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• W2602977968 abstract "This month’s Topic Update has additional content from our Guest Editor, Paul Beninger, MD, on the subject of pharmacovigilance and postmarketing surveillance.1Beninger P. Risk communication in a pharmacovigilance environment.Clin Ther. 2017; 39: 672-674Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 2Winter J. Reetz M. Kerns W. et al.Changes in asthma maintenance therapy following the 2006 long-acting beta-agonist FDA drug warning.Clin Ther. 2017; 39: 697-701Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 3Haque A. Daniel S. Maxwell T. Boerstoel M. Post-marketing safety surveillance studies: An industry perspective on the change global requirements and implications.Clin Ther. 2017; 39: 675-685Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 4Varallo F.R. Hernandez C. Nadai T.R. et al.Confounding variables and the performance of triggers in detecting unreported adverse drug reactions.Clin Ther. 2017; 39: 686-696Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 5P. Beninger Opportunities for collaboration at the interface of pharmacovigilance and manufacturing.Clin Ther. 2017; 39: 702-712Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar In 2007 the Food and Drug Administration (FDA) was authorized to require sponsors to develop a Risk Evaluation and Mitigation Strategy (REMS) whenever there was a suspicion that more information might be needed to ensure the safety of a newly marketed product.6Wu J. Juhaeri J. The US Food and Drug Administration’s Risk Evaluation and Mitigation Strategy (REMS) Program – current status and future directions.Clin Ther. 2016; 38: 2526-2532Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar A REMS is an anticipatory risk management program intended to pick up unwanted drug effects once more patients are exposed to a drug than occurred during Phase II and III studies. This usually means that problems will be detected that require exposure of more than the typical 3000 to 5000 patients seen in the two pre-NDA (New Drug Application) phases. REMSs may also be important for agents for rare or orphan diseases. Such drugs have usually been marketed after an accelerated approval process, meaning that smaller numbers of patients were exposed before marketing approval. Also, real-world usage may reveal problems from other unstudied situations such as comorbidities or drug interactions. I created the mnemonic MICE to remember the main components of a REMS program. Table I lists the FDA’s components in my rearranged order. For clinical safety purposes, the plans for implementation (eg, checking all databases, epidemiologic studies, creation of a registry) and communication (eg, a Dear Clinician letter) should occur early in the process of assuring safe use. The medication guide (an up-to-date version of a patient package insert) should flow from the planning efforts. Table II conveys an example of the types of information needed from patients included in a REMS. What the FDA cannot determine for the sponsor is what and how many unwanted events constitute a strong enough signal to initiate a full-blown REMS. This requires forthright discussions with the FDA, ideally initiated by the sponsor.Table IREMS – Risk Evaluation and Mitigation Strategies*Rearranged from the FDA Basics Webinar: A Brief Overview of Risk Evaluation and Mitigation Strategies (REMS).7.Key Components of FDA Requirements (MICE)Medication guideImplementation planCommunication planElements to assure safe useFDA = Food and Drug Administration. Rearranged from the FDA Basics Webinar: A Brief Overview of Risk Evaluation and Mitigation Strategies (REMS).7Food and Drug Administration. FDA Basics Webinar: A Brief Overview of Risk Evaluation and Mitigation Strategies (REMS). http://www.fda.gov/AboutFDA/Transparency/Basics/ucm325201.htm. Accessed 7 March 2017Google Scholar Open table in a new tab Table IIFocus on the REMS (Phase IV) Patient (EASE).EvaluateTake a thorough history to learn about any predisposing problems and comorbidities.Do a complete systems review.Do a full physical examination.Obtain relevant laboratory studies.AdviseEducate patient about the REMS and assess any other concerns.Develop a reporting plan to ensure the patients know how and when and with whom to make contact should problems occur.Be sure the patients know about any prophylactic or rescue medication.SuperviseObserve the patient during the first dose and possibly for additional doses as needed.Monitor the patient for the known risks.For late-occurring unwanted events, monitoring may need to be extended to cover any known window of vulnerability.EncourageCheck at intervals to be sure the patient has retained all needed information and continues to be aware of potential risks.REMS = Risk Evaluation and Mitigation Strategy. Open table in a new tab FDA = Food and Drug Administration. REMS = Risk Evaluation and Mitigation Strategy. In the mid-1970s, my colleagues and I were trying to find mild psychostimulants that could possibly be useful for the treatment of low mood and apathy in the elderly. We studied a combination product containing pipradrol and vitamins.8Pipradrol. https://en.wikipedia.org/wiki/Pipradrol. Accessed March 7, 2017.Google Scholar, 9Shader R.I. Harmatz J.S. Kochansky G.E. et al.Psychopharmacological investigations in healthy elderly volunteers: effects of pipradrol-vitamin (Alertonic) elixir and placebo in relation to research design.J Am Geriatr Soc. 1975; 23: 277-279Crossref PubMed Scopus (5) Google Scholar We found the product to be ineffective. From my background reading for this Note, I was surprised to learn that pipradrol is listed as a Class A-prohibited drug for Olympic athletes.10World Anti-Doping Agency. Olympic movement anti-doping code appendix A: Prohibited classes of substances and prohibited methods 2003. http://www.dopinginfo.de/rubriken/07_info/ioc_list_03.pdf. Accessed March 23, 2017.Google Scholar By contrast it was considered to be a Schedule IV drug by the Drug Enforcement Agency.8Pipradrol. https://en.wikipedia.org/wiki/Pipradrol. Accessed March 7, 2017.Google Scholar Pipradrol is no longer available in the United States as an FDA-approved agent. In 1975, the FDA approved another psychostimulant, magnesium pemoline, marketed for attention deficit hyperactivity disorder by Abbott Laboratories under the trade name Cylert.11Cylert. https://www.drugs.com/pro/cylert.html. Accessed March 7, 2017.Google Scholar I began to use pemoline in my clinical practice in 1976, especially “off label” for my apathetic elderly patients. I treated a total of seven patients with pemoline between 1976 and 2000. Five of these patients were over age 70, one was age 47, and another was age 56, and all but one were males.12Shader R.I. Drug-attributed hepatic failure: causality, risk assessment, consent, and confusion.J Clin Psychopharmacol. 2003; 23: 533-534Crossref PubMed Scopus (1) Google Scholar All responded well, and there were no problems with adverse events of any kind. Noting that monitoring of liver transaminases revealed a 1% to 2% incidence of drug-induced liver injury (DILI), the FDA required Abbott to change its product label for pemoline in 1996. Instances of liver failure had also been reported to the FDA, and a Black Box Warning (BBW) was also added to the product label. In addition, Dear Doctor letters were mailed out. I received one of those letters and, after discussion with my four patients who were on pemoline at that time, three chose, reluctantly I might add, to discontinue pemoline. I devised an informed consent for my fourth patient and had this patient discuss his continuation decision with one of my colleagues. That patient continued without incident until I retired from clinical practice. The use of pemoline declined after these warnings, and the FDA reported that no further cases were reported to them.13Food and Drug Administration. Risk Assessment and Risk Mitigation Review(s). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022406Orig1s000RiskR.pdf. Accessed March 7, 2017.Google Scholar The story did not end here. In 1999, the FDA issued a stronger BBW. This second BBW indicated that 12 of 15 cases of acute liver failure associated with pemoline resulted in transplantation or death. Pemoline was now to be used only as a second-line therapy, meaning that other agents should be tried first. This stronger warning was encouraged by Public Citizen, a not-for-profit consumer rights advocacy group.14Public Citizen. www.citizen.org. Accessed March 7, 2017.Google Scholar, 15Public Citizen. Stronger warnings about life-threatening liver toxicity with pemoline (CYylert). December 1998. Volume 4 (12). www.citizen.org/hrg/drugs/articles.cfm?ID=6163. Accessed March 7, 2017.Google Scholar While all of this was being discussed in the United States, pemoline was withdrawn from the market in the United Kingdom in 1997, and two years later, Health Canada, the Canadian counterpart to our FDA, took similar action.16Public Citizen. Petition to remove the attention deficit drug pemoline (Cylert) from the market. http://www.citizen.org/Page.aspx?pid=3141. Accessed March 7, 2017.Google Scholar In this context, it is somewhat surprising that Mallinckrodt, Inc., in March 2001 received an approval under an abbreviated new drug application (ANDA 75-726) to market generic pemoline.17Food and Drug Administration. ANDA 75-726 March 30, 2001 Mallinckrodt Inc. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2001/75726ltr.pdf. Accessed March 7, 2017.Google Scholar The approval letter actually contained these words: “…concluded that the drug is safe and effective.…” In March 2005, Public Citizen again petitioned the FDA to take the “…only responsible course of action … to remove this dangerous drug from the market.”16Public Citizen. Petition to remove the attention deficit drug pemoline (Cylert) from the market. http://www.citizen.org/Page.aspx?pid=3141. Accessed March 7, 2017.Google Scholar Later in 2005, the FDA rescinded its marketing approval for pemoline.18U.S. Food and Drug Administration. Alert for healthcare professionals: Pemoline tablets and chewable tablets (marketed as Cylert). Oct 24, 2005. http://www.fda.gov/cder/drug/InfoSheets/HCP/pemolineHCP.htm. Accessed March 7, 2017.Google Scholar You may ask why I have referred to this as a confusing case study, especially since I do not disagree with the FDA’s decision. What confuses me is how and when the signal should have been picked up. I had carefully read 13 published reports before making the decision to continue to prescribe pemoline for my patients.19Tolman K.G. Freston J.W. Berenson M.M. et al.Hepatotoxicity due to pemoline.Digestion. 1973; 9: 532-539Crossref PubMed Scopus (18) Google Scholar, 20Gilbert J.G. Donnelly K.J. Zimmer L.E. et al.Effect of magnesium pemoline and methylphenidate on memory improvement and mood in normal aging subjects.Int J Aging Human Dev. 1973; 4: 35-51Crossref PubMed Scopus (18) Google Scholar, 21Page JG, Bernstein JE, Janicky RS, et al. A multi-clinic trial of pemoline in childhood hyperkinesis. In Clinical Use of Stimulant Drugs in Children: Proceedings of a Symposium Held at Key Biscayne, Florida, 5-8 March 1972. Conners C.K. (ed). New York, Excerpta Medica. Pp 98–124, 1974.Google Scholar, 22Jaffe S.L. Pemoline and liver function [Letter].J Am Acad Child Adoles Psychiatry. 1989; 28: 45Abstract Full Text PDF Scopus (20) Google Scholar, 23Pratt D.S. Dubois R.S. Hepatotoxicity due to pemoline (Cylert): a report of two cases.J Pediatr Gastroenterol Nutr. 1990; 10: 239-241Crossref PubMed Scopus (27) Google Scholar, 24Nehra A. Mullick F. Ishak K.G. et al.Pemoline-associated hepatic injury.Gastroenterology. 1990; 99: 1517-1519Abstract Full Text PDF PubMed Google Scholar, 25Elitsur Y. Pemoline (Cylert)-induced hepatotoxicity.J Pediatr Gastroenterol Nutr. 1990; 11: 143-144Crossref PubMed Scopus (18) Google Scholar, 26Berkovitch M. Pope E. Philips J. et al.Pemoline-associated fulminant liver failure: testing the evidence for causation.Clin Pharmacol Ther. 1995; 57: 696-698Crossref PubMed Scopus (62) Google Scholar I also read the aforementioned Public Citizen petition.16Public Citizen. Petition to remove the attention deficit drug pemoline (Cylert) from the market. http://www.citizen.org/Page.aspx?pid=3141. Accessed March 7, 2017.Google Scholar Although persuasive because of the sheer number of cases included, the reported case material was incomplete. Some cases reported fatty liver as the pathology. This occurred in two 29-year-olds.16Public Citizen. Petition to remove the attention deficit drug pemoline (Cylert) from the market. http://www.citizen.org/Page.aspx?pid=3141. Accessed March 7, 2017.Google Scholar Could this have been alcohol-induced or was it nonalcoholic steatohepatitis? Some were reported as hepatocellular damage or as hepatomegaly. One case was reported simply as hepatitis; another was called autoimmune hepatitis. Were these cases all caused by pemoline? Could coincidental viral hepatitis have been the cause in any? I have found two additional related case reports.27Abbiati C. Vecchi M. Rossi G. Inappropriate pemoline therapy leading to acute liver failure and liver transplantation.Dig Liv Dis. 2002; 34: 447-451Abstract Full Text PDF PubMed Scopus (4) Google Scholar, 28Rosh J.R. Dellert S.F. Narkewicz M. et al.Four cases of severe hepatotoxicity associated with pemoline: possible autoimmune pathogenesis.Pediatrics. 1998; 101: 921-923Crossref PubMed Scopus (31) Google Scholar A paper by Shevell and Schreiber29Shevell M. Schreiber R. Pemoline-associated hepatic failure: a critical analysis of the literature.Pediatr Neurol. 1997; 16: 14-16Abstract Full Text PDF PubMed Scopus (33) Google Scholar also questioned whether a causal linkage could be established from the reports available at that time. Causality or attribution is never straightforward in DILI. There are no specific biomarkers or definitive tests. Elevated transaminase levels, a reflection of cellular damage, may not correlate with altered liver function tests. Often a DILI diagnosis is made only when no other cause can be found. In the pemoline cases, age of onset varied widely (approximately age 5 to age 50), and there was no consistent pattern to the time of onset of hepatic symptomatology. There was also no evidence for a dose-event relationship in the known cases. In the tragic case reported by Berkovitch et al,26Berkovitch M. Pope E. Philips J. et al.Pemoline-associated fulminant liver failure: testing the evidence for causation.Clin Pharmacol Ther. 1995; 57: 696-698Crossref PubMed Scopus (62) Google Scholar symptoms and signs of liver damage occurred after about 15 months on pemoline. Confounding the establishment of causality by pemoline is that this 15-year-old boy was started on concomitant methylphenidate about a month before. When he was admitted at about the 16th month, he had been jaundiced for about a week. Sadly, after two failed liver transplants, he died. The pathology report from the biopsy before the transplants were done showed multilobular necrosis with giant cells and other changes consistent with a viral cause. However, he tested negative for any known viral etiologies. Contrast this case with that of a 19-year-old woman reported by McCurry and Cronquist.30McCurry L. Cronquist S. Pemoline and hepatotoxicity (Letter).Am J Psychiatry. 1997; 154: 713-714PubMed Google Scholar This patient had been treated for many years with methylphenidate alone. She was switched to pemoline alone and then took it along with methylphenidate and then once again without it. After about 10 weeks of total exposure to pemoline she developed symptoms and signs consistent with hepatitis. Pemoline was stopped, and she gradually improved, although her transaminases and other liver tests remained high for a month. She tested negative for known viral etiologies. Both of these patients received combination therapy for some part of their treatment course. However, from the totality of cases reported to the FDA, there is no reason to implicate methylphenidate as a causal factor. It should be noted that the two cases reported by Tolman et al19Tolman K.G. Freston J.W. Berenson M.M. et al.Hepatotoxicity due to pemoline.Digestion. 1973; 9: 532-539Crossref PubMed Scopus (18) Google Scholar were also reversible. In retrospect, it is unfortunate that Abbott did not establish a registry, even though one was recommended by the FDA, nor was there any uniform assessment of the index cases in the manner suggested in Table II. I have thought about the pemoline problem a lot. The idea that where there is smoke, there must be fire may apply here. I just cannot understand how a drug-induced unwanted effect could vary so much on so many different factors. Here is one more confusing fact. Pemoline is still on the market in Japan under the trade name Betanamin where no cases of pemoline hepatic toxicity have been reported.31Ministry of Health, Labour and Welfare. Pharmaceutical and Food Safety Bureau. Safety Division. Liver damage caused by pemoline. Translated from Japanese by Gouraridis A. http://www.mhlw.go.jp/shingi/2006/01/dl/s0127-9b.pdf. Accessed March 7, 2017.Google Scholar It should be noted that exposures were likely much lower in Japan because it is solely indicated for narcolepsy. Finally, the Maria and Victorino system is one widely accepted way of inferring causality in DILI.32National Library of Medicine. Maria and Victorino (M & V) System of Causality Assessment in Drug Induced Liver Injury. https://livertox.nih.gov/MVcausality.html. Accessed March 7, 2017.Google Scholar In this scoring system (range, 6–30), scores from 6 to 9 suggest that direct causality is unlikely, scores from 10 to 13 suggest a possible linkage, scores from14 to 17 suggests a possible linkage, and scores >17 are consistent with definite causality. Using this scale, my scoring for the cases reported with sufficient data yields a typical score of 7. In my mind, the pemoline mystery is still not solved." @default.
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• W2602977968 title "Risk Evaluation and Mitigation Strategies (REMS), Pemoline, and What Is a Signal?" @default.
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