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Neurology
Clinical Outcomes Associated with Brand-to-Generic Phenytoin Interchange Shilpa A Kinikar, Thomas Delate, C Mindy Menaker-Wiener, and William H Bentley
takeholders in the neurology community have asserted that the generic interchange (ie, substitution) of branded antiepileptic drugs (AEDs) may place patients with epilepsy at risk for loss of seizure control and/or medication toxicity. Thus, the practice is largely discouraged. Both the American Academy of Neurology and the American Epilepsy Society have published similar position statements opposing AED generic interchange in patients with seizure disorder.1,2 These statements suggest that without prior knowledge and consent of patient and prescriber, such as formulary-driven generic interchange during a community pharmacy prescription dispensing, AED generic interchange should be avoided.1,2 With its complex zero-order pharmacokinetics, interchange of any kind (eg, brand-to-brand, generic-to-brand, brandto-different brand) for phenytoin has been considered potentially problematic. According to the manufacturer, branded Dilantin Kapseals 100 mg extended phenytoin sodium USP capsules were discontinued and replaced by a reformulated product, Dilantin (phenytoin sodium) 100 mg extended oral capsules.3-5 During the transition period to the new product, concerns for the supply of both
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BACKGROUND: Concerns that antiepileptic brand-to-generic interchange results in
disruption of seizure control are widespread. However, little within-patient evidence exists examining such interchanges. OBJECTIVE: To compare within-patient seizure control before and after the interchange of a branded to a single-source generic phenytoin among patients with seizures in a managed care organization. METHODS: This was a pre-post, self-controlled, retrospective study. Adults with a history of seizure who used Dilantin Kapseals 100 mg extended phenytoin sodium, USP, capsules and whose therapy was interchanged to Taro Pharmaceuticals’ ABrated generic extended phenytoin sodium capsules, USP, 100 mg between July 2007 and May 2008 were included. Study outcomes included the comparisons of the proportions of patients with at least emergency department (ED) visit/inpatient hospitalization and medical office visit/nonoffice consultation for acute seizure in the 6 months before and after interchange. Outcomes were confirmed with manual chart reviews and adjusted for potential confounding medication use. RESULTS: A total of 222 patients were included in the study. Patients were primarily middle-aged (mean 56 years), equally mixed by sex (47% female); most had nonintractable seizures. The majority of patients (~70%) were on phenytoin as monotherapy and had equivalent rates of purchases for potentially confounding medications in both pre- and postinterchange time periods (all p > 0.05). Low serum concentrations were detected more often in the postinterchange study period (adjusted p < 0.001). Despite this, there were low proportions of patients with confirmed seizure events that resulted in an ED visit/inpatient hospitalization in both pre- and postinterchange periods (both 6.3%, adjusted p = 0.937). The proportion of patients with confirmed seizure events diagnosed at a medical office visit was not significantly different between the preinterchange and postinterchange periods (12.2% vs 11.3%, adjusted p = 0.545). CONCLUSIONS: No increased proportion of seizures was observed within patients when branded phenytoin was interchanged to an AB-rated, single-source, generic equivalent. More rigorous studies should be conducted to more thoroughly evaluate patient tolerability and drug efficacy when antiepileptic drugs are interchanged from brand to generic formulations. KEY WORDS: generic substitution, phenytoin, seizures.
Ann Pharmacother 2012;46:650-8. Published Online, 1 May 2012, theannals.com, DOI 10.1345/aph.1Q601
Author information provided at end of text.
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the original and reformulated versions of branded phenytoin arose. Because of these concerns, pharmacy and therapeutics (P&T) committees began to consider interchanging formulations in patients prescribed Dilantin Kapseals 100 mg to AB-rated generic 100 mg extended phenytoin sodium capsules made by Taro Pharmaceuticals USA Inc.6 Related to these supply concerns and possible tolerability matters, the P&T committee, in consultation with the Neurology Department of the Kaiser Permanente Colorado (KPCO), a not-for-profit health maintenance organization, decided in 2007 to interchange formulations in all patients prescribed branded phenytoin to the generic version manufactured by Taro Pharmaceuticals. Implemented plan wide within usual care practice, this policy provided a unique opportunity to assess retrospectively the tolerability and effectiveness of an interchange of the original Dilantin Kapseals (not the newly reformulated version) to an ABrated generic alternative. The objective of this retrospective study was to describe the clinical outcomes associated with the pre-post interchange of branded Dilantin Kapseals 100 mg to the AB-rated generic extended phenytoin sodium 100-mg capsules made by Taro Pharmaceuticals USA Inc. among a real-world sample of patients.
generic extended oral phenytoin. When supply concerns for the Dilantin Kapseals and the newly reformulated brand phenytoin arose, the immediacy of the situation resulted in formulary changes. Consequently, the generic phenytoin 100 mg extended oral capsules manufactured by Taro Pharmaceuticals became the sole formulary phenytoin at KPCO. Because the P&T committee wished to provide notice to patients of the impending formulary change, a certified letter was sent to each potentially affected patient in advance of the interchange. This letter notified patients of the imminent interchange and asked them to call their providers with any questions or concerns. Therapy was interchanged from the branded product to the generic product at the pharmacy when patients refilled their branded product prescription. In addition, total serum phenytoin concentration measurements, to be performed 10-14 days after interchange, were ordered for all affected patients at no extra charge to the patient and at their discretion. Interchanges included in this study occurred between July 2007 and May 2008. Patients starting phenytoin therapy after October 1, 2007, initiated therapy with the generic agent and thus were not included in this study. STUDY POPULATION
Methods STUDY DESIGN
This retrospective investigation assessed the impact of a pre-post brand-to-generic phenytoin interchange on clinically relevant seizure and toxicity outcomes among a sample of patients receiving long-term phenytoin treatment. A 6-month pre- and 6-month postinterchange study design was used, with patients serving as their own controls. A self-controlled study design was used because no comparable seizure study population was available to use as a comparator resulting from the P&T committee’s plan-wide formulary decision. The study used data collected from queries of integrated electronic medical, laboratory, pharmacy, and administrative record databases during the 6 months prior to and after each included patient’s generic interchange. Additionally, to confirm the outcome, electronic medical records (EMRs) were used to conduct a chart review on each patient who experienced a potential study outcome. This retrospective analysis was reviewed and approved by the KPCO Institutional Review Board prior to data collection. STUDY SETTING
The study was conducted at KPCO, a group model, notfor-profit health maintenance organization with approximately 480,000 members at the time of the study. Prior to reformulation of the brand Dilantin by Pfizer, the manufacturer, KPCO had retained both brand (Dilantin Kapseals) and theannals.com
Patients were included in the analysis if they (1) were prescribed phenytoin for seizure disorder, (2) had purchased at least 1 prescription for Dilantin Kapseals 100 mg at least 6 months prior to brand-to-generic phenytoin therapy interchange, (3) experienced interchange by purchasing at least 1 generic phenytoin prescription between July 2007 and May 2008, (4) were aged 18 years or older at the time of interchange, (5) had continuous KPCO membership eligibility in the 6 months before and after the interchange occurred, and (6) were not institutionalized. Patients were excluded from the analysis if they (1) received phenytoin for neuropathy or pain diagnosis (International Classification of Diseases, 9th Revision [ICD -9], codes available upon request) in the 6 months before interchange, (2) had a clinical office visit with an end-stage renal disease (ESRD) diagnosis (ICD -9 codes available upon request) in the 6 months before interchange, or (3) were identified as having hypoalbuminemia (ie, albumin level 80% power to detect 13 per 100 (13%) patients with at least 1 postinterchange seizure compared to 8 per 100 patients (8%) with at least 1 preinter652
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change seizure at an α level of 0.05. To assess whether other medications may have confounded the association between study outcomes and generic interchange, patients with at least 1 purchase for a non-phenytoin AED to control seizures (carbamazepine, benzodiazepines, ethosuximide, felbamate, gabapentin, phenobarbital, oxcarbazepine, lamotrigine, levetiracetam, pregabalin, primidone, topiramate, tiagabine, valproic acid/divalproex, zonisamide) were identified in both the pre- and postinterchange periods. In addition, at least 1 purchase of medications that may induce seizures (bupropion, tramadol, venlafaxine), decrease phenytoin serum concentrations (phenobarbital, carbamazepine), or increase phenytoin serum concentrations (allopurinol, capecitabine, diltiazem, omeprazole, oxcarbazepine, sertraline, tamoxifen, valproic acid) was identified in both the pre- and postinterchange periods. Patients with a phenytoin serum concentration less than 10 µg/mL were identified, since low serum concentrations might be a precursor to a seizure. Changes in phenytoin serum concentrations were calculated by identifying the phenytoin serum concentration level that was determined closest to the interchange date in both the preinterchange and postinterchange time periods and subtracting the postinterchange concentration from the preinterchange concentration. Only patients with a concentration recorded in both time periods were included. Patient 6-month preand postinterchange average daily phenytoin doses and days’ supply of phenytoin were calculated. Days’ supplies that exceeded 180 (because of early refilling) were truncated at 180. The number of patients with a phenytoin serum concentration measure performed in the pre- and postinterchange periods was calculated. The analysis was performed at the patient level. Patient age was determined as of the date of interchange and characteristics were documented. Seizure type was based on the fifth subclassification of the epilepsy-related ICD -9 diagnosis code recorded closest to the interchange date. If a patient experienced more than 1 outcome during a study period, all events were confirmed, but only the first confirmed event was included in the analysis, since subsequent events were potentially related to the initial event (eg, laboratory value confirmation, follow-up visits) and later events may not be independent from the first and could represent follow-up of a poorly managed event rather than a distinctly new event. A seizure that resulted in both an ED visit that required inpatient hospitalization or an ED visit/inpatient hospitalization and a medical office visit/nonoffice consultation was counted only as an ED visit/inpatient hospitalization. The McNemar test and Wilcoxon signed-rank test were used to assess differences between the time periods for nominal and interval-level descriptive and outcome variables. Multivariate conditional regression was used to assess differences in the outcome variables while simultaneously controlling for the intracorrelations of self-matched
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Brand-to-Generic Phenytoin Interchange
patients and potential confounding variables in the respective study periods. For the multivariate analyses of the association between seizure events and interchange, conditional logistic regression was used and controlled for the intracorrelations of selfmatched patients, low serum concentration, and purchases of non-phenytoin AEDs to control seizures and of medications that may induce seizures. For the multivariate analyses of the association between serum concentration values and interchange, multivariate linear regression was used and controlled for the intracorrelations of self-matched patients and purchases of medications that can decrease and increase phenytoin serum concentrations. No other potential confounders were assessed, since patients were self-matched and all other factors were assumed to be equivalent before and after interchange. All analyses were performed with SAS version 9.1.3 (SAS Institute, Cary, NC). Results A total of 250 patients met the inclusion criteria. Of these, none were identified with ESRD or hypoalbuminemia, but 28 were excluded for receiving phenytoin for a
neuropathy/pain diagnosis, resulting in a final sample size of 222 patients. Included patients were primarily middleaged, equally mixed by sex, and had a modest prevalence of comorbidities (Table 1). Most patients had unspecified, nonintractable seizure types, as denoted by the use of ICD 9 codes without further fifth-digit subclassification for the presence or absence of intractable seizures. In both pre- and postinterchange periods, patients had equivalent rates of purchase of non-phenytoin AEDs to control seizures and of medications that may induce seizures, decrease phenytoin serum concentrations, or increase phenytoin serum concentrations (all p > 0.05). In addition, there were no significant differences in the median preinterchange original branded phenytoin daily doses and days’ supplies and the median postinterchange generic phenytoin daily doses and days’ supplies (both p > 0.5). No treatment was interchanged back from generic to branded newly reformulated phenytoin. Twenty-four (10.8%) and 16 (7.2%) patients had their phenytoin dose increased in the pre- and postinterchange periods, respectively (p > 0.05); 16 (7.2%) and 13 (5.9%) patients had their phenytoin dose decreased in the pre- and postinterchange periods, respectively (p > 0.05). All patients had at
Table 1. Patient Characteristics by Time Perioda Characteristic
Preinterchange
Postinterchange
Age, yc (mean, SD)
56.0 (17.0)
56.0 (17.0)
Female (n, %)
105 (47.3)
105 (47.3)
Seizure type (n, %)
p Valueb NA NA NA
generalized, nonintractable
27 (12.2)
27 (12.2)
partial, intractable
3 (1.4)
3 (1.4)
partial, nonintractable
10 (4.5)
10 (4.5)
unspecified, nonintractable
182 (82.0)
182 (82.0)
Comorbidityd (n, %) diabetes mellitus
17 (7.7)
17 (7.7)
NA
cancer
15 (6.8)
15 (6.8)
NA
obesity
8 (3.6)
8 (3.6)
NA
hypertension
41 (18.5)
41 (18.5)
NA
intracerebral hemorrhage
7 (3.2)
7 (3.2)
NA
cerebrovascular disease
8 (3.6)
8 (3.6)
NA
heart diseasee
27 (12.2)
27 (12.2)
NA
Median days’ supply of phenytoin (mean, IQR)
163.5 (146.8, 121-177)
169.0 (148.1, 122-180)
0.806
Median dose of phenytoin (mean, IQR)
320.8 (364.9, 300-400)
345.0 (359.0, 300-400)
0.846
Purchase of a non-phenytoin drug to control seizures (n, %)
65 (29.3)
64 (28.8)
0.808
Purchase of a drug that may induce seizures (n, %)
12 (5.4)
10 (4.5)
0.480
Purchase of a medication that may decrease phenytoin concentrations (n, %)
23 (10.4)
20 (9.0)
0.083
Purchase of a medication that may increase phenytoin concentrations (n, %)
44 (19.8)
47 (21.2)
0.467
IQR = interquartile range; NA = not applicable. a N = 222. b McNemar test for nominal data and Wilcoxon signed-rank test for interval-level data. c As of interchange date. d Based on an outpatient diagnosis in the 6 months prior to the interchange date. e Includes coronary artery disease, ischemic heart disease, angina, congestive heart failure, heart valve disease, and rheumatic heart disease.
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least 1 refill of original brand phenytoin in the preinterchange period and of generic phenytoin in the postinterchange period. Overall, there were low proportions of patients with confirmed seizure events that resulted in an ED visit/inpatient hospitalization in either study period (both 6.3% [n = 14], p = 1.000 from univariate analysis, p = 0.937 from multivariate analysis) (Table 2). Three (1.4%) patients experienced a seizure event in both time periods. Three (21.4%) and 4 (28.6%) patients with a confirmed seizure in the preinterchange and postinterchange periods, respectively, had a phenytoin refill in the 21 days prior to their seizure event (p = 0.897). Among patients with a confirmed seizure in the postinterchange period, the median time from the interchange date to seizure date was 64 days (interquartile range [IQR] 29-124); none experienced a seizure within 21 days of the interchange. The proportion of patients with confirmed seizure events diagnosed at a medical office visit/nonoffice consultation was not significantly different before (27, 12.2%) and after (25, 11.3%) interchange (p = 0.724 from univariate analysis, p = 0.545 from multivariate analysis). Five (18.5%) and 10 (40.0%) patients with a confirmed seizure in the preinterchange and postinterchange periods, respectively, had a phenytoin refill in the 21 days before their seizure event (p = 0.317). Among patients with a confirmed seizure in the postinterchange period (n = 25), the
median time from the interchange date to seizure date was 74 days (IQR 26-101); 5 (20.0%) experienced their seizure within 21 days after the interchange. A total of 129 (58.1%) and 199 (89.6%) patients had at least 1 phenytoin serum concentration measured in the preinterchange and postinterchange periods, respectively. Overall, there were no significant differences detected between the study periods in serum concentrations (p = 0.189 from univariate analysis, p = 0.103 from multivariate analysis). The median times from the closest date a serum concentration was drawn to the interchange date were 85 (IQR 28130) and 23 (IQR 17- 40) days for the preinterchange and postinterchange periods, respectively. There were 114 (51.3%) patients with a serum concentration recorded in both time periods. The median change in serum concentration was +1.3 µg/mL (IQR –3.4 to +4.7) and median percent change was +12.6% (IQR –22.5% to +51.8%) among patients with a serum concentration recorded in both time periods (p > 0.05). Severe toxic serum concentrations with symptom events were infrequent, and no significant differences in the proportion of patients with at least 1 severe toxic serum concentration between the study periods were detected (p = 0.317 from univariate analysis, p = 0.484 from multivariate analysis). Toxic serum concentrations with symptom events were relatively more frequent but, similarly, no significant differences were detected between the study periods (26 [11.7%] preinterchange vs 27 [12.1%] postinter-
Table 2. Study Outcomes by Time Period (N = 222) Outcome
Preinterchange
At least 1 ED visit or inpatient stay for an acute seizure (n, %) At least 1 medical office visit for an acute seizure (n, %)
14 (6.3) 27 (12.2)
Postinterchange 14 (6.3)c e
25 (11.3)
p Valuea
p Valueb
1.000
0.937d
0.724
0.545d
At least 1 phenytoin serum concentration ≥30 µg/mL with symptoms (n, %)
6 (2.7)
3 (1.4)
0.317
0.484g
At least 1 phenytoin serum concentration ≥20 µg/mL and
