ABSTRACT
BACKGROUND: A number of medications are known to interact with methotrexate through various mechanisms. The aim of this article is to apprise practitioners of a new labeling change based on the accumulating evidence for a possible drug-drug interaction between methotrexate (primarily at high doses) and proton pump inhibitors (PPIs). METHODS: The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database of spontaneous adverse event reports and the published literature were searched for cases reporting an interaction between methotrexate and PPIs. RESULTS: A search of the AERS database and existing literature found several individual case reports of drug-drug interactions and three additional supportive studies that suggest potential underlying mechanisms for the interaction. CONCLUSION: There is evidence to suggest that concomitant use of methotrexate (primarily at high doses) with PPIs such as omeprazole, esomeprazole, and pantoprazole may decrease methotrexate clearance, leading to elevated serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In several case reports, no methotrexate toxicity was found when a histamine H2 blocker was substituted for a PPI. Based on the reviewed data, the FDA updated the methotrexate label to include the possible drug-drug interaction between high-dose methotrexate and PPIs. Physicians should be alerted to this potential drug-drug interaction in patients receiving concomitant high-dose methotrexate and PPIs.
Subject(s)
Methotrexate/adverse effects , Methotrexate/pharmacology , Proton Pump Inhibitors/adverse effects , Proton Pump Inhibitors/pharmacology , Adverse Drug Reaction Reporting Systems , Drug Interactions , Drug Labeling , Humans , United States , United States Food and Drug AdministrationSubject(s)
Intestinal Perforation/chemically induced , Naltrexone/analogs & derivatives , Narcotic Antagonists/adverse effects , Analgesics, Opioid/adverse effects , Analgesics, Opioid/antagonists & inhibitors , Humans , Intestinal Perforation/epidemiology , Naltrexone/adverse effects , Naltrexone/therapeutic use , Narcotic Antagonists/therapeutic use , Palliative Care , Quaternary Ammonium Compounds/adverse effects , Quaternary Ammonium Compounds/therapeutic use , United StatesSubject(s)
Anti-Inflammatory Agents/adverse effects , Antibodies, Monoclonal/adverse effects , Inflammatory Bowel Diseases/drug therapy , Liver Neoplasms/chemically induced , Lymphoma, T-Cell/chemically induced , Splenic Neoplasms/chemically induced , Adalimumab , Adolescent , Adult , Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Drug Therapy, Combination , Female , Humans , Inflammatory Bowel Diseases/complications , Infliximab , Male , Young AdultABSTRACT
Hepatosplenic T cell lymphoma (HSTCL) are rare cancers ( approximately 100 published cases worldwide) and comprise 5% of peripheral T cell lymphomas. As of October 5, 2006, the FDA's Adverse Event Reporting System has received 8 cases of HSTCL in young patients using infliximab, a tumor necrosis factor-alpha blocking agent, to treat inflammatory bowel disease (6 of the 8 cases had a fatal outcome). All 8 patients were receiving concomitant immunosuppressant therapy (eg, azathioprine, prednisone). It has not been established that infliximab had an exclusive or primary role in the pathogenesis of these HSTCL cases; however, it appears that patients using this product may be at greater risk for developing this rare lymphoma.
Subject(s)
Antibodies, Monoclonal/adverse effects , Gastrointestinal Agents/adverse effects , Inflammatory Bowel Diseases/drug therapy , Liver Neoplasms/chemically induced , Lymphoma, T-Cell/chemically induced , Splenic Neoplasms/chemically induced , Adolescent , Adult , Child , Female , Humans , Immunosuppressive Agents/therapeutic use , Infliximab , MaleSubject(s)
Colitis, Ischemic/chemically induced , Indoles/adverse effects , Irritable Bowel Syndrome/drug therapy , Serotonin Receptor Agonists/adverse effects , Adult , Adverse Drug Reaction Reporting Systems , Aged , Aged, 80 and over , Female , Gastrointestinal Agents/adverse effects , Humans , Male , Middle AgedABSTRACT
OBJECTIVE: To assess risk factors for tardive dyskinesia (TD) in spontaneous reports of metoclopramide and TD and evaluate metoclopramide prescribing patterns before and after withdrawal of cisapride from the market in the United States. DESIGN: Retrospective and observational analyses. SETTING: International metoclopramide adverse event reports and domestic drug-use data for the continental United States. PATIENTS: Users of metoclopramide for 30 days or more who experienced adverse events reported as TD. INTERVENTIONS: Analyses of the Food and Drug Administration Adverse Event Reporting System (AERS) and IMS HEALTH data. MAIN OUTCOME MEASURES: Pharmacoepidemiological patterns in AERS reports and utilization data from IMS HEALTH. RESULTS: The case series comprised 87 reports of primarily older (mean+/-SD, 60+/-22 years ) women (67% of all cases). While average metoclopramide daily dose (33+/-14 mg) was within recommended product labeling limits, duration of use was considerably longer (753+/-951 days). Overall, 37% of the reports included concomitant drugs believed to be TD risk factors. Similarly, 18% of the reports noted comorbid diseases that are considered risk factors for development of TD. Metoclopramide utilization decreased following cisapride marketing in 1993 and increased following cisapride withdrawal in 2000. The majority (62%) of metoclopramide prescriptions were intended for women. Intended use overall increased with age and was highest in the seventh and eighth decades, with nearly one quarter of all utilization being in persons older than 70 years. CONCLUSION: Well-described TD risk factors were common in metoclopramide-associated TD reports. Given the cisapride market withdrawal and associated increased metoclopramide utilization, the incidence of TD may increase accordingly. TD risk factors relative to the intended benefit and duration of use should be considered in metoclopramide prescribing.
Subject(s)
Adverse Drug Reaction Reporting Systems , Akathisia, Drug-Induced/etiology , Cisapride/adverse effects , Metoclopramide/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Cisapride/administration & dosage , Drug Utilization , Female , Humans , Infant , Infant, Newborn , Male , Metoclopramide/administration & dosage , Middle Aged , Retrospective Studies , Risk Factors , United States , United States Food and Drug AdministrationSubject(s)
Carbolines/adverse effects , Colitis, Ischemic/chemically induced , Colonic Diseases, Functional/drug therapy , Constipation/chemically induced , Adverse Drug Reaction Reporting Systems , Carbolines/therapeutic use , Clinical Trials as Topic , Colitis, Ischemic/epidemiology , Colonic Diseases, Functional/diagnosis , Constipation/epidemiology , Evidence-Based Medicine , Female , Humans , Male , North America , Risk Assessment , Severity of Illness Index , Treatment Outcome , United States , United States Food and Drug AdministrationABSTRACT
PURPOSE: Evaluate whether a 15-minute lecture intervention will improve adverse drug reaction reporting quality on standard MedWatch forms. METHODS: Seventy-eight 4th-year medical students were randomized to intervention 'Group-A' or non-intervention 'Group-B' on the first day of a required five-day clinical pharmacology rotation. Group-A participants attended a 15-minute lecture on completing a MedWatch form with quality information considered by the Food and Drug Administration as critical to adequate adverse drug reaction reporting. Group-B participants did not attend this lecture. Both groups then watched a standardized patient interview of a recognizable adverse drug reaction and completed MedWatch forms. Four Safety Evaluators from the Food and Drug Administration (FDA) rated student responses in a blinded fashion for the primary efficacy variable of Overall Impression and six informational domins using a standardized data quality analysis form that was developed within the Office of Postmarketing Drug Risk Assessment of the FDA. RESULTS: Seventy-eight MedWatch forms were evaluated (Group-A = 40, Group B = 38). Overall MedWatch information quality scores for the intervention group were significantly higher than the non-intervention group (p < 0.004). CONCLUSIONS: As little as a 15-minute intervention can significantly improve the quality of adverse drug reaction reporting by 4th-year medical students. Academic medical centers should consider incorporating adverse drug reaction reporting curriculum into the clinical training of medical students.