VEMBER I DECEMBER 1988 VOLUME 29
`
`NUMBER 6
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2093 - 1/8
`
`

`
`29(6):787-793, 1988
`press, Ltd., New Yo~k
`.
`International League Agamst Epilepsy
`
`Adverse Reactions to Antiepileptic Drugs: A Follow-Up
`Study of 355 Patients with Chronic Antiepileptic
`Drug Treatment
`
`Collaborative Group for Epidemiology of Epilepsy*
`
`Institute fo,r Pharmacological Research "Mario Negri," Milan, Italy
`
`'• tes.
`:uaJes
`droe.
`igeno
`:ibfan
`en 19
`:vaJu.
`lobre
`l con
`:n los
`rmos
`1ente
`:s de
`~2 en
`10 se
`cam.
`
`. Three hundred fifty-five patients receiving
`·
`· drug (AED) treatment were followed
`nnt\!Pl"~lty and hospital centers for an average of 11
`to assess the effects of intensive monitoring of
`drug reactions (ADRs) on the frequency of re(cid:173)
`on the overall management of epilepsy. One
`forty-eight patients (41.6%) had one or more
`during the entire follow-up period. ADRs were re(cid:173)
`by 31% of patients at admission and by 20% at last
`with a downward trend in the number of reports.
`mcttrre:ntJV, the number of patients who were seizure(cid:173)
`rose from 24.5 to 42.8%. During the observation pe-
`
`riod, the number of prescriptions fell from 640 to 568,
`mostly for phenobarbital (PB), phenytoin (PHT), and val(cid:173)
`proate (VPA). The outcome of the most common ADR was
`only partially related to drug changes. Even with the lim(cid:173)
`itations of the unstandardized criteria used for ADR re(cid:173)
`porting, the present study shows that intensive monitor(cid:173)
`ing of drug-related clinical events is not only a valuable
`tool to provide a comprehensive survey of drug toxicity in
`clinical practice, but is also an educational effort to im(cid:173)
`prove the quality of care for patients with epilepsy. Key
`Words: Anticonvulsants-Epidemiology-Epilepsy(cid:173)
`Drug-induced abnormalities-Italy.
`
`The problem of drug toxicity in patients receiving
`· antiepileptic drug treatment has been re(cid:173)
`y emphasized (for reviews see: Reynolds,
`; Schmidt, 1982; Beghi et al., 1986b). However,
`commonest sources of information on drug tax(cid:173)
`are case reports and clinical trials (Beghi et al.,
`). In both, the reported events do not repre(cid:173)
`the ideal situation for a meaningful assessment
`the prevalence and characteristics of adverse
`reactions (ADRs) seen in daily practice. Case
`s are drawn from populations at unknown
`
`Received August 1987; revision accepted May 1988.
`*Coordinators: Ettore Beghi, Daniela Trevisan, and Gianni
`·. Members: Sonia Arrigoni, Giovanni Beretta, Ugo
`Sergio Borgheresi, Daniela Buti, Maura Buttiglione, Gio(cid:173)
`Cagnin, Cesare Cardinali, Giuseppina Chiodelli, Chiara
`·, Umberto Colangelo, Carlo A. De Fanti, Elena Gambini,
`Giuliani, Angela La Neve, Carlo Lenti, Vito Lepore,
`Lini, Manuela Molteni, Maria Luisa Monticelli, Feder(cid:173)
`Cristina Musetti, Giuseppe Olivieri, Andrea Or(cid:173)
`Perniola, Luigi Piattella, Daniele Porazzi, An-
`......... L . . uu. Maria R. Rottoli, Raffaella Silvestri, Luigi M.
`, Franco Spinogatti, Vito Toso. Marta Trizio, Gaetano
`Piergiuseppe Zagnoni, and Nelia Zamponi.
`correspondence and reprint requests to Dr. E. Beghi
`for Pharmacological Research "Mario Negri," Via
`62, 20157 Milan, Italy.
`
`risk, and patients recruited in clinical trials are not
`entirely representative of the epilepsy population at
`large. The frequency and types of ADRs recorded
`in studies dealing with intensive monitoring of clin(cid:173)
`ical practice are a better reflection of the prevalence
`and clinical implications of drug toxicity as they are
`perceived in routine health care delivery frame(cid:173)
`works. In a multicenter survey of clinical practice
`conducted in our country with 509 patients receiv(cid:173)
`ing chronic antiepileptic drug (AED) treatment
`(Collaborative Group for Epidemiology of Epi(cid:173)
`lepsy, 1986), 31% had one or more ADRs, with a
`wide range of occurrence between centers. Of the
`232 recorded events, 109 were definite, 84 were
`possible, and 26 were doubtful. Symptoms and/or
`signs of drug toxicity were ·reported by the patient
`in 54.5% of the cases, were clinically important in
`52.5%, permanent in 49.5%, and intolerable in
`13.5%. ADRs were present in 22% of monotherapy
`patients, in 34.2% of patients treated with two
`drugs, and in 44.4% of patients receiving three or
`more drugs. Occurrence of ADRs varied by drug:
`phenytoin (PHT) (33%), phenobarbital (PB) (23%),
`carbamazepine (CBZ) (15%), and valproate (VPA)
`(12%). Somnolence was the most common com-
`
`71<7
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2093 - 2/8
`
`

`
`788
`
`COLLABORATIVE GROUP FOR EPIDEMIOLOGY OF EPILEPSY
`
`plaint, followed by gingival hyperplasia, nystag(cid:173)
`mus, and ataxia.
`A random sample of 355 cohort cases was fol(cid:173)
`lowed to assess the effects of prolonged monitoring
`of drug toxicity on frequency of ADRs and on overall
`management of the disease. We report the results of
`that follow-up study.
`
`MATERIAL AND METHODS
`
`A cohort of 509 patients receiving AED treatment
`for > 3 months was recruited in the outpatient ser(cid:173)
`vices of 15 Italian university and hospital depart(cid:173)
`ments, including six epilepsy centers. Patient data,
`general characteristics of the epilepsy, drug treat(cid:173)
`ment, and ADRs have been previously reported
`(Collaborative Group for Epidemiology of Epi(cid:173)
`lepsy, 1986). Three hundred fifty-five unselected
`patients were then followed for an average period of
`11 months (range 1-36 months). The number of fol(cid:173)
`low-up visits varied between patients depending on
`the number and types of requests and on the length
`of the observation period. During each follow-up
`visit, seizure frequency and types, data relevant to
`the diagnosis or drug, and ADRs (including new oc(cid:173)
`currences) were recorded. Seizure frequency at ad-
`
`mission was calculated based on the previou
`months. All data collected during the follow~ 6
`were processed using a Statistical Package for t~p
`Special Sciences (SPSS) and, where indicated st e
`tistical analysis was done using the chi-squar~ tt
`for independent variables.
`st
`
`RESULTS
`The characteristics of the 355 follow-up patient
`generally overlapped those of the original cohort (Ta~
`ble 1). Only a significant change in seizure distribu(cid:173)
`tion was found, with a relative decrease of mixed
`and unclassified seizures and an increase of com(cid:173)
`plex partial, tonic/clonic, and absence seizures.
`One or more ADRs were reported in 148 patients
`(41.6%) during the observation period. Adverse re(cid:173)
`actions are reported in Table 2. ADRs were 284
`with 207 cases reporting none; 67 cases, one; 4g
`cases, two; 17 cases, three; and 15 cases, four or
`more. The average number of ADRs per subject
`was 1. 7 among mono therapy patients, 2 among pa(cid:173)
`tients treated with two drugs, and 2.5 among pa(cid:173)
`tients taking three or more drugs. At admission, 110
`(31%) of patients reported ADRs. The number fell to
`71 (20%) at the last follow-up visit. When the per(cid:173)
`centage of patients with ADRs was plotted against
`time (Fig. 1), there was a downward trend in the
`
`TABLE 1. Characteristics of the 355 follow-up patients with comparison to the original cohort of 509 cases
`
`Variable
`
`No. of cases
`
`A. Age distribution (yr) mean (±SE)
`B. Percent with disease duration of
`<1 yr
`1-3 yr
`4-10 yr
`>10 yr
`Not specified
`C. Percent with seizures in the previous 6 months
`None
`1-3
`4-10
`>10
`Not specified
`D. Percent with associated disordera
`None
`Anoxia/birth trauma
`Head trauma
`Infection
`Hereditary disease
`Metabolic/toxic
`Malformations
`Othersb
`E. Percent with seizure pattern (in%)
`Partial
`Generalized
`Mixed and unspecified
`Unilateral
`
`21
`66
`97
`165
`6
`
`87
`74
`54
`106
`34
`
`186
`66
`35
`21
`14
`9
`8
`40
`
`172
`131
`50
`1
`
`Follow-up
`
`24.8 (±0.9)
`
`Original
`
`23.7 (±0.7)
`
`6.0
`18.5
`27.0
`46.5
`2.0
`
`24.5
`21.0
`15.0
`30.0
`9.5
`
`52.3
`18.5
`9.8
`5.9
`3.9
`2.5
`2.2
`11.2
`
`48.0
`37.0
`14.0
`0.5
`
`7.0
`21.5
`26.5
`43.5
`1.5
`
`29.5
`20.0
`14.0
`28.0
`8.5
`
`50.5
`20.5
`11.0
`6.0
`3.5
`2.7
`2.7
`12.0
`
`49.0
`24.0
`26.0
`1.0
`
`a Percentages do not equal 100% because two or more associated disorders were concurrently present in some patients.
`b Including vascular, neoplastic, and degenerative disorders.
`
`Epilepsia, Vol. 29, No. 6, 1988
`
`--------
`
`central nel
`Somnole
`Nystagn·
`Ataxia
`Vertigo.
`Diplopia
`Tremor
`Slownes
`Head ad
`Irritabili
`Mental l
`Other"
`Skin and c
`Gingiva'
`Rash
`Acne
`Hirsutis
`Alopeci
`Enamel
`Other
`Gastrointi
`Nausea
`Liver d
`Other
`Weight
`Hypo to
`Blood<
`As then
`Early s
`Hypote
`Flushir
`Dyspni
`Total
`
`"Stupe
`(2); hype
`chosis ( l•
`b The s
`patients'
`concurre
`
`Patients w
`
`%
`30
`
`20
`
`10
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2093 - 3/8
`
`

`
`MONITORING ADVERSE AED REACTIONS
`
`789
`
`TABLE 2. Adverse drug reactions
`
`unsteadiness
`' and other ocular disorders
`and other extrapyramidal signs
`of mentation
`
`development
`
`Total
`
`181
`
`50
`
`26
`
`27
`
`62
`23
`21
`18
`12
`9
`7
`5
`5
`4
`15
`
`28
`6
`6
`5
`2
`2
`1
`
`24
`2
`
`8
`6
`6
`3
`1
`1
`1
`1
`
`dysmetria (2); depression, anxiety (2); enuresis
`hYrlert~oni<~ity (1); dysarthria (1); coma (1); hiccup (1); psy(cid:173)
`); status epilepticus (1); insomnia (1).
`sum of the adverse reactions is more than the number of
`with ADRs because in 81 cases two or more ADRs were
`
`-
`
`r--_
`
`,____
`
`-
`
`r--
`
`-~---
`
`number of reports (27% at 6 months, 20% at 12
`months, and 11.5% at 16 months).
`Seizure frequency and treatment regimens at ad(cid:173)
`mission and at last visit are illustrated in Table 3.
`The proportion of seizure-free patients rose from
`24.5% at admission to 42.8% at last visit. The num(cid:173)
`ber of patients with > 20 seizures decreased from 20
`to 8. 7%. Among the 87 seizure-free patients at ad(cid:173)
`mission, 26% had ADRs, as compared to 32% of
`cases with uncontrolled seizures (chi-square: 1.11;
`p = NS). Conversely, at the last visit, the percent(cid:173)
`ages of patients with ADRs in the two groups were
`15 and 24%, respectively (chi-square: 3.93; p <
`0.05). Overall, previously recorded ADRs had dis(cid:173)
`appeared at last visit in 62.2% of seizure-free pa(cid:173)
`tients and in 22.2% of cases with relapses.
`During the follow-up, there was a slight increase
`of the number of monotherapy cases ( 40.5-50%)
`and a concurrent decrease of patients taking three
`or more drugs (18-10%). The number of prescrip(cid:173)
`tions fell from 640 to 568, mostly for PB, PHT, and
`VP A. The drug most frequently prescribed at the
`last visit was CBZ. Drugs containing fixed combi(cid:173)
`nations of PHT and PB were withdrawn in 25 of 38
`patients (66%).
`The percentage of adverse reactions varied ac(cid:173)
`cording to the number of drugs concurrently taken,
`although a lower percentage of patients had ADRs
`at the last visit than at admission (Table 4). There
`were also fewer ADRs for the individual drugs, ex(cid:173)
`cept for barbiturates and benzodiazepines.
`At last visit, drug plasms levels were assayed in
`23% of patients with ADRs (37 of 161) and in 18% of
`patients without ADRs (34 of 194) (chi-square: 1.31;
`p == NS). Overall, plasma levels values were within
`
`FIG. 1. Percentage of adverse
`drug reactions (ADRs) during
`follow-up. Numbers in paren(cid:173)
`theses refer to patients in each
`interval. Patients seen for >16
`months were not considered
`because they were few. A: first
`study visit.
`
`r--
`
`r---
`
`-
`
`1--
`
`'-
`16
`14 · 15
`l3
`12
`11
`10
`9
`8
`7
`6
`5
`4
`3
`2
`1
`A
`(355) (355) (352) (336) (308) (297) (284) (273) (263) (255) (242) (234) (201) (115) ( 76) (55) ( 35)
`
`months
`
`Epilepsia, Vol. 29, No. 6, 1988
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2093 - 4/8
`
`

`
`790
`
`COLLABORATIVE GROUP FOR 1:-r>IDEMIOLOGY OF EPILEPSY
`
`TABLE 3. Seizure frequency and treatment at first study visit and at last study visit in
`355 patients with chronic AED treatment
`
`Variable
`
`No. of cases
`
`%
`
`No. of cases
`
`%
`
`disappe
`
`First visit
`
`Last visit
`
`Seizure frequencya
`None
`1-3
`4-10
`11-20
`>20
`Not specified
`Antiepileptic treatment
`No. of drugs
`None
`1
`2
`3+
`Drug
`Phenobarbital and other barbiturates
`Carbamazepine
`Phenytoin
`Valproate
`Primidone
`Benzodiazepines
`Ethosuximide
`Other
`Total no. of prescriptions
`
`AED, antiepileptic drug.
`a See text for explanation.
`
`87
`74
`54
`35
`71
`34
`
`144
`147
`64
`
`219
`124
`102
`99
`38
`33
`18
`7
`
`640
`
`(24.5)
`(20.8)
`(15.2)
`(9.9)
`(20)
`(9.6)
`
`(-)
`(40.5)
`(41.5)
`(18)
`
`(34)
`(19.5)
`(16)
`(15.5)
`(6)
`(5)
`(3)
`(1)
`
`(100)
`
`152
`39
`76
`45
`31
`12
`
`3
`177
`137
`38
`
`176
`140
`88
`77
`40
`29
`12
`6
`
`568
`
`(42.8)
`(11)
`(21.7)
`(12.7)
`(8.7)
`(3.4)
`
`(1)
`(50)
`(50)
`(10)
`
`(31)
`(25)
`(15.5)
`(13.5)
`(7)
`(5)
`(2)
`(1)
`
`(100)
`
`normal limits in 78% of cases with and in 81% of
`cases without ADRs (chi-square: 0.04; p = NS). Of
`31 patients with abnormal plasma level values, only
`one had a toxic plasma drug concentration.
`The most common ADRs (i.e., those with 10 +
`reports) are shown in Fig. 2 along with the clinical
`decision on whether treatment was altered. Somno(cid:173)
`lence disappeared during follow-up in two-thirds of
`cases, 47% of which had changes in treatment. Gin(cid:173)
`gival hyperplasia improved in one-third of cases,
`56% without change in treatment. Ataxia evolved
`
`TABLE 4. Percentage of patients with ADRs by
`number of drugs and drug at first and last study visit
`
`Variable
`
`No. of drugs
`1
`2
`3+
`Druga
`ESM
`PHT
`VPA
`BZD
`PB and other barbiturates
`CBZ
`PRM
`
`First visit
`(% ADRs)
`
`Last visit
`(% ADRs)
`
`20.0
`37.5
`40.5
`
`50.0
`36.0
`31.5
`20.0
`17.0
`15.5
`
`15.0
`22.0
`34.0
`
`29.0
`7.0
`33.0
`19.0
`7.0
`
`ESM, ethosuximide; PHT, phenytoin; VPA, valproate; BZD,
`benzodiazepines; PB, phenobarbital; CBZ, carbamazepine;
`PRM, primidone.
`- a Only monotherapy patients were considered.
`
`Epilepsia, Vol. 29, No. 6, 1988
`
`favorably in 86% of cases, mostly after changes in
`treatment. Drug changes were made in the majority
`of patients with diplopia, all of whom had complete
`recovery. Both vertigo and nystagmus disappeared
`in 61% of cases, mostly without changes in treat(cid:173)
`ment. Treatment modifications were recorded in
`50% of cases with gastrointestinal (Gl) distur(cid:173)
`bances, and symptoms did not recur in the majority
`of patients.
`
`DISCUSSION
`
`Patients receiving chronic treatment with AEDs
`are at high risk of developing symptoms and/or
`signs of drug toxicity. In the present survey, ADRs
`were present in 41.6% of patients surveyed for an
`average period of 11 months. The high frequency of
`reports can be due in part to incorrect use of AEDs.
`Our findings indicate that intensive surveillance of
`ADRs can lead to a progressive decrease in ADRs,
`resulting in a better diagnostic assessment (a.s
`shown by the decreasing number of unclassified sei·
`zures) and an improved therapeutic approach (as
`shown by the smaller percentage of cases with un·
`controlled seizures).
`There are a number of reports on the improve·
`ment of the quality of care to patients with epilepsY
`after intensive surveillance, with concurrent reduc·
`tion in the number of seizures in the so-called ''re·
`
`'~ unchan g
`
`fractor:
`rative 1
`thorne
`studies
`ment i1
`signs o
`Theod<
`lation 1
`tient, a
`expost
`stresse
`ticularl
`dition
`(Reyn<
`may h
`drawal
`edly n
`(CNS)
`pie), e
`selli et
`Sauer
`' Con
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2093 - 5/8
`
`

`
`MONITORING ADVERSE AED REACTIONS
`
`791
`
`Therapy changed
`
`0
`rz:zJ Therapy unchanged
`
`FIG. 2. Outcome of most com(cid:173)
`mon adverse drug reactions
`(ADRs) (i.e., with 10 + reports)
`and related clinical decisions.
`Number of reports for each ADR
`is given in Table 2. Outcome of
`ADR was unknown in some
`cases: somnolence, 2; gingival
`hyperplasia, 1; gastrointestinal
`disturbances, 1; nystagmus, 1;
`vertigo, 3; and diplopia, 4.
`
`V"'
`:::::>
`::e
`(,!)
`<
`1-
`V"'
`>-
`z
`
`<
`X
`<
`1-
`<
`
`0
`(,!)
`i=
`0::
`UJ
`>
`
`<
`a:
`0
`...J
`a.
`0
`
`...J
`
`< z
`
`i=V"'
`V"'UJ
`UJU
`1-Z
`z<
`-co
`Oa::
`a::=>
`!;;t;
`<-
`(.!)0
`
`~disappeared
`80
`
`70
`
`60
`
`so
`
`40
`
`30
`
`20
`
`10
`
`10
`
`20
`
`30
`
`40
`
`so
`
`60
`
`UJ u
`z
`UJ
`...J
`0 z
`::e
`0
`V"'
`
`<
`v;
`<
`...J...J
`<a.
`>O::
`-w
`<.!>a.
`~>-
`<.!>:X:
`
`epilepsies" (Lund, 1974; Milano Collabo-
`Group for Studies on Epilepsy, 1977; Caw(cid:173)
`and Silas, 1981; Beghi et al., 1987). Other
`have shown that optimization of drug treat(cid:173)
`is followed by a reduction of symptoms and
`of drug toxicity (Shorvon and Reynolds, 1979;
`et al., 1983). We found a positive corre(cid:173)
`between ADRs and number of drugs per pa(cid:173)
`and an overall decrease in the number of drug
`s during follow-up. This finding further
`the appropriateness of monotherapy, par(cid:173)
`because the benefit expected from the ad(cid:173)
`of a second drug is small in most instances
`~p,,~,.,.·~-~~ and Shorvon, 1981). Another factor that
`have reduced the number of ADRs is with(cid:173)
`al of drugs like PHT or PB, which are report(cid:173)
`more toxic to the central nervous system
`(a common site of involvement in our sam-
`' especially when given in combination (Mor(cid:173)
`et al., 1971; Lambie et al., 1976; Windorfer and
`' 1977).
`Control of ADRs was more difficult among pa-
`
`tients who had recurrent seizures during the obser-
`;
`vation period. This finding may be due to the much
`more complex management problems of patients
`with more severe epilepsy, with a higher risk of
`drug toxicity (Shorvon and Reynolds, 1979).
`The lack of correlation between ADRs and toxic
`PL values is worth noting. This is a limitation to use
`of PL measurement, even in the presence of symp(cid:173)
`toms or signs of drug toxicity, and confirms that
`clinical judgment still provides the most valid basis
`for the evaluation of drug toxicity.
`However, we do not know to what extent clinical
`judgment may have influenced ADR reporting dur(cid:173)
`ing follow-up. In an uncontrolled setting, drug
`changes may have influenced physicians' expecta(cid:173)
`tions about the outcome of the reported events.
`Likewise, an ADR may be thought to persist in the
`absence of any clinical decision. However, the ev(cid:173)
`olution of ADRs did not invariably follow physi(cid:173)
`cian's intervention, as in a remarkable percentage
`of cases the two events were totally independent.
`The synoptic presentation of the interplay between
`
`Epilepsia, Vol. 29, No. 6, 1988
`
`ler changes in
`in the majority
`t had complete
`1s disappeared
`anges in treat(cid:173)
`·e recorded in
`.1 (GI) distur·
`in the
`
`survey,
`Jrveyed for
`:h frequency of
`t use of AEDs.
`surveillance of
`·ease in ADRs,
`ssessment (as
`tnclassified sei~
`; approach (as
`cases with un·
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2093 - 6/8
`
`

`
`792
`
`COLLABORATIVE GROUP FOR EPIDEMIOLOGY OF EPILEPSY
`
`an expectant attitude and a change in treatment pro(cid:173)
`vides in this sense a highly suggestive and provok(cid:173)
`ing picture. Several explanations can be given for
`this discrepancy. First, a spontaneous regression of
`symptoms or signs of drug toxicity is frequently re(cid:173)
`ported with AEDs (Schmidt, 1982). This is particu(cid:173)
`larly true for somnolence in patients taking PB or
`benzodiazepines, and for GI disturbances ·with
`VPA. Tolerance or sometimes simple modifications
`of the daily schedule may account for the improve(cid:173)
`ment or disappearance of the symptoms in the ab(cid:173)
`sence of apparent drug, changes. Second, the per(cid:173)
`sistance of ADR despite treatment changes and
`even after withdrawal of the offending drug can be
`explained by the assumption that some aspects of
`chronic drug toxicity probably reflect structural
`changes. For instance, experimental evidence
`shows that PHT has marked effects on the chemical
`composition of skin through increased deposition of
`insoluble dermal collagen and insoluble scleropro(cid:173)
`tein with concurrent loss of fat (Houck et al., 1972).
`This may explain in part the occurrence of persis(cid:173)
`tent gum hyperplasia, facial skin changes, and Du(cid:173)
`puytren's contracture with PHT, even after drug
`cessation. Third, since our physicians used un(cid:173)
`standardized and often subjective criteria for the
`definition of drug toxicity (Collaborative Group for
`Epidemiology of Epilepsy, 1986), a clear-cut cause(cid:173)
`effect relationship between drugs and events in(cid:173)
`tended as ADRs could not be invariably stated, thus
`raising the suspicion that some of those reports may
`be independent events. Up to 80% of symptoms and
`signs commonly interpreted as ADRs have also
`been reporteciin untreated patients (Reidenberg and
`Lowenthal, 1968).
`1 Even with these limitations, the prospective re(cid:173)
`porting of drug-related clinical events appears to be
`a valuable tool to provide a comprehensive survey
`of drug toxicity in routine clinical practice. In addi(cid:173)
`tion, investigation and reporting of ADRs to AEDs
`becomes an educational effort for the practicing
`physicians which leads not only to less drug toxicity
`but also to overall improvement in the quality of the
`care for patients with epilepsy.
`
`Acknowledgment: This study was supported by Na(cid:173)
`tional Research Council Grant No. 85/00447.56 on Pre(cid:173)
`ventive and Rehabilitative Medicine.
`
`REFERENCES
`
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`mechanism of action. !tal J New·ol Sci 1986a;7:209-22.
`Beghi E, Di Mascio R, Tognoni G. Adverse effects of anticon(cid:173)
`vulsant drugs-a critical review. Adv Drug React Ac Pais
`Rev 1986b;2:63-86.
`Beghi E, Bellini P, DiMascio R, Cerisola N, Merloni T, Manghi
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`Epilepsia, Vol. 29, No. 6, 1988
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`actions to antiepileptic drugs: a multicenter survey of c~~e_re.
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`practice. Epilepsia 1986;27:323-30.
`Ca]
`Houck JC, Cheng RF, Waters MD. Dyphenylhydantoin· eff
`on connective tissue and wound repair. In: Woodb~ry ~~ts
`Penry JK, Schmidt RP, eds. Antiepileptic drugs. New y 11k1:
`Raven Press, 1972:267-74.
`or .
`Lambie DG, Nanda RM, Johnson RH, Shakir RA. Therap
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`and pharmacokinetic effects of increasing phenytotut.Ic
`chronic epilepsies on multiple drug therapy. Lancet 1~7~~
`2:386-9.
`.
`Lund L. Anticonvulsant effect of diphenylhydantoin relative 10
`plasma levels. Arch Neural 1974;31:289-94.
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`intensive monitoring in the difficult patient. Preliminary r~
`s_ults of 16 months of observations-us~fuln~ss and limita(cid:173)
`tions. In: Gar~ne:-Th?rpe C, Janz ~' ~emardt H, Pippenger
`CE, eds. Antlepzleptzc drug monztorzng. Tunbridge Wells·
`Pitman Medical, 1977:197-213.
`·
`Morselli PL, Rizzo M, Garattini S. Interaction between pheno(cid:173)
`barbital and diphenylhydantoin in animals and in epileptic
`patients. Ann NY Acad Sci 1971 ;179:88-107.
`Reidenberg MM, Lowenthal DT. Adverse non drug reactions. N
`Eng/ J Med 1968;279:678-9.
`Reynolds EH. Chronic antiepileptic toxicity: a review. Epilepsia
`1975;16:319-52.
`Reynolds EH, Shorvon SD. Monotherapy or polytherapy for
`epilepsy? Epilepsia 1981 ;22: 1-10.
`Schmidt D. Adverse effects of antiepileptic drugs. New York:
`Raven Press, 1982.
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`Shorvon D, Reynolds EH. Reduction in polypharmacy for epi(cid:173)
`lepsy. Br Med J 1979;2:1023-5.
`Theodore WH, Schulman EA, Porter RJ. Intractable seizures:
`long-term follow-up after prolonged inpatient treatment in an
`epilepsy unit. Epilepsia 1983;24:336-43.
`Windorfer A Jr, Sauer W. Drug interactions during anticonvul(cid:173)
`sant therapy in childhood: diphenylhydantoin, primidone.
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`and dipropylacetate. Neuropediatrie 1977;8:29-41.
`
`RESUME
`
`355 patients traites de fa<;:on chronique par medicaments anti·
`epileptiques ont ete suivis dans 15 centres universitaires ethos·
`pitaliers pendant une moyenne de 11 mois afin de determiner les
`consequences d'une surveillance intensive des effets collateraux
`aux medicaments (ECM) sur la frequence des phenomenes rap·
`partes et sur la prise en charge globale de l'epilepsie. Au total.
`148 patients (41.6%) ont presente au mains 1 ECM pendant l'en·
`semble du sui vi. Des ECM ont ete signales par 31% des patient.s
`au moment de I' entree dans l'etude, et par 20% lors de Ia derm·
`ere consultation, avec une tendance a Ia decroissance dans k
`nombre de signalisations. Parallelement, Ie nombre de patients
`ne presentant plus de crises s'est eleve de 24.5 a 42.8%. Pendant
`la periode d'observation, le nombre total des prescriptions a
`chute de 640 a 568, avec le plus souvent phenobarbital, pheny(cid:173)
`toi:ne et valproate. L'evolution des ECM Ies plus frequents n 3
`ete que partiellement liee aux changements de traitement. ~~al·
`gre les limites entrainees par }'utilisation de criteres non standar·
`dises pour la signalisation des ECM, cette etude montre qu'une
`surveillance intensifiee des effets secondaires cliniques d~'
`medicaments est un outil utile pour obtenir un panorama de 3
`toxicite medicamenteuse en pratique clinique, mais represet
`aussi un effort educatif d'amelioration dans la prise en charge e)
`patients epileptiques.
`
`(P. Genton, Marseillei
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2093 - 7/8
`
`

`
`MONITORING ADVERSE AED REACTIONS
`
`793
`
`RESUMEN
`
`ZUSAMMENFASSUNG
`
`determinar los efectos de una monitorizacion intensiva de
`·
`adversas de las medicaciones (ADR) y de su fre(cid:173)
`en las publicaciones que tratan del manejo general de Ia
`se han estudiado 355 enfermos que estaban en tra(cid:173)
`cronico con drogas antiepilepticas. Un total de 148 pa-
`41.6%) tenfan una o mas ADR durante el periodo com-
`seguimiento. Las ADR se identificaron en un 31% en Ia
`y en un 20% en la ultima visita con una tendecia de(cid:173)
`te en el numero de informes. Simultaneamente el
`de enfermos que estaban sin ataques aumento de 24.5%
`Durante el periodo de observacion el numero total de
`bajo de 640 a 568 sobre todo del Fenobarbital, la Feni(cid:173)
`el Valproato. Los resultados de las ADR mas comunes
`relacionados, solo parcialmente con los cambios de med(cid:173)
`incluso con las limitaciones de los criterios no estanda(cid:173)
`utilizados para Ia publicacion de las ADR. El estudio
`stra que Ia monitorizacion intensiva de los aconte-
`clfnicos relacionados con la droga no solo es un in(cid:173)
`valido para proporcionar una vision comprensiva de
`en Ia practica clfnica, sino tambien un esfuerzo ed(cid:173)
`para mejorar Ia calidad de Ia asistencia de los pacientes
`epilepsfa.
`
`355 Patienten mit chronischer Antiepileptika-Therapie wurden
`von 15 UniversiUitskliniken und anderen Zentren im
`Durchschnitt 11 Monate lang beobachtet, urn den Effekt der in(cid:173)
`tensiven Medikamenteniiberwachung beziiglich der Haufigkeit
`von Nebenwirkungen (ADR) und allgemeiner Auswirkung auf
`die Epilepsie festzustellen. Insgesamt hatten 148 Patienten
`(41.6%) eine oder mehrere ADR wahrend des Beobachtungszei(cid:173)
`tral)mes. ADR wurden in 31% zu Beginn und in 20% bei der
`letzten Vorstellung gefunden, allerdings mit deutlichem Abwart(cid:173)
`strend. Im Verlauf stieg die Zahl der anfallsfreien Patienten von
`24.5% auf 42.8%. Wahrend der Studie fiel die Verordnungshau(cid:173)
`figkeit von 640 auf 568 ab, meist Phenobarbital, Phenytoin oder
`Valproat. Der Verlauf der haufigsten ADR war z.T. durch
`Medikamentenanderung bedingt. Unter Beriicksichtigung der
`Grenzen unstandardisierter Kriterien zum Erfassen von ADR,
`zeigt die vorliegende Studie doch, daf3 intensives 'drug(cid:173)
`monitoring,' orientiert an klinischen Ereignissen, ein brauch(cid:173)
`bares Werkzeug darstellt, urn Arzneimitteltoxizitat im klinischen
`Alltag umfassend darzustellen. Zusatzlich wird die Qualitat der
`Betreuung von Patienten mit Epilepsie verbessert.
`
`(A. Portera-Sanchez, Madrid)
`
`(C. G. Lipinski, Heidelberg-Neckargemiind)
`
`Epilepsia, Vol. 29, No. 6, 1988
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2093 - 8/8