- ---
`
`The Journal of the International League Against Epilepsy
`
`New Developments in
`
`Antiepileptic Drug Therapy
`
`American Epilepsy Socie!J Annual Course
`December 1994, New Orleans. louisiana
`
`Guest Editor
`Elaine Wyllie, M.D.
`
`Univ. of Minn.
`Bio-Medical
`Library
`6 13 95
`
`995
`
`VOLUME 36
`
`SUPPLEMENT 2
`
`RAVEN PRESS
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2001 page 1
`
`

`
`Epilepsia, 36(Suppl. 2):SI3-S26, 1995
`Raven Press, Ltd ., New York
`© International League Against Epilepsy
`
`Efficacy and Adverse Effects of Established and New
`Antiepileptic Drugs*
`
`Richard H. Mattson
`
`Yale University School of Medicine, New Haven, and Veterans Administration Medical Center,
`West Haven, Connecticut , U.S.A .
`
`I
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`
`I
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`
`I
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`I'
`
`)
`
`I
`~
`
`Summary: Antiepileptic drug (AED) selection is based
`primarily on efficacy for specific seizure types and epi(cid:173)
`leptic syndromes. However, efficacy is often similar for
`the different AEDs, and other properties such as adverse
`effects, pharmacokinetic properties , and cost may also be
`of importance. For idiopathic generalized epilepsies with
`absence, tonic-clonic , and myoclonic seizures , the AED
`of choice is valproate (VPA). Secondarily generalized ep(cid:173)
`ilepsies with tonic , atonic , and other seizure types are
`difficult to treat with any single AED or combination of
`AEDs. The AEDs of choice for absence seizures are
`ethosuximide (ESM) and VPA . For control of primary
`generalized tonic-clonic seizures, any of the other major
`AEDs can ~e effective. If VPA cannot be prescribed,
`carbamazepme (CBZ), phenobarbital (PB), phenytoin
`(PHT), or primidone (PRM) may be effective, but ESM or
`a benzodiazepine (BZD) must be added to control asso(cid:173)
`ciated absence or myoclonic seizures. The AEDs of first
`choice for partial epilepsies with partial and secondarily
`generalized tonic-clonic seizures are CBZ and PHT. In-
`
`creasing evidence suggests that VP A is a good alternative
`when CBZ and PHT fail. PB and PRM are second-choice
`selections because of adverse effects. A combination of
`two of the five standard AEDs may be necessary to treat
`intractable seizures , but no studies have been done to
`indicate an optimal combination . Other epilepsy syn(cid:173)
`dromes such as neonatal and infantile epilepsies, febrile
`epilepsy, alcoholic epilepsy , and status epilepticus re(cid:173)
`quire specific AED treatment. Ultimately , AED selection
`must be individualized. No "drug of choice" can be
`named for all patients. The expected efficacy for the sei(cid:173)
`zure type , the importance of the expected adverse ef(cid:173)
`fect s, the pharmacokinetics , and the cost of the AEDs all
`must be weighed and discussed with the patie~t before a
`choice is made. A number of new AEDs w1th umque
`mechanisms of action, pharmacokinetic properties, and
`fewer adverse effects hold important promise of Im(cid:173)
`proved epilepsy treatment. Key Words: Epilepsy(cid:173)
`Seizures-Anticonvulsants-Adverse effects-Neuro(cid:173)
`logic diagnosis .
`
`With the recent or anticipated introduction of five
`new antiepileptic drugs [AEDs; felbamate (FBM),
`gabapentin (GBP), lamotrigine (LTG), oxcarba(cid:173)
`zepine (OCBZ), and vigabatrin (VGB)], a wide ar(cid:173)
`ray of medications is now available to prevent the
`recurrence or decrease the severity of convulsive or
`nonconvulsive seizures. Converging evidence from
`many studies has made increasingly clear the ad(cid:173)
`vantages and disadvantages of the well-established
`AEDs, including carbamazepine (CBZ), ethosuxi(cid:173)
`mide (ESM), phenobarbital (PB), phenytoin (PHT),
`primidone (PRM), and valproate (VPA) . The role of
`the new AEDs is less clear. Most of the new AEDs
`are different from the older ones in their mecha(cid:173)
`nisms of action, pharmacokinetics, and adverse ef(cid:173)
`fects, which may mean that they eventually will find
`
`*Reprinted , with adaptations, from Antiepi/eptic Drugs,
`Fourth edition , Levy RH, Mattson RM , Meldrum BS , eds. New
`York: Raven Press, 1995.
`Address correspondence and reprint requests to Dr. R. H.
`Mattson at Neurological Services, Veterans Administration
`Medical Center, 950 Cambell Avenue, West Haven, CT 06516,
`U.S. A.
`
`an important place in the treatment of epilepsy.
`However, the relative efficacy of these AEDs has
`not been established, their safety for long-term use
`is not yet proven, and they will cost more than the
`standard AEDs. It is expected that the standard
`AEDs will be used until they fail to provide good
`treatment or until cumulative evidence from con(cid:173)
`trolled clinical trials suggests that one of the newer
`compounds should be the AED of first choice.
`
`EFFICACY AS A SELECTION FACTOR
`
`The selection of an AED is based primarily on its
`efficacy for specific types of seizures and epilepsy.
`Certain epileptic syndromes can be recognized on
`the basis of a constellation of characteristics , in(cid:173)
`cluding not only types of seizures but also , for ex(cid:173)
`ample, age at onset , electroencephalographic
`(EEG) findings , and etiology . Classifications of sei(cid:173)
`zure types (Table 1) and epileptic syndromes (Table
`2) have been proposed by the International League
`Against Epilepsy (Commission, 1981 , 1989). AI-
`
`513
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2001 page 2
`
`

`
`EFFECTS OF ESTABLISHED AND NEW AEDs
`
`SJ5
`
`seizure control after the dosage is increased to the
`Point of causing side effects. For more difficult
`P~oblems, a combination of the two AEDs may pro(cid:173)
`VIde better control (Rowan et al., 1983). Several
`other AEDs provide variable success in control of
`absence seizures and are most often used in patients
`Who are unable to tolerate ESM or VP A because of
`adverse effects. Acetazolamide (AZM) is moder(cid:173)
`ately efficacious, although no controlled trials are
`available. Its side effects are minimal, but evidence
`?f tolerance limits its efficacy in long-term admin(cid:173)
`IStration (Lombroso and Forsythe, 1960). Similarly,
`the benzodiazepines (BZDs), including diazepam
`(DZP), clonazepam (CZP), and nitrazepam (NZP),
`provide good control but may lose efficacy after
`several months of administration (Browne, 1976).
`BZDs usually produce much more sedation than
`ESM or VPA. The oxazolidinediones [trimethadi(cid:173)
`one (TMO) and paradione (PMO)] are used infre(cid:173)
`quently. These compounds have more frequent and
`serious side effects than the AEDs currently avail(cid:173)
`a?Ie. Because the teratogenic risk of TMO is espe(cid:173)
`Cially high, it should not be administered to fertile
`wo~en (Yerby, 1992). The other commonly pre(cid:173)
`scnbed AEDs have little efficacy in the treatment of
`absence seizures, and there is some evidence that
`CBZ may increase the frequency of attacks (Shields
`and Saslow, 1983; Snead and Hosey, 1985).
`
`Myoclonic seizures
`. M~oclonic seizures are associated with many ep(cid:173)
`Ileptic syndromes. Successful seizure control is
`more often associated with the epileptic syndrome
`than with the seizure type. Myoclonic seizures oc(cid:173)
`~urring in generalized idiopathic epilepsy, such as
`~uvenile myoclonic epilepsy, can be fully controlled
`m 75- 90% of patients (Delgado-Escueta and Enrile(cid:173)
`Bascal, 1984; Bourgeois et al., 1987; Chadwick,
`19_87). Myoclonic seizures occurring with degener(cid:173)
`ative central nervous system disease or postanoxic
`encephalopathy may be refractory to any form of
`therapy. Despite the variable probability of good
`control with treatment, VPA is the AED of choice
`in most cases. ESM is less effective, but methsux(cid:173)
`imide (MSM) has been tried with some success in
`patients unresponsive to other AEDs . The BZDs
`are quite effective but cause sedative side effects,
`and in many patients some loss of efficacy is noted
`after several months of treatment.
`
`Primary generalized tonic- clonic seizures
`Tonic--clonic or clonic- tonic- clonic seizures as(cid:173)
`sociated with generalized idiopathic epilepsy occur
`alone or with absence and/or myoclonic seizures.
`Their response to treatment is excellent. Seizures in
`
`' )
`
`>
`
`' )
`
`75-85% of patients can be completely controlled
`with VPA monotherapy. Some studies did not
`clearly distinguish between primary and secondari(cid:173)
`ly generalized tonic-clonic seizures, but the re(cid:173)
`sponse was especially favorable in patients with
`generalized idiopathic epilepsy (Bourgeois et al.,
`1987; Chadwick, 1987). Control was the same or
`better than that obtained with administration of
`PHT or CBZ (Shakir et al., 1981; Convanis et a!.,
`1982; Wilder et al., 1983; Turnbull et al., 1985;
`Chadwick , 1987). Half of the patients in the study of
`Bourgeois et al. ( 1987) were not controlled with
`other AEDs, including CBZ, PB, or PHT alone or in
`combination with other AEDs. In refractory pa(cid:173)
`tients with generalized idiopathic epilepsy, we were
`able to obtain complete seizure control with VPA
`monotherapy in 80% of patients who had not re(cid:173)
`sponded to CBZ, PB, PHT, or a combinat_ion _ of
`these AEDs, in addition to ESM or BZDs. This high
`success rate was achieved only after a lengthy
`crossover and high dosages of VPA initially (Matt(cid:173)
`son and Cramer, 1988). No entirely satisfactory
`controlled clinical trial has yet been done to com(cid:173)
`pare all available AEDs for this seizure type. Ear(cid:173)
`lier studies suggest that PB and PRM are _as effe~­
`tive as CBZ and PHT for control of tomc--clomc
`·Seizures and could be used as alternative drugs for
`this seizure type if VPA is ineffective or not toler(cid:173)
`ated because of adverse effects.
`
`Secondary epilepsies (symptomatic)
`
`.
`West syndrome
`West syndrome is characterized by myoclomc
`seizures (infantile spasms), a hypsarrhythmic EEG
`pattern and, in most cases, mental retardati~n. The
`seizures begin in the first 2 years of life, parti~ularly
`between 4 and 6 months of age. Adrenocorticotro(cid:173)
`pic hormone (ACTH) or corticosteroids are usually
`considered the treatment of choice (Hrachovy et
`al., 1983; Lombroso, 1983; Aicardi, 1986). Contro(cid:173)
`versy continues as to whether ACTH or corticoste(cid:173)
`roids have a better effect on the long-term outcome
`than AEDs such as VPA. In a prospective study of
`high-dosage VPA treatment (associated with a high
`mean plasma VPA concentration of 113 JJ.g/ml), 20
`of 22 patients achieved total seizure control after 6
`months, an outcome comparable to that achieved
`with ACTH treatment and with less adverse effects
`(Siemes et al., 1988). This result is somewhat better
`than that found with NZP or other BZDs (Lacy and
`Penry, 1976). However, VPA carries an increased
`risk for idiosyncratic metabolic hepatotoxicity in
`this age group. Some early evidence (Chiron et al.,
`1991) suggests that VGB may be helpful in this syn-
`
`Epi/epsia, Vol. 36, Supp/ . 2, /995
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2001 page 3
`
`

`
`S/4
`
`R . H. MATTSON
`
`TABLE 1. International classification of
`epilep tic seizures
`
`I. Partial (focal, local) seizures
`A. Simple partial seizures
`B. Complex partial seizures
`I. With impairment of consciousness at onset
`2. Simple partial onset followed by impairment of
`consciousness
`C. Partial seizures evolving to generalized tonic-clonic
`seizures (GTCS)
`I. Simple partial seizures evolving to GTCS
`2. Complex partial seizures evolving to GTCS,
`including those with simple partial onset .
`II. Generalized seizures (convulsive or nonconvuls1ve)
`A. Absence seizures
`B. Atypical abse nce seizures
`C. Myoclonic seizures
`D. Clonic seizures
`E. Tonic seizures
`F. Tonic-clonic seizures
`G. Atonic seizures
`III . Unclassified epileptic seizures, including some neonatal
`seizures
`
`Modified and adapted from Commission (198 1) .
`
`though admittedly imperfect , these classifications
`provide our best current understanding and serve as
`a frame of reference for communication.
`
`GENERALIZED EPILEPSIES AND
`EPILEPTIC SYNDROMES
`
`The generalized epilepsies and epileptic syn(cid:173)
`dromes comprise in part the idiopathic epilepsies
`with age-related onset and the secondary (idio(cid:173)
`pathic or symptomatic) epilepsies, such as infantile
`spasms (West syndrome) and Lennox- Gastaut syn(cid:173)
`drome. This classification also includes symptom(cid:173)
`atic epilepsies with a nonspecific etiology, such as
`early myoclonic encephalopathy, and epileptic syn(cid:173)
`dromes associated with some di seases, such as
`Ramsay-Hunt syndrome.
`
`Idiopathic epilepsies
`The generalized idiopathic epilepsies usually be(cid:173)
`gin in childhood, but some, includingjuvenile myo(cid:173)
`clonic epilepsy, may not appear until adolescence.
`It is unusual for these epileptic syndromes to begin
`after the second decade of life, although preexisting
`absence or myoclonic seizures may not be medi(cid:173)
`cally documented until tonic-clonic seizures occur
`in adulthood. The generalized epilepsies sometimes
`remit, but many patients continue to be susceptible
`to recurrent seizures throughout most or all of their
`adult lives. No specific etiology is known for this
`group of disorders, other than a significant genetic
`factor associated with some syndromes. Evidence
`for other brain dysfunction or disease is not found ,
`except coincidentally. The electroencephalographic
`(EEG) pattern associated with these epilepsies is
`
`Epilepsia, Vol. 36, Supp/. 2, 1995
`
`generalized spike-and-wave or polyspike-and-wave
`discharges. These epilepsies are manifested by ab(cid:173)
`sence , myoclonic , and tonic- clonic seizures.
`VPA is usually the drug of choice for the gener(cid:173)
`alized idiopathic epilepsies. Its efficacy is equal to
`or greater than that of CBZ or PHT for tonic-clonic
`seizures (Convanis et al., 1982; Callaghan et al.,
`1985 ; Bourgeois et al., 1987; Chadwick, 1987; Matt(cid:173)
`son and Cramer, 1988) and equal to that of ESM for
`absence seizures (Sato et al., 1982; Kaneko et al.,
`1988). VPA is the only AED that can control all
`seizure types when patients have combinations of
`tonic-clonic , absence , and/or myoclonic seizures.
`Low to moderate dosages and blood VPA levels
`often suffice (Bourgeois et al., 1987). Because mod(cid:173)
`est doses of VPA can be administered, few neuro(cid:173)
`logic or systemic side effects, except perhaps
`weight gain, are evident with long-term use (Dine(cid:173)
`sen et al., 1984; Bourgeois et al., 1987 ; Herranz et
`al., 1988 ; Mattson et al., 1992).
`
`Absence seizures
`Absence seizures respond well to both ESM and
`VPA. Controlled clinical trials indicate that either
`AED can effect marked or virtually complete sei(cid:173)
`zure control in 70% to 90% of patients (Suzuki et
`al., 1972; Sherwin et al., 1973 ; Sato et al., 1982;
`Bourgeois et al., 1987). Although efficacy is com(cid:173)
`parable between the two AEDs, ESM is usually se(cid:173)
`lected for patients with pure childhood absence ep(cid:173)
`ilepsy (pyknolepsy) because side effects are usually
`fewer or less serious than those of VPA. A trial of
`VPA is indicated when ESM provides inadequate
`
`TABLE 2. International classification of epilepsies and
`epileptic syndromes
`
`I. Localization-related (focal, local, partial) epilepsies and
`epileptic syndromes
`A. Idiopathic with age-related onset
`I. Benign childhood epilepsy with centrotemporal
`spikes
`2. Childhood epilepsy with occipital paro xys ms
`B. Symptomatic
`II . Generalized epilepsies and epileptic syndromes
`A. Idiopathic with age-related onset
`I. Benign neonatal epilepsy
`2. Childhood absence epilepsy (pyknolepsy)
`3. Juven~le myoclonic epilepsy (impulsive petit mal)
`4. Juvemle absence ep!lepsy with generalized
`tonic-clonic seizures on awakening
`B. Secondary (idiopathic or symptomatic)
`I. West syndrome (infantile spasms)
`2. Lenno x-Gastaut syndrome
`C. Symptomatic
`I. Nonspecific etiology (earl y myoclonic
`encephalopathy)
`2. Specific syndromes (epileptic seizures that may
`complicate many diseases, e.g., Ramsay- Hunt
`synd rome, Unverricht's disease)
`
`Modified and abbreviated from Commission (1989).
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2001 page 4
`
`

`
`EFFECTS OF ESTABLISHED AND NEW AEDs
`
`S/5
`
`seizure control after the dosage is increased to the
`point of causing side effects. For more difficult
`problems, a combination of the two AEDs may pro(cid:173)
`vide better control (Rowan et a!., 1983). Several
`other AEDs provide variable success in control of
`absence seizures and are most often used in patients
`who are unable to tolerate ESM or VPA because of
`adverse effects. Acetazolamide (AZM) is moder(cid:173)
`ately efficacious, although no controlled trials are
`available. Its side effects are minimal, but evidence
`of tolerance limits its efficacy in long-term admin(cid:173)
`istration (Lombroso and Forsythe, 1960). Similarly,
`the benzodiazepines (BZDs), including diazepam
`(DZP), clonazepam (CZP), and nitrazepam (NZP),
`provide good control but may lose efficacy after
`several months of administration (Browne, 1976).
`BZDs usually produce much more sedation than
`ESM or VPA. The oxazolidinediones [trimethadi(cid:173)
`one (TMO) and paradione (PMO)] are used infre(cid:173)
`quently. These compounds have more frequent and
`serious side effects than the AEDs currently avail(cid:173)
`able. Because the teratogenic risk of TMO is espe(cid:173)
`cially high, it should not be administered to fertile
`women (Yerby, 1992). The other commonly pre(cid:173)
`scribed AEDs have little efficacy in the treatment of
`absence seizures, and there is some evidence that
`CBZ may increase the frequency of attacks (Shields
`and Saslow, 1983; Snead and Hosey, 1985).
`
`Myoclonic seizures
`Myoclonic seizures are associated with many ep(cid:173)
`ileptic syndromes. Successful seizure control is
`more often associated with the epileptic syndrome
`than with the seizure type. Myoclonic seizures oc(cid:173)
`curring in generalized idiopathic epilepsy, such as
`juvenile myoclonic epilepsy, can be fully controlled
`in 75-90% of patients (Delgado-Escueta and Enrile(cid:173)
`Bascal, 1984; Bourgeois et a!., 1987; Chadwick,
`1987). Myoclonic seizures occurring with degener(cid:173)
`ative central nervous system disease or postanoxic
`encephalopathy may be refractory to any form of
`therapy. Despite the variable probability of good
`control with treatment, VPA is the AED of choice
`in most cases. ESM is less effective, but methsux(cid:173)
`imide (MSM) has been tried with some success in
`patients unresponsive to other AEDs . The BZDs
`are quite effective but cause sedative side effects,
`and in many patients some loss of efficacy is noted
`after several months of treatment.
`
`Primary generalized tonic-clonic seizures
`Tonic-clonic or clonic-tonic- clonic seizures as(cid:173)
`sociated with generalized idiopathic epilepsy occur
`alone or with absence and/or myoclonic seizures.
`Their response to treatment is excellent. Seizures in
`
`75-85% of patients can be completely controlled
`with VPA monotherapy. Some studies did not
`clearly distinguish between primary and secondari(cid:173)
`ly generalized tonic-clonic seizures, but the re(cid:173)
`sponse was especially favorable in patients with
`generalized idiopathic epilepsy (Bourgeois et a!.,
`1987; Chadwick, 1987). Control was the same or
`better than that obtained with administration of
`PHT or CBZ (Shakir et a!., 1981; Convanis et a!.,
`1982; Wilder et a!., 1983; Turnbull et a!., 1985;
`Chadwick, 1987). Half of the patients in the study of
`Bourgeois et a!. (1987) were not controlled with
`other AEDs, including CBZ, PB, or PHT alone or in
`combination with other AEDs. In refractory pa(cid:173)
`tients with generalized idiopathic epilepsy, we were
`able to obtain complete seizure control with VPA
`monotherapy in 80% of patients who had not re(cid:173)
`sponded to CBZ, PB, PHT, or a combination of
`these AEDs, in addition to ESM or BZDs. This high
`success rate was achieved only after a lengthy
`crossover and high dosages of VPA initially (Matt(cid:173)
`son and Cramer, 1988). No entirely satisfactory
`controlled clinical trial has yet been done to com(cid:173)
`pare all available AEDs for this seizure type. Ear(cid:173)
`lier studies suggest that PB and PRM are as effec(cid:173)
`tive as CBZ and PHT for control of tonic-clonic
`-seizures and could be used as alternative drugs for
`this seizure type if VPA is ineffective or not toler(cid:173)
`ated because of adverse effects.
`
`Secondary epilepsies (symptomatic)
`
`.
`West syndrome
`West syndrome is characterized by myoclomc
`seizures (infantile spasms), a hypsarrhythmic EEG
`pattern and, in most cases, mental retardati~n. The
`seizures begin in the first 2 years of life , parttcularly
`between 4 and 6 months of age. Adrenocorticotro(cid:173)
`pic hormone (ACTH) or corticosteroids are usually
`considered the treatment of choice (Hrachovy et
`al., 1983; Lombroso, 1983; Aicardi, 1986). C:ontro(cid:173)
`versy continues as to whether ACTH or corttcoste(cid:173)
`roids have a better effect on the long-term outcome
`than AEDs such as VPA. In a prospective study of
`high-dosage VPA treatment (associated with a high
`mean plasma VPA concentration of 113 1-l-g/ml) , 20
`of 22 patients achieved total seizure control after 6
`months an outcome comparable to that achieved
`with ACTH treatment and with less adverse effects
`(Siemes et al., 1988). This result is somewhat better
`than that found with NZP or other BZDs (Lacy and
`Penry , 1976). However, VPA carries an increased
`risk for idiosyncratic metabolic hepatotoxicity in
`this age group. Some early evidence (Chi ron et al.,
`1991) suggests that VGB may be helpful in this syn-
`
`Epi/epsia, Vol. 36, Supp/. 2, 1995
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2001 page 5
`
`

`
`/
`
`Sl6
`
`R. H. MATTSON
`
`drome, especially in patients with symptomatic in(cid:173)
`fantile spasms due to tuberus sclerosis.
`
`Lennox-Gastaut syndrome
`Lennox-Gastaut syndrome begins in early child(cid:173)
`hood, and the seizures rarely remit entirely. The
`seizures are of multiple types, with tonic, myoclon(cid:173)
`ic, atonic, and atypical absence attacks occurring
`with great frequency. Tonic-clonic seizures or frag(cid:173)
`ments thereof, as well as partial seizures, may also
`occur. The patients have a slow spike-and-wave
`EEG pattern and some degree of mental retarda(cid:173)
`tion. Variations on these characteristics can be seen
`in individual patients.
`Treatment is difficult with any single AED or
`combination of AEDs. Seizures often occur many
`times daily, although occasionally remissions occur
`for weeks without obvious explanation. VPA has
`the greatest spectrum of activity for treatment of
`the multiple seizure types. The dosage should be
`increased until side effects appear, and a month or
`more of therapy should be tried before other med(cid:173)
`ications are added or substituted. CBZ, PHT, and
`PB may be useful in controlling the tonic-clonic or
`tonic seizures, and CZP or other BZDs are quite
`effective, at least temporarily, in controlling the
`myoclonic or absence attacks. ESM is also effective
`for treatment of the absence attacks, although these
`atypical, sometimes prolonged confusional states
`are much less responsive than those associated with
`generalized idiopathic epilepsy. The inability to ob(cid:173)
`tain adequate control often leads to the administra(cid:173)
`tion of multiple AED combinations with increased
`side effects and questionable benefit. Subsequent
`attempts to discontinue a BZD or a barbiturate may
`be difficult owing to exacerbation of seizures during
`discontinuation. In controlled clinical trials, FBM
`has proven to be effective in this syndrome and
`occasionally results in major improvement (Fel-
`
`bamate Study Group, 1993). The reports of aplastic
`anemia and hepatic failure must be weighed in the
`risk-benefit analysis of FBM (FDA Talk Paper,
`1994). One study also suggests that LTG may be
`especially helpful in Lennox-Gastaut syndrome
`(Timmings and Richens, 1992).
`
`Localization-related epilepsies and
`epileptic syndromes
`Localization-related (focal, local, partial) epilep(cid:173)
`sies and epileptic syndromes are responsive to a
`number of AEDs (Smith et al., 1983). Because more
`than half of all patients with this type of epilepsy
`have both partial and secondarily generalized tonic(cid:173)
`clonic seizures at some time (Mattson et al., 1985),
`it is reasonable to select the AEDs most likely to
`provide optimal efficacy against both types of sei(cid:173)
`zures. In general, CBZ and PHT show the best bal(cid:173)
`ance of seizure control, with fewer adverse effects
`than PB or PRM, for the treatment of partial epi(cid:173)
`lepsy, as evidenced by successful long-term mono(cid:173)
`therapy in the first Veterans Administration Coop(cid:173)
`erative Study (VA study), a double-blind, con(cid:173)
`trolled clinical trial involving 622 adults (Mattson et
`al., 1985). Life-table analyses demonstrated that pa(cid:173)
`tients treated with CBZ or PHT were satisfactorily
`managed for at least I year (Fig. 1), and even as
`long as 3 years, the mean follow-up period. PB was
`almost as successful as CBZ and PHT for many
`patients, and is an option when other drugs prove
`unsatisfactory. In some studies (Henricksen and Jo(cid:173)
`hannessen, 1982; Loiseau et al., 1984; Callaghan et
`al., 1985; Turnbull et al., 1985; Chadwick, 1987; De
`Silva et al., 1989; Heller et al., 1989; Mattson,
`1990), VPA appeared to be equally as effective and
`to have fewer adverse effects. However, a second
`large VA study (Mattson, 1994), using the same de(cid:173)
`sign as the first one, found better efficacy and better
`overall long-term outcome for CBZ than VPA for
`
`100
`
`80
`
`<.!)
`
`z
`:::>
`~ 60
`1-
`z
`0
`u
`I- 40
`z
`w
`u
`a:
`w 20
`0..
`
`\~::' .. ___
`\t-:--..
`.............
`\
`\, ~---=::::..:-.. --... _
`________ ..,...
`-<>---a-:-:-. __
`"'--....,_
`---
`.........
`-<>--~-=--~----
`·--o---3.:=:=-• ---a
`--.... ----.....
`--.... ___
`-
`... ---.._
`----""'-----... _____ .... _----·----,...----,... ___ .....,. ____ .....
`
`'.o...
`
`- ·PB
`• - -·PHT
`•- --- ~·PRM
`o -
`- --o•CBZ
`
`6
`
`9
`
`12
`
`15
`
`18
`
`21
`
`24
`
`27
`
`30
`
`33
`
`36
`
`MONTHS
`
`FIG. 1. Percentage of patients successfully
`treated w1th phenobarbital (PB), phenytoin
`(PHT), primidone (PRM), and carbamazepine
`(CBZ) during 36 months of follow-up. From
`Mattson et al. (1985).
`
`Epilepsia, Vol . 36, Suppl. 2, /995
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2001 page 6
`
`

`
`EFFECTS OF ESTABLISHED AND NEW AEDs
`
`Sll
`
`complex partial seizures . Other investigations
`(Loiseau eta!., 1984; Callaghan eta!., 1985; Turn(cid:173)
`bull et a!., 1985; De Silva et a!. , 1989; Heller et a!.,
`1989; Richens et a!., 1994) have not shown these
`efficacy differences.
`
`Idiopathic benign childhood epilepsy with
`centrotemporal spikes
`Idiopathic benign childhood epilepsy is charac(cid:173)
`terized by partial and secondarily generalized
`tonic-clonic seizures occurring in early to mid(cid:173)
`childhood, which usually remit spontaneously dur(cid:173)
`ing adolescence (BJorn and Heijbel, 1982; Loiseau
`et a!., 1988). Despite the focal character of the sei(cid:173)
`zures associated with this syndrome, no evidence
`by medical history, neurologic examination, or di(cid:173)
`agnostic imaging indicates structural brain disease.
`Characteristic bilateral centrotemporal sharp
`waves and spikes often occur independently and are
`prominent during light sleep. The manifestations of
`this relatively benign condition may be so infre(cid:173)
`quent and mild that no treatment is required, par(cid:173)
`ticularly if the attacks are of the partial type and are
`limited to occurrence in sleep. When treatment is
`advisable, CBZ or PHT is quite effective, and com(cid:173)
`plete control is often possible with a modest dosage.
`The occasional cosmetic side effects of PHT, espe(cid:173)
`cially in this age group, make CBZ the drug of
`choice (Lefebvre eta!., 1972; Dodson, 1987; Her(cid:173)
`ranz et a!., 1988). PB and PRM may also prove
`effective, but behavioral or sedative side effects
`may make them less desirable (Trimble, 1987; Vin(cid:173)
`ing eta!. , 1987). No controlled , comparative clinical
`trials of VPA have been performed in this subgroup
`of patients. Information on the effectiveness of the
`newer AEDs for this syndrome is lacking.
`
`Symptomatic epilepsies
`The localization-related symptomatic epilepsies
`are the most common, may begin at any time of life,
`and have multiple etiologies. Among the most fre(cid:173)
`quent causes are head trauma (including birth in(cid:173)
`jury), vascular lesions , neoplasms , and infection.
`The neurologic examination, brain imaging, and
`EEG may indicate areas of abnormal brain function
`that are responsible for the seizures. In a consider(cid:173)
`able number of patients, the etiology or the site of
`abnormality may escape detection despite all diag(cid:173)
`nostic efforts. When possible, the cause of the ep(cid:173)
`ilepsy should be corrected, but in most cases AED
`therapy is necessary. In general, differences in the
`efficacy of the AEDs available to treat symptomatic
`partial epilepsies are modest. However, there are
`considerable differences in their adverse effects,
`pharmacokinetics, pharmaceutical properties, and
`cost, which should be considered in selecting an
`
`AED most likely to be appropriate for a patient
`(Mattson, 1990).
`
`Secondarily generalized tonic-clonic seizures
`Multiple controlled trials have failed to demon(cid:173)
`strate evidence of superiority of any single AED for
`control of secondarily generalized tonic-clonic sei(cid:173)
`zures. In the first VA study (Mattson eta!., 1985) of
`622 adults with partial epilepsy and secondarily gen(cid:173)
`eralized tonic-clonic seizures, equal efficacy for
`CBZ, PB, PHT, and PRM was found with follow-up
`for I, 2, or 3 years. Outcome measures included
`seizure rate , total number of seizures, seizure se(cid:173)
`verity , time to first seizure, 100% seizure control ,
`and a special seizure rating scale (Cramer et a!.,
`1983). Complete seizure control can be expected in
`approximately half of the patients during the first
`year of treatment. In many patients, seizures will
`continue during the first 6 to 12 months of therapy
`before remitting. Comparative studies of the effi(cid:173)
`cacy of VPA (Wilder et a!., 1983; Callaghan et a!.,
`1985; Turnbull eta!. , 1985; Chadwick, 1987; Heller
`et a!. , 1989; Mattson et a!., 1992; Richens et a!.,
`1994) indicate that VPA also is comparable to the
`other AEDs in preventing secondarily generalized
`tonic-clonic seizures . Consequently, the choice of
`AED may be based primarily on other consider(cid:173)
`ations.
`
`Partial seizures
`Although the International Classification of Epi(cid:173)
`leptic Seizures (Table I) separates partial seizures
`into simple and complex types, with various sub(cid:173)
`groups in each category, no studies have shown se(cid:173)
`lective efficacy for one subtype of partial seizure.
`Indeed , it may be difficult to determine exactly
`whether partial seizures are of the simple or com(cid:173)
`plex type, and many patients have both types at
`different times. In the first VA study (Mattson et
`a!., 1985), CBZ, PB, PRM, and PHT showed few
`differences in efficacy for treatment of partial sei(cid:173)
`zures. As with tonic-clonic seizures, there were no
`statistically significant differences in seizure num(cid:173)
`ber seizure rate time to first seizure, or seizure
`rati~g score. On; clinically important efficacy out(cid:173)
`come was found: complete control was more fre(cid:173)
`quently achieved with CBZ than with the barbitu(cid:173)
`rates at I, 2, and 3 years of follow-up. At the 18-
`month follow-up visit, this result reached statistical
`significance (p < 0.04), and similar values were ob(cid:173)
`served at every one of the 12 visits throughout the
`3-year follow-up . There was no statistically signifi(cid:173)
`cant difference between CBZ and PHT or PHT and
`the barbiturates.
`In the second VA study (Mattson et a!. , 1992),
`480 patients with predominantly complex partial or
`
`Epilepsia , Vol . 36, Supp/. 2, 1995
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2001 page 7
`
`

`
`SIB
`
`R. H. MATTSON
`
`secondarily generalized seizures received CBZ or
`VPA and were treated for a minimum of 12 months
`unless AED failure occurred. Overall, the success
`rate was similar for both AEDs (Fig. 2). CBZ had
`greater efficacy in complex partial seizures_, as mea(cid:173)
`sured by seizure number, seizure rate, seizure r~t­
`ing score, and time to first seizure. Other studies
`(Loiseau et al., 1984; Call