An update of the Hong Kong Epilepsy Guideline: consensus statement on the use of antiepileptic drugs in Hong Kong
Jason KY Fong, FHKCP, FHKAM (Medicine)1; Eric LY Chan, FHKCP, FHKAM (Medicine)2; Howan Leung, FHKCP, FHKAM (Medicine)3; Iris Chan, PhD4; Richard SK Chang, FHKCP, FHKAM (Medicine)5; Gardian CY Fong, FHKCP, FHKAM (Medicine)1; Eva LW Fung, FHKCP, FHKAM (Paediatrics)6; Colin HT Lui, FHKCP, FHKAM (Medicine)7; Ben BH Fung, FHKCP, FHKAM (Medicine)8; TL Poon, FCSHK, FHKAM (Surgery)9; Deyond Siu, FHKCR, FHKAM (Radiology)10; HT Wong, FCSHK, FHKAM (Surgery)11; Eric Yeung, FHKCP, FHKAM (Medicine)12; Ada WY Yung, FHKCP, FHKAM (Paediatrics)13; Cannon XL Zhu, FRCS, FHKAM (Surgery)14; Subcommittee on the Consensus Statement of The Hong Kong Epilepsy Society
1 Private practice, Hong Kong
2 Department of Medicine and Geriatrics, Tuen Mun Hospital, Tuen Mun, Hong Kong
3 Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, Hong Kong
4 Department of Medicine, Queen Elizabeth Hospital, Jordan, Hong Kong
5 Department of Medicine, Queen Mary Hospital, Pokfulam, Hong Kong
6 Department of Paediatrics, Prince of Wales Hospital, Shatin, Hong Kong
7 Department of Medicine, Tseung Kwan O Hospital, Tseung Kwan O, Hong Kong
8 Department of Medicine, United Christian Hospital, Kwun Tong, Hong Kong
9 Department of Neurosurgery, Queen Elizabeth Hospital, Jordan, Hong Kong
10 Department of Radiology, Kwong Wah Hospital, Yaumatei, Hong Kong
11 Department of Neurosurgery, Kwong Wah Hospital, Yaumatei, Hong Kong
12 Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
13 Department of Paediatrics, Queen Mary Hospital, Pokfulam, Hong Kong
14 Department of Surgery, Prince of Wales Hospital, Shatin, Hong Kong
Corresponding authors: Dr Howan Leung (email@example.com)
Objective: New information about antiepileptic drugs has arisen since the publication of the Hong Kong Epilepsy Guideline in 2009. This article set out to fill the knowledge gap between 2007 and 2016 on the use of antiepileptic drugs in Hong Kong.
Participants: Between May 2014 and April 2016, four consensus meetings were held in Hong Kong, where a group comprising 15 professionals (neurologists, paediatricians, neurosurgeons, radiologists, and clinical psychologists) from both public and private sectors aimed to review the best available evidence and update all practising physicians on a range of clinical issues including drug-related matters. All participants were council members of The Hong Kong Epilepsy Society.
Evidence: A literature review of the clinical use of antiepileptic drugs as monotherapy suggested Level A evidence for levetiracetam and Level B evidence for lacosamide. No change in the level of evidence was found for oxcarbazepine (Level A evidence) or pregabalin (undesignated), and no evidence was found for perampanel. A literature review on the clinical use of antiepileptic drugs as adjunctive therapy suggested Level A evidence for both lacosamide and perampanel. No change to the level of evidence was found for levetiracetam (Level A evidence), oxcarbazepine (Level A evidence), or pregabalin (Level A evidence). A literature search on the use of generic antiepileptic drugs suggested Level A evidence for the use of lamotrigine in generic substitution.
Consensus process: Three lead authors of the Subcommittee drafted the manuscript that consisted of two parts—part A: evidence on new antiepileptic drugs, and part B: generic drugs. The recommendations on monotherapy/adjunctive therapy were presented during the meetings. The pros and cons for our health care system of generic substitution were discussed. The recommendations represent the ‘general consensus’ of the participants in keeping with the evidence found in the literature.
Conclusions: Recommendations for the use of levetiracetam, lacosamide, oxcarbazepine, pregabalin, and perampanel were made. The consensus statements may provide a reference to physicians in their daily practice. Controversy exists over the use of generic products among patients who are currently taking brand medications. In this regard, approvals from prescriber and patient are pivotal. Good communication between doctors and patients is essential, as well as enlisting the assistance of doctors, nurses, and pharmacists, therapeutic blood monitoring if available, and the option of brand antiepileptic drug as a self-financed item. The physical appearance of generic drugs should be considered as it may hamper drug compliance. Support from medical services is recommended. In the longer term, the benefit of flexibility and the options to have a balance between the generic and brand drug market may need to be addressed by institutions and regulatory bodies.
Epilepsy is a chronic neurological condition that places a high economic burden on patients from childhood to senescence. In Hong Kong alone, more than 70 000 patients have seizures as a chronic condition and many more have developed seizures as a result of an acute symptomatic medical condition; both of which may require the use of antiepileptic drugs (AEDs). There are currently 155 registered pharmaceutical products in Hong Kong classed as AEDs and approved by the Department of Health, excluding drugs that are prescribed off-label. The general guiding principles for physicians in the selection of AEDs are derived from evidence-based medicine and the last version of The Hong Kong Epilepsy Guideline already provides ample advice.1 As the number of published papers and meta-analysis is fast-growing, The Hong Kong Epilepsy Society (HKES) considers it important to review the best available evidence and to update all practising physicians with regard to their position on a range of clinical issues including drug-related matters. As such, HKES prepared a series of consensus statements to supplement The Hong Kong Epilepsy Guideline of 2009.
Four consensus meetings were convened between May 2014 and April 2016 during which time a group of 15 professionals consisting of neurologists, paediatricians, neurosurgeons, radiologists, and clinical psychologists participated in structured discussions in four major areas: AEDs, status epilepticus, refractory epilepsy, and women and epilepsy. The participants represented both the public and private sectors. They were all council members of HKES. The current paper addresses the topic of AEDs.
In part A of this consensus statement, we have compiled all the papers and studies published in 2007 or later, using the citation index from PubMed, Ovid and Google Scholar, that are concerned with the clinical use of AEDs as either monotherapy or adjunctive therapy. The research papers must be written in English with seizure outcome as their primary endpoint. Only AEDs licensed in Hong Kong after 2001 are included in this review. Studies pertaining to benzodiazepine and intravenous preparations only of any AED were not reviewed, nor were those that focused exclusively on subgroups of patients in which prognosis may be affected by parameters other than drug treatment (eg neurosurgical cohorts).
The research papers were rated as randomised controlled trial, cohort study (including retrospective study), meta-analysis or review, and where possible, graded as class I, II, or III level of evidence, in line with the previous version of The Hong Kong Epilepsy Guideline.1 Level A evidence is defined as the availability of one Class I study or more, or meta-analysis suggesting a similar rating. Level B evidence is defined as the availability of one Class II study or more, or meta-analysis suggesting a similar rating. Level C evidence is defined as the presence of more than two Class III studies.
In part B of this consensus statement, we have compiled all the studies published in 2007 or later, using the citation index from PubMed, Ovid and Google Scholar, that are related to human studies of generic preparations of AEDs. The same classification of evidence is employed. The analyses in both parts A and B are of particular importance to local health care providers, because Hong Kong has a special health-financing situation in which the majority of patients are treated under the public hospital system. As a result, hospital-based practice is likely to influence the standard of care delivered to the majority of chronic epilepsy patients and the health care costs of medical treatment.
Part A: evidence on new antiepileptic drugs
A total of 95 eligible papers were submitted for the purpose of writing this consensus statement. Articles that focused on zonisamide, eslicarbazepine, and brivaracetam were not reviewed because these agents were not registered with Department of Health at the time of writing. Papers pertaining to topiramate were not reviewed as the drug was registered in Hong Kong before 2001. Papers on retigabine were not reviewed as this drug has currently limited usage in Hong Kong following an alert from the Food and Drug Administration (FDA) of the United States. The remaining drugs of interest were collated based on their indications.
Two Class I studies, 10 Class II studies, and 16 Class III studies were found under this indication for levetiracetam (LEV). One Class I study that randomised patients to LEV or carbamazepine found non-inferiority of LEV.2 Another Class I study randomised paediatric patients with juvenile absence epilepsy to LEV or placebo and reported a non-significant superiority in terms of seizure response.3 One Class II study compared LEV with lamotrigine (LTG) and another Class II study compared LEV with carbamazepine or sodium valproate. Both studies demonstrated that LEV was as efficacious as the other standard regimens.4 5
The evidence in the paediatric population was generally positive.3 4 6 7 At the opposite end of the spectrum, geriatric patients were also shown in a Class II study to benefit from LEV monotherapy.8 One Class II study detailed the conversion of treatment in patients with existing partial-onset epilepsy to extended-release LEV monotherapy.9 In the Chinese population, one Class III study demonstrated the usefulness of LEV monotherapy.10 The overall level of conclusion is supported by an expedited review from the International League Against Epilepsy (ILAE).11
Statement 1: The level of evidence for LEV monotherapy reaches Level A.
Four Class III studies and one meta-analysis were found under this indication for oxcarbazepine (OXC). Another three Class III studies recruited patients with mixed indications (Table 112 13 14 15 16 17 18 19). The evidence in the paediatric subgroup suggested that OXC may be useful in children across a range of conditions, from idiopathic to symptomatic and cryptogenic epilepsy.12 Of interest, one study that recruited Chinese patients for the purpose of both mono- and adjunctive therapy showed that OXC was as effective as LTG or topiramate.13 Oxcarbazepine is already indicated as monotherapy in partial epilepsy. The recommendation for the use of OXC remains unchanged.
Statement 2: The level of evidence for OXC monotherapy remains unchanged (Level A).
Lacosamide (LCS) produces slow inactivation of neuronal sodium channels. We found one Class II study and two Class III studies on the use of LCS monotherapy and two Class III studies with mixed indications (Table 220 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45). One conversion study showed that 425 patients completed LCS maintenance with a favourable safety profile at a nominal dose of 400 mg per day.20 In another study, the seizure-free rate was 72.3% at 1 year and the withdrawal rate was 15%.21 In the study by Lattanzi et al,22 58 patients were converted from a background single AED to LCS with just over half (55.2%) becoming seizure-free. Only 20.8% of patients reported mild-to-moderate adverse events. The FDA has approved use of LCS as monotherapy in epilepsy since September 2014 and there was a plan to seek its approval for use with the same indication in Europe in 2016.
Table 2. A review of the use of lacosamide as an antiepileptic drug20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
Statement 3: The level of evidence for LCS monotherapy reaches Level B.
Pregabalin (PGB) has binding properties to the alpha-2-delta units of calcium channels. We found one Class I study, one Class II study, and one meta-analysis for PGB under this indication (Table 314 46 47 48 49 50 51 52 53 54 55 56 57). Pregabalin was compared with LTG in a study of 330 patients using a double-blind, non-inferiority design with the primary efficacy endpoint being the proportion of patients to achieve seizure freedom for 6 months. In the study, however, PGB was inferior to LTG on both intention-to-treat and per-protocol analyses.46 In the study by French et al,14 conversion from a first or second AED to PGB was undertaken in 125 patients and the results showed that PGB monotherapy was safe and efficacious in partial epilepsy. No recommendation may be given at this stage regarding the use of PGB monotherapy in epilepsy.
Table 3. A review of the use of pregabalin as an antiepileptic drug14 46 47 48 49 50 51 52 53 54 55 56 57
Statement 4: The level of evidence for PGB monotherapy remains unchanged (not designated).
No study on the use of perampanel (PER) monotherapy could be found using the current search criteria. Other information pertaining to PER is shown in Table 4.58 59 60 61 62 63 64 65 66 67 68 69
Table 4. A review of the use of perampanel as an antiepileptic drug58 59 60 61 62 63 64 65 66 67 68 69
Statement 5: The level of evidence for PER monotherapy remains unchanged (no recommendation).
One Class I and two Class III studies were identified using the search criteria. In addition, two Class III studies reported mixed indications and two meta-analyses were published (Table 52 3 4 5 6 7 8 9 10 13 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94). In the only Class I study available for this indication, patients with idiopathic generalised epilepsy were randomised to receive LEV 3000 mg per day or placebo. The results suggested that a reduction by ≥50% of myoclonic seizures may be achieved in 58.3% of patients.70 One Class III study reported the use of LEV among patients with rolandic epilepsy or variants: a >50% reduction in seizure frequency was achieved by 62.5% of patients.71 There is no new recommended level of evidence for LEV under this indication.
Table 5. A review of the use of levetiracetam as an antiepileptic drug2 3 4 5 6 7 8 9 10 13 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94
A review of the behavioural side-effects of LEV revealed possible variation among paediatric and adult subjects. Nervousness, aggression, and hostile behaviour have been reported as putative behavioural adverse events. In paediatric cohorts, the proportion of such adverse events was 20% to 30%.70 71 72 94 By comparison, the behavioural side-effects in adults were less prominent.72 73 74 75 94
Statement 6: The level of evidence for LEV adjunctive therapy remains unchanged (Level A).
One Class I study and three Class III studies (with mixed indications) were identified (Table 112 13 14 15 16 17 18 19). In the study by the PROSPER Investigators Study Group, adjunctive OXC reduced seizure magnitude by 38.2% to 42.9%. Adverse event rates and safety profiles suggested improved tolerability.95 Oxcarbazepine is currently licensed for adjunctive therapy in epilepsy and no change to the current recommended level of evidence was made.
Statement 7: The level of evidence for OXC adjunctive therapy remains unchanged (Level A).
Three pivotal clinical studies outlined the clinical usefulness of LCS in patients with refractory epilepsy: one Phase II and two Phase III studies.76 96 97 These 12-week, randomised, double-blind, placebo-controlled, multicentre trials enrolled subjects with partial-onset seizures with or without secondary generalisation who were not adequately controlled with one to three concomitant AEDs. Study 1 compared doses of LCS 200, 400, and 600 mg/day with placebo.96 Study 2 compared doses of LCS 400 and 600 mg/day with placebo.76 Study 3 compared doses of LCS 200 and 400 mg/day with placebo.97 Following an 8-week phase to establish baseline seizure frequency, subjects were titrated to the randomised dose. During the titration phase in all three trials, treatment was initiated at 100 mg/day (50 mg given twice daily) and increased by weekly increments of 100 mg/day to the target dose. The titration phase lasted 6 weeks in Study 1 and Study 2 and 4 weeks in Study 3. In all three trials, the titration phase was followed by a maintenance phase for 12 weeks. The primary endpoint was reduction in 28-day seizure frequency (baseline to maintenance phase) compared with the placebo group. A statistically significant effect was observed with LCS treatment at doses of 200 mg/day (Study 3), 400 mg/day (Study 1, 2, and 3), and 600 mg/day (Study 1 and 2).
An observational phase IV open-label study to assess the efficacy, safety, tolerability, and additional outcomes of LCS in Hong Kong patients aged ≥18 years showed that LCS had efficacy and adverse effects similar to those described in the literature from other parts of the world. In a cohort of 105 patients, the proportion who achieved a 50% reduction in seizure frequency was 54.5 with a mean titration time of 6.75 weeks and a mean maintenance dose of 158.6 mg/day. The efficacy profile was satisfactory whether or not LCS was combined with concomitant sodium channel blockers (45.8% vs 46.5%). The side-effect profile included apprehension and aggression, drowsiness and tiredness, headache, memory problems, dizziness, numbness, and gait disturbance (local data).
Statement 8: The level of evidence for LCS as adjunctive therapy reaches Level A.
Three Class I studies, four Class III studies, and four meta-analyses were found pertaining to PGB under this indication (Table 314 46 47 48 49 50 51 52 53 54 55 56 57). One study evaluated the efficacy and tolerability of adjunctive PGB as a controlled-release formulation. The 50% responder rate (ie percentage of patients achieving 50% reduction in seizure frequency) was 45.9% for a daily dose of 330 mg.98 Another randomised study tested PGB versus LEV in a head-to-head comparison in 409 patients. The drug PGB was non-inferior to LEV with a similar tolerability to LEV as adjunctive therapy.47 In a multicentre, randomised study of PGB versus placebo, PGB was effective and tolerable as adjunctive therapy in the Asian population.48 This drug is currently licensed for adjunctive therapy in epilepsy and there is no change to the level of evidence regarding its recommended use.
Statement 9: The level of evidence for PGB as adjunctive therapy remains unchanged (Level A).
A total of four Class I clinical studies demonstrated the efficacy of PER among patients with refractory epilepsy.58 59 60 61 These were all double-blind studies and all evaluated the 50% responder rate as a seizure outcome. The corresponding risk ratio for 50% responder rate for 4 mg, 8 mg, and 12 mg were 1.54, 1.8, and 1.72. The most common treatment-emergent adverse effects were dizziness, drowsiness, headache, fatigue, and nasopharyngitis. The pooled results suggested that a higher dose was more efficacious if the side-effects could be tolerated.62 There was one ongoing study on the use of PER among patients with secondary generalised seizures.
Statement 10: The level of evidence for PER as adjunctive therapy reaches Level A.
Part B: Generic drugs
The last version of The Hong Kong Epilepsy Guideline gave advice on the use of generic drugs, details of which can be revisited in the original guideline of 2009.1 There might be a perceived difference between pharmaceutical equivalence, which is the requirement of the exact product, and bioequivalence, which is the concept of assigning no difference among products in terms of drug absorption. There have been positional statements that outline the possible risks involved when switching antiepileptic agents from a brand to a generic preparation.99 Clinicians are understandably perturbed by the prospect of inadvertent seizures and loss of quality of life for their patients. The criteria applied by authorities to license generic products give rise to various issues. For instance, the concept of bioequivalence does not require the generic product to demonstrate clinical efficacy among patients. Most bioequivalence studies are performed among healthy subjects rather than individual patients. Antiepileptic drugs are placed in the same category as immunosuppressants and psychotropic drugs, in which generic substitution is necessarily given consideration before implementation. The benefit of generic AEDs is clear in countries where health care financing is either state-run or public-funded, but may still be important in terms of patient choice in countries where private health care or an insurance-based system is practised because patients may want to lower their premium by using generic products. It may be argued that the use of generic products will increase the potential availability of drugs to a broader population of patients including those who are underprivileged or resident in communities where the drug budget is restricted.
There is a growing need for review and update of recommended guidelines on issues related to generic products as the evidence for newer drugs has become more eminent. The prescription of and expenditure on newer agents has risen sharply over the last 5 to 10 years. Clinicians now have a far greater number of AEDs at their disposal compared with a decade ago. There is divided opinion in the professional community about the use of generic products and when it will be considered optimal and safe for epilepsy patients. In general, communities that rely on a state-financed or government-funded health care system are under greater pressure to consider generic product prescription, compared with private-funded or out-of-pocket payment health care financing systems.
Our literature search identified 13 studies published in or after 2007 that fulfilled the initial inclusion criteria. Four studies were of the Class I category, one of the Class II category, and eight of the Class III category (Table 6100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116). Six studies had LTG as the study AED.100 101 102 103 104 105 Two studies had topiramate as the study focus106 115 and the remaining studies adopted multiple drug regimens.107 108 109 110 111 A good level of evidence came from a randomised controlled trial of ‘generic-brittle’ patients in a double-blind, multiple-dose, steady-state, fully replicated crossover bioequivalence study of LTG. The study demonstrated that the generic product was bioequivalent to the brand medication. Such observations were supported by the secondary outcomes of seizure control and tolerability—32 of 35 patients reported no deterioration of seizures, and dose-related adverse events were experienced by 14 patients while on the generic product and 15 patients while on the brand product. The study highlighted the use of the therapeutic level as a guide over a period of time while the patient is switched from brand to generic or vice versa.100 Two Class I studies with preliminary results disseminated during the annual meeting of the American Epilepsy Society in 2015 showed no deviation from FDA’s bioequivalence standards in Cmax and area under the curve when comparing two most disparate generic products in a single dose and chronic disease model respectively (methodology given in Diaz et al in 2013101). One well-designed study of 35 patients randomised patients from six epilepsy centres to receive LTG as one of two treatment sequences that comprised four study periods of 14 days each, during which time balanced doses of an oral generic LTG product were given every 12 hours. Disparate generic LTG in patients with epilepsy demonstrated bioequivalence with no detectable difference in clinical effects.102 A similar result was found from the only Class II study from our literature search.103 The best level of evidence in epilepsy patients supported the switch of LTG (sodium channel blocker) from brand to generic preparation. It remains controversial whether these findings can be extrapolated to other AEDs because LTG is by far one of the most widely used first-line AEDs.
Table 6. Compilation of studies published in 2007 or after related to human studies of generic preparations of antiepileptic drugs100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116
Most Class III studies indicated an opposite result compared with the Class I and II studies. These studies showed that generic substitution may result in increased acute seizure–related events and higher use of medical services. The switch-back rates for AEDs from generic to brand were higher in these studies. Of note, these studies had larger sample sizes but all the studies were retrospective in nature. These studies might also have involved a wide range of prescribing practices and some patient factors might not have been taken into account.
Overall, most studies suggested bioequivalence of brand and generic AEDs. This result was also in keeping with a meta-analysis which concluded that if only the highest level of evidence is considered, there is no significant difference in terms of seizure control, whether or not the patient is taking brand or generic products.117 A UK pharmacovigilance body, the Medicine and Healthcare products Regulatory Agency, issued guidelines regarding the use of generic products in 2013 and specifically divided AEDs into three categories, each of which had specific recommendations regarding the switching of brand to generic products (Appendix).118 Category 1 relates to products among which a specific manufacturer’s product should be ensured (eg phenytoin, carbamazepine, phenobarbital, and primidone). Category 2 relates to products for which generic switching is considered neutral, but clinical judgement should be exercised in so doing (eg sodium valproate, LTG, OXC, topiramate). Category 3 relates to products for which generic substitution is considered safe (eg LEV, gabapentin) [Table 6100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116]. The UK National Institute for Health and Care Excellence guideline119 recommended that a consistent supply should be made available to the epilepsy patient unless the prescriber, in consultation with the patient, considers that this is not a concern.
Appendix. Medicines and Healthcare products Regulatory Agency (MHRA) guideline 2014118
We acknowledge the controversy about switching from a brand to a generic product. There appears to be a divide in the positional statements and guidelines between countries with public-funded health care and those with private health care. Many associations, including the Italian League Against Epilepsy,112 American Academy of Neurology,114 and the French Chapter of ILAE113 have expressed concerns about generic substitution of AEDs, emphasising the uniqueness of epilepsy as a class of disease in which generic substitution is problematic when carried out for this indication. The latest position statement from the American Epilepsy Society acknowledges the bioequivalence of brand and FDA-approved generic products and the fact that substitution may reduce cost without compromising efficacy. The Society advises the importance of using either immediate-release or extended-release preparations uniformly throughout the switching process. They acknowledge that tablet or capsule colour or shape may impact drug compliance. They also state that the counselling of switching should include an indication of bioequivalence and not inferiority when the information is conveyed to the patient(s) and their family members.114
A pilot study pioneered by the Hospital Authority Head Office on the switching of phenytoin from a generic back to a brand product due to supplier issues suggested that proper counselling and follow-up logistics in conjunction with a pre- and post-drug level at 2 weeks may be adequate for the exercise. In 40 patients recruited from the Prince of Wales Hospital and Queen Mary Hospital, no patients developed a toxic level of plasma phenytoin during the switching process (four patients had a toxic-level pre-switching that remained post-switching). Plasma phenytoin concentration increased in 23 patients and decreased in 17. The conclusion was that there was no consistent trend in the change of plasma drug level (personal communication). Apart from isolated cases of reported dizziness, no serious adverse event occurred. The rate of hospitalisation as a result of the switch in that study was not available to us at the time of writing this review.
Statement 11: There is Level A evidence for generic substitution of LTG (a sodium channel blocker), taking into account the drug’s pharmacodynamics and pharmacokinetics.
The HKES upholds the safety of patients above all else. Following a review of the current evidence, the HKES has made the following revisions for the reference of physicians. Doctors can initiate treatment in patients with epilepsy with either a brand or generic product. Switching from a brand to a generic product or between generic products requires great care by clinicians and health care administrators. Automatic substitution at a pharmacy level is not recommended. If switching takes place as a result of cost considerations, prescriber and patient approval must be sought, in liaison with the pharmacist. Prescriber approval is not equivalent to a medical decision. The course of treatment, including choice of drug and dosage, is determined by the doctor and forms part of a medical decision. When the use of generic drugs is based on cost-effective analyses, prescriber approval is a logistic and economic decision. Depending on the type of health care setting, a request for generic substitution may begin with the patient or the health administrator, in liaison with the attending doctor/pharmacist. Patient approval may not be equivalent to medical consent. This can be a requirement of the health care system to which the patient belongs or a self-initiated step from the patient who has subscribed to insurance plans with affordable premiums. The physician should discuss any switch with the patient from both a medical and layman’s perspective. Good communication is considered fundamental to the provision of care.120 Therefore, in a private health care system, the choice for generic drugs may begin with a patient’s request, followed by prescriber approval. In a public health care system, the choice for generic drugs may begin with prescriber’s request, followed by patient approval. Follow-up and monitoring logistics should be mutually agreed to ensure patient safety. A change in the physical appearance of medications may hinder compliance. This facet of the switch must be taken into account by all parties. In the special situation where switching from a brand to a generic product takes place among patients who have achieved remission while on antiepileptic therapy, clinicians must take into account the drug’s pharmacokinetics and the support of medical services. Assistance from nursing staff, enlisting therapeutic blood monitoring, and the option to use the AED as a self-financed item (both public and private setting) should be made available.
Statement 12: Controversy exists over the use of generic products among patients who are currently taking brand medications. Prescriber and patient approval is pivotal. There should be good communication between doctors and patients; enlisting assistance from doctors, nurses, and pharmacists; therapeutic blood monitoring if available; and the option of brand AED as a self-financed item. The physical appearance of generic drugs may hamper drug compliance. Support from medical services is recommended. In the longer term, the benefit of flexibility and the option to have balanced use of generic and brand drugs may need to be addressed by institutions and regulatory bodies.
New evidence on AEDs has arisen since the publication of the Hong Kong Epilepsy Guideline in 2009. There is Level A evidence for LEV monotherapy and Level B evidence for LCS monotherapy. There is Level A evidence for LCS and PER adjunctive therapy. No change to the level of evidence is evident for LEV, OXC, and PGB. The use of generic preparations of AEDs should be considered following prescriber and patient approval, with support from medical services (doctors, nurses, pharmacists). It is important to emphasise that a generic preparation is not inferior, that shape and colour of tablets may be different, there may be therapeutic blood monitoring (if available), and patients may have the option of self-financing items.
Additional material related to this article can be found on the HKMJ website. Please go to http://www.hkmj.org>, and search for the article.
This project was supported in part by an unrestricted grant from the Hong Kong Epilepsy Society.
This consensus statement is designed to assist clinicians by providing an analytical framework for the drug treatment of epilepsy. It is not intended to establish a community standard of care, replace a clinician’s medical judgement, or establish a protocol for all patients.
1. Guideline Development Group, Hong Kong Epilepsy Society. The Hong Kong Epilepsy Guideline 2009. Hong Kong Med J 2009;15 Suppl 5:6S-28S.
2. Brodie MJ, Perucca E, Ryvlin P, et al. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007;68:402-8. CrossRef
3. Fattore C, Boniver C, Capovilla G, et al. A multicenter, randomized, placebo-controlled trial of levetiracetam in children and adolescents with newly diagnosed absence epilepsy. Epilepsia 2011;52:802-9. CrossRef
4. Rosenow F, Schade-Brittinger C, Burchardi N, et al. The LaLiMo Trial: lamotrigine compared with levetiracetam in the initial 26 weeks of monotherapy for focal and generalised epilepsy—an open label, prospective, randomised controlled multicenter study. J Neurol Neurosurg Psychiatry 2012;83:1093-8. CrossRef
5. Trinka E, Marson AG, Van Paesschen W, et al. KOMET: an unblinded, randomised, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy. J Neurol Neurosurg Psychiatry 2013;84:1138-47. CrossRef
6. Coppola G, Franzoni E, Verrotti A, et al. Levetiracetam or oxcarbazepine as monotherapy in newly diagnosed benign epilepsy of childhood with centrotemporal spikes (BECTS): An open-label, parallel group trial. Brain Dev 2007;29:281-4. CrossRef
7. Borggraefe I, Bonfert M, Bast T, et al. Levetiracetam vs. sulthiame in benign epilepsy with centrotemporal spikes in childhood: A double-blinded, randomized, controlled trial (German HEAD study). Eur J Paediatr Neurol 2013;17:507-14. CrossRef
8. Werhahn KJ, Trinka E, Dobesberger J, et al. A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy. Epilepsia 2015;56:450-9. CrossRef
9. Chung S, Ceja H, Gawlowicz J, et al. Levetiracetam extended release conversion to monotherapy for the treatment of patients with partial-onset seizures: A double-blind, randomised, multicentre, historical control study. Epilepsy Res 2012;101:92-102. CrossRef
10. Zhu F, Lang SY, Wang XQ, et al. Long-term effectiveness of antiepileptic drug monotherapy in partial epileptic patients: A 7-year study in an epilepsy center in China. Chin Med J (Engl) 2015;128:3015-22. CrossRef
11. Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013;54:551-63. CrossRef
12. Franzoni E, Gentile V, Pellicciari A, et al. Prospective study on long-term treatment with oxcarbazepine in pediatric epilepsy. J Neurol 2009;256:1527-32. CrossRef
13. Kang HC, Hu Q, Liu XY, et al. A follow-up study on newer anti-epileptic drugs as add-on and monotherapy for partial epilepsy in China. Chin Med J (Engl) 2012;125:646-51.
14. French J, Kwan P, Fakhoury T, et al. Pregabalin monotherapy in patients with partial-onset seizures: a historical-controlled trial. Neurology 2014;82:590-7. CrossRef
15. Koch MW, Polman SK. Oxcarbazepine versus carbamazepine monotherapy for partial onset seizures. Cochrane Database Syst Rev 2009;(4):CD006453. CrossRef
16. Eun SH, Kim HD, Chung HJ, et al. A multicenter trial of oxcarbazepine oral suspension monotherapy in children newly diagnosed with partial seizures: A clinical and cognitive evaluation. Seizure. 2012;21:679-84. CrossRef
17. Dogan EA, Usta BE, Bilgen R, Senol Y, Aktekin B. Efficacy, tolerability, and side effects of oxcarbazepine monotherapy: A prospective study in adult and elderly patients with newly diagnosed partial epilepsy. Epilepsy Behav 2008;13:156-61. CrossRef
18. Lee SA, Heo K, Kim WJ, et al. Clinical feasibility of immediate overnight switching from slow-release carbamazepine to oxcarbazepine in Korean patients with refractory partial epilepsy. Seizure 2010;19:356-8. CrossRef
19. Seneviratne U, D’Souza W, Cook M. Long-term assessment of oxcarbazepine in a naturalistic setting: a retrospective study. Acta Neurol Scand 2008;117:367-9. CrossRef
20. Wechsler RT, Li G, French J, et al. Conversion to lacosamide monotherapy in the treatment of focal epilepsy: Results from a historical-controlled, multicenter, double-blind study. Epilepsia 2014;55:1088-98. CrossRef
21. Giráldez BG, Toledano R, García-Morales I, et al. Long-term efficacy and safety of lacosamide monotherapy in the treatment of partial-onset seizures: a multicenter evaluation. Seizure 2015;29:119-22. CrossRef
22. Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Lacosamide monotherapy for partial onset seizures. Seizure 2015;27:71-4. CrossRef
23. Husain A, Chung S, Faught E, Isojarvi J, McShea C, Doty P. Long-term safety and efficacy in patients with uncontrolled partial-onset seizures treated with adjunctive lacosamide: results from a Phase III open-label extension trial. Epilepsia 2012;53:521-8. CrossRef
24. Runge U, Arnold S, Brandt C, et al. A noninterventional study evaluating the effectiveness and safety of lacosamide added to monotherapy in patients with epilepsy with partial-onset seizures in daily clinical practice: The VITOBA study. Epilepsia 2015;56:1921-30. CrossRef
25. Stephen LJ, Kelly K, Parker P, Brodie MJ. Adjunctive lacosamide—5 years’ clinical experience. Epilepsy Res 2014;108:1385-91. CrossRef
26. Pasha I, Kamate M, Didagi SK. Efficacy and tolerability of lacosamide as an adjunctive therapy in children with refractory partial epilepsy. Pediatr Neurol 2014;51:509-14. CrossRef
27. Rosenfeld W, Fountain NB, Kaubrys G, et al. Safety and efficacy of adjunctive lacosamide among patients with partial-onset seizures in a long-term open-label extension trial of up to 8 years. Epilepsy Behav 2014;41:164-70. CrossRef
28. Gulati P, Cannell P, Ghia T, et al. Lacosamide as adjunctive therapy in treatment-resistant epilepsy in childhood. J Paediatr Child Health 2015;51:794-7. CrossRef
29. Rosenow F, Kelemen A, Ben-Menachem E, et al. Long-term adjunctive lacosamide treatment in patients with partial-onset seizures. Acta Neurol Scand 2015 Jul 2. Epub ahead of print.
30. Geffrey AL, Belt OD, Paolini JL, Thiele EA. Lacosamide use in the treatment of refractory epilepsy in tuberous sclerosis complex. Epilepsy Res 2015;112:72-5. CrossRef
31. Flores L, Kemp S, Colbeck K, et al. Clinical experience with oral lacosamide as adjunctive therapy in adult patients with uncontrolled epilepsy: a multicentre study in epilepsy clinics in the United Kingdom (UK). Seizure 2012;21:512-7. CrossRef
32. Kamel JT, DeGruyter MA, D’Souza WJ, Cook MJ. Clinical experience with using lacosamide for the treatment of epilepsy in a tertiary centre. Acta Neurol Scand 2013;127:149-53. CrossRef
33. Verrotti A, Loiacono G, Pizzolorusso A, et al. Lacosamide in pediatric and adult patients: comparison of efficacy and safety. Seizure 2013;22:210-6. CrossRef
34. Toupin JF, Lortie A, Major P, et al. Efficacy and safety of lacosamide as an adjunctive therapy for refractory focal epilepsy in paediatric patients: a retrospective single-centre study. Epileptic Disord 2015;17:436-43.
35. Zadeh WW, Escartin A, Byrnes W, et al. Efficacy and safety of lacosamide as first add-on or later adjunctive treatment for uncontrolled partial-onset seizures: A multicentre open-label trial. Seizure 2015;31:72-9. CrossRef
36. Rastogi RG, Ng YT. Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study. J Child Neurol 2012;27:492-5. CrossRef
37. Grosso S, Parisi P, Spalice A, Verrotti A, Balestri P. Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy. Eur J Paediatr Neurol 2014;18:55-9. CrossRef
38. Grosso S, Coppola G, Cusmai R, et al. Efficacy and tolerability of add-on lacosamide in children with Lennox-Gastaut syndrome. Acta Neurol Scand 2014;129:420-4. CrossRef
39. Lee JW, Alam J, Llewellyn N, et al. Open label trial of add on lacosamide versus high dose levetiracetam monotherapy in patients with breakthrough seizures. Clin Neuropharmacol 2016;39:128-31. CrossRef
40. Buck ML, Goodkin HP. Use of lacosamide in children with refractory epilepsy. J Pediatr Pharmacol Ther 2012;17:211-9. CrossRef
41. Paquette V, Culley C, Greanya ED, Ensom MH. Lacosamide as adjunctive therapy in refractory epilepsy in adults: a systematic review. Seizure 2015;25:1-17. CrossRef
42. Biton V, Gil-Nagel A, Isojarvi J, et al. Safety and tolerability of lacosamide as adjunctive therapy for adults with partial-onset seizures: Analysis of data pooled from three randomized, double-blind, placebo-controlled clinical trials. Epilepsy Behav 2015;52:119-27. CrossRef
43. Sawh SC, Newman JJ, Deshpande S, Jones PM. Lacosamide adjunctive therapy for partial-onset seizures: a meta-analysis. PeerJ 2013;1:e114. CrossRef
44. Yorns WR Jr, Khurana DS, Carvalho KS, Hardison HH, Legido A, Valencia I. Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy. J Child Neurol 2014;29:23-7. CrossRef
45. Novy J, Bartolini E, Bell GS, Duncan JS, Sander JW. Long-term retention of lacosamide in a large cohort of people with medically refractory epilepsy: a single centre evaluation. Epilepsy Res 2013;106:250-6. CrossRef
46. Kwan P, Brodie MJ, Kälviäinen R, Yurkewicz L, Weaver J, Knapp LE. Efficacy and safety of pregabalin versus lamotrigine in patients with newly diagnosed partial seizures: a phase 3, double-blind, randomised, parallel-group trial. Lancet Neurol 2011;10:881-90. CrossRef
47. Zaccara G, Almas M, Pitman V, Knapp L, Posner H. Efficacy and safety of pregabalin versus levetiracetam as adjunctive therapy in patients with partial seizures: a randomized, double-blind, noninferiority trial. Epilepsia 2014;55:1048-57. CrossRef
48. Lee BI, Yi S, Hong SB, et al. Pregabalin add-on therapy using a flexible, optimized dose schedule in refractory partial epilepsies: a double-blind, randomized, placebo-controlled, multicenter trial. Epilepsia 2009;50:464-74. CrossRef
49. Zhou Q, Zheng J, Yu L, Jia X. Pregabalin monotherapy for epilepsy. Cochrane Database Syst Rev 2012;(10):CD009429. CrossRef
50. Valentin A, Moran N, Hadden R, et al. Pregabalin as adjunctive therapy for partial epilepsy: an audit study in 96 patients from the South East of England. Seizure 2009;18:450-2. CrossRef
51. Tsounis S, Kimiskidis VK, Kazis D, et al. An open-label, add-on study of pregabalin in patients with partial seizures: a multicenter trial in Greece. Seizure 2011;20:701-5. CrossRef
52. Stephen LJ, Parker P, Kelly K, Wilson EA, Leach V, Brodie MJ. Adjunctive pregabalin for uncontrolled partial-onset seizures: findings from a prospective audit. Acta Neurol Scand 2011;124:142-5. CrossRef
53. Ryvlin P, Kälviäinen R, Von Raison F, Giordano S, Emir B, Chatamra K. Pregabalin in partial seizures: a pragmatic 21-week, open-label study (PREPS). Eur J Neurol 2010;17:726-32. CrossRef
54. Pulman J, Hemming K, Marson AG. Pregabalin add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2014;(3):CD005612. CrossRef
55. Lozsadi D, Hemming K, Marson AG. Pregabalin add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2008;(1):CD005612.
56. Gil-Nagel A, Zaccara G, Baldinetti F, Leon T. Add-on treatment with pregabalin for partial seizures with or without generalisation: pooled data analysis of four randomised placebo-controlled trials. Seizure 2009;18:184-92. CrossRef
57. Uthman BM, Bazil CW, Beydoun A, et al. Long-term add-on pregabalin treatment in patients with partial-onset epilepsy: pooled analysis of open-label clinical trials. Epilepsia 2010;51:968-78. CrossRef
58. French JA, Krauss GL, Wechsler RT, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy. A randomized trial. Neurology 2015;85:950-7. CrossRef
59. French JA, Krauss GL, Steinhoff BJ, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia 2013;54:117-25. CrossRef
60. French JA, Krauss GL, Biton V, et al. Adjunctive perampanel for refractory partial-onset seizures. Randomized phase III study 304. Neurology 2012;79:589-96. CrossRef
61. Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306. Adjunctive perampanel for refractory partial-onset seizures. Neurology 2012;78:1408-15. CrossRef
62. Kwan P, Brodie MJ, Laurenza A, FitzGibbon H, Gidal BE. Analysis of pooled phase III trials of adjunctive perampanel for epilepsy: Impact of mechanism of action and pharmacokinetics on clinical outcomes. Epilepsy Res 2015;117:117-24. CrossRef
63. Juhl S, Rubboli G. Perampanel as add-on treatment in refractory focal epilepsy. The Dianalund experience. Acta Neurol Scand 2016;134:374-7. CrossRef
64. Brodie MJ, Stephen LJ. Prospective audit with adjunctive perampanel: Preliminary observations in focal epilepsy. Epilepsy Behav 2016;54:100-3. CrossRef
65. Shah E, Reuber M, Goulding P, Flynn C, Delanty N, Kemp S. Clinical experience with adjunctive perampanel in adult patients with uncontrolled epilepsy: A UK and Ireland multicentre study. Seizure 2016;34:1-5. CrossRef
66. Steinhoff BJ, Hamer H, Trinka E, et al. A multicenter survey of clinical experiences with perampanel in real life in Germany and Austria. Epilepsy Res 2014;108:986-8. CrossRef
67. Kramer LD, Satlin A, Krauss GL, et al. Perampanel for adjunctive treatment of partial-onset seizures: A pooled dose-response analysis of phase III studies. Epilepsia 2014;55:423-31. CrossRef
68. Steinhoff BJ, Bacher M, Bast T, et al. First clinical experiences with perampanel—The Kork experience in 74 patients. Epilepsia 2014;55 Suppl 1:16-8. CrossRef
69. Hsu WW, Sing CW, He Y, Worsley AJ, Wong IC, Chan EW. Systematic review and meta-analysis of the efficacy and safety of perampanel in the treatment of partial-onset epilepsy. CNS Drugs 2013;27:817-27. CrossRef
70. Noachtar S, Andermann E, Meyvisch P, et al. Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures. Neurology 2008;70:607-16. CrossRef
71. von Stulpnagel C, Kluger G, Leiz S, Holthausen H. Levetiracetam as add-on therapy in different subgroups of “benign” idiopathic focal epilepsies in childhood. Epilepsy Behav 2010;17:193-8. CrossRef
72. Mbizvo GK, Dixon P, Hutton JL, Marson AG. Levetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane Review. Cochrane Database Syst Rev 2012;(9):CD001901. CrossRef
73. Werhahn KJ, Klimpe S, Balkaya S, Trinka E, Krämer G. The safety and efficacy of add-on levetiracetam in elderly patients with focal epilepsy: A one-year observational study. Seizure 2011;20:305-11. CrossRef
74. Droz-Perroteau C, Dureau-Pournin C, Vespignani H, et al. The EULEV cohort study: rates of and factors associated with continuation of levetiracetam after 1 year. Br J Clin Pharmacol 2011;71:121-7. CrossRef
75. Kuba R, Novotná I, Brázdil M, et al. Long-term levetiracetam treatment in patients with epilepsy: 3-year follow up. Acta Neurol Scand 2010;121:83-8. CrossRef
76. Chung S, Ceja H, Gawłowicz J, McShea C, Schiemann J, Lu S. Levetiracetam extended release for the treatment of patients with partial-onset seizures: A long-term, open-label follow-up study. Epilepsy Res 2016;120:7-12. CrossRef
77. Suresh SH, Chakraborty A, Virupakshaiah A, Kumar N. Efficacy and safety of levetiracetam and carbamazepine as monotherapy in partial seizures. Epilepsy Res Treat 2015;2015:415082. CrossRef
78. Jung DE, Yu R, Yoon JR, et al. Neuropsychological effects of levetiracetam and carbamazepine in children with focal epilepsy. Neurology 2015;84:2312-9. CrossRef
79. Consoli D, Bosco D, Postorino P, et al. Levetiracetam versus carbamazepine in patients with late poststroke seizures: a multicenter prospective randomized open-label study (EpIC Project). Cerebrovasc Dis 2012;34:282-9. CrossRef
80. Hakami T, Todaro M, Petrovski S, et al. Substitution monotherapy with levetiracetam vs older antiepileptic drugs: A randomized comparative trial. Arch Neurol 2012;69:1563-71. CrossRef
81. Xiao F, An D, Deng H, Chen S, Ren J, Zhou D. Evaluation of levetiracetam and valproic acid as low-dose monotherapies for children with typical benign childhood epilepsy with centrotemporal spikes (BECTS). Seizure 2014;23:756-61. CrossRef
82. Bertsche A, Neininger MP, Dahse AJ, et al. Initial anticonvulsant monotherapy in routine care of children and adolescents: levetiracetam fails more frequently than valproate and oxcarbazepine due to a lack of effectiveness. Eur J Pediatr 2014;173:87-92. CrossRef
83. Stephen LJ, Kelly K, Parker P, Brodie MJ. Levetiracetam monotherapy—outcomes from an epilepsy clinic. Seizure 2011;20:554-7. CrossRef
84. Verrotti A, Parisi P, Loiacono G, et al. Levetiracetam monotherapy for childhood occipital epilepsy of gastaut. Acta Neurol Scand 2009;120:342-6. CrossRef
85. Belcastro V, Costa C, Galletti F, et al. Levetiracetam in newly diagnosed late-onset post-stroke seizures: A prospective observational study. Epilepsy Res 2008;82:223-6. CrossRef
86. Verrotti A, Cerminara C, Domizio S, et al. Levetiracetam in absence epilepsy. Dev Med Child Neurol 2008;50:850-3. CrossRef
87. Kutlu G, Gomceli YB, Unal Y, Inan LE. Levetiracetam monotherapy for late poststroke seizures in the elderly. Epilepsy Behav 2008;13:542-4. CrossRef
88. Perry S, Holt P, Benatar M. Levetiracetam versus carbamazepine monotherapy for partial epilepsy in children less than 16 years of age. J Child Neurol 2008;23:515-9. CrossRef
89. Verrotti A, Cerminara C, Coppola G, et al. Levetiracetam in juvenile myoclonic epilepsy: long-term efficacy in newly diagnosed adolescents. Dev Med Child Neurol 2008;50:29-32. CrossRef
90. Belcastro V, Costa C, Galletti F, et al. Levetiracetam monotherapy in Alzheimer patients with late-onset seizures: a prospective observational study. Eur J Neurol 2007;14:1176-8. CrossRef
91. Sharpe DV, Patel AD, Abou-Khalil B, Fenichel GM. Levetiracetam monotherapy in juvenile myoclonic epilepsy. Seizure 2008;17:64-8. CrossRef
92. Khurana DS, Kothare SV, Valencia I, Melvin JJ, Legido A. Levetiracetam monotherapy in children with epilepsy. Pediatr Neurol 2007;36:227-30. CrossRef
93. Verrotti A, Coppola G, Manco R, et al. Levetiracetam monotherapy for children and adolescents with benign rolandic seizures. Seizure 2007;16:271-5. CrossRef
94. Lo BW, Kyu HH, Jichici D, Upton AM, Akl EA, Meade MO. Meta-analysis of randomized trials on first line and adjunctive levetiracetam. Can J Neurol Sci 2011;38:475-86. CrossRef
95. French JA, Baroldi P, Brittain ST, Johnson JK; PROSPER Investigators Study Group. Efficacy and safety of extended-release oxcarbazepine (Oxtellar XR) as adjunctive therapy in patients with refractory partial-onset seizures: a randomized controlled trial. Acta Neurol Scand 2014;129:143-53. CrossRef
96. Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia 2007;48:1308-17. CrossRef
97. Halász P, Kälviäinen R, Mazurkiewicz-Beldzińska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia 2009;50:443-53. CrossRef
98. French J, Brandt C, Friedman D, et al. Adjunctive use of controlled-release pregabalin in adults with treatment-resistant partial seizures: a double-blind, randomized, placebo-controlled trial. Epilepsia 2014;55:1220-8. CrossRef
99. Liow K, Barkley GL, Pollard JR, Harden CL, Bazil CW; American Academy of Neurology. Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy. Neurology 2007;68:1249-50. CrossRef
100. Ting TY, Jiang W, Lionberger R, et al. Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: A field test of the FDA bioequivalence standard. Epilepsia 2015;56:1415-24. CrossRef
101. Diaz FJ, Berg MJ, Krebill R, et al. Random-effects linear modeling and sample size tables for two special crossover designs of average bioequivalence studies: the four-period, two-sequence, two-formulation and six-period, three-sequence, three-formulation designs. Clin Pharmacokinet 2013;52:1033-43. CrossRef
102. Privitera MD, Welty TE, Gidal BE, et al. Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial. Lancet Neurol 2016;15:365-72. CrossRef
103. Srichaiya A, Longchoopol C, Oo-Puthinan S, Sayasathid J, Sripalakit P, Viyoch J. Bioequivalence of generic lamotrigine 100-mg tablets in healthy Thai male volunteers: A randomized, single-dose, two-period, two-sequence crossover study. Clin Ther 2008;30:1844-51. CrossRef
104. Andermann F, Duh MS, Gosselin A, Paradis PE. Compulsory generic switching of antiepileptic drugs: High switchback rates to branded compounds compared with other drug classes. Epilepsia 2007;48:464-9. CrossRef
105. LeLorier J, Duh MS, Paradis PE, et al. Clinical consequences of generic substitution of lamotrigine for patients with epilepsy. Neurology 2008;70(22 Pt 2):2179-86. CrossRef
106. Duh MS, Paradis PE, Latrémouille-Viau D, et al. The risks and costs of multiple-generic substitution of topiramate. Neurology 2009;72:2122-9. CrossRef
107. Zachry WM 3rd, Doan QD, Clewell JD, Smith BJ. Case-control analysis of ambulance, emergency room, or inpatient hospital events for epilepsy and antiepileptic drug formulation changes. Epilepsia 2009;50:493-500. CrossRef
108. Rascati KL, Richards KM, Johnsrud MT, Mann TA. Effects of antiepileptic drug substitutions on epileptic events requiring acute care. Pharmacotherapy 2009;29:769-74. CrossRef
109. Labiner DM, Paradis PE, Manjunath R, et al. Generic antiepileptic drugs and associated medical resource utilization in the United States. Neurology 2010;74:1566-74. CrossRef
110. Gagne JJ, Avorn J, Shrank WH, Schneeweiss S. Refilling and switching of antiepileptic drugs and seizure-related events. Clin Pharmacol Ther 2010;88:347-53. CrossRef
111. Chaluvadi S, Chiang S, Tran L, Goldsmith CE, Friedman DE. Clinical experience with generic levetiracetam in people with epilepsy. Epilepsia 2011;52:810-5. CrossRef
112. Perucca E, Albani F, Capovilla G, Bernardina BD, Michelucci R, Zaccara G. Recommendations of the Italian League Against Epilepsy working group on generic products of antiepileptic drugs. Epilepsia 2006;47 Suppl 5:16-20. CrossRef
113. French Chapter of the International League Against Epilepsy (LFCE): Recommendations on the use of generics for the treatment of epilepsy. Available from: http://www.ilae.org/visitors/MeetingProceedings/documents/PRESSRELEASEONGENERICAEDsFRENCHCHAPTER OFTHEILAE_000.pdf. Accessed Mar 2016.
114. American Epilepsy Society. Substitution of different formulations of antiepileptic drugs for the treatment of epilepsy. Available from: https://www.aesnet.org/about_aes/generic-position-statement. Accessed Mar 2016.
115. Piñeyro-López A, Piñeyro-Garza E, Gómez-Silva M, et al. Bioequivalence of single 100-mg doses of two oral formulations of topiramate: An open-label, randomized-sequence, two-period crossover study in healthy adult male Mexican volunteers. Clin Ther 2009;31:411-7. CrossRef
116. Cañadillas-Hidalgo FM, Sánchez-Alvarez JC, Serrano-Castro PJ, Mercadé-Cerdá JM; en representación de la Sociedad Andaluza de Epilepsia. Consensus clinical practice guidelines of the Andalusian Epilepsy Society on prescribing generic antiepileptic drugs [in Spanish]. Rev Neurol 2009;49:41-7.
117. Yamada M, Welty TE. Generic substitution of antiepileptic drugs: a systematic review of prospective and retrospective studies. Ann Pharmacother 2011;45:1406-15. CrossRef
118. Medicines & Healthcare products Regulatory Agency. Available from: https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency. Accessed Mar 2016.
119. NICE guidance CG137. Epilepsies: diagnosis and management. Available from: https://www.nice.org.uk/guidance/cg137. Accessed Mar 2016.
120. The Medical Council of Hong Kong. Available from: http://www.mchk.org.hk/code.htm. Accessed Mar 2016.