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Correspondence: When an article is eligible for submission of Correspondence, a link to the response form is available within the full-text article. You must be a current subscriber who has activated the online portion of your subscription in order to send a Correspondence. Any reader can read published Correspondence.
Correspondence to:
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Correspondence:Correspondence published:
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Reply to Jefferys, Sherry, Rackley, and Stetz
- Ilo Leppik (16 March 2005)
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Lower phenytoin serum levels in persons switched from brand to generic phenytoin
- Shanna A Stetz, Pharm.D., Thomas Bechtel, Pharm.D. (16 March 2005)
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Lower phenytoin serum levels in persons switched from brand to generic phenytoin
- Russell J. Rackley (16 March 2005)
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Lower phenytoin serum levels in persons switched from brand to generic phenytoin
- James H. Sherry (15 March 2005)
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Lower phenytoin serum levels in persons switched from brand to generic phenytoin
- Richard J Jefferys (15 March 2005)
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Lower phenytoin serum levels in persons switched from brand to generic phenytoin
- Cody C. Wiberg (22 December 2004)
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Reply to Wiberg
- Ilo E. Leppik, MD (22 December 2004)
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Editors' Response
- Steven R. Schwid, MD, Robert A. Gross, MD, PhD; Jonathan W. Mink, MD, PhD, Robert C. Griggs, MD (22 December 2004)
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Reply to Perron
- Ilo Leppik, MD, James C. Cloyd III, PharmD (22 December 2004)
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Lower phenytoin serum levels in persons switched from brand to generic phenytoin
- Reed Perron (22 December 2004)
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Ilo Leppik, Director of Research, MINCEP Epilepsy Care Suite 200, 5775 Wayzata Boulevard, Minneapolis, MN 55416
Send Correspondence to journal:
mincepmail{at}mincep.com Ilo Leppik
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Mr. Jefferys found a website which lists all of the companies with whom I had a relationship over the last 25 years of active involvement in antiepileptic drug research. The disclosures listed in the article are contemporary. Parke-Davis was purchased by Pfizer, the current manufacturer of Dilantin. The letters by Sherry and Rackley of Mylan Laboratories indicate a lack of appreciation for the role of observational reports in alerting practicing physicians to potential problems. We fully agree that our brief report is not a definitive study. The methods were fully disclosed to the reviewers and are provided in the article, which allows the reader to judge the validity of our findings. Nevertheless, it illustrates the problems that can develop if physicians are not made aware when substitutions are made among phenytoin formulation or products in patients whose dose has been carefully titrated to balance optimal benefit with side effects. Phenytoin is particularly problematic because it exhibits dramatic non-linear kinetics. Patients who have levels above 15 mg/ml are at greatest risk for small changes in bioavailability. The FDA studies were done with doses much lower than used clinically; any further studies should be done under clinically relevant conditions. The report by Shanna Stetz confirms our experience, and we appreciate her performing a careful observational study regarding this issue. |
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Shanna A Stetz, Pharm.D., The Ohio State University Medical Center, Arthur G. James Cancer Hospital Room 368 Doan Hall, 410 West 10th Ave, Columbus, OH 43210, Thomas Bechtel, Pharm.D.
Send Correspondence to journal:
stetz-2{at}medctr.osu.edu Shanna A Stetz, Pharm.D., et al.
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We read with interest the report by Burkhardt et al [1] detailing their experience with the switch from brand to generic phenytoin in their MINCEP population. We have encountered a similar problem in our bone marrow transplant (BMT) population. High-dose busulfan has been used for over 20 years as an integral component of conditioning regimens prior to BMT and has been shown to readily diffuse into the CSF of patients undergoing this therapy. [2] Subsequent reports of seizure activity in these patients [3,4,5] has lead to the use of prophylactic anticonvulsant therapy in an effort to control any untoward neurotoxicity. Our regimen consists of an oral loading dose of phenytoin, followed by maintenance doses while on busulfan and for 48 hours after its completion (5-6 days total). Each patient is given a prescription for an oral phenytoin load (15 mg/kg, rounded to the nearest 100mg), and are instructed to take the dose in increments no larger than 400 mg and at no less than 4 hour intervals the day before admission. Upon admission, a total phenytoin level is obtained to confirm the loading dose was taken, the serum level is within the therapeutic range, and to determine if extra doses are needed before busulfan dosing is initiated. We identified 19 consecutive BMT patients receiving phenytoin for busulfan seizure prophylaxis, then confirmed whether their prescriptions were filled with Dilantin® brand (6 patients) or Mylan generic (13 patients). Even though we calculated the median total phenytoin value the morning after the loading dose to be the same, 11 mg/dL, for both brand and generic, the range was greater for the generic (5.5-14.5 mg/dL) than the brand (9.3-13.6 mg/dL). This broad variability seen with the generic is of concern because it can lead to delays in starting busulfan therapy if extra phenytoin doses are needed. Since the brand product seems to deliver more consistent, predictable levels, extra doses may become unnecessary, and therapy can be started on schedule. This coupled with the minimal cost differences at doses used in this population, has led our BMT service to modify their policy so that all busulfan patients will receive prescriptions for brand product only. References 1) Burkhardt RT, Leppik IE, Blesi K, et al. Lower phenytoin serum levels in persons switched from brand to generic phenytoin. Neurology. 2004;63:1494-1496 2) Hassan M, Öberg G, Ehrsson H, et al. Pharmacokinetic and metabolic studies of high-dose busulfan in adults. Eur. J. Clin. Pharmacol. 1989;36:525-530. 3) Vassal F, Deroussent A, Hartmann O, et al. Dose-dependent neurotoxicity of high-dose busulfan in children: A clinical and pharmacological study. Cancer Research 1990;50:6203-6207. 4) Martell RW, Sher C, Jacobs P, et al. High-dose busulfan and myoclonic epilepsy. Ann. Intern. Med. 1987;107:173 5) Marcus RE, Goldman JM. Convulsions due to high-dose busulfan. The Lancet 1984;2:1463. The authors report no conflicts of interest. |
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Russell J. Rackley, Executive Director, Pharmacokinetics and Drug Metabolism, Mylan Pharmaceuticals Inc. 3711 Collins Ferry Rd., Morgantown, WV 26505
Send Correspondence to journal:
rrackley{at}mylanlabs.com Russell J. Rackley
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According to Burkhardt et al [1], Mylan’s generic phenytoin did not result in equivalent serum phenytoin concentrations relative to Dilantin Kapseals® in some patients. The methodology and data provided were insufficient to elucidate the underlying basis of the findings. There are numerous unanswered questions that could invalidate the conclusion regarding the interchangeability of phenytoin available from Parke Davis and Mylan. Some of these concerns are: What were the dates for initiation of therapy, times of sampling relative to the dose, dosing regimens? Were there outlier values for any individuals? Were additional concentrations determined before or after the 5-month period? How was compliance assured? Has the potential for drug interactions with other therapies, other than AEDs, been taken into consideration? Missing from previous Correspondence is an estimate of intra-subject variability, a fundamental parameter which Dr. Leppik has previously recognized and placed considerable importance. [2-4] How do the differences in concentrations reported after substitution compare to the differences seen in other patients when no product substitution occurred? Did variability change, within subject, over the course of change from Dilantin to generic and back to Dilantin? Based on the concentrations estimated from Figure 1 for the first Dilantin (D1), Mylan (M) and the second Dilantin (D2) treatments, the following ratios were constructed: Subj. 1 - D1/D2 = 0.80, M/D1 = 1.07; Subj. 2 - D2/D1 = 0.78, M/D2 = 0.74; Subj. 3 - D1/D2 = 0.92, M/D1 = 0.85; Subj. 5 – D2/D1 = 0.92, M/D2 = 0.90; Subj. 6 – D1/D2 = 0.96, M/D1 = 0.90; and Subj. 9 - D1/D2 - 0.66, M/D1 = 0.76. Thus with the exception of Subj. 4 and 11, the differences between Mylan and one of the Dilantin doses are comparable to those of Dilantin to itself. This analysis suggests the presence of some underlying factors which might explain the authors’ data, other than a change of products. Given the extremely small sample size and lack of relevant information, one has to question the conclusions from the Burkhardt communication regarding interchangeability of the Mylan product and Dilantin Kapseals. We reviewed the study by Wilder et al [5] and concluded that Mylan’s generic extended phenytoin sodium is bioequivalent to the brand product under fed conditions. This is further supported by another fed study conducted by Mylan at a 300-mg dose. References 1. Burkhardt RT, Leppik IE, Blesi K, et al., "Lower phenytoin serum levels in persons switched from brand to generic phenytoin" Neurology, 63:1494-1496, 2004. 2. Leppik IE; "Variability of phenytoin, carbamazepine, and valproate concentrations in a clinic population"; in Compliance in Epilepsy, Schmidt D and Leppik IE, Eds.; Elsevier Science Publishers, Biomedical Division; 1988, Chapter 7. 3. Leppik IE, Cloyd JC, Sawchuk RJ, et al., "Compliance and variability of plasma phenytoin in epileptic patients", Ther Drug Mon, 1:475-483, 1979. 4. Birnbaum A, Hardie NA, Leppik IE, et al., "Variability of total phenytoin serum concentrations within elderly nursing home residents", Neurology, 60:555-559, 2003. 5. Wilder BJ, Leppik I, Hietpas TJ, et al., "Effects of food on absorption of Dilantin Kapseals and Mylan extended phenytoin sodium capsules", Neurology, 57:582-589, 2001. |
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James H. Sherry, Medical Director, Mylan Laboratories Inc. 781 Chestnut Ridge Road, P.O. Box 4310, Morgantown, WV 26504-4310
Send Correspondence to journal:
jsherry{at}mylanlabs.com James H. Sherry
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Burkhardt et al [1] identified a case series of “…adult patients whose seizures increased enough to require intervention”. The authors determined that of the 11 cases, 10 had been switched from brand to generic phenytoin and concluded that use of the generic product resulted in lower phenytoin blood levels than the brand product in eight of these patients. We can not assess the strength of the finding from the information provided in the publication. Additional information provided by the authors has been insufficient. The case definition and methods used for case identification are unclear. We expected that the authors would have used a well-defined denominator of patients and a control group of patients who were candidates to switch from brand to generic phenytoin and matched by disease severity. Both groups would be followed to determine the rate of lowered phenytoin blood levels and worsening of underlying seizure control. Such a study would need data on the time that the last phenytoin blood level was measured before the switch and ideally, blood levels would have been measured just prior to the switch. Patients that have significant underlying seizure disorders that are poorly controlled may be difficult to assess regarding the clinical status of their seizure disorder. No information was provided in the publication on the timing of the last phenytoin blood level before the switch and no clinical information was provided for either the cases or the cohort of patients from which the case series was derived. Finally, no information was provided on how the products were administered. Approximately 54% [2] of total prescriptions for extended phenytoin sodium are filled with Mylan’s product. Mylan monitors, using a prospectively designed risk assessment tool, record all phenytoin adverse events reported to the pharmacovigilance database. Lack of effect reports have been received by Mylan where the product was crushed and added to food. These events resolved with discontinuation of this practice. Although there have been reports of decreased drug levels and breakthrough seizures, there is nothing unique about such reports since they are not unexpected and reported with all anticonvulsants including branded phenytoin. Based on our internal review there is no evidence that use of generic phenytoin results in lower phenytoin blood levels. References 1. Burkardt RT, Leppik IE, Blesi K, et al.Neurology, 63:1494-1496, 2004. 2. IMS Data as of December 2004 on file. |
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Richard J Jefferys, Treatment Action Group 611 Broadway, Suite 608, New York, NY 10012
Send Correspondence to journal:
richard.jefferys{at}verizon.net Richard J Jefferys
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The disclosure included in this article states: "Dr. Leppik has received honoraria from Abbott Laboratories, Pfizer, and UCB Pharma. Dr. Cloyd has received honoraria from Elan Pharmaceuticals and GlaxoSmithKline, honoraria in excess of $10,000 from Abbott Laboratories and Ovation Pharmaceuticals, and a grant in excess of $10,000 from Novartis." But on another website (http://www.princetoncme.com/public/2004-79- 4/) I found the following disclosure: "Ilo E. Leppik, MD: Honoraria/Consultant/Speaker/Grant–Abbott Laboratories, AstraZeneca, Athena, Bristol-Myers Squibb, Carter-Wallace, Cephalon, Ciba-Geigy, Cognetix, Cyberonics, Dainippon, Elan Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, Hoechst Marion Roussel, MedPointe, Medtronic, Merck Sharp & Dohme, Novartis, Ortho- McNeil, Parke-Davis, Pfizer, Shire, Synthe Labo, UCB Pharma, Inc., Upshire -Smith, Wyeth Ayerst, Xcel Pharmaceuticals." Since my understanding is that Parke-Davis manufacture brand name phenytoin, I would suggest that these differences deserve explanation. And perhaps a follow-up study of the bioequivalence of generic and brand name phenytoin by a different, independent group is in order. |
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Cody C. Wiberg, Minnesota Department of Human Services 444 Lafayette Road St. Paul, MN 55155-3853
Send Correspondence to journal:
cody.c.wiberg{at}state.mn.us Cody C. Wiberg
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While not disputing the authors’ findings in the article "Lower phenytoin serum levels in persons switched from brand to generic phenytoin", [1] I would like to point out some factual errors. The Minnesota Department of Human Services (DHS), not the Department of Health, administers the state Medical Assistance program. DHS is advised on pharmacy and prescription drug issues by the Drug Formulary Committee (DFC), four physicians, four pharmacists and a consumer representative. DHS has never taken any action to require the use of generic phenytoin 100mg extended capsules for persons enrolled in the health care programs we administer. A state law ( Minnesota Statute 151.21)requires mandatory generic substitution for all prescriptions filled in the state – not just those for Medical Assistance recipients. The law also directs the DFC to establish a list of drugs exempt from the mandatory generic substitution requirements. However, even if a drug is on the list, pharmacists may substitute the generic product if they believe it is safe to do so. In May 1999, the DFC voted to remove phenytoin 100mg extended capsules from the list of drugs exempt from mandatory generic substitution. Even though the drug was removed from the list, pharmacists would not have been required to dispense the generic product if they felt it was not safe to do so. At the request of Dilantin’s manufacturer, the issue was reconsidered by the DFC in January 2000 Testimony was heard from two of the articles’ authors, Drs. Cloyd and Leppik. Several other physicians and pharmacists also testified, some in favor of adding the drug back to the list and some opposed. In a split vote, the DFC added phenytoin 100mg extended capsules back to the list, where it remains. DHS does effectively require the use of a generic product only when we set a maximum reimbursement rate lower than the cost of the brand name product. When we do that, pharmacists lose money if they dispense the brand name product. We have not done that for phenytoin 100mg extended capsules. Consequently, the patients described in the article were switched to the generic product at the professional discretion of the pharmacists who filled their prescriptions. Although we do not require the use of the generic product, our claims data indicates that 3,192 recipients are currently receiving the generic product compared to 3,736 who are on brand name Dilantin. References 1) Burkhardt RT, Leppik IE, Blesi K, Scott S, Gapany SR, Cloyd, JC. Lower phenytoin serum levels in persons switched from brand to generic phenytoin Neurology 2004; 63: 1494-1496. |
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Ilo E. Leppik, MD, MINCEP Epilepsy Care 5775 Wayzata Blvd., Minneapolis, MN 55416
Send Correspondence to journal:
kathy_pieper{at}urmc.rochester.edu Ilo E. Leppik, MD
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We appreciate the clarification of the bureaucratic and legal complexities provided by Dr. Wilberg. What is of great concern is that, as Dr. Wilberg points out, pharmacists can switch drugs without involvement of the treating physician and precipitate a costly and potentially life- threatening situation. Yet, it is the physician who needs to identify the cause and treat the complications of the "professional discretion" of the pharmacist who may be using financial incentives to make decisions. |
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Steven R. Schwid, MD, Department of Neurology-Neuroimmunology 601 Elmwood Ave., Box 605, University of Rochester, Rochester, NY 14642, Robert A. Gross, MD, PhD; Jonathan W. Mink, MD, PhD, Robert C. Griggs, MD
Send Correspondence to journal:
steven_schwid{at}urmc.rochester.edu Steven R. Schwid, MD, et al.
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Conflicts between our primary aims (e.g., publishing valid observations and fair interpretations) and legitimate, but subordinate aims (e.g., earning a living, funding a research program, gaining prestige) are ubiquitous in research, clinical practice, and every other facet of our daily lives. Our main concern is not that these conflicts of interest exist, but whether they are causing bias. However, such judgments are often very difficult to make. To minimize this possibility, conflicts are prohibited, limited, and disclosed.[1] Consistent with statements from the International Committee of Medical Journal Editors, [2] Neurology’s policy is described in the Information for Authors (www.neurology.org), stating in part that “clear statements of industry- sponsored research and author participation in corporate activities are required for evaluation of a manuscript.” Such disclosures should include all relevant relationships, whether they are with study sponsors or their competitors. These disclosures are one of the factors that must be considered by editors and peer-reviewers when deciding whether to publish a manuscript, and should also be considered by readers after publication. We make great efforts to ensure that everything printed in Neurology represents valid, unbiased work. We will also continue to provide readers information that may affect their own judgments. References 1. Kieburtz K. Avoiding conflicts of interest: responsibilities of authors, reviewers, and editors. Neurology 1998; 51:1527-1528. 2. International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. JAMA 1997; 277:927-934. |
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Ilo Leppik, MD, MINCEP Epilepsy Care 5775 Wayzata Blvd., Minneapolis, MN 55416, James C. Cloyd III, PharmD
Send Correspondence to journal:
kathy_pieper{at}urmc.rochester.edu Ilo Leppik, MD, et al.
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The letter from Dr. Perron does not raise any specific scientific questions. Rather, he implies that what we observed was not reported accurately. We take exception to his conclusions. |
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Reed Perron, Neurology Group of Bergen County, PA 1200 E Ridgewood Avenue, Ridgewood, NJ 07450
Send Correspondence to journal:
rcperron{at}aol.com Reed Perron
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I read with interest the article by Burkhardt et al. Their findings may be of great importance in the management of seizure patients but it makes one dizzy to note the honoraria two of the authors have received from drug manufacturers, none of whom manufacture Mylan, the drug found lacking in this research. Readers are grateful to Neurology for publishing authors' potential copnflicts of interest. Yet these conflicts must detract somewhat from our trust in the validity of the research. |
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