Occurrence and risk assessment of glycidyl and 3-monochloropropanediol esters in infant formulas marketed in Taiwan.

Glycidyl esters (GEs) and 3-monochloropropanediol esters (3-MCPDEs) are process contaminants commonly found in refined edible oils which are often added to infant formulas. The Taiwan Food and Drug Administration (TFDA) launched regulations for GEs in infant formulas that went into effect on 1 July 2021. To investigate levels of GEs and 3-MCPDEs in infant formula powder, 45 products were sampled and analysed during 2020-2021. The contents of GEs and 3-MCPDEs in formulas of different brands significantly varied, but their concentrations in all of the formulas complied with European Union (EU) regulations. Infant formulas containing palm oil had significantly higher 3-MCPDE levels in both extracted oils and milk powder than those without palm oil. Concentrations of GEs and 3-MCPDEs in infant formula powder and extracted oils were significantly lower in products from Europe than those from Australia and New Zealand. Infants aged 0-1 years in Taiwan who consumed only infant formula showed a margin of exposure (MoE) exceeding 25,000. Mean consumer exposures to 3-MCPDEs stayed below the tolerable daily intake (TDI), while high exposures at the 95th percentile (P95) exceeded the TDI by 1.7-fold. Herein, we present the changing trends in the risk assessment results of infant formula across various countries in the decade. Implementation of regulations and mitigation strategy effectively reduced the risk of infants being exposed to GEs and 3-MCPDEs through infant formula.

Monochloropropanediol in edible vegetable oils from Hangzhou market in China: occurrence and exposure risk assessment.

In this study, 241 vegetable-oil food samples were collected from the Hangzhou market in China and analysed for fatty acid esters of 3- and 2-monochloropropanediol (3-MCPD and 2-MCPD) using non-derivative gas chromatography tandem mass spectrometry (GC-MS/MS). Food consumption data were taken from a food consumption survey of urban and rural residents in Hangzhou city performed in 2010-2011. Levels of 3-MCPD esters in edible oil ranged from not detected to 7.98 mg/kg, and the highest mean levels were found in tea seed oil, with concentrations of 2.94 mg/kg. Esters of 2-MCPD levels ranged from not detected to 4.03 mg/kg, and the highest mean levels were also found in tea seed oil, containing 1.49 mg/kg. The range of mean dietary intake of 3-MCPD esters in different groups of edible oil was from 0.096 to 1.54 µg/kg body weight (bw) per day, which is lower than the tolerable daily intake (TDI) established by the European Food Safety Authority (EFSA) (2 µg/kg bw/day). For people aged above 6 years old, the dietary intake of 3-MCPD from edible oil was 0.42 µg/kg bw per day (mean) and 1.22 µg/kg bw per day (P97.5). The range of mean dietary intake of 2-MCPD esters in different groups of edible oil was from 0.025 to 0.79 µg/kg bw/day, and 2-MCPD esters intake was 0.20 µg/kg bw per day (mean) and 0.60 µg/kg bw per day (P97.5). In addition, the dietary intake exposure to 3-MCPD and 2-MCPD esters for urban residents was lower than that for rural residents. The findings indicate that the potential health risks caused by dietary 3-MCPD esters from edible oils were of low concern for most of the Hangzhou residents. However, the exposure risk for consumers with excessive consumption of certain kind of edible oil calls for attention.

Pharmacokinetics and Pharmacodynamics of Cenerimod, A Selective S1P1 R Modulator, Are Not Affected by Ethnicity in Healthy Asian and White Subjects.

Cenerimod is a sphingosine-1-phosphate 1 receptor (S1P1 R) modulator in phase II development for treatment of systemic lupus erythematosus. Its pharmacokinetics (PKs), pharmacodynamics (PDs), as well as safety and tolerability were investigated in white and Asian subjects to allow for recruitment of Asian patients in future studies. A randomized, double-blind, placebo-controlled parallel-group study was performed in 20 healthy male subjects (n = 10 per ethnicity). A single, oral dose of 4 mg cenerimod or placebo (ratio 8:2) was administered under fasted conditions. The PKs of cenerimod were similar in white and Asian subjects indicated by geometric mean ratios (90% confidence interval) of 0.99 (0.80-1.21) for maximum plasma concentration, 0.96 (0.75-1.24) for area under the plasma concentration-time curve from 0 to infinity, and 1.04 (0.86-1.25) for terminal half-life. Accordingly, the extent and time course of reduction in lymphocyte count (as PD biomarker) were also similar in white and Asian subjects as compared with placebo. As observed for other S1PR modulators, a transient mean (SD) heart rate reduction in white (15.1 (14.8) bpm) and Asian (11.8 (6.16) bpm) subjects was observed following administration of cenerimod. The drug was safe and well-tolerated indicated by occurrence of a single adverse event of chemical conjunctivitis in a white subject that was not suspected as study drug related. In conclusion, the determined absence of any relevant PK or PD differences supports using the same doses of cenerimod in white and Asian patients in upcoming late-phase studies.

Safety assessment of a newly synthesized copolymer for micellar delivery of hydrophobic caffeic acid phenethyl ester.

Caffeic acid phenethyl ester (CAPE), a major pharmacologically active component of poplar type propolis, is known for its proapoptotic, anti-inflammatory, antioxidant, antiviral, and enzyme inhibiting activities. The aim of this study was to perform an in vitro and in vivo safety assessment of a micellar system based on a newly synthesized copolymer, consisting of polyglycidol and poly(allyl glycidyl ether) (C12-PAGE-PG) as a drug delivery platform for CAPE. The in vitro studies on HepG2 and L929 cells by MTT and LDH assays after treatment with the empty and CAPE-loaded micelles showed no cytotoxic effects of the empty micelles and retained cytotoxic activity of CAPE loaded in the micelles. No hemolysis or stimulation of mouse lymphocytes or macrophages was observed in vitro. In vivo hematological, biochemical, and histological assays on rats, treated with the empty (2580 and 5160 µg/kg) or CAPE-loaded (375 and 750 µg CAPE/kg) micelles did not reveal pathological changes of any of the parameters assayed after 14-days' treatment. In conclusion, initial toxicological data characterize C12-PAGE-PG as a non-toxic and promising copolymer for development of micellar drug delivery systems, particularly for a hydrophobic active substance as CAPE.

Environmental impact assessment model for substitution of hazardous substances by using life cycle approach.

Regulations that are indirectly driving the substitution of hazardous chemicals, such as the EU REACH regulation, necessitate improvements in chemical alternatives assessment frameworks. In those frameworks, life cycle thinking lacks some important aspects such as systematic and quantitative occupational safety methods and risks from intermediate chemicals that are not released to the environment under normal operating conditions. Concerns of companies about regulatory drivers regarding substances of very high concern often lead to inadequate evaluation of the baseline situation; an issue also overlooked by the frameworks. Moreover, life cycle assessment is optional for assessors with limited resources, such as small and medium enterprises. However, the success of substitution should not be evaluated without life cycle concerns. An environmental impact assessment model has been suggested to overcome these shortcomings of the chemical alternatives assessment frameworks. The model was applied to a case study of primed metal sheet production, where the company was driven to substitute reprotoxic 2-methoxypropanol used in their formulations. The results show that the proposed model is promising for solving the mentioned shortcomings, informing the assessor about substances of very high concern along the life cycle, and it has the potential to be further improved with the help of supporting software and databases. Particularly, in the occupational safety area that concerns risks of accidents at work, improvements to the EU occupational health database can drastically increase the accuracy of the assessments. Besides, the development of methodologies for the quantification of the impacts of reprotoxic, bioaccumulative and endocrine disruptor substances is necessary.

Tacrolimus-loaded lecithin-based nanostructured lipid carrier and nanoemulsion with propylene glycol monocaprylate as a liquid lipid: Formulation characterization and assessment of dermal delivery compared to referent ointment.

Nanostructured lipid carriers (NLC) and nanoemulsions (NE) are colloid carriers which could improve dermal delivery of tacrolimus. The aims of this study were to evaluate effects of different formulation and process parameters on physicochemical characteristics and stability of lecithin-based NLC with glyceryl palmitostearate as solid and propylene glycol monocaprylate as liquid lipid and to compare the influence of different inner structure of tacrolimus-loaded NLC and corresponding NE on physicochemical characteristics, stability, entrapment efficiency, in vitro drug release and overall skin performance. Solid/liquid lipid ratio, total amount of lipids, homogenization pressure and cooling after the preparation were identified as critical variables in NLC development. Moreover, tacrolimus-loaded NLC emerged as more stabile carrier than NE. Differential stripping performed on porcine ear skin revealed significantly higher tacrolimus amount in stratum corneum from nanocarriers compared to referent ointment (Protopic®). Similarly the highest amount of tacrolimus in hair follicles was obtained using NLC (268.54 ±â€¯92.38 ng/cm2), followed by NE (128.17 ±â€¯48.87 ng/cm2) and Protopic® (77.61 ±â€¯43.25 ng/cm2). Contrary, the highest permeation rate through full-thickness porcine ear skin was observed for Protopic®, implying that the selection of experimental setup is critical for reliable skin performance assessment. Overall, developed NLC could be suggested as promising carrier in a form of lotion for tacrolimus dermal delivery.

Metabolic Engineering of a Homoserine-Derived Non-Natural Pathway for the De Novo Production of 1,3-Propanediol from Glucose.

Engineering a homoserine-derived non-natural pathway allows heterologous production of 1,3-propanediol (1,3-PDO) from glucose without adding expensive vitamin B12. Due to the lack of efficient enzymes to catalyze the deamination of homoserine and the decarboxylation of 4-hydroxy-2-ketobutyrate, the previously engineered strain can only produce 51.5 mg/L 1,3-PDO using homoserine and glucose as cosubstrates. In this study, we systematically screened the enzymes from different protein families to catalyze the two corresponding reactions and further optimized the selected enzymes by protein engineering. Together with the improvement of homoserine supply by systematic metabolic engineering, an engineered Escherichia coli strain with an optimal combination of aspartate transaminase ( aspC) from E. coli, pyruvate decarboxylase ( pdc) from Zymomonas mobiliz, and alcohol dehydrogenase yqhD from E. coli can produce 0.32 g/L 1,3-PDO from glucose in shake flask cultivation. The titer of 1,3-PDO was further increased to 0.49 g/L or 0.63 g/L by introducing a point mutation of I472A into pdc gene or constructing a fusion protein between aspC and pdc. This study lays the basis for developing a potential process for 1,3-PDO production from sugars without using expensive coenzyme B12.

Clostridium butyricum population balance model: Predicting dynamic metabolic flux distributions using an objective function related to extracellular glycerol content.

BACKGROUND: Extensive experimentation has been conducted to increment 1,3-propanediol (PDO) production using Clostridium butyricum cultures in glycerol, but computational predictions are limited. Previously, we reconstructed the genome-scale metabolic (GSM) model iCbu641, the first such model of a PDO-producing Clostridium strain, which was validated at steady state using flux balance analysis (FBA). However, the prediction ability of FBA is limited for batch and fed-batch cultures, which are the most often employed industrial processes. RESULTS: We used the iCbu641 GSM model to develop a dynamic flux balance analysis (DFBA) approach to predict the PDO production of the Colombian strain Clostridium sp IBUN 158B. First, we compared the predictions of the dynamic optimization approach (DOA), static optimization approach (SOA), and direct approach (DA). We found no differences between approaches, but the DOA simulation duration was nearly 5000 times that of the SOA and DA simulations. Experimental results at glycerol limitation and glycerol excess allowed for validating dynamic predictions of growth, glycerol consumption, and PDO formation. These results indicated a 4.4% error in PDO prediction and therefore validated the previously proposed objective functions. We performed two global sensitivity analyses, finding that the kinetic input parameters of glycerol uptake flux had the most significant effect on PDO predictions. The other input parameters evaluated during global sensitivity analysis were biomass composition (precursors and macromolecules), death constants, and the kinetic parameters of acetic acid secretion flux. These last input parameters, all obtained from other Clostridium butyricum cultures, were used to develop a population balance model (PBM). Finally, we simulated fed-batch cultures, predicting a final PDO production near to 66 g/L, almost three times the PDO predicted in the best batch culture. CONCLUSIONS: We developed and validated a dynamic approach to predict PDO production using the iCbu641 GSM model and the previously proposed objective functions. This validated approach was used to propose a population model and then an increment in predictions of PDO production through fed-batch cultures. Therefore, this dynamic model could predict different scenarios, including its integration into downstream processes to predict technical-economic feasibilities and reducing the time and costs associated with experimentation.

Physical and chemical assessment of 1,3 Propanediol as a potential substitute of propylene glycol in refill liquid for electronic cigarettes.

Electronic cigarette has the potential to serve as a tobacco cessation aid if the prerequisites which are safety and efficacy in term of nicotine delivery are achieved. The nicotine-based liquids are mainly composed by propylene glycol and glycerol playing the important role of airborne carriers. 1,3 propanediol is proposed as a propylene glycol substitute to potentially improve the thermal stability, nicotine delivery and to decrease inhaled flavors concentrations. We have implemented various thermal, physicochemical and computational methods to evaluate the use of 1,3 propanediol as a substitute (or additional ingredient) to propylene glycol in e-liquids compositions. Our results indicate that 1,3 propanediol is stable upon heating when electronic cigarette are used in recommended conditions. We demonstrate that 1,3 propanediol gave better thermic profile compared to propylene glycol and glycerol, showing less thermal decomposition by-products. In addition, 1,3 propanediol gives to nicotine a more basic environment ensuring a high level of free base nicotine form. We have also established a quantum mechanical based computational method to validate e-liquids as flavor enhancer. Our findings showed that globally 1,3 propanediol seems to have better flavoring properties than glycerol and propylene glycol. Finally, 1,3 propanediol seems to induce quite similar aerodynamic properties compared to propylene glycol and glycerol.

Safety Assessment of Tromethamine, Aminomethyl Propanediol, and Aminoethyl Propanediol as Used in Cosmetics.

The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed the safety of tromethamine, aminomethyl propanediol, and aminoethyl propanediolas used in cosmetics. All 3 ingredients are reported to function in cosmetics as pH adjusters, and tromethamine and aminomethyl propanediol are also reported to function as fragrance ingredients. The Panel reviewed relevant animal and human data related to these ingredients, along with a previous safety assessment of aminomethyl propanediol. The Panel concluded that tromethamine, aminomethyl propanediol, and aminoethyl propanediol are safe in cosmetics in the practices of use and concentration as given in this safety assessment.

In vitro and in vivo assessment of delivery of hydrophobic molecules and plasmid DNAs with PEO-PPO-PEO polymeric micelles on cornea.

The stability and bio-distribution of genes or drug complexes with poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO, Pluronic F-68) polymeric micelles (PM) are essential for an effective nanosized PM delivery system. We used Förster resonance energy transfer (FRET) pairs with PM and measured the FRET ratio to assess the stability of PM in vitro and in vivo on the cornea. The FRET ratio reached a plateau at 0.8 with 3% PM. Differential scanning calorimetry measurement confirmed the complex formation of FRET pairs with PM. Confocal imaging with the fluorophores fluorescein isothiocyanate isomer I (FITC) and rhodamine B base (RhB) also showed the occurrence of FRET pairs in vitro. The fluorophores were mixed with 3% PM solution or the FITC-labeled PEO-PPO-PEO polymers (FITC-P) were mixed with RhB-labeled plasmids (RhB-DNA). In addition, the in vitro corneal permeation of FRET pair complexes with PM reached a 0.8 FRET ratio. One hour after eye drop administration, FRET pairs colocalized in the cytoplasm, and surrounded and entered the nuclei of cells in the cornea, and the polymers were located in the corneal epithelial layers, as detected through anti-PEG immunohistochemistry. Furthermore, fluorescence colocalization in the cytoplasm and cell nucleus of the corneal epithelium was confirmed in tissues where RhB or RhB-DNA complexed with FITC-P was found to accumulate. We demonstrate that at a concentration of 3%, PM can encapsulate FRET pairs or RhB-DNA and retain their integrity within the cornea 1 h after administration, suggesting the feasibility and stability of PEO-PPO-PEO polymers as a vehicle for drug delivery.

Functional genomic assessment of 2, 2-bis (bromomethyl)-1, 3-propanediol induced cytotoxicity in a single-gene knockout library of E. coli.

Functional gene fingerprinting of chemicals could be used to understand the direct gene-chemical interaction in the process of toxification from a genome-wide scale. 2, 2-bis (bromomethyl)-1, 3-propanediol (BMP) is a brominated flame retardant with widespread production but with very limited toxicological data. Here the cytotoxicity of BMP was assessed by Escherichia coli (E. coli) functional genome-wide knockout mutants screening and the underlying molecular mechanism was investigated. The median inhibition concentration (IC50) of BMP was 1.608 ± 0.078 mg/ml after 24 h exposure. 119 initial, including 66 sensitive and 53 resistant single gene mutants, were identified by a full library screening of BMP at the concentration of IC50. The resistant genes were significantly enriched in nucleobase-containing compound biosynthetic process (GO: 0034654) by gene ontology (GO) biological process analyses, which suggested that the pathway of DNA repair is a critical cellular process in the survival of cells exposed to BMP. Meanwhile, function annotation of all BMP responsive genes suggested the mechanism of BMP was associated with DNA damage, oxidative stress and cellular transmembrane transport process. Many genes were exclusively responsive to BMP comparing with other chemicals that has been assessed by E. coli mutant screening approach, which indicated that BMP has a distinct mode of toxic action. Overall, the functional genomic screening approach presented here provides a great tool to assess the cellular toxicological mechanism of environmental chemicals.

In vitro cytotoxicity assessment of a West Virginia chemical spill mixture involving 4-methylcyclohexanemethanol and propylene glycol phenyl ether.

Thousands of gallons of industrial chemicals, crude 4-methylcyclohexanemethanol (MCHM) and propylene glycol phenyl ether (PPh), leaked from industrial tanks into the Elk River in Charleston, West Virginia, USA, on January 9, 2014. A considerable number of people were reported to exhibit symptoms of chemical exposure and an estimated 300,000 residents were advised not to use or drink tap water. At the time of the spill, the existing toxicological data of the chemicals were limited for a full evaluation of the health risks, resulting in concern among those in the impacted regions. In this preliminary study, we assessed cell viability and plasma membrane degradation following a 24-h exposure to varying concentrations (0-1000 µM) of the two compounds, alone and in combination. Evaluation of different cell lines, HEK-293 (kidney), HepG2 (liver), H9c2 (heart), and GT1-7 (brain), provided insight regarding altered cellular responses in varying organ systems. Single exposure to MCHM or PPh did not affect cell viability, except at doses much higher than the estimated exposure levels. Certain co-exposures significantly reduced metabolic activity and increased plasma membrane degradation in GT1-7, HepG2, and H9c2 cells. These findings highlight the importance of examining co-exposures to fully understand the potential toxic effects.

Safety Assessment of Alkyl PEG/PPG Ethers as Used in Cosmetics.

The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of 131 alkyl polyethylene glycol (PEG)/polypropylene glycol ethers as used in cosmetics, concluding that these ingredients are safe in the present practices of use and concentration described in this safety assessment when formulated to be nonirritating. Most of the alkyl PEG/PPG ethers included in this review are reported to function in cosmetics as surfactants, skin-conditioning agents, and/or emulsifying agents. The alkyl PEG/PPG ethers share very similar physiochemical properties as the alkyl PEG ethers, which were reviewed previously by the CIR Expert Panel and found safe when formulated to be nonirritating. The alkyl PEG ethers differ by the inclusion of PPG repeat units, which are used to fine-tune the surfactant properties of this group. The Panel relied heavily on data on analogous ingredients, extracted from the alkyl PEG ethers and PPG reports, when making its determination of safety.

[Current status of bio-based materials industry in China].

In recent years, bio-based materials are becoming a new dominant industry leading the scientific and technological innovation, and economic development of the world. We reviewed the new development of bio-based materials industry in China, analyzed the entire market of bio-based materials products comprehensively, and also stated the industry status of bio-based chemicals, such as lactic acid, 1,3-propanediol, and succinic acid; biodegradable bio-based polymers, such as co-polyester of diacid and diol, polylactic acid, carbon dioxide based copolymer, polyhydroxyalknoates, polycaprolactone, and thermoplastic bio-based plastics; non-biodegradable bio-based polymers, such as bio-based polyamide, polytrimethylene terephthalate, bio-based polyurethane, and bio-based fibers.

The PANGAEA study design - a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice.

BACKGROUND: Fingolimod (Gilenya) is an oral medication for patients with highly active relapsing-remitting Multiple Sclerosis (RRMS). Clinical trials and post-marketing experience on more than 114,000 patients have established a detailed safety profile. Total patient exposure now exceeds 195,000 patient-years as stated in the last financial report (Dec 2014) of the Novartis Pharma AG, Basel, Switzerland. However, less is known about the safety of long-term fingolimod use in daily practice. Here, we describe the study design of PANGAEA (Post-Authorization Non-interventional German sAfety of GilEnyA in RRMS patients), a prospective, multicenter, non-interventional, long-term study to collect safety, efficacy, and pharmacoeconomic data on RRMS patients treated with fingolimod (0.5 mg/daily) under real-world conditions in Germany. METHODS: PANGAEA is striving to assess a real-world safety and efficacy profile of fingolimod, based on data from 4,000 RRMS patients, obtained during a 60-month observational phase. A pharmacoeconomic sub-study of 800 RRMS patients further collects patient-reported outcome measures of disability, quality of life, compliance, treatment satisfaction, and usage of resources during a 24-month observational phase. Descriptive statistical analyses of the safety set as well as of stratified subgroups such as patients with concomitant diabetes mellitus and pretreated patients (e.g., natalizumab) will be conducted. DISCUSSION: PANGAEA seeks to confirm the current safety profile of fingolimod obtained in phase I-III clinical trials. The study design presented here will additionally provide guidance on the therapeutic use of fingolimod in clinical practice and possibly assists physicians in making evidence-based decisions.

Cost effectiveness of fingolimod, teriflunomide, dimethyl fumarate and intramuscular interferon-ß1a in relapsing-remitting multiple sclerosis.

OBJECTIVE: The aim of the study was to compare the cost effectiveness of fingolimod, teriflunomide, dimethyl fumarate, and intramuscular (IM) interferon (IFN)-ß(1a) as first-line therapies in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A Markov model was developed to evaluate the cost effectiveness of disease-modifying drugs (DMDs) from a US societal perspective. The time horizon in the base case was 5 years. The primary outcome was incremental net monetary benefit (INMB), and the secondary outcome was incremental cost-effectiveness ratio (ICER). The base case INMB willingness-to-pay (WTP) threshold was assumed to be US$150,000 per quality-adjusted life year (QALY), and the costs were in 2012 US dollars. One-way sensitivity analyses and probabilistic sensitivity analysis were conducted to test the robustness of the model results. RESULTS: Dimethyl fumarate dominated all other therapies over the range of WTPs, from US$0 to US$180,000. Compared with IM IFN-ß(1a), at a WTP of US$150,000, INMBs were estimated at US$36,567, US$49,780, and US$80,611 for fingolimod, teriflunomide, and dimethyl fumarate, respectively. The ICER of fingolimod versus teriflunomide was US$3,201,672. One-way sensitivity analyses demonstrated the model results were sensitive to the acquisition costs of DMDs and the time horizon, but in most scenarios, cost-effectiveness rankings remained stable. Probabilistic sensitivity analysis showed that for more than 90% of the simulations, dimethyl fumarate was the optimal therapy across all WTP values. CONCLUSION: The three oral therapies were favored in the cost-effectiveness analysis. Of the four DMDs, dimethyl fumarate was a dominant therapy to manage RRMS. Apart from dimethyl fumarate, teriflunomide was the most cost-effective therapy compared with IM IFN-ß(1a), with an ICER of US$7,115.

Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management.

IMPORTANCE: Varicella-zoster virus (VZV) infections increasingly are reported in patients with multiple sclerosis (MS) and constitute an area of significant concern, especially with the advent of more disease-modifying treatments in MS that affect T-cell-mediated immunity. OBJECTIVE: To assess the incidence, risk factors, and clinical characteristics of VZV infections in fingolimod-treated patients and provide recommendations for prevention and management. DESIGN, SETTING, AND PARTICIPANTS: Rates of VZV infections in fingolimod clinical trials are based on pooled data from the completed controlled phases 2 and 3 studies (3916 participants) and ongoing uncontrolled extension phases (3553 participants). Male and female patients aged 18 through 55 years (18-60 years for the phase 2 studies) and diagnosed as having relapsing-remitting MS were eligible to participate in these studies. In the postmarketing setting, reporting rates since 2010 were evaluated. INTERVENTIONS: In clinical trials, patients received fingolimod at a dosage of 0.5 or 1.25 mg/d, interferon beta-1a, or placebo. In the postmarketing setting, all patients received fingolimod, 0.5 mg/d (total exposure of 54,000 patient-years at the time of analysis). MAIN OUTCOMES AND MEASURES: Calculation of the incidence rate of VZV infection per 1000 patient-years was based on the reporting of adverse events in the trials and the postmarketing setting. RESULTS: Overall, in clinical trials, VZV rates of infection were low but higher with fingolimod compared with placebo (11 vs 6 per 1000 patient-years). A similar rate was confirmed in the ongoing extension studies. Rates reported in the postmarketing settings were comparable (7 per 1000 patient-years) and remained stable over time. Disproportionality in reporting herpes zoster infection was higher for patients receiving fingolimod compared with those receiving other disease-modifying treatments (empirical Bayes geometric mean, 2.57 [90% CI, 2.26-2.91]); the proportion of serious herpes zoster infections was not higher than the proportion for other treatments (empirical Bayes geometric mean, 1.88 [90% CI, 0.87-3.70]). Corticosteroid treatment for relapses might be a risk factor for VZV reactivation. CONCLUSIONS AND RELEVANCE: Rates of VZV infections in clinical trials were low with fingolimod, 0.5 mg/d, but higher than in placebo recipients. Rates reported in the postmarketing setting are comparable. We found no sign of risk accumulation with longer exposure. Serious or complicated cases of herpes zoster were uncommon. We recommend establishing the patient's VZV immune status before initiating fingolimod therapy and immunization for patients susceptible to primary VZV infection. Routine antiviral prophylaxis is not needed, but using concomitant pulsed corticosteroid therapy beyond 3 to 5 days requires an individual risk-benefit assessment. Vigilance to identify early VZV symptoms is important to allow timely antiviral treatment.