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Epilepsia, 48(3):464–469, 2007
Blackwell Publishing, Inc.
C 2007 International League Against Epilepsy Compulsory Generic Switching of Antiepileptic Drugs: High Switchback Rates to Branded Compounds Compared with Other ∗Frederick Andermann, Mei Sheng Duh, Antoine Gosselin, and Pierre Emmanuel Paradis ∗Montreal Neurological Institute and Hospital, McGill University, Montr´eal, Qu´ebec, Canada; †Analysis Group, Inc., Boston, Massachusetts, U.S.A.; and ‡Groupe d’Analyse, Lt´ee, Montr´eal, Qu´ebec, Canada Summary: Purpose: Compulsory generic substitution of
Results: The 1,354 patients (403 monotherapy, 951 polyther- antiepileptic drugs (AEDs) may lead to adverse effects in apy) were prescribed generic LTG, of whom 12.9% switched epilepsy patients because of seizure recurrence or increased tox- back to Lamictal (11.7% monotherapy, 13.4% polytherapy).
icity. The study objectives were (a) to quantify and compare the Switchback rates of other AEDs were ∼20% for CLB and switchback rates from generic to brand-name AEDs versus non- VPA. The switchback rates for AEDs were substantially higher AEDs, and (b) to assess clinical implications of switching from than for non-AEDs (1.5–2.9%). Significant increases in LTG branded Lamictal to generic lamotrigine (LTG) and whether sig- doses were observed after generic substitution for those who did nals exist suggesting outcome worsening.
not switch back (6.2%; p < 0.0001). The average number of Methods: By using a public-payer pharmacy-claims database codispensed AEDs and non-AED drugs significantly increased from Ontario, Canada, switchback rates from generic to branded (p < 0.0001) after LTG generic entry, especially in the generic AEDs [Lamictal, Frisium (clobazam; CLB), and Depakene (VPA; divalproex)] were calculated and compared with non- Conclusions: These results reflect poor acceptance of switch- AED long-term therapies, antihyperlipidemics and antidepres- ing AEDs to generic compounds. They may also indicate sants, in January 2002 through March 2006. We then assessed increased toxicity and/or loss of seizure control associated pharmacy utilization and AED dosage among LTG patients with generic AED use. Key Words: Epilepsy—Antiepileptic
switching back to branded Lamictal compared with those staying drugs—Generic substitution—Lamictal—Lamotrigine.
In recent years, increasing medical costs have forced (AUC) and peak plasma concentration (Cmax) lie within healthcare systems to adopt measures to limit expendi- an interval of 80% to 125% (Borgherini, 2003). The FDA ture and maximize cost savings. A common example has accepts −20% to 25% variation in AUC and Cmax that been the encouragement or mandatory requirement for are considered bioequivalent, whereas the brand standard the use of cheaper generic medicines instead of branded ranges from −5% to +5% (Borgherini, 2003). Therefore products. However, as generic medications are required to it is theoretically possible for a patient to receive an al- demonstrate only short-term bioequivalence to be granted most 50% increase in serum concentration if switched product license, their bioavailability may differ from that from a low-bioavailability generic formulation to a high- of their branded counterparts, which could lead to de- bioavailability one (Feely et al., 2005). An additional con- creased efficacy and/or tolerability. Specifically, the U.S.
cern is that bioavailability studies are carried out on a small Food and Drug Administration (FDA) criteria for bioe- number of healthy volunteers by using single doses of a quivalence are designed to achieve 90% confidence that drug. These studies may not represent a clinical practice the ratios of the test to reference log-transformed mean setting, where patients have a wide range of characteris- values for area under the plasma concentration–time curve tics, may have other concomitant diseases, and can usepotentially interacting drugs (Besag, 2000).
In medication classes in which a “narrow therapeutic Accepted December 8, 2006.
Address correspondence and reprint requests to Dr. F. Ander- index” is present, such as antiepileptic drugs (AEDs), mann at Department of Neurology and Paediatrics, McGill Univer- generic substitution raises particular concern. In addition sity, 3801 University Street, Montreal QC H3A 2B4, Canada. E-mail: to individual response, tolerability and toxicity are im- portant considerations when selecting an AED therapy.
ADVERSE OUTCOMES WITH GENERIC SWITCHING TO LAMOTRIGINE Many AEDs are CNS depressants and may produce in Ontario before and after the government-mandated undesirable sedation impact on activities requiring skilled switch, by using LTG as a case-study example.
coordination and alertness (Sander, 2004). Discontinua-tion of or changeover from one AED to another must be done gradually to avoid precipitating seizures. For a Data source
patient in stable long-term control, prevention of seizure We used a public-payer database from Ontario, Canada, recurrence is paramount, as even a single breakthrough comprising patient-level prescription drug dispensing seizure could have serious consequences, on both a per- claims paid for by the Ontario Drug Benefit (ODB) Formu- sonal (loss of driver’s license, employment, injury to self, lary. Data elements included patient demographics, drug etc.) and a social level (injury to others, increased health use, product manufacturer, strength, form, and treatment cost to society) (Feely, 2005; Crawford, 2006). As short- term bioequivalence may not translate to equivalent ef-ficacy with respect to long-term seizure control, generic Study design
AEDs may be less acceptable and paradoxically increase The objectives of the study were twofold. First, we aimed to quantify the switchback rates from generic to Increased toxicity or intolerance and/or breakthrough brand-name AEDs in comparison with other drugs used seizures have been reported after generic substitutions of over the long term. Second, we documented the poten- AEDs, including phenytoin (PHT) (Tyrer et al., 1970), val- tial adverse clinical consequences of generic switching, proic acid (VPA) (Macdonald, 1987), primidone (PRM) (Wyllie et al., 1987) and carbamazepine (CBZ) (Gilman To address the first objective, the switchback rates were et al., 1993). In a survey of 301 neurologists in the United calculated from generic to three branded AEDs: Lamictal, States, 67.8% reported breakthrough seizures, and 56% re- Frisium, and Depakene, in comparison with other com- ported increased side effects in their patients after a switch monly used long-term medications, antihyperlipidemics from brand-name to generic AEDs (Wilner, 2004). In the (Statin 1: simvastatin, Zocor) and antidepressants [se- largest patient survey reported to date, involving 251 pa- lective serotonin reuptake inhibitor (SSRI) 1: fluoxetine, tients who had been switched to generic AEDs, 10.8% Prozac; and SSRI 2, citalopram, Celexa]. In every case, experienced a confirmed breakthrough seizure or toxicity only one brand name was available for each of these prod- attributable to the substitution (Crawford et al., 1996).
ucts, whereas five different generic formulations exist for Analyses have suggested that the cost saved by generic Lamictal, six for Frisium, 15 for Depakene, and >10 switching of AEDs could be outweighed by the price generic formulations for other non-AEDs. To be selected of increased monitoring and loss of seizure control.
in this study, the drug had to be on the market only as a (Crawford et al., 1996; Jobst and Holmes, 2004). An- branded version in 1995 or later, and then a generic for- other problem is that physicians typically underestimate mulation had to be introduced in 2004 or before. Of all the frequency of generic substitution taking place at the the possible AED candidates, only Neurontin (gabapentin) pharmacy (Guberman and Corman, 2000; Wilner, 2004).
was excluded, as it is also widely used for indications other Consequently, many recommend that physicians be more vigilant in their prescription-writing practices to pre- “Switchback” was defined as switching a patient from vent unwarranted generic substitution (Wilner, 2004). The the branded drug to the generic, and then back to the American Academy of Neurology has issued a guideline branded drug. Switchback rates were estimated for pa- recommending that switching between proprietary and tients initially taking the branded drug during a time when generic formulations of AEDs be avoided unless medi- no generic version was available in Ontario and who were cally indicated (American Academy of Neurology, 1990).
then switched to a generic formulation. Among those pa- tients, those who were converted back to the branded drug Brentford, Middlesex, U.K.] is a newer drug in the AED were considered switchback patients. Figure 1 lists the formulary that has a narrow therapeutic index, but better drugs under study, their therapeutic class, and the date toxicity profile and less drug interaction compared with (quarter/year) of generic entry on the Ontario market.
older AEDs. It is one of the first of the new-generation For all these medications, the study populations com- AEDs to have a generic version, and understanding the prised patients who continuously used the branded drugs effect of substitution of branded Lamictal to generic LTG for ≥3 months in the 6 months preceding generic entry.
would further the knowledge in the generic substitution of “Continuous use” was defined as drug supplies without new AEDs. Starting in January 2003, the province of On- a gap of >30 days, or a time interval between two dis- tario required that all branded prescriptions of Lamictal pensing dates of ≤60 days. The study period ranged from be switched to its generic version. In this study, we assess 1 year before generic entry until March 2006. Because the impact of generic substitution by comparing pharmacy generic substitution is compulsory in Ontario, the use of a claims data on cohorts of epilepsy patients receiving AEDs branded medication is not allowed without a physician FIG. 1. Patient disposition. SSRI, selective serotonin reuptake inhibitor.
letter of medical necessity. Therefore we did not use Potential adverse clinical consequences associated with the few patients who remained taking their branded switching from Lamictal to lamotrigine medication after generic entry as a comparator group, as The following outcomes were used as proxies for possi- it was too small (∼2%) for a reliable statistical analysis.
ble adverse clinical consequences: mean and median daily For the second objective, we assessed the potential clin- Lamictal or LTG doses and utilization of concomitant ical consequences of switching from branded Lamictal to AED and non-AED medications. These outcomes were generic LTG by using two cohorts of patients: (a) those compared in the following time periods: 90-day base- switching back to branded Lamictal after being converted line branded Lamictal period, generic LTG period, and to generic LTG (switchback group), and (b) those stay- switchback to branded Lamictal period among those who ing with generic LTG after generic entry (generic group) as of January 1, 2003. The baseline dosages and numberof entities for this case study were calculated by using a Statistical analysis
90-day period of Lamictal use before generic substitution Univariate statistics were calculated to describe popula- occurred. Similar to the switchback analysis, the follow-up tion characteristics, switchback rates, and dosages. Statis- period lasted until March 2006. A stratified analysis was tical comparisons of means of continuous variables before conducted on Lamictal patients receiving monotherapy and after generic entry were conducted by using paired versus polytherapy of AEDs. Monotherapy was defined Student’s t-tests. Comparisons of medians were tested as patients taking only Lamictal during the 90 days before based on Signed Rank tests. Linear regressions were used generic entry, whereas polytherapy referred to Lamictal to measure changes occurring during the generic period.
patient using at least one other AED at the baseline pe- Statistical significance was defined at a two-sided 0.05 α level. All statistical analyses were performed by usingSAS release 9.1.3 (SAS Institute, Inc., Cary, NC, U.S.A.).
Outcome measures
Switchback rates were estimated by using the Kaplan– Meier method, which is a conditional probability approach Patient characteristics
based on the subjects who were on the generic drug at Figure 1 depicts the patient disposition and sample size the beginning of the interval. This calculation yields the for each of the seven drugs under study, stratified by probability that a patient will eventually switch back to the monotherapy and polytherapy. A large share of branded branded drug after being switched to the generic. Patients products users (83% to 93%) received generic dispens- who were lost to follow-up were censored. The switch- ings after generic availability. Most AED patients were back rate was calculated as the cumulative probability of polytherapy users (59% to 91%), meaning that they also a patient switching back to the branded drug, given that received another AED during the baseline period. Almost he was on the generic drug at each time interval.
all patients taking Statin 1 were receiving polytherapy ADVERSE OUTCOMES WITH GENERIC SWITCHING TO LAMOTRIGINE TABLE 1. Baseline characteristics of study populations
TABLE 2. Patient disposition and baseline characteristics of
Patients in 90-day baseline with at least SSRI, selective serotonin reuptake inhibitor.
bSum could differ from patient disposition because of unknown (96%), whereas a majority of SSRI 1 (9%) and SSRI 2(20%) users were not.
Table 1 describes the age and gender distributions of rate was higher among those taking polytherapy of AEDs patients in each drug-user cohort. Compared with other compared with monotherapy (13.4 vs. 11.7%). A larger AED users, Depakene patients were older (mean age, 44.4 share of polytherapy patients switched back in the case for years), whereas Lamictal was used by more female pa- Depakene (21.3 vs. 20.6%), but not for Frisium (19.8vs.
tients (53.5%). In the other three non-AED groups, Statin 27.1%). In contrast, the switchback rates for non-NTI 1 and SSRI 2 patients were older than SSRI 1 patients drugs were substantially lower at 1.5–2.9% for the statins (73.8 years, 69.0 years, and 56.0 years, respectively), and the proportion of female patients was higher for SSRI 1 Dosing patterns
Table 3 shows the dosing patterns of Lamictal and LTG, Table 2 describes the patient disposition and charac- before and after generic entry. Among the switchback teristics of patients in the Lamictal case study. Because group, the average daily prescription dose of Lamictal was this was a large subset of the previous Lamictal cohort, at 252.2 mg during the baseline period before generic en- their age and gender characteristics were almost identical try, and this average dosage barely increased to 254.6 mg (mean age, 38.5 years; 53.2% female patients).
(0.9% increase; p = 0.6925) during the generic period, fol- Switchback rates
lowed by a decrease to 250.7 mg when switched back to Figure 2 compares the switchback rates from generic branded Lamictal (−1.5%; p = 0.8836). The median daily to branded drugs under study. AEDs had much higher prescription dose remained constant at 200 mg during the switchback rates compared with other long-term drugs.
Depakene (20.9%) and Frisium (20.7%) patients experi- Among the generic group, the average daily dispensed enced the highest switchback rates, followed by 12.9% for dose of Lamictal was 255.3 mg at baseline, with a Lamictal patients. In the case of Lamictal, the switchback significant dose increase to 271.1 mg (6.2% increase; FIG. 2. Switchback rates: Kaplan–Meier
estimations. SSRI, selective serotonin re-
uptake inhibitor.
TABLE 3. Dosing patterns of branded Lamictal and generic lamotrigine
Mean, Paired t test testing whether the dose change when switching from brand to generic is significantly different from zero; median, signed rank p < 0.0001) during the generic period. The corresponding −4.6%; p = 0.125; non-AEDs, −8.8%; p = 0.042). In median dose also increased from a baseline of 200 mg to the generic group, both numbers of entities increased and 232.5 mg after the generic switch (16.3%; p < 0.0001).
were statistically significant (AED, 13.4%; p < 0.0001; To further characterize the dosage pattern for the generic non-AED, +19.3%; p < 0.0001).
group, a regression analysis was performed. The regres-sion coefficient suggested that the dose increase was at15.4mg/day (p < 0.0001) at generic entry, with an aver- DISCUSSION
age trend increase of 0.43 mg/day (p < 0.0001) during the We addressed an important and often underrated issue regarding generic prescribing. The findings illustrate howand why AEDs are different from other medications when Use of concomitant medications
it comes to the desirability of switching to generic equiva- Table 4 presents the impact of generic entry on the use of lents. To the best of our knowledge, the present study is the AED and non-AED medications, both of which increased first to assess the switchback rates from generic to branded significantly for all patients (AED, 11.0%; p < 0.0001; AEDs compared with switchback rates for non-AEDs. The non-AED, +15.6%; p < 0.0001). The number of codis- high rate of switchback to branded AEDs (12.9 to 20.9%) pensed entities decreased in the switchback group (AEDs, compared with non-AEDs (1.5 to 2.9%) observed in thisstudy is particularly impressive in light of the strict Ontariorules favoring generics and the fact that the switchback to TABLE 4. Use of concomitant medications: branded Lamictal
branded medications is not allowed without a physicianletter of medical necessity.
The ODB imposes a steep hurdle to prevent patients from switching back to a brand-name drug without doc-umented medical necessity from the attending physician.
Taking LTG as an example: since generic LTG was avail- able in the ODB formulary in January 2003, all branded Lamictal prescriptions had to be switched to generic LTG at the pharmacy level, even if the prescription mentioned “do not substitute.” Doctors would have to petition to let a patient continue to take Lamictal by filing an adversedrug reaction form to Health Canada with all the required Paired t-test testing indicated whether the change in the number of entities when switching from brand to generic is significantly different documentation, for the plan to pay for the brand medica- tion. Therefore the fact that such a significant proportion ADVERSE OUTCOMES WITH GENERIC SWITCHING TO LAMOTRIGINE of patients and physicians would go to these extents to der or neuropathic pain may also have been included in the switch back to the original branded AED reflects both their study population, which may explain the relatively large experience and their sentiments toward generic AEDs.
share of polytherapy users in this study (Sander, 2004).
These high switchback rates may reflect a common at- Second, the motive for drug selection cannot be deter- titude among patients with epilepsy who are anxious to mined from claims data. It is possible that the decision avoid having a recurrence, actual loss of seizure control, process to switch to generic or back to brand was driven by nontherapeutic factors, such as inability to afford the Our findings add to the literature surrounding generic branded drug, provincial rules governing generic substi- switching of AEDs and support prior studies demonstrat- tution, or absence of a particular drug in the pharmacy ing that generic AEDs could be less effective or tolerable stock. Finally, our study is subject to limitations inherent compared with their branded counterparts (MacDonald, to claims data, including potential inaccuracies in billing, 1987; Welty, 1992; Jain, 1993; Wyllie, 2004; Crawford et dispensing dates, drug doses, and drug codes.
The high switchback rates and dosing changes found in Although results based on claims data must be in- this study may be associated with adverse clinical conse- terpreted with caution, this significant increase in AED quences due to compulsory switching of branded AEDs to and non-AED drug dispensing after the generic switch generic. These findings further abet the guidelines set by is nonetheless intriguing and could potentially reflect ad- the American Academy of Neurology to avoid switching verse effects associated with generic LTG. Regardless of between proprietary and generic formulations of AEDs the pharmacokinetic data for generic versus brand-name preparations of AEDs, this study shows that patients with Acknowledgment: This research was funded by Glaxo-
epilepsy are less likely to be satisfied with generic switches than are patients with other long-term medical conditions.
The reasons for this phenomenon are beyond the dataavailable in this article, but on this issue, the motivation is REFERENCES
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