1%; 95% CI: -9.8 to 26.0%) and fexofenadine administration (-8.0%; 95% CI: -26.7 to 10.6%). Similarly, subjective sleepiness was not significantly different between the two antihistamines and placebo. Neither subjective sleepiness nor plasma concentrations was significantly correlated with the brain H1RO of the two antihistamines. Conclusion: At therapeutic dose, levocetirizine does not bind significantly to the brain H1Rs and does not induce significant sedation.
    Expert Opinion on Drug Safety 12/2014;
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    ABSTRACT: Antipsychotics are frequently and increasingly prescribed off-label for the treatment of behavioral and psychological symptoms associated with dementia, despite their modest efficacy. Instead, the safety profile of antipsychotics has been questioned repeatedly in recent years with various concerns, including death. Meta-analyses of randomized controlled trials found that one of the major causes of death associated with atypical antipsychotics use was pneumonia. Only few observational studies, however, have investigated the risk of pneumonia in elderly patients, especially among those receiving conventional antipsychotics. The aim of this editorial is to synthesize the current evidence from observational studies regarding the risk of pneumonia in elderly patients receiving either conventional or atypical antipsychotics. The studies conducted so far document that the risk of pneumonia is two- to threefold increased in a dose-dependent fashion with both classes compared to nonuse, with a possibly higher risk attributable to atypical antipsychotics. The risk seems to peak at the beginning of treatment (e.g., 7 - 30 days), and dissipates over time for both conventional and atypical antipsychotics. The risk-benefit ratio suggests that there will be 1 excess hospitalization for pneumonia for every 2 - 5 patients receiving any clinical improvement in symptoms. Considering the modest improvement in terms of efficacy, the risks associated with antipsychotics in elderly patients may outweigh their benefit.
    Expert Opinion on Drug Safety 11/2014;
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    ABSTRACT: Introduction: Histamine-2 receptor antagonists (H2RA) and proton pump inhibitors (PPI) are frequently used to prevent stress-related mucosal bleeding (SRMB). A paucity of data implicates these agents with pneumonia and Clostridium difficile infection (CDI). Areas covered: This review comparatively evaluates the effectiveness of H2RAs and PPIs and delineates their associations with these infectious complications. A literature review through 30 September 2014 was performed. Expert opinion: The rate of SRMB is declining, likely due better resuscitation strategies and the early provision of enteral nutrition. Therefore, gastric acid-suppressing therapies arguably reduce SRMB. However, they may contribute to pneumonia and CDI. The risks of these infectious complications depend on the extent of acid suppression and may vary by patient population. PPIs are associated with the greatest hazard for these infections, likely because they provide stronger acid suppression. Intermittent administration of H2RAs has theoretical advantages over continuous H2RA or PPI therapies as this dosing strategy does not fully suppress gastric acid and may limit infection risk. Placebo-controlled studies are warranted because clinical equipoise exists as the detrimental outcomes of these infections may outweigh the benefit of preventing SRMB given the infrequent occurrence of SRMB.
    Expert Opinion on Drug Safety 11/2014;
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    ABSTRACT: Objective: To evaluate the safety and efficacy of rapid rituximab infusion (RRI) plus chemotherapy in patients with CD20+ non-Hodgkin’s lymphoma (NHL).Research design and methods: A total of 177 patients received 4 – 6 cycles of rituximab-based chemotherapy. The first cycle was given with standard schedule. In the second and subsequent cycles, RRI was initiated. Rituximab was administered as 20% of the dose infused in the first 30 min and the remaining 80% was given over 60 min. Benadryl and dexamethasone were given before infusions. Vital signs were measured at baseline and during infusion.Results: In the first cycle, 48 patients experienced grade I – II infusion reactions and two patients showed grade III – IV infusion reactions. Six patients experienced infusion reactions during RRI. Two patients showed grade III infusion reactions to RRI and dropped out of the study. With a median follow up of 37.5 months, the 3-year overall survival and progression-free survival rates of the whole cohort were 93.1 and 81.1%, respectively.Conclusions: Our preliminary observations suggested that RRI may be safe and feasible for patients with CD20+ NHL.
    Expert Opinion on Drug Safety 11/2014;
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    ABSTRACT: Introduction: Ketoconazole was the first broad-spectrum oral antifungal approved by the FDA in 1981. Post-marketing reports of drug-related hepatotoxicity, endocrine dysregulation and drug interactions resulted in market withdrawal of the drug in some countries and strict product relabeling in others. Areas covered: This drug safety review summarizes reports of oral ketoconazole-related adverse events retrieved from a search of the PubMed database using the search strategy 'ketoconazole OR Nizoral AND hepat*', references from relevant publications, and data from the FDA Adverse Event Reporting System. Expert opinion: Although oral ketoconazole is effective in treating fungal infections, the potential for drug interactions, endocrine dysregulation, and hepatotoxicity may outweigh its benefits. Newer oral antifungals have similar or greater efficacy in treating dermatologic conditions and are associated with less risk. Likewise, newer agents with specific targets and fewer drug interactions have been developed to treat systemic fungal infections. Therefore, by the time ketoconazole prescribing guidelines were amended, its use had already largely been replaced with newer antifungals. Being that ketoconazole was the first broad-spectrum oral antifungal, experience with the drug made patient safety, and especially hepatic safety, an important consideration in future antifungal development.
    Expert Opinion on Drug Safety 11/2014;
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    ABSTRACT: Introduction: Second-generation antipsychotics (SGAs) are widely used in several psychiatric disease entities and exert to a different extent a risk for antipsychotic-induced weight gain (AIWG). As AIWG is associated with an increase in metabolic syndrome or cardiovascular events, knowledge of these risks is crucial for further monitoring and the initiation of counteractive measures. Areas covered: We searched PubMed and Web of Sciences for randomized-controlled trials and naturalistic observational studies published between 2010 and 2014 with sample sizes exceeding 100, including all marketed SGAs apart from zotepine, and providing data on weight increase. We also summarized relevant systematic reviews and meta-analyses of head-to-head comparisons. Expert opinion: Recently published data still support the hierarchical ranking of SGAs already proposed in previous reviews ranking clozapine and olanzapine as having the highest risk, followed by amisulpride, asenapine, iloperidone, paliperidone, quetiapine, risperidone and sertindole in the middle, and aripiprazole, lurasidone and ziprasidone with the lowest risk. Number needed to harm varied considerably in our meta-analysis. Younger patients and patients with a lower baseline body mass index are most vulnerable. The greatest amount of weight gain occurs within the first weeks of treatment. AIWG occurs in all diagnostic groups and is also common in treatment with first-generation antipsychotics; therefore, awareness of this adverse event is essential for anyone prescribing antipsychotics.
    Expert Opinion on Drug Safety 11/2014;
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    ABSTRACT: Introduction: Over the past decade, the introduction of a new class of anti-TNFα drugs has dramatically changed the approach taken to the management of Crohn's disease (CD). An increasing number of patients are receiving treatment with these advanced biological therapies, and the risk of adverse events that may be associated with their use must be carefully evaluated. Areas covered: Safety data about the three anti-TNFα drugs currently approved for use in CD patients (infliximab, adalimumab, and certolizumab pegol) is critically evaluated, including data coming from randomized clinical trials and post-marketing reports. Possible side effects of anti-TNFα agents are presented as drug-, class- and disease-specific adverse events. Management strategies to minimize the occurrence of side effects are summarized. Expert opinion: The safety profile of the three anti-TNFα drugs approved for clinical use in CD patients appears to be comparable among drugs. Data from clinical trials and a growing body of information from post-marketing surveillance indicate that anti-TNFα agents are generally safe, and that most of the observed side effects are mild and easily manageable. Nonetheless, serious short- and long-term adverse events may occur. Accurate selection of patients, careful pre-treatment evaluation, and regular follow-up during therapy could potentially reduce the rate of adverse events related to the use of anti-TNFα drugs.
    Expert Opinion on Drug Safety 11/2014;
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    ABSTRACT: Introduction: Antiretroviral (ARV) drug use during pregnancy significantly reduces mother-to-child HIV transmission, delays disease progression in the women and reduces the risk of HIV transmission to HIV-serodiscordant partners. Pregnant women are susceptible to the same adverse reactions to ARVs as nonpregnant adults as well as to specific pregnancy-related reactions. In addition, we should consider adverse pregnancy outcomes and adverse reactions in children exposed to ARVs during intrauterine life. However, studies designed to assess the safety of ARV in pregnant women are rare, usually with few participants and short follow-up periods. Areas covered: In this review, we discuss studies reporting adverse reactions to ARV drugs, including maternal toxicity, adverse pregnancy outcomes and the consequences of exposure to ARV in infants. We included results of observational studies, both prospective and retrospective, as well as randomized clinical trials, systematic reviews and meta-analyses. Expert opinion: The benefits of ARV use during pregnancy outweigh the risks of adverse reactions identified to date. More studies are needed to assess the adverse effects in the medium- and long term in children exposed to ARVs during pregnancy, as well as pregnant women using lifelong antiretroviral therapy and more recently available drugs.
    Expert Opinion on Drug Safety 11/2014;
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    ABSTRACT: Introduction: The treatment of cancer during pregnancy is challenging because of the involvement of two individuals and the necessity of a multidisciplinary approach. An important concern is the potential impact of chemotherapy on the developing fetus. Areas covered: The authors review the available literature on neonatal and long-term outcome of children prenatally exposed to chemotherapy. Chemotherapy administered during first trimester of pregnancy results in increased congenital malformations (7.5 - 17% compared to 4.1 - 6.9% background risk), whereas normal rates are found during second or third trimester. Intrauterine growth restriction is seen in 7 - 21% (compared to 10%), but children develop normal weight and height on the long term. Children are born preterm in 67.1%, compared to 4% in general population. Normal intelligence, attention, memory and behavior are reported, although intelligence tends to decrease with prematurity. Global heart function remains normal, although small differences are seen in ejection fraction, fractional shortening and some diastolic parameters. No secondary cancers or fertility problems are encountered, but follow up periods are limited. Expert opinion: Most evidence is based on retrospective studies with small samples and limited follow up periods, methodology and lack of control groups. A large prospective case-control study with long-term follow up is needed in which confounding factors are well considered.
    Expert Opinion on Drug Safety 11/2014;
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    ABSTRACT: Introduction: Pregnancy may be complicated by new onset or preexisting asthma. Asthma is one of the most common potentially serious medical problems to complicate pregnancy, and it may adversely affect both maternal quality of life and perinatal outcomes. Optimal management of asthma during pregnancy is thus important for both mother and baby. Areas covered: This article reviews the recognition and management of asthma during pregnancy, paying close attention to the general principles of asthma medication use during pregnancy. Further, the article reviews the safety of asthma medications commonly used during pregnancy. In this article, the most pertinent recent publications are reported. Electronic databases, such as PUBMED, were searched for terms pregnan* or perinat* or obstet* and asthma or wheeze and treatment. Expert opinion: Because pregnant women are generally excluded from clinical trials, there is a lack of adequate safety information for most medications taken during pregnancy. One of the most important requirements for the future is the availability of further safety information for asthma medications used during pregnancy that can also account for asthma control.
    Expert Opinion on Drug Safety 11/2014;
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    ABSTRACT: Introduction: 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.Areas covered: This article reviews the pivotal trials leading to the approval of DMF for MS and the pharmacological literature related to the extensive use of oral fumaric acid esters for psoriasis over the last quarter century. Anecdotal reports of serious adverse reactions to DMF-MEF are also reviewed in this report.Expert opinion: 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.
    Expert Opinion on Drug Safety 11/2014;