Table 1. Selected AEDs introduced in the United
`States
`
`AED generic name
`
`Phenobarbjtal
`Phenytoin
`Primidone
`Carbarnazepjne
`Clonazepam
`Vaiproic acid
`Clorazepate dipotassium
`
`AED
`trade name
`
`Year
`introduced
`
`Luminal
`Dilantin
`Mysoline
`Tegretol
`Kionopin
`Depakene
`Tranxene
`
`1912
`1938
`1954
`1974
`1975
`1978
`1981
`
`Approved as adjunctive treatment.
`AED Antiepileptic drug.
`
`--
`
`-
`
`-A
`
`—A-— =PB
`—•— =PHT
`•.e,-- =PRM
`--0- CBZ
`
`C0Ca0IC
`
`C
`
`,
`
`C00 C‘
`
`5aa
`
`-
`
`3
`
`6
`
`9
`
`18
`
`21
`
`24
`
`27
`
`30
`
`3336
`
`Months
`
`Figure 1. Cumulative percentage ofpatients successfully
`treated with each drug during 36 months offollow-up.
`There were 275 patients at 12 months, 164 at 24 months,
`and 97 at 36 months. PB phenobarbital; FHT =
`phenytoin; PRM primidone; CBZ = carbamazepine.
`(Adapted from Mattson et al.17)
`though no efficacy differences between carbamaze
`pine and phenytoin existed on other measures of con
`trol.
`Overall, monotherapy with carbamazepine or phe
`nytoin was most likely to be successful; however, each
`of the AEDs could provide both adequate control and
`tolerability in selected patients. Differences in toxic
`ity were the most significant factors that distinguished
`each of the four AEDs.’7’242” Approximately 75% of the
`patients were adequately managed on carbamazepine
`or phenytoin monotherapy; however, complete seizure
`control was observed in only approximately 40% of pa
`tients with partial epilepsy. Approximately 60 to 70%
`of patients were adequately treated by monotherapy
`with the first drug they received (figure 1).’ Of those
`patients in whom treatment failed with the first drug
`and who were switched to a second drug (not all pa
`tients who failed the first drug were crossed to a second
`drug), 55% were successfully treated with the second
`drug as monotherapy.
`More recently, a second large Veterans Admin
`istration study in which carbamazepine was com
`pared with vaiproate for the treatment of complex
`partial seizures and secondarily generalized tonic-
`clonic seizures in adults was completed.iS These
`June 1994 NEUROLOGY 44 (Suppi 5) S5
`
`,..,j subsequent major clinical studies also was
`It was conceivable that, with greater at
`to clinical subclassification of partial and gen
`•7ed seizures and other clinical factors, variation
`::ponsiveness to specific AEDs might become ap
`- rent for each seizure type and allow rational and
`‘sal AED selection.
`n with recognized shortcomings in the evalua
`0f traditional AEDs, it was evident that new
`, Vs were needed, and substantial efforts were di
`‘ed to this goal.’7’2 By the mid-1980s, many new
`fj)e had reached the clinical phase of development
`rldwi, and the need to provide updated guide-
`• s for the clinical evaluation of AEDs was widely
`,njzed to be of paramount importance.13 Although
`w new AEDs had become available outside the
`‘ted States, no new AEDs had been pending mar
`inf approval in the United States since the ap
`val of valproic acid in 1978, and none had been
`proved in over a decade (table 1).
`jevera1 new AEDs—felbamate, gabapentin, lam
`guile, and vigabatrin—that are now, or will soon
`available are the result of significant research
`d development efforts in the last decade. The ex
`,a’e clinical use of these AEDs with the resultant
`,uation of their ultimate efficacy and impact on
`EIJ therapy has been widely anticipated.
`
`Ifficacy of AEDs. In the context of the emerging
`Ds and the decades of inconclusive clinical trials
`4 reports with the traditional AEDs, it is worth
`lewing the available data on the efficacy of the
`w AEDs. Relatively few trials comparing AED
`rotherapy for the treatment of partial or secon
`rilv generalized tonic-clonic seizures have been
`formed 2,3,14.23 Most of the studies have found no
`.ndicant differences in efficacy among carbamaz
`‘oe, phenytoin, and valproate, but because of the in
`uacies of clinical trials mentioned above, the re
`of these studies were difficult to evaluate corn
`-tively.
`It many of the trials, the number of patients was
`small to detect modest differences in antiepileptic
`“cts however, two large monotherapy trials have
`Performed by the Veterans Administration Epi
`H (ooperative Study Group in the United States’7
`bY several collaborating groups in the United
`gdom. 15,16,21
`lb the Veterans Administration study of partial
`cpsy, 622 patients were randomized to receive
`“1tflazepjne phenobarbjtal, phenytoin, or primi
`and were followed for up to a mean of 36 months.
`Utnient groups were randomized by predominant
`re type. This large study yielded several key
`flgs. In the treatment of tonic-clonic and partial
`S. flO differences in efficacy among these AEDs
`iOUd Using measures that included seizure
`Percentage of seizure-free patients, seizure
`- tilDe to first seizure, and seizure remission,
`°ne exception 37.24 j the treatment of partial
`‘ES, carbainazepine provided significantly better
`Control than phenobarbjtal or primidone, al
`
`Current challenges in the
`treatment of epilepsy
`
`Richard H. Mattson, MD
`
`Article abstract—Significant progress in the classification, diagnosis, and pharmacologic managempjj
`seizures has occurred over the past two decades, but epilepsy remains a therapeutic challenge. Clinical studies
`that most patients with epilepsy can have complete or almost complete seizure control with optimally managed moo5,
`apy that employs a traditional antiepileptic drug (AED). About half of the remaining patients can obtain imps-oved n
`control with combination antiepileptic drug therapy, but usually with more adverse effects. In the other half, seizur
`main refractory to treatment with available antiepileptic drugs, or treatment remains problematic because of drug
`tolerance. Advances in understandnig the pathogenesis of epilepsy and the mechanisms of action of antiepileptic drug, h
`provided a basis for the development of new AEDs that hold promise for difficult-to-treat patients. In this decade, a
`ber of new AEDs that may overcome some of the disadvantages of traditional AEDs and offer clinicians and patie
`added therapeutic options will become clinically available. These will be more fully evaluated for their clinical potetu,
`to meet existing challenges of epilepsy treatment.
`NEUROLOGYl994;44(suppl 5):S4
`
`Substantial progress in the classification, diagnosis,
`and pharmacologic management of epileptic seizures
`has been made during the past two decades, but epi
`lepsy remains a significant therapeutic challenge.
`Symptomatic localization-related (partial) epilepsies
`continue to be more difficult to treat successfully than
`absence, myoclonic, and tonic-clonic seizures of gen
`eralized onset that occur in a variety of idiopathic
`epilepsy syndromes. Partial seizures also are more
`difficult to treat effectively than secondarily gener
`alized tonic-clonic seizures. Although traditional anti-
`epileptic drugs (AEDs) allow for successful treatment
`of many patients,’-3 a significant number of patients
`with epilepsy either have seizures that are refrac
`tory to therapy with these agents or do not tolerate
`them well.2-5
`Advances in the understanding of the pathogene
`sis of epilepsy and the mechanisms of action of AEDs
`have enabled the development of AEDs that appear
`promising for this difficult-to-treat patient group. In
`this decade, a number of new AEDs will become clin
`ically available that may overcome some of the rec
`ognized shortcomings of traditional AEDs and offer
`clinicians and patients added therapeutic options.”
`Historical perspective on AED evaluation. Over
`a decade ago, my colleagues and I reviewed a cen
`tury of published literature on the four most com
`mon AEDs used for the treatment of partial and gen
`eralized tonic-clonic seizures in adults (phenobarbital,
`phenytoin, primidone, carbamazepine) as part of a
`broader effort to address the apparent shortcomings
`
`-
`
`of AED clinical trials that had been conduct
`date.9 Despite a large volume of reports, it was cjg
`that relatively few comparative studies had been pr
`lished and that there was an insufficient sciet11
`basis to justify the recommendation of a single AL
`for a specific seizure type in adults. Even fewer g
`ies attempted to correlate efficacy with toxicity higf
`tations.
`Selection of an AED for an individual patient
`usually based on the clinician’s personal bias andi
`ticipated or perceived risk of toxicity rather thati
`documented efficacy or specific intolerance. Despi
`experimental evidence that the most commonly US
`AEDs exhibited considerable pharmacologic dê
`ences, studies that had been performed to date fail
`to indicate any clear differences in the clinical ef
`cacy or relative toxicities of these agents, emphil
`ing the need for further critical clinical evaluatR
`and a new approach to the comparative evaluabS
`of AEDs.
`Of the 27 comparative clinical studies publi
`from 1920 to 1970, which involved the four aS
`AEDs, only two had a double-blind design to COfli!
`for bias. We identified at least 10 principal ifl’
`quacies and limitations of the AED clinical tnal
`ported to 1970. Most notable was the lack of a doaw
`blind, randomized study design. Correspond11g P
`ciples and standards for subsequent AED c1aflK
`als were outlined and discussed.’°
`A method of quantification for the evalUat
`Cra’
`AED therapy that included explicit nunierl
`scales for efficacy and toxicity and would be U
`
`-
`
`.
`
`.
`
`From the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut.
`Address correspondence and reprint requests to Dr. Richard H. Mattson, Yale University School of Medicine, 333 Cedar St., New Haven, CT
`
`S4 NEUROLOGY 44 (Suppi 5) June 1994
`
`MYLAN - EXHIBIT 1033
`
`

`
`_calca
`
`Single-Drug Treatment
`
`[ii Controlled
`65%
`
`Unsatisfactory Control
`35%
`
`I
`
`Two-Drug Treatment
`4.’
`
`Well Controlled
`10%
`
`Unsatisfactory Control
`25%
`
`Multiple-Drug Treatment
`
`[ii Controlled
`5%
`
`unsatisfactory ci
`20%
`
`Experimental Drug Therapy
`IFew Csntrslledl
`
`Figure 3. Expected outcome ofAED treatment in adIt,
`with new-onset localization-related epilepsy. (Mocljfled
`with permission from Mattson.2,)
`
`some patients.”6”7’° In the first Veterans Admj,
`tration study, 32 of 82 (39%) patients inadequat€iji
`treated with monotherapy improved with two-dr
`therapy, but only nine patients (11%) remained
`zure-freeJ7 The degree of increased seizure cuatm
`often was counterbalanced by an increase in advert
`effects.
`Evidence is unclear whether three- or four-dnt
`combinations can provide additional benefit. A
`proximately 10 to 15% of patients become well co
`trolled with add-on therapy.28 Thus, despite optima
`management with multiple-drug therapy, approIi
`mately 15 to 20% of patients cannot be adequat*b
`treated with currently available AEDs, in part
`cause of inadequate efficacy but also because o[I
`tolerance associated with low therapeutic indit
`Clearly, the need for new AEDs continues. NotO
`are sizable numbers of patients inadequately cc
`trolled, but, in addition, many who obtain contit1
`must tolerate some adverse effects and other dra
`backs that result from complex pharmacokiIletw &t
`properties, including interactions with other drug’
`and limited formulations for administration.
`
`AED desirable properties and selectiOfl cri(
`na. Despite the progress in understaudg
`pathogenesis of epilepsy and the mechan1
`action of traditional AEDs, selection of an AED”
`determined principally by expected efficacy
`zure control or reduction in seizure severitY’
`sequently, for a specific seizure type, tolerabil4Y
`plays a major role in AED selection and disCr°
`tion,”24’5 and frequently it is the balance betW
`clinical efficacy and toxicity that guides
`tion.1’3 In addition to individual variab1t
`responsiveness, factors such as pharmaceutit,
`pharmacokinetic properties and cost consid
`may also play significant roles in the selection
`
`Figure 2. Percentage ofpatients remaining seizure-free
`(time to the first seizure). During the 12-month period,
`patients in the group with complex partial seizures who
`were taking valproate (VPA) had recurrences earlier than
`those who were taking carbamazepine (CBZ) (p < 0.02).
`When the patients in both seizure groups were combined,
`seizures of any type were still found to recur significantly
`earlier in those taking VPA (p < 0.03). There were no
`significant differences between the VPA and the CBZ
`recipients in the group with generalized tonic-clonic
`seizures, according to the life-table analysis. A total of
`395 patients could be evaluated at 3 months, 235 at 6
`months, 162 at 9 months, and 74 at 12 months.’8
`(Adapted from Mattson et al. 18)
`drugs were shown to be comparably effective for the
`treatment of generalized tonic-clonic seizures, but
`by several measures carbamazepine provided better
`control of complex partial seizures. Carbamazepine
`was associated with more acute, but fewer, long-
`term adverse effects.
`As in the first Veterans Administration study, ap
`proximately 70 to 80% of patients were adequately
`managed for 12 months of therapy, but only about
`40% of patients on either drug remained seizure-free
`after 12 months of treatment (figure 2).’ Of those
`patients who had seizures during the first 6 months,
`however, many entered remissions and had no fur
`ther seizures, so that at 12 months an average of 63%
`of patients in both studies were under control. The
`results of these two major trials indicate that (1) most
`patients can be adequately controlled with monother
`apy, but the degree of complete seizure control is un
`satisfactory, and (2) about one third of patients will
`have inadequate treatment with monotherapy with
`available AEDs (figure 3)2
`The results of the Veterans Administration stud
`ies, which were conducted in a selective population of
`adult males, are in agreement with results in other
`patient populations, including women and children,
`in that only approximately 40% of patients will not
`experience a seizure during the first 12 months of
`therapy.’5”6’21’26
`For patients inadequately controlled despite tri
`als of several .AEDs used alone, combination therapy
`with two or three AEDs can provide improvement in
`
`S6 NEUROLOGY 44 (Suppi 5) June 1994
`
`ce of treatment for individual patients.”6’8
`For a specific type of epilepsy, most din
`1dies to date have failed to identify significant
`‘,ces in efficacy between AEDs. Although most
`seizures can be adequately controlled with
`AEDs, there is continued need to increase
`lcITree of seizure control and to provide thera
`for patients whose seizures remain re
`orV to treatment or who are unable to tolerate
`ip’ with existing AEDs. Desirable properties of
`.,ED include a mechanism of action that would
`1de a rational basis for a new degree or duration
`,ntrOl, an increased spectrum of efficacy, or one or
`13f these effects when the agent is used in corn
`.,tiofl therapY.
`Curently used AEDs, as well as some of the emerg
`EDs, are known to act primarily at three neu
`..,mtnjtter-receptor or ion channels (voltage-de
`,jent sodium or calcium channels and GABAA re
`tar channels).” Although the mechanisms of action
`edbamate, gabapentin, and lamotrigine are un
`r, gabapefltifl and felbamate may at least have
`ye’ mechanisms of action, which may in part ac
`jnt for their efficacy when used as add-on therapy.
`Wider use and study of these new AEDs may pro
`de new insights. Advances in research at the cel
`ir and molecular levels are likely to aid in the de
`of new AEDs that act more specifically at known
`different receptors or channels and offer new or
`t’anced efficacy.
`dverse effects. Increased tolerability, preferably
`ociated with an increased therapeutic index,
`8rIv is a desirable property of a new AED. Toxicity
`raditional AEDs often has been dose limiting or a
`or consideration in selection of a specific agent.
`the first Veterans Administration study, treat
`nt failures were found to occur principally in the
`6 months of therapy and to result equally from
`temic toxicity, neurotoxicity, and seizures that oc
`red at dosages resulting in adverse effects.’7’25 The
`suggest that a population of patients exists who
`‘usceptible to systemic toxicity for each drug sep
`tely. These results underscore the significance of
`xfity in the individual response to traditional AEDs
`I their clinical use.
`\hhough serious adverse effects occur infrequently
`traditional AEDs, they often occur in the acute
`of therapy.ii’72s A minimal risk of serious ad
`effects would therefore be desirable for new
`Ds, Serious adverse reactions associated with tra
`)IIaIAED5 often include idiosyncratic or hyper
`tlVIty reactions, particularly rash. With the ex
`vaiproate, which rarely causes a hyper
`reaction, traditional AEDs cause hyper
`LIVIty reactions (frequently dermatologic) in ap
`-. Innately 5 to 10% of patients. In the first Veter
`dmin,stratjon study, dermatologic reactions
`ne most frequent reason for treatment fail-
`low risk of hypersensitivity reactions would
`o a practical difficulty encountered by clini
`and patients.
`
`-
`
`Other adverse effects that can occur in the acute
`phase of therapy are relatively common to most of
`the traditional AEDs and include nervous system
`and gastrointestinal effects.”3”2’ Primidone is most
`likely and phenobarbital least likely to cause these
`effects.”7’2’ Acute adverse effects potentially can con
`tribute to early treatment failure. If these adverse
`effects are unavoidable, it is desirable that they be
`transient and mild to moderate in severity.
`With traditional AEDs, the risk of systemic toxic
`ity tends to decrease with time.25 The adverse effects,
`however, often differ among the agents following long-
`term therapy and may differ from those that occur
`in the acute phase of treatment.3’24 For example, re
`sults from the first Veterans Administration study
`indicate that the highest rate of toxicity occurs in pa
`tients who receive primidone (almost exclusively in
`the first 1 or 2 months of treatment). If patients are
`able to tolerate primidone, however, results from be
`havioral toxicity testing suggest that they might sub
`sequently fare at least as well as, or better than, pa
`tients who receive carbamazepine or phenytoin, in
`terms of neuropsychologic performance 24
`Chronic systemic adverse effects seen with the use
`of traditional AEDs include hyponatremia with car
`bamazepine, connective tissue disorder with pheno
`barbital, gum hypertrophy and hirsutism with phe
`nytoin, and weight gain with valproate.”3 Chronic
`neurotoxicity also has been reported following long-
`term therapy with these AEDs. Long-term tolerabil
`ity with a decreased risk of chronic toxicity would be
`a welcome property of a new AED, given the often
`prolonged nature of epilepsy treatment.
`Another important safety-related feature in a new
`AED would be a lack of teratogenic potential. This
`potential presents a continuing area of controversy.5
`The management of females with childbearing po
`tential who have epilepsy requires careful consider
`ation of many factors. These include contraceptive
`implications and the relative risks of seizures, preg
`nancy complications, and fetal malformations and
`anomalies.’2 AEDs with minimal or no risk of ter
`atogenicity are needed.
`Pharmaceutics and pharmacokinetics. Pharma
`ceutic properties of AEDs can be significant in Se
`lected patients and circumstances. The availability
`of an AED in multiple dosage formulations and its
`ability to be administered and adequately absorbed by
`multiple routes of administration (usually but not
`always associated with increased aqueous solubility)
`extends the clinical application of an agent. This flex
`ibility can be advantageous for individual patients
`and clinical situations.”
`Because several of the most commonly used tra
`ditional AEDs exhibit nonlinear pharmacokinetics
`or metabolic complexities, pharmacokinetic proper
`ties have been a significant consideration in AED se
`lection and optimal treatment of epilepsy.2’4’33’34 Phar
`macokinetics has been an important criterion in the
`selection and development of new AEDs.6’8 A simple
`pharmacokinetic profile is desirable, one that would
`allow for ease of administration and straightforward
`June 1994 NEUROLOGY 44 (Suppi 5) S7
`
`

`
`Table 2. Summary of desirable AED properties
`
`Selection criteria Desirable properties
`
`Efficacy
`
`Adverse effects
`
`Pharmaceutics
`
`Pharmacokinetics
`
`Selective for seizure type
`Additive or synergistic with other
`AEDs
`Sustained
`Novel mechanism of action
`Increased therapeutic index
`Lack of serious or chronic adverse
`effects
`Acute effects, if present, are mild and
`transient
`Lack of teratogenic potential
`Multiple dosage formulations
`Administered by multiple routes
`(water soluble)
`
`Simple profile
`Not protein bound
`Not metabolized
`Does not induce hepatic enzymes
`Does not inhibit metabolism of
`other drugs
`Does not interact with other AEDs or
`other drugs
`
`AED Antiepileptic drug.
`
`dosing considerations. Because of their metabolic
`pathways, effects on each other’s metabolism, and
`high degrees of protein binding, traditional AEDs
`frequently interact among themselves and with other
`drugs, resulting in considerable toxicity and clinical
`difficulties.8’33’34
`Carbamazepine causes autoinduction, phenytoin
`exhibits saturable metabolism, and vaiproate has
`concentration-dependent protein binding. C arba
`mazepine, phenobarbital, phenytoin, and valproate
`are oxidatively metabolized. Phenobarbital and phe
`nytoin also induce hepatic enzymes, and carbamaze
`pine and vaiproate can inhibit the metabolism of
`other AEDs and other drugs. Ideally, new AEDs
`would not be protein-bound or metabolized, and they
`would not induce hepatic enzymes or inhibit the
`metabolism of other drugs. By their not interacting
`with other AEDs or other drugs, these new AEDs
`perhaps would simplify treatment, minimize the need
`for extensive monitoring and dosage adjustments,
`and maximize concomitant drug therapy (eg, in el
`derly patients).
`Gabapentin, one of the new AEDs, appears to ex
`hibit many of the desirable pharmacokinetic charac
`teristics.6’34-36 Lamotrigine and vigabatrin have some
`minor interactions, but, in general, have favorable
`pharmacokinentics, also.
`Conclusions. Clinical studies over the past two
`decades have shown that most patients with epilepsy
`can have complete or nearly complete seizure con
`trol with optimally managed monotherapy that em
`ploys a traditional AED. About half of the remain
`S8 NEUROLOGY 44 (Suppi 5) June 1994
`
`ing patients can achieve improved seizure
`with combination AED therapy, but USU
`ally
`more adverse effects. The other half relnai
`n dif
`to treat with available AEDs.
`New AEDs are becoming available as a regg1
`considerable research and development effop
`may overcome some of the disadvantages Of
`tional AEDs. The desirable properties of flew
`have been reviewed and are summarized in b}e a b
`this decade, a number of new AEDs will be mom%
`evaluated for their clinical potential to meet ti
`isting challenges of epilepsy treatment.
`
`References
`1. Mattson RH. Selection of drugs for the treatnent ofepdt
`Semin Neurol 1990;10:406-413.
`2. Mattson RH. Drug treatment of partial epilepsy. In: Cl
`P, Delgado-Escueta AV, et al, eds. Adv Neurol jg
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`3. Mattson RH, Cramer JA. The choice of antiepilepti ‘ln.a
`focal epilepsy. In: Wyllie E, ed. The treatment of epilepsy
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`
`j Wilder BJ, Berger JR, et al. A double-blind study
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`hens A, Davidson DLW, Cartlidge NEF, at al, and the Adult
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`j Neurol Neurosurg Psychiatry (in press).
`DM, Rawlins MD, Weightman D, et al. A comparison
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`tptiC patients. J Neurol Neurosurg Psychiatry 1982;45:55-
`‘hr l3J. Ramsay RE, Murphy JV, et al. Comparison of val
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