Challenges in Pharmacovigilance: Variability in the Criteria for Determining Drug-Associated Acute Kidney Injury in Retrospective, Observational Studies.

BACKGROUND: Drug-associated acute kidney injury (D-AKI) accounts for 19-26% of acute kidney injury (AKI) events in hospitalized patients and results in outcomes similar to patients with AKI from other etiologies. Diagnosing D-AKI is complex and various criteria have been used. SUMMARY: To highlight the variability in D-AKI determination, a review was conducted between January 2017 and December 2022 using PubMed. Search terms included adaptations of "drug associated kidney injury" to identify a sampling of literature discussing definitions and criteria for D-AKI evaluation. The search yielded 291 articles that were uploaded to Rayyan, a software tool used to screen and select studies. Retrospective, observational electronic health record (EHR) studies conducted in hospitalized patients were included. The final sample contained 16 studies for data extraction, representing mostly adult populations (n = 13, 81.3%) in noncritical or unspecified inpatient settings (n = 12, 75%). Nine studies (56.3%) utilized the recommended Kidney Disease: Improving Global Outcome guidelines (KDIGO) criteria to define AKI. Baseline creatinine or laboratory criteria for kidney function were provided in 10 studies (62.5%). Eleven studies (68.8%) established a temporal sequence assessment linking nephrotoxin drug exposure to an AKI event, but these criteria were inconsistent among studies using time frames as soon as 3 months prior to AKI. CONCLUSION: This review highlights the substantial variability in D-AKI criteria in select studies. Minimum expectations about what should be reported and criteria for the elements reported are needed to assure transparency, consistency, and standardization of pharmacovigilance strategies.

Assessing adverse drug reaction reports for antidiabetic medications approved by the food and drug administration between 2012 and 2017: a pharmacovigilance study.

Objective: Between 2012 and 2017, the U.S. Food and Drug Administration (FDA) approved 10 antidiabetic indicated therapies. Due to the limited literature on voluntarily reported safety outcomes for recently approved antidiabetic drugs, this study investigated adverse drug reactions (ADRs) reported in the FDA Adverse Event Reporting System (FAERS). Research Design and Methods: A disproportionality analysis of spontaneously reported ADRs was conducted. FAERS reports from January 1, 2012 to March 31, 2022 were compiled, allowing a 5-year buffer following drug approval in 2017. Reporting odds ratios were calculated for the top 10 ADRs, comparing new diabetic agents to the other approved drugs in their therapeutic class. Results: 127,525 reports were identified for newly approved antidiabetic medications listed as the primary suspect (PS). For sodium-glucose co-transporter-2 (SGLT-2) inhibitors, the odds of blood glucose increased, nausea, and dizziness being reported was greater for empagliflozin. Dapagliflozin was associated with greater reports of weight decreased. Canagliflozin was found to have a disproportionally higher number of reports for diabetic ketoacidosis, toe amputation, acute kidney injury, fungal infections, and osteomyelitis. Assessing glucagon-like peptide-1 (GLP-1) receptor agonists, dulaglutide and semaglutide were associated with greater reports of gastrointestinal adverse drug reactions. Exenatide was disproportionally associated with injection site reactions and pancreatic carcinoma reports. Conclusion: Pharmacovigilance studies utilizing a large publicly available dataset allow an essential opportunity to evaluate the safety profile of antidiabetic drugs utilized in clinical practice. Additional research is needed to evaluate these reported safety concerns for recently approved antidiabetic medications to determine causality.

Adverse drug reactions reported for antidiabetic medications Introduction: This study investigated the trends in voluntary reporting of adverse drug reactions for recently approved antidiabetic medications. Methods: Data from the FDA Adverse Events Reporting System were evaluated. The top 10 adverse drug reactions were compared between antidiabetic medications in the same therapeutic class. Results: We identified 127,525 adverse drug reaction reports for the newer approved antidiabetic medications. For SGLT-2 inhibitors, empagliflozin was associated with greater reports of blood glucose increase, nausea, and dizziness; weight decreased was reported more often for dapagliflozin; and diabetic ketoacidosis, toe amputation, acute kidney injury, fungal infections, and osteomyelitis were reported more commonly for canagliflozin. Assessing GLP-1 receptor agonists, the odds of gastrointestinal adverse drug reactions being reported was greater for dulaglutide and semaglutide. Exenatide was disproportionally associated with injection site reactions and pancreatic carcinoma reports. Conclusion: Medication safety studies using a large publicly available dataset allows an essential opportunity to evaluate the safety profile of antidiabetic drugs in the real-world setting. Additional research is needed to determine if the reported safety concerns for recently approved antidiabetic medications to determine causality.

Expert Consensus on the Nephrotoxic Potential of 195 Medications in the Non-intensive Care Setting: A Modified Delphi Method.

INTRODUCTION: Nephrotoxin exposure is significantly associated with acute kidney injury (AKI) development. A standardized list of nephrotoxic medications to surveil and their perceived nephrotoxic potential (NxP) does not exist for non-critically ill patients. OBJECTIVE: This study generated consensus on the nephrotoxic effect of 195 medications used in the non-intensive care setting. METHODS: Potentially nephrotoxic medications were identified through a comprehensive literature search, and 29 participants with nephrology or pharmacist expertise were identified. The primary outcome was NxP by consensus. Participants rated each drug on a scale of 0-3 (not nephrotoxic to definite nephrotoxicity). Group consensus was met if ≥ 75% of responses were one single rating or a combination of two consecutive ratings. If ≥ 50% of responses indicated "unknown" or not used in the non-intensive care setting, the medication was removed for consideration. Medications not meeting consensus for a given round were included in the subsequent round(s). RESULTS: A total of 191 medications were identified in the literature, with 4 medications added after the first round from participants' recommendations. NxP index rating consensus after three rounds was: 14 (7.2%) no NxP in almost all situations (rating 0); 62 (31.8%) unlikely/possibly nephrotoxic (rating 0.5); 21 (10.8%) possibly nephrotoxic (rating 1); 49 (25.1%) possibly/probably nephrotoxic (rating 1.5); 2 (1.0%) probably nephrotoxic (rating 2); 8 (4.1%) probably/definite nephrotoxic (rating 2.5); 0 (0.0%) definitely nephrotoxic (rating 3); and 39 (20.0%) medications were removed from consideration. CONCLUSIONS: NxP index rating provides clinical consensus on perceived nephrotoxic medications in the non-intensive care setting and homogeneity for future clinical evaluations and research.

A Pharmacovigilance Study of Adverse Drug Reactions Reported for Cardiovascular Disease Medications Approved Between 2012 and 2017 in the United States Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

PURPOSE: Between 2012 and 2017, the FDA approved 29 therapies for a cardiovascular disease (CVD) indication. Due to the limited literature on patient safety outcomes for recently approved CVD medications, this study investigated adverse drug reports (ADRs) reported in the FDA Adverse Event Reporting System (FAERS). METHODS: A disproportionality analysis of spontaneously reported ADR was conducted. Reports in FAERS from Quarter 1, 2012, through Quarter 1, 2019, were compiled, allowing a 2-year buffer following drug approval in 2017. Top 10 reported ADRs and reporting odds ratios (ROR; confidence interval (CI)), a measure of disproportionality, were analyzed and compared to drugs available prior to 2012 as appropriate. RESULTS: Of 7,952,147 ADR reports, 95,016 (1.19%) consisted of reports for newly approved CVD medications. For oral anticoagulants, apixaban had significantly lower reports for anemia and renal failure compared to dabigatran and rivaroxaban but greater reports for neurological signs/symptoms, and arrhythmias. Evaluating heart failure drugs, sacubitril/valsartan had greater reports for acute kidney injury, coughing, potassium imbalances, and renal impairment but notably, lower for angioedema compared to lisinopril. Assessing familial hypercholesterolemia drugs, alirocumab had greater reports for joint-related-signs/symptoms compared to other agents in this category. A newer pulmonary arterial hypertension treatment, selexipag, had greater reports of reporting for bone/joint-related-signs/symptoms but riociguat had greater reports for hemorrhages and vascular hypotension. CONCLUSION: Pharmacovigilance studies allow an essential opportunity to evaluate the safety profile of CVD medications in clinical practice. Additional research is needed to evaluate these reported safety concerns for recently approved CVD medications.

Assessing Adverse Drug Reactions Reported for New Respiratory Medications in the FDA Adverse Event Reporting System Database.

BACKGROUND: Between 2012 and 2017, 25 new medications or combination products were approved by the Food and Drug Administration (FDA) for use in treatment of chronic lower respiratory diseases (CLRDs). With limited data on post-marketing patient exposure to these drugs, their safety profiles remain unknown. This study aims to provide post-marketing surveillance of these medications. METHODS: A list of new CLRD medications approved between 2012 and 2017 was generated through searches on Drugs.com (https://www.drugs.com), FDA.gov (https://www.fda.gov), and IBM Micromedex (https://www.micromedexsolutions.com/home/dispatch/ssl/true). Data describing adverse drug reactions (ADRs) were collected from the FDA Adverse Event Reporting System for analysis. Of the 25 identified medications, we selected 4 medications indicated for asthma or COPD with at least 500 reports. Only ADRs catalogued with these medications as the primary suspect were analyzed. Reporting odds ratios were calculated for the top 10 ADRs of each CLRD medication. RESULTS: A total of 61,682 ADR reports were collected for newly approved CLRD medications (n = 27,190 older adults; n = 30,502 male). Reports of COPD medications (umeclidinium and umeclidinium/vilanterol) indicate that umeclidinium/vilanterol yielded a higher reporting odds ratio than umeclidinium alone for reports of pain. Fluticasone furoate/vilanterol had higher reporting odds ratios for cough, pain, and dizziness than budesonide/formoterol and fluticasone propionate/salmeterol. CONCLUSIONS: Our findings suggest that the incidence of different adverse events experienced by patients in post-marketing reports resembles the incidence reported in pre-marketing clinical trials for COPD medications, except for fluticasone furoate/vilanterol, which has several differences.