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Wednesday, 28.10.2020

Jose de Leon: 23. Valproate Case 2. Safety
Jose de Leon: Reply to Hector Warnes’ and Michael R Goldberg’s Commentaries


I would like to start by thanking Dr. Warnes, whom I have never met, for being so kind in positively evaluating and then defending my presentation: “23. Valproate Case 2. Safety.”

Currently, my psychopharmacology course, which is freely provided, has an introduction and 29 Power Point lectures which are subject to criticism. Therefore, I am extremely grateful that an interested spectator joined in to help me defend one of them since, as I will explain, my available time is very limited. On 4/26/16, I completed Lecture 29 on lithium and was looking forward to completing Lectures 30 and 31 on the pharmacokinetics and pharmacodynamics of antiepileptic drugs. I completed 90% of Lecture 30 and started Lecture 31. Unfortunately, the information technology department of my university hospital made a mistake and destroyed the hard drive of my laptop. I had not been diligent enough in backing up files and Lectures 30 and 31 were lost. I had scheduled time to finish the lectures for the course in May of 2016, but after losing them I have not been able to find time to rewrite the two lost lectures. A typical presentation can easily take 40-50 hours of studying/writing. Currently, I do not have that amount of time available since I work 60 hours/week on my paid job, my scientific articles and the mentoring of young scientists in several countries via Skype. In addition to the time I spend on these presentations, Lorraine Maw, M.A., edits all my presentations and has reviewed each of them several times. Some of the longer, more complicated presentations, such as the ones I lost, can take two or three times longer to develop. I was aware that on 7/27/17, Dr. Goldberg criticized the details of this presentation, but my priority was to find time to finish the two missing lectures. As I do not know when I will find time to finish them, I am going to answers some of the comments from Dr. Goldberg (MG):

MG: This review is based on my experience as a safety physician and clinical pharmacologist in the US pharmaceutical industry.

I am convinced that Dr. Goldberg and I have remarkably different opinions of the pharmaceutical industry. To avoid personal controversies with him, I am going to refer the reader to Dr. Blackwell’s article titled “Corporate Corruption in the Psychopharmaceutical Industry” (Blackwell 2016).

MG: From a pharmaceutical industry medical perspective, the Package Circular and Summary of Product Characteristics (SPC) are the most appropriate source documents for information on a product as they are prepared by a drug’s sponsor from registration trials, updated based on post-marketing reports, including the medical literature and approved by regulatory agencies. These are the legal data sources to be used by a practicing physician to inform a patient on risks of treatment, when prescribing a product.

I do not disagree that the package insert is a legal document. Another completely different issue is to determine the best scientific source for gaining information on adverse drug reactions (ADRs). Ionnanidis, one of the most influential medical scientists, has written an editorial I recommend to the reader: “Adverse events in randomized trials: neglected, restricted, distorted, and silenced” (Ionnanidis 2009).

MG: My perspective is that communication of product information between physicians (especially in an educational setting) should be consistent with product labeling. In general, the experience of an individual physician is unlikely to be greater or more accurate than the prescribing information, except when an unusual finding is observed. The case described by Dr. de Leon may be an example of such a finding, although careful review of product labeling does contain information consistent with this report.

I completely disagree. Trusting pharmaceutical companies and package inserts appears risky to me. Issa et al. (2007) reported that a mean of 1.5 drugs per year has been withdrawn from the market since 1993. The best proof of the major weakness of the valproate package insert is that the drug was introduced in the United States (US) market in 1978, yet more than 30 years later in 2011 the Food and Drug Administration (FDA) had no choice but to ask for modification of valproate’s package insert concerning the risk of using it during pregnancy. Very recently in 2018

the European Union (EU) drug agency endorsed further restrictions during pregnancy (Anderson 2018).

MG: Certain rare events such as osteoporosis, Parkinsonism and others may represent isolated post-marketing reports to an agency or the manufacturer, or published case reports.

That slide provided references suggesting that these ADRs were not described as isolated case reports. Any interested reader looking at the slide can click on it to access the reference. For example, the slide describing Parkinsonism has a link to an article posted on PubMed ( providing details (Ristić et al. 2006).

MG: Several events are labeled in the prescribing information as Warnings and Precautions and discussed as potentially lethal events. I leave the assessment of these as potential risks to those who prescribe the drug. It is fair to emphasize these in the presentation; however, there are Warnings and Precautions which are not discussed. These include such as eosinophilic syndrome (which could be related to the pleural effusion case report), interaction with carbapenem antibiotics, hypothermia and use in patients with mitochondrial disorders.

It is obvious to any unbiased reader that one of my three valproate presentations cannot describe all aspects of valproate treatment. As a matter of fact, “24. Valproate Case 3. Formulations” describes a drug-drug interaction with carbanapem. Another presentation, “12. Clozapine Case 5. High Clozapine Doses,” also includes information on valproate. In the future, if I find time and there is reader interest, I can develop more valproate presentations using real cases. Peer-reviewed journals have published my articles on an additional five patients taking valproate (Jackson et al. 2015; Chopra and de Leon 2016; Lana et al. 2016a, 2016b), which could lead to another five presentations substantially focused on valproate.

MG: These touch on methods for use of controlled trials to assemble the core safety information, challenges associated with evaluation of a drug for multiple indications at multiple doses, the understanding of pharmacokinetic and pharmacodynamic drug-drug interactions, assessment of drug-disease interactions and the use of post-marketing safety data. Also raised are questions related to the most appropriate

sources of drug information, causality assessments for a particular adverse event and use of a product for unlabeled indications.

My opinion on package inserts has been published in a peer-reviewed editorial (de Leon 2016) that summarized as follows:

“To conclude, this commentary proposes that physicians become familiar with the changes implemented in 2006 by the FDA1,4 the highlights for new drugs, and the DailyMed website. In addition, new and more widespread reforms are urgently needed. The first suggestion is simple and may save money: the FDA should recommend that pharmaceutical companies send the prescribers highlights instead of full package inserts. The second suggestion may cost pharmaceutical companies money as they market new drugs: DDI studies should reflect the real world and provide real-world instructions. The third suggestion may not cost economically, but it may be politically difficult: move control of the already developed package inserts and their highlights from the pharmaceutical companies supervised by the FDA to a new system that allows physicians and scientific experts familiar with each drug to modify them according to peer-reviewed publications under FDA supervision.”


Anderson P. EU body endorses restrictions on valproate in pregnancy. Medscape March 27, 2018.

Blackwell B. Corporate corruption in the psychopharmaceutical industry. September 1, 2016.

Chopra N, de Leon J. Clozapine-induced myocarditis may be associated with rapid titration: A case report verified with autopsy. International Journal of Psychiatry in Medicine 2016; 51:104-115.

de Leon J. Highlights of drug package inserts and the website DailyMed: the need for further improvement in package inserts to help busy prescribers. Journal of Clinical Psychopharmacology 2011; 31:263-265.

Ioannidis JP. Adverse events in randomized trials: neglected, restricted, distorted, and silenced. Archives of Internal Medicine 2009; 169:1737-1739.

Issa AM, Phillips KA, Van Bebber S, Nidamarthy HG, Lasser KE, Haas JS, Alldredge BK, Wachter RM, Bates DW. Drug withdrawals in the United States: a systematic review of the evidence and analysis of trends. Current Drug Safety 2007; 2:177-185.

Jackson J, McCollum B, Ognibene J, Diaz FJ, de Leon J. Three patients needing high doses of valproic Acid to get therapeutic concentrations. Case Reports in Psychiatry 2015; 542862.

Lana F, Martí-Bonany J, Fuster J, de Leon J. Reduction in serum concentration of valproic acid secondary to the intake of ibuprofen as an example of valproic acid auto-induction metabolism. Actas Española de Psiquiatría 2016a; 44:136-144.

Lana F, Martí-Bonany J, de Leon J. Ibuprofen may increase pharmacological action of valproate by displacing it from plasma proteins: a case report. American Journal of Psychiatry 2016b; 173: 941-942.

Ristić AJ, Vojvodić N, Janković S, Sindelić A, Sokić D. The frequency of reversible parkinsonism and cognitive decline associated with valproate treatment: a study of 364 patients with different types of epilepsy. Epilepsia. 2006 Dec;47(12):2183-5.

August 23, 2018