Presence of metallic components in transdermal drug delivery systems and risk of skin burns. / [Artículo traducido] Presencia de partículas metálicas en parches transdérmicos de medicamentos y riesgo de quemaduras.

OBJECTIVE: Skin burns are associated with the presence of metallic components in transdermal drug delivery systems during Magnetic Resonance Imaging, cardioversion or defibrillation procedures. The aim of the study was to review the presence of metallic components in marketed products of transdermal drug delivery systems in Spain. METHOD: For each presentation, the summary of product characteristics was reviewed. If the information was not provided, manufacturers were contacted. RESULTS: We identified 59 marketed products of transdermal drug delivery systems of 12 different active substances. 59.3% of patches contained metallic components or their presence could not be ruled out. Information regarding the need to remove the patch was only included in 8 summaries of product characteristics (13.6%). A table was elaborated and included the following aspects: product, active substance, manufacturer, need to remove the patch before the exposure to magnetic or electric fields and references. CONCLUSION: More than a half of the patches at the time of the study contained metals or their absence could not be confirmed by the manufacturer. However, this information was only included in 13.6% of summaries of product characteristics.

Treatment with Rasburicase in Hospitalized Patients with Cardiorenal Syndrome: Old Treatment, New Scenario.

Cardiorenal syndrome (CRS) involves joint dysfunction of the heart and kidney. Acute forms share biochemical alterations like hyperuricaemia (HU) with tumour lysis syndrome (TLS). The mainstay treatment of acute CRS with systemic overload is diuretics, but rasburicase is used in TLS to prevent and treat hyperuricaemia. An observational, retrospective study was performed to assess the effectiveness and safety of a single dose of rasburicase in hospitalized patients with cardiorenal syndrome, worsening renal function and uric acid levels above 9 mg/dL. Rasburicase improved diuresis and systemic congestion in the 35 patients included. A total of 86% of patients did not need to undergo RRT, and early withdrawal was possible in the remaining five. Creatinine (Cr) decreased after treatment with rasburicase from a peak of 3.6 ± 1.27 to 1.79 ± 0.83 mg/dL, and the estimated glomerular filtration rate (eGFR) improved from 17 ± 8 to 41 ± 20 mL/min/1.73 m2 (p = 0.0001). The levels of N-terminal type B Brain Natriuretic Peptide (Nt-ProBNP) and C-reactive protein (CRP) were also significantly reduced. No relevant adverse events were detected. Our results show that early treatment with a dose of rasburicase in patients with CRS and severe HU is effective to improve renal function and systemic congestion, avoiding the need for sustained extrarenal clearance, regardless of comorbidities and ventricular function.

Presence of metallic components in transdermal drug delivery systems and risk of skin burns.

OBJECTIVE: Skin burns are associated with the presence of metallic components in transdermal drug delivery systems during Magnetic Resonance Imaging, cardioversion, or defibrillation procedures. The aim of the study was to review the presence of metallic components in marketed products of transdermal drug delivery systems in Spain. METHOD: For each pharmaceutical form, the summary of product characteristics was reviewed. If the information was not provided, manufacturers were contacted. RESULTS: We identified 59 marketed products of transdermal drug delivery systems of 12 different active substances. 59.3% of patches contained metallic components or their presence could not be ruled out. Information regarding the need to remove the patch was only included in 8 summaries of product characteristics (13.6%) A table was elaborated and included the following aspects: product, active substance, manufacturer, need to remove the patch before the exposure to magnetic or electric fields, and references. CONCLUSION: More than a half of the patches at the time of the study contained metals or their absence could not be confirmed by the manufacturer. However, this information was only included in 13.6% of summaries of product characteristics.

Medication guide for dose adjustment and management of cardiotoxicity and lipid metabolic adverse events of oral antineoplastic therapy.

Objective: The management of cardiotoxicity concerning the use of oral antineoplastic agents (OAAs) is a challenge for healthcare professionals. Our objective was to create a comprehensive medication management guide with dose adjustment recommendations on OAAs concerning cardiotoxic and lipid metabolic adverse events (AEs) to assist healthcare professionals when prescribing OAAs. Materials and methods: A review of the available information on all dose adjustments necessary to safely prescribe and dispense OAAs concerning cardiotoxicity was conducted. In January 2023, we identified all OAAs authorized by the European Medicines Agency (EMA). For each drug, the latest summary of product characteristics (SPC) approved by the EMA and the tertiary data source Lexicomp® were reviewed. Cardiotoxic AEs were recorded, namely, QT interval prolongation, decrease in left ventricular ejection fraction (LVEF), imbalances in blood pressure (hypertension and hypotension), alterations in heart rate (tachycardia and bradycardia), and thrombosis. Any available dose adjustment recommendations in case of an occurrence of these adverse events were collected. Results: In all, 93 different OAAs had been approved by the EMA and were reviewed. Among them, 51.6% have recognized cardiotoxic AEs and 10.8% can cause alterations in lipid metabolism. A total of 27 (29.0%) OAAs had specific recommendations regarding QT prolongation; 88.9% were listed in the SPC and 59.3% in Lexicomp®. Eight OAAs (9.68%) have reported a decrease in LVEF, and four of these drugs, namely, encorafenib, lorlatinib, ripretinib, and sunitinib, have specific management recommendations. Almost half (49.5%) of currently approved OAAs can potentially alter blood pressure; 34 (36.6%) of them have been reported to cause hypertension and 12 (12.9%) are related to hypotension. Tachycardia and/or bradycardia are associated with 22.6% and 8.6% of the evaluated drugs, respectively. Regarding thrombosis, 30 (32.3%) of the drugs analyzed included the appearance of a thrombus as a possible AE. Conclusions: More than half of the OAAs can produce cardiotoxic effects, with the most frequent being blood pressure alteration and QT interval prolongation with a non-depreciable incidence of LV dysfunction or thrombosis. Before starting the treatment, it is necessary to stratify baseline cardiovascular risk, plan a surveillance schedule, and consider referral to cardio-oncology units.

Pharmacogenetics in the Treatment of Huntington's Disease: Review and Future Perspectives.

Huntington's disease (HD) is an autosomal dominant progressive brain disorder, caused by a pathological expansion of a CAG repeat that encodes the huntingtin gene. This genetic neurodegenerative rare disease is characterized by cognitive, motor, and neuropsychiatric manifestations. The aim of the treatment is symptomatic and addresses the hyperkinetic disorders (chorea, dystonia, myoclonus, tics, etc.) and the behavioural and cognitive disturbances (depression, anxiety, psychosis, etc.) associated with the disease. HD is still a complex condition in need of innovative and efficient treatment. The long-term goal of pharmacogenetic studies is to use genotype data to predict the effective treatment response to a specific drug and, in turn, prevent potential undesirable effects of its administration. Chorea, depression, and psychotic symptoms have a substantial impact on HD patients' quality of life and could be better controlled with the help of pharmacogenetic knowledge. We aimed to carry out a review of the available publications and evidence related to the pharmacogenetics of HD, with the objective of compiling all information that may be useful in optimizing drug administration. The impact of pharmacogenetic information on the response to antidepressants and antipsychotics is well documented in psychiatric patients, but this approach has not been investigated in HD patients. Future research should address several issues to ensure that pharmacogenetic clinical use is appropriately supported, feasible, and applicable.

Achieving excellence in the pharmaceutical care of the surgical patient. / Hacia la excelencia en la atención farmacéutica al paciente quirúrgico.

The perioperative setting is one of the hospital areas with the highest prevalence of medication errors. Despite the wide experience of hospital pharmacists in developing medication safety programs and improvement initiatives, the surgical environment has remained one of the areas in which there is less experience. Clinical pharmacist should be integrated into the multidisciplinary care teams so that they can be involved in the different surgical phases of care, which include from the preoperative assessment to inpatient stay, and finally discharge from hospital. Their work will consist of coordinating and implementing strategies that have been demonstrated to reduce medication errors throughout the perioperative process. The aim of this paper is to introduce a specialized pharmaceutical care program to achieve excellence in the pharmaceutical care of surgical patients. This program is especially aimed at promoting the figure of the clinical pharmacist in the perioperative setting to guarantee the highest quality and safety in pharmacotherapeutic care throughout all the surgical phases of care.

[Translated article] Achieving excellence in the pharmaceutical care of the surgical patient.

The perioperative setting is one of the hospital areas with the highest prevalence of medication errors. Despite the wide experience of hospital pharmacists in developing medication safety programs and improvement initiatives, the perioperative setting has remained one of the areas in which there is less experience. Clinical pharmacist should be integrated into the multidisciplinary care team so that they can be involved in the different surgical phases of care, which include from the preoperative assessment to inpatient stay, and finally discharge from hospital. Their work will consist of coordinating and implementing strategies that have been demonstrated to reduce medication errors during the perioperative process. The aim of this paper is to introduce a specialized pharmaceutical care program to achieve excellence in the pharmaceutical care of surgical patients. This program is especially aimed at promoting the figure of the clinical pharmacist in the perioperative setting to guarantee the highest quality and safety in pharmacotherapeutic care throughout all the surgical phases of care.

Hacia la excelencia en la atención farmacéutica al paciente quirúrgico / Achieving excellence in the pharmaceutical care of the surgical patient

El proceso quirúrgico es una de las áreas del hospital con más prevalencia de errores de medicación. A pesar de la amplia experiencia del farmacéutico en el desarrollo de prácticas seguras de utilización de los medicamentos, el bloque quirúrgico ha sido una de las áreas en las que menos experiencia existe.El farmacéutico especialista debe integrarse en el equipo multidisciplinar, de tal forma que pueda estar presente en todas las etapas de atención al enfermo (prehospitalización, precirugía, intracirugía, postcirugía y alta). Su función será coordinar y diseñar la puesta en marcha de diferentes estrategias que han demostrado reducir el riesgo de errores de medicación durante todo el proceso perioperatorio.El objetivo del presente trabajo es presentar un programa de atención farmacéutica especializada para alcanzar la excelencia en la atención farmacéutica del paciente quirúrgico. Este programa está dirigido especialmente a visibilizar la figura del farmacéutico en el entorno perioperatorio, para que pueda colaborar en garantizar una atención farmacoterapéutica de máxima calidad y seguridad en todas las etapas. (AU)

The perioperative setting is one of the hospital areas with the highest prevalence of medication errors. Despite the wide experience of hospital pharmacists in developing medication safety programs and improvement initiatives, the surgical environment has remained one of the areas in which there is less experience.Clinical pharmacist should be integrated into the multidisciplinary care teams so that they can be involved in the different surgical phases of care, which include from the preoperative assessment to inpatient stay, and finally discharge from hospital. Their work will consist of coordinating and implementing strategies that have been demonstrated to reduce medication errors throughout the perioperative process.The aim of this paper is to introduce a specialized pharmaceutical care program to achieve excellence in the pharmaceutical care of surgical patients. This program is especially aimed at promoting the figure of the clinical pharmacist in the perioperative setting to guarantee the highest quality and safety in pharmacotherapeutic care throughout all the surgical phases of care. (AU)

PCSK9 inhibitors revisited: Effectiveness and safety of PCSK9 inhibitors in a real-life Spanish cohort.

INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have emerged as a therapeutic option for patients with hypercholesterolemia who do not attain low-density lipoprotein cholesterol (LDL-C) goals and/or are intolerant to other lipid-lowering drugs. Our aim was to analyze the effectiveness and safety of PCSK9i in routine clinical practice and factors related to poor outcomes. MATERIALS AND METHODS: We conducted an ambispective study in 115 patients who recieved alirocumab or evolocumab, in a tertiary level hospital. From February 2017 to April 2020, patients were recruited and followed up for a median of 20.4 months. The main outcomes were relative reduction in LDL-C, percentage of patients achieving the therapeutic goals established by 2016 ESC/EAS guidelines, incidence of major cardiovascular events (MACEs) and drug-related adverse events (ADRs). RESULTS: The median LDL-C achieved was 57.0 mg/dL (relative reduction of 59.9% from baseline, p< 0.001). After adjusting for confounders, smaller LDL-C reductions were related to female sex, absence of concomitant lipid-lowering therapy and treatment with alirocumab. Overall, 84.6% of the patients achieved the therapeutic goals. During follow-up, 7 MACEs were detected. ADRs, generally considered mild, affected 38.1% of the participants (mainly mialgias and arthralgias) and triggered discontinuations in 8.7% of cases. CONCLUSIONS: PCSK9i are effective and safe, although certain factors may influence their effectiveness. Interestingly, our results suggest that alirocumab and evolocumab may not be therapeutic equivalents, as initially suggested.

Pharmacogenetics to Avoid Adverse Reactions in Cardiology: Ready for Implementation?

Cardiovascular Diseases (CVs) are one of the main causes of mortality and disability around the world. Advances in drug treatment have greatly improved survival and quality of life in the past decades, but associated adverse events remain a relevant problem. Pharmacogenetics can help individualize cardiovascular treatment, reducing associated toxicities and improving outcomes. Several scientific societies and working groups periodically review available studies and provide consensus recommendations for those gene-drug pairs with a sufficient level of evidence. However, these recommendations are rarely mandatory, and the indications on how to adjust treatment can vary between different guidelines, which limits their clinical applicability. The aim of this review is to compile, compare and discuss available guidelines and recommendations by the main Pharmacogenetics Consortiums (Clinical Pharmacogenetics Implementation Consortium (CPIC); Dutch Pharmacogenetics Working Group (DPWG); the French Network of Pharmacogenetics (Réseau national de pharmacogénétique (RNPGx) and The Canadian Pharmacogenomics Network for Drug Safety (CPNDS) regarding how to apply pharmacogenetic results to optimize pharmacotherapy in cardiology. Pharmacogenetic recommendations included in European or American drug labels, as well as those included in the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) and the American Heart Association (AHA) treatment guidelines are also discussed.

DPYD Exome, mRNA Expression and Uracil Levels in Early Severe Toxicity to Fluoropyrimidines: An Extreme Phenotype Approach.

Dihydropyrimidine dehydrogenase deficiency is a major cause of severe fluoropyrimidine-induced toxicity and could lead to interruption of chemotherapy or life-threatening adverse reactions. This study aimed to characterize the DPYD exon sequence, mRNA expression and in vivo DPD activity by plasma uracil concentration. It was carried out in two groups of patients with extreme phenotypes (toxicity versus control) newly treated with a fluoropyrimidine, during the first three cycles of treatment. A novel nonsense gene variant (c.2197insA) was most likely responsible for fluoropyrimidine-induced toxicity in one patient, while neither DPYD mRNA expression nor plasma uracil concentration was globally associated with early toxicity. Our present work may help improve pharmacogenetic testing to avoid severe and undesirable adverse reactions to fluoropyrimidine treatment and it also supports the idea of looking beyond DPYD.

Clinical evaluation of pulmonary hypertension using patient-reported outcomes: a cross-sectional study.

BACKGROUND: Patients with pulmonary hypertension (PH) have progressive and disabling symptoms, as well as a burden of treatments and a difficult clinical evaluation that make health-related quality of life a particularly relevant endpoint in this disease. The objective of the study was to evaluate patient-reported outcomes of patients receiving specific treatment for PH in a tertiary hospital using a specific questionnaire (Cambridge Pulmonary Hypertension Outcome Review-CAMPHOR) in the pharmacy consultation. METHODS: A cross-sectional, observational, descriptive study was conducted. It included all patients receiving specific treatment for PH in a tertiary hospital in Madrid, Spain. The inclusion period comprised between August to December 2019. CAMPHOR questionnaires containing three domains: symptoms, activities and quality of life were completed by the patients at the pharmacy consultation. Demographic and clinical variables, including WHO Functional Class (WHO FC), PH-specific tests and hemodynamic parameters, were recorded. Non-parametric analyses to assess relations between variables and CAMPHOR domains were performed. RESULTS: Thirty-six patients consented to participate in the study and completed the questionnaire. Median scores for symptoms, activities, and quality of life domains were 5.5 (2.5-10), 8.0 (4.5-10.5) and 3.5 (1-7.5), respectively. Statistically significant differences were found in the three domains when comparing by WHO FC, in the activities domain for 6-m walking test and in the quality of life domain for patients who had emergency visits or hospitalizations in the last year. CONCLUSIONS: The CAMPHOR questionnaire could be useful as a complementary test to achieve an integrated evaluation of PH patients, who could complete it easily during their routine pharmacy visits.

Valganciclovir-Ganciclovir Use and Systematic Therapeutic Drug Monitoring. An Invitation to Antiviral Stewardship.

Valganciclovir (VGCV) and ganciclovir (GCV) doses must be adjusted according to indication, renal function and weight. No specific therapeutic exposure values have been established. We aimed to evaluate the adequacy of VGCV/GCV doses, to assess the interpatient variability in GCV serum levels, to identify predictive factors for this variability and to assess the clinical impact. This is a prospective study at a tertiary institution including hospitalized patients receiving VGCV/GCV prophylaxis or treatment. Adequacy of the antiviral dose was defined according to cytomegalovirus guidelines. Serum levels were determined using High-Performance Liquid Chromatography. Blood samples were drawn at least 3 days after antiviral initiation. Outcome was considered favorable if there was no evidence of cytomegalovirus infection during prophylaxis or when a clinical and microbiological resolution was attained within 21 days of treatment and no need for drug discontinuation due to toxicity. Seventy consecutive patients [74.3% male/median age: 59.2 years] were included. VGCV was used in 25 patients (35.7%) and GCV in 45 (64.3%). VGCV/GCV initial dosage was deemed adequate in 47/70 cases (67.1%), lower than recommended in 7/70 (10%) and higher in 16/70 (22.9%). Large inter-individual variability of serum levels was observed, with median trough levels of 2.3 mg/L and median peak levels of 7.8 mg/L. Inadequate dosing of VGCV/GCV and peak levels lower than 8.37 or greater than 11.86 mg/L were related to poor outcome. Further studies must be performed to confirm these results and to conclusively establish if VGCV/GCV therapeutic drug monitoring could be useful to improve outcomes in specific clinical situations.

Levels of tacrolimus after treatment for chronic hepatitis C with direct antiviral agents in solid organ transplant recipients.

Background and objective The main objective was to evaluate the impact of Hepatitis C Virus treatment with direct-acting antiviral agents on tacrolimus blood levels in recipients of kidney and heart allografts. Method We analysed Hepatitis C Virus infected adult patients who received tacrolimus as immunosuppressive maintenance therapy and received direct-acting antiviral agents treatment in a tertiary hospital with solid transplant multidisciplinary program in Madrid, Spain. Liver and renal function, tacrolimus dose and blood levels were analysed before and 12 weeks after the end of treatment. Results We identified 7 kidney and 2 heart transplant recipients. All patients achieved sustained virologic response at 24 weeks. At week 12 after treatment, all liver functionality tests improved significantly with no significant changes in renal function. A decrease in the tacrolimus blood level/dose ratio for every patient was observed (370.04 ± 253.93 vs. 186.44 ± 123.74 ng/mL per mg/kg; p < 0.05). The requirements of tacrolimus dose increased after Hepatitis C Virus treatment (0.03 ± 0.04 vs. 0.04 ± 0.03 mg/kg/day, p < 0.05) to reach lower blood levels than before treatment (6 ± 2.25 vs. 4.67 ± 1.51 ng/mL, p < 0.05). Conclusion Caution is advised to clinicians; close monitoring of tacrolimus levels after direct-acting antiviral agents is recommended in order to avoid infradosification that could pose a risk of graft rejection.

Genetic Predictors of Long-term Response to Antitumor Necrosis Factor Agents in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Inflammatory bowel disease (IBD) is more complex in children and they will have to live with the disease for much longer. For this reason, it is necessary to optimize treatment. The polymorphisms associated with the response to anti-tumor necrosis factor (TNF) drugs in adults with IBD have not been analyzed in children. The aim of the study was to identify genetic variants associated with the long-term response to anti-TNF drugs in children with IBD. METHODS: An observational, longitudinal, ambispective cohort's study was conducted. We recruited 209 anti-TNF-treated children diagnosed with IBD and genotyped 21 polymorphisms previously studied in adults with Crohn disease (CD) using real-time PCR. The association between single-nucleotide polymorphisms (SNPs) and time-to-failure was analyzed using the log-rank test. RESULTS: After multivariate analysis, 3 SNPs in IL10, IL17A and IL6 were significantly associated with response to anti-TNF treatment among patients diagnosed with CD (rs1800872-HR, 4.749 (95% confidence interval [CI] 1.156-19.517), P value < 0.05; rs2275913-HR, 0.320 [95% CI 0.111-0.920], P value  < 0.05; and rs10499563-HR, 0.210 [95% CI 0.047-0.947], P value 0.05, respectively). None of these SNPs were associated with response to infliximab in adults diagnosed with CD. Among patients diagnosed with ulcerative colitis (UC), 1 SNP in LY96 was significantly associated with response to anti-TNF treatment (rs-11465996-HR, 10.220 [95% CI 1.849-56.504] P value < 0.05). CONCLUSIONS: Genotyping of these DNA variants before starting treatment may help to identify children who are long-term responders to anti-TNF drugs, and thus tailor treatment of pediatric IBD.

New DPYD variants causing DPD deficiency in patients treated with fluoropyrimidine.

PURPOSE: Several clinical guidelines recommend genetic screening of DPYD, including coverage of the variants c.1905 + 1G>A(DPYD*2A), c.1679T>G(DPYD*13), c.2846A>T, and c.1129-5923C>G, before initiating treatment with fluoropyrimidines. However, this screening is often inadequate at predicting the occurrence of severe fluoropyrimidine-induced toxicity in patients. METHODS: Using a complementary approach combining whole DPYD exome sequencing and in silico and structural analysis, as well as phenotyping of DPD by measuring uracilemia (U), dihydrouracilemia (UH2), and the UH2/U ratio in plasma, we were able to characterize and interpret DPYD variants in 28 patients with severe fluoropyrimidine-induced toxicity after negative screening. RESULTS: Twenty-five out of 28 patients (90%) had at least 1 variant in the DPYD coding sequence, and 42% of the variants (6/14) were classified as potentially deleterious by at least 2 of the following algorithms: SIFT, Poly-Phen-2, and DPYD varifier. We identified two very rare deleterious mutations, namely, c.2087G>A (p.R696H) and c.2324T>G (p.L775W). We were able to demonstrate partial DPD deficiency, as measured by the UH2/U ratio in a patient carrying the variant p.L775W for the first time. CONCLUSION: Whole exon sequencing of DPYD in patients with suspicion of partial DPD deficiency can help to identify rare or new variants that lead to enzyme inactivation. Combining different techniques can yield abundant information without increasing workload and cost burden, thus making it a useful approach for implementation in patient care.

Improving surgical antibiotic prophylaxis adherence and reducing hospital readmissions: a bundle of interventions including health information technologies.

OBJECTIVES: Infection following orthopaedic surgery is a feared complication and an indicator of the quality of the hospital. Surgical antibiotic prophylaxis (SAP) guidelines are not always properly followed. Our aim was to describe and evaluate the impact of a multidisciplinary intervention on antibiotic prophylaxis adherence to hospital guidelines and 30-day postoperative outcomes. METHODS: The study was carried out from January to May 2016 and consisted of creating a multidisciplinary team, updating institutional guidelines and embedding the recommendations in the computerised physician order entry system which is linked to dose and renal function alerts, educational activities and pharmaceutical bedside care of patients in the orthopaedic department. A prospective pre-post study was carried out in accordance with the Declaration of Helsinki. The following information was recorded: patient and surgery characteristics, adherence to SAP guidelines, surgical site infections, length of hospital stay and rate of readmission 30 days after discharge. Statistical analyses were performed using SPSS 18.0. RESULTS: Eighty three orthopaedic patients of mean±SD age 68.2±17.0 years (44.6% male, 40 in the pre-intervention group and 43 in the intervention group) were included. Cefazolin was the recommended and most commonly administered antibiotic agent. In the intervention group, an improvement in global adherence to guidelines was achieved (76.7% vs 89.9%; p=0.039): antibiotic duration (75.0% vs 97.7%), correct dosage post-surgery (55.0% vs 76.7%), timing of administration (57.5% vs 72.1%), antibiotic pre-surgery prescription (92.5% vs 97.7%). Three surgical site infections were detected in the pre-intervention group and none in the intervention group (p>0.05). Length of hospital stay was reduced by 1 day and readmission decreased by 15% (p=0.038). CONCLUSIONS: SAP is used in daily practice in most orthopaedic patients. The implementation of a multidisciplinary programme based on health technology improved the adherence to guidelines and appeared to reduce the readmission rate.

Evaluating the role of ENOSF1 and TYMS variants as predictors in fluoropyrimidine-related toxicities: An IPD meta-analysis.

To assess the proposed associations of the c.742-227G>A (rs2612091) polymorphism within the Enolase Superfamily Member 1 gene (ENOSF1) and two variants in the adjacent Thymidylate Synthase gene (TYMS): the 5'VNTR 28bp-repeat (rs45445694) and 3'UTR 6bp-indel (rs11280056) with severe toxicity in fluoropyrimidine-treated cancer patients, we performed an individual patient data meta-analysis. Only studies investigating all three-abovementioned variants with fluoropyrimidine-related toxicities were considered for meta-analysis. Associations were tested individually for each study using multivariate regression. Meta-analysis was performed using a random-effects model. One-stage multivariate regressions including tests for independent SNP effects were applied to investigate individual effects of the variants. Multivariate haplotype regression analyses were performed on a pooled dataset to test multi-SNP effects. Of four studies including 2'067 patients, 1'912 were eligible for meta-analysis. All variants were exclusively associated with severe hand-foot-syndrome (HFS) (TYMS 2R: OR = 1.50, p = 0.0002; TYMS 6bp-ins: OR = 1.42 p = 0.0036; ENOSF1 c.742-227G: OR = 1.64 p < 0.0001, per allele). We observed independent effects for ENOSF1 c.742-227G>A and the TYMS 28bp-repeat: each toxicity-associated allele increased the risk for severe HFS (OR = 1.32 per allele, p < 0.0001). Patients homozygous for both variants were at the 3-fold higher risk for severe HFS compared to wild-type patients. Our results confirm an essential role for ENOSF1 c.742-227G and TYMS 2R-alleles in the development of fluoropyrimidine-related HFS. This suggests an important function of these genes in the development of severe HFS. Furthermore, these variants might help stratify patients in studies investigating measures of HFS prevention.