I AUGUST 1991
`
`VOLUME32
`
`NUMBER4
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2097 - 1/7
`
`

`
`Epilepsia, 32(4):554-559, 1991
`Raven Press, Ltd., New York
`© International League Against Epilepsy
`
`Allergic Rash Due to Antiepileptic Drugs: Clinical
`Features and Management
`
`J. Pelekanos, P. Camfield, C. Camfield, and K. Gordon
`
`IWK Children's Hospital, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada
`
`Summary: Optimal management of allergic rash from an(cid:173)
`tiepileptic drugs (AEDs) is unclear. We identified 50 pa(cid:173)
`tients with 68 reactions (36 to one AED, 10 to two AEDs,
`and four to three AEDs). The AEDs implicated were car(cid:173)
`bamazepine, 30; phenobarbital (PB), 20; phenytoin, 16;
`ethosuximide, one; and AED combination, one. Sixty(cid:173)
`three reactions were cutaneous eruptions, three exfolia(cid:173)
`tive dermatitis, and two Stevens-Johnson syndrome.
`Forty-six reactions were mild (rash only), 18 moderate
`(systemic symptoms or other organ system involvement),
`and four life-threatening (all with PB). In most patients
`with > 1 reaction, the second and third reactions were not
`more severe than the first. Prior antibiotic allergies or
`nonmedication allergies were no more common than in a
`control group without reactions. The AED was ceased
`
`abruptly in 59 patients (22 of whom did not receive a new
`AED), tapered in five, and continued unchanged in four.
`Despite ~his, t~ere was no status epile~tic~s (SE) during
`the reactiOn or Its treatment, and no patient s seizure con(cid:173)
`trol deteriorated. In 40 cases, a new AED was added-16
`after the reaction had resolved and 24 before total reso(cid:173)
`lution. Rash recurred with the new AED in 50 and 42%
`respectively (NS). We conclude that, though allergic
`rashes to AEDs are usually mild, the rare occurrence of
`severe reactions indicates that the AED should be
`ceased. This can be done abruptly with minimal risk of
`SE. A new AED can be added, if necessary, prior to the
`resolution of the rash without increasing the risk of fur(cid:173)
`ther reactions. Key Words: Allergic-Rash-Anticon(cid:173)
`vulsant.
`
`Idiosyncratic side effects to antiepileptic drugs
`(AEDs) warrant stopping medication in 15-20% of
`patients with epilepsy (Cowan et al., 1989; Camfield
`et al., 1985; Wolf and Forsyth, 1978). Several recent
`reviews have addressed the problem of reactions to
`AEDs (Booker, 1975; Plaa, 1975; Reynolds, 1975),
`mainly in adults. In childhood, the incidence of side
`effects to phenobarbital (PB) (Wolf and Forsyth~
`1978; Camfield et al., 1979) and valproate (VPA)
`(Egger and Brett, 1981; Dreifuss et al., 1987) are
`well-documented, but reactions to other AEDs
`have not been studied as thoroughly.
`Skin reactions occur in 2-3% of patients receiving
`carbamazepine (CBZ) (Sillanpaa, 1981), and proba(cid:173)
`bly a similar percentage for PB and phenytoin
`(PHT). Most of these skin reactions are mild, but
`optimal management is uncertain, with most au(cid:173)
`thors recommending that the AED be stopped im(cid:173)
`mediately (Schmidt, 1985; Rail and Schleifer, 1985;
`Abu-Arafeh and Wallace, 1988). Of special concern
`
`are patients who have suffered life-threatening re(cid:173)
`actions or those who have had reactions to several
`AEDs, since the choice of further medications may
`be limited.
`Practical management questions about the child
`with epilepsy who develops a skin reaction include
`the following: If the AED needs to be ceased, can
`this be done abruptly, or should it be tapered to
`decrease the chance of status epilepticus (SE)? If
`the AED is stopped, should another AED be
`added? If so, should it be added immediately, or
`should the reaction resolve prior to adding the next
`drug? Will seizure control change during the reac(cid:173)
`tion and its management? Will the epilepsy be more
`difficult to control because certain AEDs can no
`longer be used?
`In this study we surveyed the precursors, accom(cid:173)
`paniments, management, and outcome of 50 chil(cid:173)
`dren from a pediatric epilepsy clinic with idiosyn(cid:173)
`cratic skin reactions associated with AEDs.
`
`METHODS
`
`Received January 1990; revision accepted April 1990.
`Address correspondence and reprint requests to Dr. P. R.
`Camfield at IWK Children's Hospital, P.O. Box 3070, Halifax,
`Nova Scotia B3J 309, Canada.
`
`Patients who had experienced an idiosyncratic
`skin rash from an AED within the past 10 years
`were identified by review of our epilepsy clinic
`
`554
`
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`RCT EX. 2097 - 2/7
`
`

`
`ALLERGIC RASH DUE TO ANT/EPILEPTIC DRUGS
`
`555
`
`records and inpatient hospital charts coded as hav(cid:173)
`ing adverse reactions to AEDs. We also sent a brief
`questionnaire to 824 clinic patients with epilepsy
`who had been seen over the past 3 years. A single
`mailing had a 44% response rate.
`When a patient was identified as having had an
`allergic rash, the records were reviewed, and if suf(cid:173)
`ficient data could not be abstracted from the chart,
`the family was contacted directly. This telephone
`contact was used only to verify information in the
`medical record and to assess the rate of other aller(cid:173)
`gies. Issues such as concomitant medications or vi(cid:173)
`ral illness were not established from the telephone
`contact. If the child was receiving 'more than one
`AED at the time of the reaction, the reaction was
`ascribed to the most recently added drug. The study
`was approved by our hospital ethics committee.
`The study was not designed to assess the overall
`risk of rash with the prescription of each AED, and
`therefore this information was not gathered.
`
`RESULTS
`
`The overall results are summarized in Table 1.
`
`Clinical details
`We identified 50 children (22 girls, 28 boys) who
`had experienced a total of 68 rashes. Thirty-six pa(cid:173)
`tients had a reaction to one AED, 10 to two AEDs,
`and four to three AEDs. The mean age at onset of
`the initial reaction for all patients was 90.1 months
`(range 16-197 months, ±43.7 SD). The AEDs im(cid:173)
`plicated were CBZ, 30; PB, 20; PHT, 16; ethosux(cid:173)
`imide (ESM), one; and AED combination, one
`(concurrent PB, PHT, and CBZ).
`Indications for AED treatment were complex or
`simple partial seizures in 18, generalized tonic(cid:173)
`clonic or secondarily generalized seizures in 19,
`generalized absence in two, Lennox-Gastaut syn(cid:173)
`drome in two, benign sylvian seizures in two, my(cid:173)
`oclonus in one, febrile seizures in one, acute head
`trauma in four, and prophylaxis after neurosurgery
`in one.
`
`Type and severity of reaction
`Of the 68 reactions, 63 were cutaneous eruptions
`(maculopapular, erythematous, morbilliform, ur(cid:173)
`ticarial, or vesicular eruptions, or erythroderma),
`three were exfoliative dermatitis, and two were
`Stevens-Johnson syndrome.
`Forty-four reactions were mild (rash only), 20
`moderate (systemic symptoms or other organ in(cid:173)
`volvement), and four life-threatening. Of the 20
`moderate cases, the clinical features in addition to
`rash were as follows: fever only, 11; fever and joint
`
`TABLE 1. Summary of clinical features of patients with
`antiepileptic drug (AED) reaction
`
`Number of patients
`Reaction to 1 AED
`Reaction to 2 AEDs
`Reaction to 3 AEDs
`Severity of reactions
`Mild
`Moderate
`Severe
`Average time of treatment before rash
`Prior antibiotic reaction
`Controls
`Nonmedication allergies
`Controls
`Abrupt cessation of AED with reaction
`Taper of AED with reaction
`AED continued through reaction
`New AED added
`After resolution of reaction
`Recurrent rash
`Before resolution of reaction
`Recurrent rash
`Status epilepticus with reaction
`Rechallenge with the AED
`Recurrence
`
`50 (68 reactions)
`36
`10
`4
`
`44
`20
`4
`14.9 ± 18.7 days
`8%
`11.5%
`32%
`27.5%
`59
`5
`4
`40
`16
`8
`24
`10
`0
`7
`6
`
`symptoms, three; fever and petechiae, one; fever,
`petechiae, and elevated serum glutamic-oxaloacetic
`transaminase, one; fever and clinical hepatitis, one;
`fever, hepatitis, and neutropenia and thrombocy(cid:173)
`topenia, one; fever and anemia, one; and fever, ane(cid:173)
`mia, and thrombocytopenia, one.
`The clinical features of the four cases who suf(cid:173)
`fered life-threatening reactions are outlined in Ta(cid:173)
`ble 2.
`
`Duration of treatment prior to onset of the reaction
`The mean duration of treatment prior to the onset
`of the rash in all 68 reactions was 14.9 days (range
`1-140 days, SD ± 18.7). It appeared that those with
`multiple reactions tended to have subsequent reac(cid:173)
`tions after similar intervals.
`Time to the onset of reaction varied with the
`drug: PB, median 9 days (range 1-19 days); PHT,
`median 12 days (range 1-47), and CBZ, median 10
`days (range 1-140) (Fig. 1). Only one CBZ reaction
`occurred after 28 days. This 13-year-old boy devel(cid:173)
`oped exfoliative dermatitis, fever, lethargy, mucous
`membrane lesions, and mild arthralgia 140 days af(cid:173)
`ter start of CBZ. After 6 days of worsening symp(cid:173)
`toms CBZ was stopped, the fever resolved within·
`24 h, and he recovered. No alternative explanation
`for this reaction was identified.
`
`Patients who reacted to multiple AEDs
`When children reacted to more than one medica(cid:173)
`tion, the medications were always PB, CBZ, or
`PHT, with no consistent pattern in the sequence of
`treatment with these three AEDs. Children who re-
`
`Epilepsia, Vol. 32, No.4, 1991
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2097 - 3/7
`
`

`
`556
`
`J. PELEKANOS ET AL.
`
`TABLE 2. Clinical features of the life-threatening reactions
`
`reaction (mo)
`Sex
`AED
`Indication for
`AED
`
`Reaction type
`
`Duration of AED
`prior to onset
`of rash (days)
`Duration of AED
`after onset of
`rash (days)
`Previous exposure to
`offending AED
`Other medications at
`time of rash
`
`Intercurrent
`infection
`Recovery (days)
`Sequelae
`Treatment of
`reaction
`
`50
`M
`CBZ + PB + PHT
`Lennox-Gastaut
`
`Toxic
`erythroderma,
`lymphadenopathy,
`splenomegaly,
`D.I.C ..
`
`<40
`
`9
`
`No
`Adrenocorticotropic
`hormone,
`ethosuximide
`No
`
`14
`None
`Steroids
`
`109
`F
`PB
`. 1 SeizQre,
`abnormal EEG
`
`Stevens-Johnson
`syndrome,
`pulmonary,
`cardiac, renal,
`arrest
`
`19
`
`2
`
`No
`
`None
`
`Possible
`mycoplasma
`90
`None
`Steroids,
`ventilation
`dialysis
`
`96
`M
`PB
`Prophylactic
`after
`neurosurgery
`Hematologic,
`lymphadenopathy,
`mucosal lesions
`
`16
`
`2
`
`No
`
`86
`F
`PB
`Complex
`partial
`seizures
`Bullae,
`hematologic,
`hepatic,
`coma, renal
`
`10
`
`10
`
`No
`
`Dexamethasone
`
`Penicillin
`
`No
`120
`Blindness
`Steroids,
`antihistamine
`
`Unknown
`25
`None
`Steroids
`
`AED, antiepileptic drug; CBZ, carbamazipine; PB, phenobarbital; PHT, phenytoin; D.I.C., disseminated intravascular coagulation.
`
`acted to multiple AEDs appeared to be slightly
`older than those with one reaction. The mean age at
`the time of reaction was 84.4 months (range 16-172
`months, SD ± 39.6) for single reactors. For patients
`with two reactions, the mean age for the first reac(cid:173)
`tion was 93.4 months (range 18-167 months, SD ±
`47.5). For those with three reactions, mean age at
`the first reaction was 133.3 months (range 60-197
`months, SD ± 55.3).
`Of the 14 patients with > 1 reaction, the subse(cid:173)
`quent reactions were of the same severity in nine
`cases, more severe in two cases, and less severe in
`three cases.
`
`Possible risk factors for severe or multiple reactions
`In only four of 68 reactions had the patient been
`previously exposed to that AED, and in two of
`these, the rash occurred within 24 h of reintroduc(cid:173)
`ing the AED.
`A history of previous medication or nonmedica(cid:173)
`tion allergic reactions did not appear to predict an
`AED skin reaction. For example, prior antibiotic
`allergies occurred in 8% of patients with reactions
`compared with 11.5% of questionnaire respondents
`without reactions. Nonmedication allergies (skin,
`
`Epilepsia, Vol. 32, No.4, 1991
`
`respiratory, or gastrointestinal) had occurred in
`32% of patients with reactions and 27.5% of ques(cid:173)
`tionnaire respondents without AED reactions.
`Only six of 68 reactions were suspected of being
`associated with an intercurrent infection, although a
`total of eight patients were receiving antibiotics at
`the time of the reaction (three of six with intercur(cid:173)
`rent infection). Four of these eight had moderate or
`severe reactions.
`For the eight patients receiving concomitant an(cid:173)
`tibiotics, a clinical decision was made that the AED
`was the most likely causative agent based on the
`duration of treatment and previous exposure to the
`antibiotic. For 8 of 68 reactions, the child was re(cid:173)
`ceiving two AEDs at the ti~pe of reaction, although
`the reaction was thought to be due to the most re(cid:173)
`cently added drug.
`
`Outcome of reactions
`There were no fatalities. Severe permanent mor(cid:173)
`bidity occurred in one child with a Stevens-Johnson
`syndrome, who developed blindness from corneal
`scarring (Table 2). With the exception of this child,
`the median time to complete recovery was 7 days
`(range 1-90).
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2097 - 4/7
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`

`
`ALLERGIC RASH.DUE TO ANTIEPILEPTIC DRUGS
`
`557
`
`Phenytoin
`
`management of seizures may have been rendered
`mote problematic by a lack of a suitable alternative
`AED following 17 of 68 reactions.
`
`0
`10
`
`Phenobarbital
`
`Carbamazepine *
`
`.....
`0
`
`...
`(J)
`
`J,l e
`=' :z:e
`
`0
`
`3
`
`6
`
`9
`
`12 15 18 21 24 27 30 33 36 39
`
`Treatment Duration Prior to Rash
`FIG. 1. Duration of treatment (in days) prior to onset of re(cid:173)
`action. *A single patient receiving carbamazepine had the
`reaction at 140 days.
`
`Seven patients were rechallenged with the AED
`and six of seven recurred. Five of six rechallenged
`within 12 days of resolution of the initial reaction
`had a recurrent reaction. One other patient was re(cid:173)
`challenged shortly after an initial moderately severe
`reaction to CBZ and recurred. Five years later he
`was rechallenged with CBZ using the "desensiti(cid:173)
`zation'' protocol of Purvis and did not react again
`(Purvis et al. , 1988).
`
`Seizure control during and after reaction
`The AED was ceased abruptly in 59 patients (22
`of whom did not receive a new AED), tapered in
`five, and continued unchanged in four. There were
`no episodes of SE during the reaction or its treat(cid:173)
`ment. The seizure frequency remained unchanged
`in 28 cases, decreased by 50% in one case, and in 39
`there were no ·seizures during the reaction; No pa(cid:173)
`tients had deterioration in seizure control during the
`reaction.
`In 40 cases, a new AED was added, 16 after the
`reaction had totally resolved and 24 before resolu(cid:173)
`tion. Rash recurred with the new AED in 50 and
`42% respectively (p = NS). For 29 of 40, the AED
`was added prophylactically and in 11 because of
`seizures. The mean interval between ceasing the
`first AED and adding the second AED was 3.8
`days. Although it is difficult to ascertain, the future
`
`DISCUSSION
`
`The most important finding of this study is that no
`patient's seizure control deteriorated, and there
`were no episodes of SE, despite the fact that the
`majority of cases had the AED ceased abruptly
`when a skin reaction was detected. It has long been
`held that the sudden cessation of AEDs can precip(cid:173)
`itate seizures, in particular SE. Two recent papers
`have reviewed SE in childhood (Dunn, 1988; Yager
`et al., 1988). In one study, inadequate blood levels
`of AEDs were thought to play a role in precipitating
`SE in 32 of 60 episodes in children with prior sei(cid:173)
`zures (Dunn, 1988). Another study, however, failed
`to mention previous AEDs as playing a role in SE in
`52 children (Yager et al., 1988). Theodore et al.
`(1987) found no relationship between the rate of PB
`discontinuation and seizure frequency. In these
`studies it should be noted that the patients had been
`receiving AEDs for prolonged periods of time prior
`to drug discontinuation, while our patients had re(cid:173)
`ceived AEDs for an average of only 15 days before
`abruptly stopping. While four of our patients con(cid:173)
`tinued receiving the AED and the reaction resolved,
`two of four patients with severe reactions appeared
`to continue their AEDs for relatively long times af(cid:173)
`ter the onset of their reaction (7 and 9 days, Ta(cid:173)
`ble 2).
`Our case finding method likely tended to overem(cid:173)
`phasize severe reactions; however, 65% of the re(cid:173)
`actions were mild, which is comparable to previous
`reports (Sillanpaa, 1981). The time from starting
`AED to the onset of the reactions for CBZ and PB
`were almost identical. All except one CBZ reaction
`occurred within 3 weeks of starting the AED. One
`reaction linked to CBZ after 140 days of treatment
`draws attention to the fact that late reactions are
`rare but possible. The time to onset of reaction for
`PHT was slightly different than that for PB and
`CBZ, with a fairly even distribution of occurrence
`up to about 6 weeks after start of AED (Fig. 1). We
`are unable to explain this difference.
`Delattre et al. (1988) recently introduced the con(cid:173)
`cept that several factors could act in synergy to
`precipitate the development of severe skin reac(cid:173)
`tions. They reported eight cases of severe cutane(cid:173)
`ous reactions following the combination of PHT
`therapy with radiotherapy. None of our patients
`was receiving radiotherapy at the time of reaction.
`We were not able to identify predictive factors for
`patients with single, multiple, or very severe reac-
`
`Epilepsia, Vol. 32, No.4, 1991
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2097 - 5/7
`
`

`
`558
`
`J. PELEKANOS ET AL.
`
`tions. Patients who reacted to multiple AEDs
`tended to be older at the time of their first reaction
`(mean age 133 months for the triple reactors) com(cid:173)
`pared to those who reacted to one AED (mean age
`85 months). One of the four children with life(cid:173)
`threatening reactions was receiving concurrent an(cid:173)
`tibiotics. However, for all of our patients, there did
`not appear to be any relationship between their re- ·
`actions and concurrent medications, intercurrent
`infections, or previous allergic manifestations.
`Thus, it seems unlikely that common clinically rec(cid:173)
`ognizable factors will be available for predicting
`skin reactions to AEDs in children. Special labora(cid:173)
`tory tests such as those studied by Spielberg et al.
`(1981) may eventually be of great value in avoiding
`severe reactions.
`When a child with epilepsy develops a reaction to
`an AED, usually a new AED is indicated. The best
`time to start the new AED is unclear. The rash re(cid:173)
`curred in eight of 16 cases when the second AED
`was introduced after the reaction had totally re(cid:173)
`solved. On the other hand, in 10 of 24 cases, the
`rash recurred when a new AED was started prior to
`resolution of the initial reaction. We noted that for
`those with multiple reactions, the subsequent reac(cid:173)
`tion tended to be no more severe than the first.
`Thus, it appears that the decision of when to start a
`new AED after a reaction can be based on the like(cid:173)
`lihood of further seizures without increasing the
`risk of a severe reaction. The high frequency of
`recurrent rashes (45%) in our series may partially be
`the result of our case selection methods.
`Overall, the effect of the reactions on the success
`of treatment of the child's epilepsy was usually mi(cid:173)
`nor; however, we judged that following 25% of the
`reactions, treatment options were significantly lim(cid:173)
`ited. We note that for two of the patients with life(cid:173)
`threatening reactions (Table 2), the indications for
`the AED were marginal (single seizure in case 2 and
`prophylaxis in case 3), which emphasizes the value
`of a cautious approach to AED use.
`Although allergic rashes to AEDs are usually
`mild, the rare occurrence of severe reactions indi(cid:173)
`cates that the AED should be ceased abruptly with
`minimal risk of precipitating SE. A new AED can
`be added, if necessary, prior to the resolution of the
`rash without increasing the risk of further reactions.
`
`Acknowledgment: We are grateful to lone Anderson,
`Helene Whitford, and Catherine Pelekanos for secretarial
`assistance.
`
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`
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`drugs. Dev Med Child Neural 1988;30:117-21.
`
`Epilepsia, Vol. 32, No. 4, 1991
`
`Booker HE. Idiosyncratic reactions to the antiepileptic drugs
`Epilepsia 1975;16:171-81.
`·
`Camfield CS, Chaplin S, Doyle AB, Shapiro S, Cummings c
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`Camfield PR, Camfield CS, Smith EC, Tibbles JAR. Newly
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`Cowan LD, Bodensteiner JB, Leviton A, Doherty L. Prevalence
`of the epilepsies in children and adolescents. Epilepsia
`1989;30:94-106.
`Delattre J-Y, Safai B, Posner JB. Erythema multiforme and
`Stevens-Johnson syndrome in patients receiving cranial irra(cid:173)
`diation and phenytoin. Neurology 1988;38:194-8.
`Dreifuss FE, Santilli N, Langer DH, Sweeney KP, Moline KA
`Menander KB. Valproic acid hepatic fatalities: a retrospec:
`tive review. Neurology 1987;37:379-85.
`Dunn DW. Status epilepticus in children: etiology, clinical fea(cid:173)
`tures and outcome. J Child Neuro/1988;3:167-73.
`Egger J, Brett EM. Effects of sodium valproate in 100 children
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`Plaa, GL. Acute toxicity of antiepileptic drugs. Epilepsia
`1975;16: 183-91.
`Purvis SJ, Hashimoto SA, Tse KS. Successful desensitization of
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`Reynolds EH. Chronic antiepileptic toxicity: a review. Epilepsia
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`.
`Schmidt D. Adverse effects. In: Frey H-H, Janz D, eds. Hand(cid:173)
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`Sillanpaa M. Carbamazepine: pharmacology and clinical uses.
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`Spielberg S, Gordon G, Blake D, et al. Predisposition to phen(cid:173)
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`Theodore WH, Porter RJ, Raubertas RF. Seizures during bar(cid:173)
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`1987;22:644-7.
`Wolf SM, Forsyth A. Behaviour disturbance, phenobarbital and
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`
`RESUME
`La conduite a tenir devant un rash allergique cause par un
`medicament anti-epileptique (MAE) n'est pas claire. Les auteurs
`ont identifie 50 patients ayant presente 68 reactions (36 a 1 MAE,
`10 a 2 MAE, 4 a 3 MAE). Les medicaments impliques etaient: Ia
`carbamazepine 30 fois, le phenobarbital20 fois, Ia phenytoi:ne 16
`fois, !'ethosuximide I fois, et une association d'anti-epileptiques
`1 fois. 63 reactions etaient a type d'eruption cutanee, 3 de der(cid:173)
`matite exfoliante, et 2 de syndrome de Stevens-Johnson. 46 re(cid:173)
`actions ont ete mineures (rash isole), 18 de gravite moyenne
`(symptomes systemiques ou implication d'autres organes), et 4
`ont ete graves, avec menace vitale (toutes sous phenobarbital).
`Chez Ia plupart des patients ayant presente plus d'une reaction,
`les 2eme 3eme et reactions n'ont pas ete plus severes que Ia
`premiere. Des antecedents d'allergies aux antibiotiques ou
`d'allergies non medicamenteuses n'ont pas ete plus frequents
`chez les patients que dans un groupe-controle n' ayant pas
`presente de reactions au MAE. Le MAE a ete interrompu bru(cid:173)
`talement dans 59 cas (dont 22 n'ont pas rec;u un nouveau traite(cid:173)
`ment anti-epileptique), diminue progressivement dans 5 cas eta
`ete maintenu inchange dans 4 cas. En depit de cela, il n'y a pas
`eu d'etat de mal epileptique pendant la reaction ou pendant,!:
`traitement de cette reaction, et le controle des crises n'a ete
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2097 - 6/7
`
`

`
`ALLERGIC RASH DUE TO ANT/EPILEPTIC DRUGS
`
`559
`
`influence de fa<;on negative chez aucun patient. Dans 40 cas, un
`nouvel anti-epileptique a ete ajoute: apres resolution de la re(cid:173)
`action dans 16 cas, avant resolution totale dans 24 cas. Un rash
`a recidive avec le nouvel anti-epileptique dans 50% et 42% des
`cas respectivement (ns). Les auteurs concluent que les rashes au
`MAE sont habituellement sans gravite, mais que la survenue rare
`de reactions severes indique que le MAE devrait etre arrete.
`Ceci peut etre fait de fa<;on brutale avec un risque minime d'etat
`de mal epileptique. On peut ajouter un nouvel anti-epileptique si
`necessaire, avant la resolution du rash cutane, sans augmenter le
`risque de reaction ulterieure.
`
`(P. Genton, Marseille)
`
`RESUMEN
`
`El manejo 6ptimo de las erupciones alergicas a debidas a an(cid:173)
`tiepilepticos (AEDs) no esta claro. Se han identificado 50 pa(cid:173)
`cientes con 68 reacciones (36 reacciones a 1 AED, 10 a 2 AEDs,
`y 4 a 3 AED.s). Las AEds implicadas fueron la carbamacepina 30,
`el fenobarb1tal 20, la fenitofna 16, la etosuximida 1 y una com(cid:173)
`binaci6n de AEDs 1. Se observaron 63 erupciones cutaneas, 3
`dermatitis esfoliativas y 2 sfndromes de Stevens-Johnson. 46 re(cid:173)
`acciones fueron leves (solamente erupci6n), 18 moderadas (sfn(cid:173)
`tomas sistemicos o afectaci6n de otros 6rganos), y 4 con riesgo
`de vida (todos con fenobarbital). En la mayorfa de los pacientes
`con mas de una reacci6n, la 2° y 3a reacciones no fueron mas
`severas que la 1 a. La existencia de alergias pre vias a antibi6ticos
`o de alergias no-medicamentosas no fueron mas frecuentes que
`en el grupo control. Las AEDs se interrumpieron repentina(cid:173)
`mente en 59 casos (22 de los cuales no recibieron una AED
`nuev~), se redujeron gradualmente en 5 y se continuaron, sin
`cambw alguno, en 4. A pesar de eso, no se observ6 un "status
`epilepticus" durante la reacci6n o su tratamiento ·y el control de
`los ataques no se deterior6 en ningun enfermo. En 40 casos, se
`aii.adi6 una nueva AED, 16 despues de la reacci6n cesara y 24
`antes de la total desaparici6n. La erupci6n reapareci6 con la
`nueva medicaci6n en el 50% yen el 42% respectivamente (ns).
`Concluimos que a pesar de que las erupciones alergicas se(cid:173)
`cundarias a las AEDS son generalmente leves, la rara aparici6n
`de reacciones severas indica que la AED debe ser interrumpida.
`
`Esta interrupci6n puede realizarse repentinamente con riesgos
`n:fnif!l.OS de "sestatus epilepticus". Si es necesario, se puede
`a!lad1r una. nueva AED antes de la desaparici6n de la erupci6n
`sm que se mcremente el riesgo de nuevas reacciones.
`(A. Portera-Sanchez, Madrid)
`
`ZUSAMMENFASSUNG
`
`Es ?esteht keine Klarheit iiber die optimale Behandlung von
`allerg1schen Ausschlagen unter Antiepileptika (AED). Wir un(cid:173)
`tersuchten 50 Patienten mit 68 Reaktionen (36 auf ein AED, 10
`auf 2 AEDs und 4 auf 3 AEDs). Die involvierten AEDs waren
`Carbamazepin in 30, Phenobarbital in 20, Phenytoin in 16, Etho(cid:173)
`suximid in 1 und eine AED-Kombination in einem Fall. 63 Reak(cid:173)
`tionen waren Hautausschlage, dreimal eine exfoliative Dermati(cid:173)
`tis und zweimal ein Stevens-Johnson-Syndrom. 46 Reaktionen
`waren mild (nur Rotung), 18 ma~ig (systemische Symptome oder
`andere Organmanifestationen) und vier Lebensbedrohlich (alle
`bei Phenobarbital). Bei den meisten Patienten mit mehr als einer
`Reaktion waren die zweiten und dritten Reaktionen nicht starker
`als die erste. Vorausgehende Antibiotika-Allergien oder nicht(cid:173)
`medikamentose Allergien waren nicht haufiger als in einer Kon(cid:173)
`trollgruppe ohne Reaktionen. Die AEDs wurden in 59 Fallen
`sofort abgesetzt (22 der Patienten erhielten kein neues AED), in
`5 Fallen wurde ausgeschlichen und in 4 Fallen unverandert weit(cid:173)
`ergegeben. Es kam zu keinem Status epilepticus wahrend der
`Reaktionen oder ihrer Behandlung, bei keinem Patienten kam es
`zu einem Verlust der Anfallskontrolle. in 40 Fallen wurde ein
`neues AED hinzugegeben; dabei war bei 16 Patienten die Reak(cid:173)
`tion bereits vollstandig abgeklungen, bzw. in 24 Fallen noch
`nicht. Mit dem neu hinzugegebenen AED trat ein erneuter Aus(cid:173)
`schlag in 50% resp. 42% auf (ns). Obwohl allergische Reaktionen
`auf AEDs normalerweise mild verlaufen, folgern wir, da~ das
`seltene Auftreten von schweren Reaktionen das Absetzen des
`AED nahelegt. Dies kann mit nur geringem Risiko eines Status
`epilepticus auf einmal geschehen. Ein neues AED kann sofern
`notwendig, hinzugefugt werden noch bevor der Ausschlag ver(cid:173)
`schwunden ist, ohne das Risiko fiir weitere Reaktionen zu er(cid:173)
`hohen.
`
`(C. Benninger, Heidelberg)
`
`Epilepsia, Vol. 32, No. 4, 1991
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2097 - 7/7