Drugs - Real World Outcomes (2016) 3:209-221
`DOI 10.1007/s40801-016-0077-2
`
`riMPINIMPMW LE
`
`I
`
`CrossMark
`
`Systematic Adverse Drug Reaction Monitoring of Patients Under
`Newer Antiepileptic Drugs Using Routine Clinical Data
`of Inpatients
`
`Annika Hilgers1'2'3 • Marion Schaefer;
`
`Published online: 25 May 2016
`© The Author(s) 2016. This article is published with open access at Springerlink.com
`
`Abstract
`Background Based on data of clinical trials, new agents
`are receiving approval to the pharmaceutical market, for
`which information concerning safety issues under real-life
`conditions is not yet available.
`Objectives The aim was to evaluate the tolerability of
`newer antiepileptic drugs (AEDs), such as topiramate,
`levetiracetam, zonisamide, pregabalin, extended-release
`oxcarbazepine, lacosamide and eslicarbazepine, under real-
`life conditions by means of an assessment of routine clin-
`ical data of inpatients.
`Method Over 2.75 years data of all inpatients receiving
`one of the newer AEDs were documented. Occurring
`adverse drug reactions (ADRs) were classified according to
`the WHO-UMC Causality Assessment concerning their
`likely relationship to the prescribed AEDs. For each AED,
`
`Electronic supplementary material The online version of this
`article (doi:10.1007/s40801-016-0077-2) contains supplementary
`material, which is available to authorized users.
`
`Annika Hilgers
`annika.hilgers@evkb.de
`
`the total number of patients without and with ADRs,
`assessed as at least possibly related to the particular drug,
`was calculated and corresponding incidences compared
`with reference data provided in the Summary of Product
`Characteristics (SmPC). For statistical evaluation Spear-
`man correlation (rs), estimated relative risk and logistic
`regression analysis were used.
`Results In total, the data of 562 patients were assessed, of
`which 90 % received up to six different AEDs. The pro-
`portion of off-label use with regard to dosage varied
`between 6.4 and 64.7 %. Levetiracetam and oxcarbazepine
`as an extended-release formulation were most commonly
`used, and levetiracetam showed the best tolerance. By
`using logistic regression, the occurrence of ADRs was
`significantly associated with the number of AEDs
`(p < 0.001) as well as the defined daily doses (p = 0.003).
`In total, ADRs of AEDs were documented for 318 patients
`(56.6 %). The most common referred to electrolyte
`imbalance, e.g., low sodium (n = 79, 14.1 %) and potas-
`sium (n = 25, 4.4 %) levels, the central nervous system,
`including dizziness (n = 61, 10.9 %), disturbed vision
`(n = 47, 8.4 %), fatigue (n = 40, 7.1 %), nystagmus
`(n = 36, 6.4 %) and ataxia (n = 29, 5.2 %), or cognitive
`deficits, especially disturbance of speech (n = 37, 6.6 %),
`memory impairment (n = 36, 6.4 %) and mental slowing
`(n = 32, 5.7 %). By comparing the assessed ADR inci-
`dences with specification data, for some ADRs, a probable
`underestimation by the SmPC of respective risk could be
`assumed.
`Conclusion During inpatient treatment, valuable data are
`generated, which are currently rarely utilized for pharma-
`coepidemiologic or pharmacovigilance purposes. A sys-
`tematic evaluation of these data can increase the
`probability of detecting ADRs and can promote real-life—
`related drug surveillance.
`ARGENTUM Exhibit 1072
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`Ev. Krankenhaus Bielefeld gGmbH, Bethesdaweg 10, 33617
`Bielefeld, Germany
`
`Epilepsiezentrum Bethel, Krankenhaus Mara gGmbH, 33617
`Bielefeld, Germany
`
`Charite Universitatsmedizin Berlin, Institut far klinische
`Pharmakologie, 10115 Berlin, Germany
`
`2
`
`3
`
`Adis
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`210
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`Key Points
`
`Summary of Product Characteristics data may
`underestimate the risk of adverse drug reactions.
`
`Continuous tolerability and safety surveillance is
`necessary to align approval data with real-life
`experience.
`
`Frequent risk evaluation of drugs by means of
`routine clinical data could provide a new quality of
`drug surveillance.
`
`1 Introduction
`
`Based on submitted quality, efficacy and safety data, doz-
`ens of new agents are receiving approval to the pharma-
`ceutical market every year. Despite their promising
`advantage to medical care, at the time of approval, there
`can be no certainty that these drugs are completely safe [1].
`Information about specific population groups can fre-
`quently be assumed to be missing as well as data about rare
`adverse drug reactions (ADRs) or drug interactions. It is
`therefore necessary to establish methods of large-scale
`post-marketing surveillance to gather real-life data espe-
`cially with regard to safety issues. In most countries a
`spontaneous reporting system (SRS) for collecting data of
`suspected ADRs is used. Reported data are assessed by the
`responsible authority in a global database, which thus
`contains a vast data pool of ADRs relating to a wide range
`of drugs, in support of its main objective of generating
`signals of unknown, rare or serious ADRs [2-4]. This is a
`very cost-effective method. However, this kind of drug
`safety monitoring also has many limitations, the most
`frequently mentioned being the subject of underreporting.
`The mentioned reasons for this are manifold, including lack
`of time, large effort, fear of being prosecuted, unawareness
`of the requirement to report or the estimation that a par-
`ticular ADR is not worth noting [3-5]. Also, SRSs are often
`believed to be exclusively designed for detecting rare and
`serious ADRs, but for general drug safety, the monitoring
`of all undesirable reactions is necessary [4]. For the most
`accurate relative risk (RR) assessment, exact data of
`application or drug utilization is required, which, however,
`is only available by approximation. Thus, an SRS has not
`got the impact to determine the prevalence rate of a specific
`ADR reliably and bears a risk of delay in signal detection.
`In the case of diseases requiring lifelong treatment, more
`detailed knowledge about the efficacy and tolerability of a
`
`/\ Adis
`
`A. Hilgers, M. Schaefer
`
`drug, attention to ADRs as well as awareness of patients'
`needs are necessary to achieve the best therapeutic out-
`come. For epilepsy, as one of these diseases, the occurrence
`of ADRs has been shown to have an important influence on
`patients' quality of life [6-9]. Approximately 20 % of all
`patients with epilepsy, in the case of refractory epilepsy,
`even about 50 %, are on polytherapy, bearing an increased
`risk for ADRs and drug interactions [10-13]. Many of
`these patients have tried most of the available drugs and are
`therefore a target group for new treatment options aimed at
`reducing seizure frequency while maintaining or even
`optimizing tolerability. Especially in patients suffering
`from seizure recurrence, optimizing therapy can be a bal-
`ancing act between increasing the drug dosage to maximize
`the therapeutic effect and running the risk of ADRs [14,
`15]. Over the past 25 years, more than 15 new antiepileptic
`drugs (AEDs) with modified acting mechanisms and/or
`side effect profiles have become available for epilepsy
`treatment, resulting in a major challenge for health pro-
`fessionals and post-marketing surveillance in respect of
`specified knowledge about tolerability and drug interaction.
`Such a level of competence can hardly be generated by
`relying only upon a tool like an SRS for monitoring drug
`safety. In fact, long-term supervision of medicated patients,
`increased sensitivity towards recognizing accumulation of
`specific ADRs and deriving remedial measures from these
`observations are recommended as vital for a comprehen-
`sive risk—benefit evaluation [14]. Accordingly, the sys-
`tematic assessment and evaluation of routine inpatient data
`was assumed to be one way of obtaining this relevant
`knowledge and was therefore investigated in this survey.
`
`2 Methods
`
`2.1 Data Collection
`
`Between May 2008 and December 2010, an in-house
`pharmacist attended the Consultants' ward round once a
`week on four different wards of the Bethel Epilepsy Centre,
`Bielefeld, Germany, a tertiary reference center for epi-
`lepsy. All information taken as part of clinical routine
`during the ward round was documented in the patients'
`chart as usual and, for later digitalization, concurrently
`transcribed to an adjusted record form by the pharmacist.
`For every patient a new record form was used for each
`week. All inpatients receiving one of the newer AEDs, i.e.,
`topiramate (TPM), levetiracetam (LEV), zonisamide
`(ZNS), pregabalin (PGB), extended-release oxcarbazepine
`[OXC(ER)], lacosamide (LCM) and eslicarbazepine (ESL),
`were included. Documented data comprised the specific
`drug, all AEDs in use, corresponding daily dosages and
`serum levels, if available, age, gender, concomitant
`
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`Systematic ADR Monitoring in Epilepsy Therapy Using Routine Clinical Data (cid:9)
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`211
`
`medication, patient and actual case number. In addition, all
`patient-reported and medically diagnosed ADRs were
`documented in an unstructured format, and for each one,
`the current causality concerning the administered AEDs
`was assessed by interprofessional exchange (i.e., physician,
`pharmacist, nursing staff). To this end, the temporal pattern
`of association between its occurrence and change of med-
`ication and all available information concerning concomi-
`tant disorders, diseases or medication were taken into
`account. For the classification of causality, the WHO-UMC
`Causality Categories were used (see the electronic sup-
`plementary material, Online Resource 1) [16]. Any severe
`or unknown suspected ADRs were immediately reported
`via the SRS to the responsible regulatory authority.
`
`2.2 Data Entry
`
`All relevant data were recorded by the pharmacist in an
`internal database, using IBM SPSS for Windows 20.0.
`Patient data were documented by assigning an individual
`patient number, case number, gender, age and date of
`observation. In order to enable the evaluation, the initially
`documented ADRs were coded numerically according to
`the system organ classes (SOCs) of the MedDRA (Medical
`Dictionary for Regulatory Activities) terminology, and the
`specific symptom. Also, corresponding causality categories
`were entered numerically. For every documented ADR and
`week, a single data set containing patient details, medica-
`tion, daily dosage and causality category for every given
`AED was generated. Where the same ADR was docu-
`mented more than once for one patient, the first docu-
`mented observation and accordingly the one with the
`lowest AED dosages was included for analysis only. For
`patients without ADRs, the highest AED dosage was
`considered. To rule out possible input errors, the data were
`entered twice at different times. Asserted discrepancies
`were clarified by re-checking the record forms.
`
`2.3 Data Evaluation
`
`Demographic and clinical characteristics of the patients
`were evaluated by using the first documented contact after
`hospitalization. For every newer AED, the total number of
`patients without and with ADRs, assessed with at least
`possible causality, and the corresponding dosages were
`calculated. Additionally, the same analysis was performed
`including only data sets of patients being treated off-label
`with regard to the maximum recommended daily dosage in
`the Summary of Product Characteristics (SmPC). In both
`analyses, every patient was included only once. Further-
`more, for every AED, the incidence of the respective ADR
`was determined with reference to the number of patients
`experiencing this ADR while taking the particular AED
`
`divided by the total number of patients where this AED
`was part of the therapy. All estimated incidence rates were
`compared with the respective data provided in the SmPC of
`each AED [17-23]. The correlation between the number of
`AEDs and the total drug load, calculated as sum of the
`defined daily doses (DDDs), was determined by Spearman
`correlation. For assessing the impact of number of AEDs
`and sum of DDDs on the occurrence of ADR, logistic
`regression was used.
`Concerning tolerability of each AED, the RR of ADR
`occurrence was calculated. For this purpose, the data of
`LEV were used as the reference, as being the most fre-
`quently applied AED in this survey, the first recommended
`for treatment of focal epilepsy out of this selection and also
`proven as well tolerated [24-28].
`
`3 Results
`
`In total, data of 562 cases were assessed, which equals
`around one quarter of the total number of in-house
`patients on the attended wards in the same time period.
`The corresponding patients' characteristics, length of stay
`and number of AEDs in concomitant usage [mean, median
`and standard deviation (SD)] are summarized in Table 1.
`For further specification of the antiepileptic therapy, the
`number and percentage distribution of patients receiving
`antiepileptic monotherapy versus polytherapy of up to six
`different AEDs were evaluated on the basis of each ini-
`tially documented observation per patient. Hence, 57
`patients (10.1 %) were on monotherapy, 192 patients
`(34.2 %) were treated with two different AEDs, 205
`patients (36.5 %) with three, 88 (15.7 %) with four, 19
`(3.4 %) with five and just one patient (0.2 %) with six.
`The number of AEDs correlated significantly with the
`total drug load as sum of DDDs (rs = 0.661, p < 0.001).
`The mean drug load (± SD) per patient increased with an
`increasing number of AEDs from 1.15 ± 0.60 in patients
`on monotherapy to 2.42 ± 0.98 in patients on two con-
`comitant AEDs, 3.33 ± 1.33 in those on three,
`4.50 ± 1.35 in those on four and 5.56 ± 1.28 in those on
`five or six.
`In monotherapy, as well as in a combination of two
`different AEDs, OXC(ER) and LEV were the ones most
`commonly used. This is the case for more than 40 % of the
`patients. For further information concerning the percentage
`of each AED in antiepileptic polytherapy see Fig. 1. LEV
`and OXC(ER) were further the most frequently used at all,
`with applications documented for 367 and 183 patients,
`respectively. For TPM and LCM, the data of 109 and 102
`patients were assessed, whereas ZNS (68 patients), PGB
`(61 patients) and ESL (17 patients) were a less frequently
`used component of the antiepileptic therapy.
`
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`212
`
`Table 1 Patients'
`characteristic? of 562 in-house
`patients treated at the tertiary
`reference center for epilepsy
`who were receiving at least one
`of the newer AEDs
`
`A. Hilgers, M. Schaefer
`
`N
`
`Total (%) Mean
`
`Median
`
`SD
`
`Min.
`
`Max.
`
`Gender
`Male
`Female
`Epilepsy syndrome
`Focal
`Generalized
`Focal + generalized
`Non-epileptic disorder"
`Age (years)
`Length of stay (days)
`No. of AEDs per patient
`Drug load of AEDs (DDD)`
`
`293
`269
`
`446
`83
`24
`9
`562
`562
`562
`562
`
`52.1
`47.9
`
`79.4
`14.8
`4.3
`1.6
`
`37.2
`60.6
`2.64
`3.14
`
`36.0
`51.0
`3.00
`3.02
`
`14.6
`38.7
`1.00
`1.53
`
`16.0
`6.0
`1.00
`0.25
`
`89.0
`238.0
`6.00
`10.82
`
`AED antiepileptic drug, DDD defined daily dose, SD standard deviation
`a Calculated by including every first documented observation of each patient
`" Differential diagnosis of a paroxysmal non-epileptic disorder obtained during hospitalization
`Sum of DDD according to the WHO DDD list
`
`n 1 AED
`in 2 AED
`N3 AED
`a 4 AED
`5 AED
`n6 AED
`
`0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70%
`
`Fig. 1 Percentage of patients treated with the respective AED,
`stratified by monotherapy and the different kinds of polytherapy (left
`to right). Total percentage of patients taking respective drug either as
`monotherapy or part of polytherapy: LEV 66.19 %, OXC(ER)
`32.38 %, TPM 19.4 %, LCM 18.15 %, ZNS 12.1 %, PGB 10.68 %,
`
`and ESL 3.02 %. AED antiepileptic drug, ESL eslicarbazepine, LCM
`lacosamide, LEV levetiracetam, OXC(ER) oxcarbazepine extended-
`release formulation, PGB pregabalin, TPM
`topiramate, ZNS
`zonisamide
`
`In total, ADRs of AEDs were documented for 318
`patients (56.6 %). Logistic regression indicated that the
`occurrence of ADRs was significantly associated with the
`number of AEDs in polytherapy regime (p < 0.001) as
`well as the total drug load as sum of DDDs (p = 0.003),
`whereas each predictor was analyzed separately.
`
`For each of the focused AEDs, the number of cases
`without and with an ADR of at least possible causality and
`corresponding dosages are listed in Table 2. For none of
`these AEDs the sum of percentage of cases without and
`with possibly related ADRs achieved 100 %. The differ-
`ences, ranging from 4 to 15 %, represent ADRs assessed as
`
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`Systematic ADR Monitoring in Epilepsy Therapy Using Routine Clinical Data (cid:9)
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`213
`
`Table 2 Patients without and
`with at least possibly related
`ADRs, stratified by the
`respective AEDs, including
`details of particular daily
`dosages
`
`N (cid:9)
`
`Total8 (%) RR6
`
`Cl (cid:9)
`
`Daily dosage (mg)
`
`Mean Median SD Min. Max.
`
`LEV
`Without ADR
`With possible ADR
`PGB
`Without ADR
`With possible ADR
`ZNS
`Without ADR
`With possible ADR
`OXC(ER)
`Without ADR
`With possible ADR
`LCM
`Without ADR
`With possible ADR
`TPM
`Without ADR
`With possible ADR
`ESL
`Without ADR
`With possible ADR
`
`203 55.3
`120 32.7
`
`11.00]
`
`2596
`2465
`
`3000
`2500
`
`1107
`1096
`
`250 6000
`250 7000
`
`26 42.6
`28 45.9
`
`26 38.2
`32 47.1
`
`73 39.9
`97 53.0
`
`37 36.3
`55 53.9
`
`31 28.4
`65 59.6
`
`2 11.8
`14 82.4
`
`1.31
`
`0.89-1.93
`
`1.40
`
`0.98-2.02
`
`487
`321
`
`256
`338
`
`600
`275
`
`250
`300
`
`1.57
`
`1.26-1.95 1715
`1646
`
`1800
`1800
`
`1.63
`
`1.24-2.13
`
`1.97
`
`1.56-2.47
`
`326
`269
`
`223
`213
`
`350
`250
`
`150
`200
`
`187
`194
`
`164
`148
`
`677
`530
`
`144
`139
`
`203
`119
`
`75
`75
`
`50
`100
`
`750
`750
`
`600
`600
`
`450 3850
`450 3000
`
`50
`50
`
`25
`50
`
`600
`600
`
`800
`500
`
`2.30
`
`1.75-3.02 1800
`1514
`
`1800
`1600
`
`849 1200 2400
`501
`800 2400
`
`AED antiepileptic drug, ADR adverse drug reaction, CI confidence interval, ESL eslicarbazepine, LCM
`lacosamide, LEV levetiracetam, OXC(ER) oxcarbazepine extended-release formulation, PGB pregabalin,
`RR relative risk for the occurrence of possibly related ADRs compared with the occurrence of these under
`levetiracetam, SD standard deviation, TPM topiramate, ZNS zonisamide
`8 For calculation, the total number of documented cases per AED was used; the missing percentage up to
`100 % fall upon ADRs assessed as unlikely, conditional or not causally linked to the particular AED
`b For calculation of RR, patients taking both of the specifically compared AEDs were excluded
`
`unlikely, conditional or not causally linked to the particular
`AED. In the case of TPM, this applied to 13 patients, for
`LEV to 44, PGB to seven, ZNS to ten, OXC(ER) to 13,
`LCM to ten and ESL to just one patient.
`By referring exclusively to the overall tolerability, LEV
`emerged as best tolerated. The calculated RRs of ADR
`occurrence per AED compared with LEV, which was set as
`reference, ranged between 1.31 and 2.30, whereas again
`just the total number of possibly related ADRs was taken
`into account, not the clinical relevance of every single
`ADR nor other tolerability influencing factors.
`By means of the maximum applied dosages (Table 2), it
`becomes apparent that in some cases the maximum applied
`AED dosage exceeded the maximum permissible dosage
`according to the particular SmPC [17-23]. For LCM, that
`dosage was specified as 400 mg per day, for TPM and
`ZNS, as 500 mg/day each, and for PGB, as 600 mg/day;
`for ESL, OXC(ER) and LEV, the maximum approved
`dosage was determined as 1200, 2400 and 3000 mg/day,
`respectively. The proportion of off-label usage concerning
`
`the maximum recommended daily dosage in the SmPC
`varied between 6.4 and 64.7 % with regard to the total
`number of patients the respective AED was part of therapy.
`For further differentiation, the corresponding data of every
`single AED, with and without ADR, is summarized in
`Table 3. Comparing the calculated RR for each AED used
`off-label to its application as recommended by the SmPC
`revealed no relevant risk change. Though, the number of
`patients for these evaluations was small.
`Concerning the documented ADRs, the most common
`were related to electrolyte imbalance, e.g., low sodium
`(n = 79, 14.1 %) and potassium (n = 25, 4.4 %) levels,
`the central nervous system, including dizziness (n = 61,
`10.9 %), disturbed vision (n = 47, 8.4 %), fatigue
`(n = 40, 7.1 %), nystagmus (n = 36, 6.4 %) and ataxia
`(n = 29, 5.2 %), or cognitive deficits, especially distur-
`bance of speech (n = 37, 6.6 %), memory impairment
`(n = 36, 6.4 %) and mental slowing (n = 32, 5.7 %). In 24
`patients (4.3 %), the observed ADRs were considered as
`severe, rare, very distinctive or currently unknown and
`
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`214 (cid:9)
`
`Table 3 Patients under off-
`label use concerning dose,
`without and with at least
`possibly related ADRs, stratified
`by the respective AEDs,
`including details of particular
`daily dosages
`
`A. Hilgers, M. Schaefer
`
`N (cid:9)
`
`Totala (%) RR (cid:9)
`
`CI (cid:9)
`
`Daily dosage (mg)
`
`Mean Median
`
`SD Min. Max.
`
`TPM
`Off-label use
`Without ADR
`With possible ADR
`LCM
`Off-label use
`Without ADR
`With possible ADR
`LEV
`Off-label use
`Without ADR
`With possible ADR
`PGB
`Off-label use
`Without ADR
`With possible ADR
`OXC(ER)
`Off-label use
`Without ADR
`With possible ADR
`ESL
`Off-label use
`Without ADR
`With possible ADR
`ZNS
`Off-label use
`Without ADR
`With possible ADR
`
`7
`4
`2
`
`18
`8
`8
`
`91
`50
`27
`
`6
`3
`3
`
`20
`8
`11
`
`11
`1
`9
`
`7
`2
`4
`
`6.4
`3.7
`1.8
`
`17.6
`7.8
`7.8
`
`24.8
`13.6
`7.4
`
`9.8
`4.9
`4.9
`
`10.9
`4.4
`6.0
`
`64.7
`5.9
`52.9
`
`10.3
`2.9
`5.9
`
`0.49
`
`0.16-1.54
`
`638
`650
`
`600
`650
`
`111
`71
`
`550
`600
`
`800
`700
`
`0.84
`
`0.50-1.40
`
`513
`500
`
`500
`500
`
`58
`53
`
`450
`450
`
`600
`600
`
`0.95
`
`0.68-1.33
`
`3945
`4102
`
`4000
`4000
`
`408
`701
`
`3500
`3500
`
`6000
`7000
`
`0.96
`
`0.42-2.24
`
`725
`708
`
`750
`700
`
`43
`38
`
`675
`675
`
`750
`750
`
`1.02
`
`0.68-1.52
`
`2994
`2832
`
`3000
`2700
`
`401
`316
`
`2550
`2500
`
`3850
`3600
`
`1.03
`
`0.78-1.36
`
`2400
`1822
`
`2400
`1600
`
`2400
`1600
`
`2400
`2400
`
`353
`
`1.21
`
`0.66-2.23
`
`600
`588
`
`600
`600
`
`0
`25
`
`600
`550
`
`600
`600
`
`AED antiepileptic drug, ADR adverse drug reaction, CI confidence interval, ESL eslicarbazepine, LCM
`lacosamide, LEV levetiracetam, OXC(ER) oxcarbazepine extended-release formulation, PGB pregabalin,
`RR relative risk for the occurrence of possibly related ADRs comparing off-label use concerning dose to the
`particular applications of the same drug used on-label, i.e., according to the recommended dosage by the
`Summary of Product Characteristics, SD standard deviation, TPM topiramate, ZNS zonisamide
`a For calculation, the total number of documented cases per AED was used
`
`therefore reported via the SRS to the responsible regulatory
`authority. Among these reports were one case of an
`arrhythmia absoluta under the combination of LCM and
`LEV as a potentially life-threatening ADR, three of suici-
`dal ideation (two under LEV, one under the combination of
`OXC(ER)/LCM), three of myoklonia [two under
`OXC(ER), one under LEV], two of peripheral edema under
`OXC(ER), one of paresthesia under LEV, one of anorexia
`under TPM and one case of anxiety under LEV.
`For comparing the frequency of occurrence of particular
`ADRs in relation to the information mentioned in the
`SmPC, the incidence of the ADR was calculated for each
`
`AED separately. The detailed results are shown in Table 4.
`Although, SmPC data express a very rough classification
`for ADR frequency by using categories differing by one
`power of ten only, e.g., >0.1 % for an uncommon
`and >10 % for a very common occurrence, for some reg-
`istered ADRs probable underestimation was assumed. This,
`for example, was apparent in the case of cognitive
`impairment related to TPM and electrolyte imbalance
`concerning potassium under therapy with an carbonic
`anhydrase (CA) inhibitor (i.e., TPM, ZNS) or sodium level
`by application of dibenzazepine anticonvulsants (i.e.,
`OXC, ESL).
`
`/\ Adis
`
`Page 00006
`
`

`
`Systematic ADR Monitoring in Epilepsy Therapy Using Routine Clinical Data (cid:9)
`
`215
`
`Table 4 Incidence rates of all ADRs, assessed as at least possibly related to the antiepileptic drug, compared with corresponding frequency data
`by the SmPC (nonexhaustive list; occurred ADRs mentioned only)
`
`TPM
`
`Obs. (cid:9)
`
`SmPC
`
`LEV
`
`Obs.
`
`SmPC
`
`PGB
`
`Obs.
`
`SmPC
`
`ZNS
`
`Obs.
`
`OXC(ER)
`
`LCM
`
`SmPC
`
`Obs.
`
`SmPC
`
`Obs.
`
`SmPC
`
`ESL
`
`Obs.
`
`SmPC
`
`>1
`
`>1
`
`>0.1
`
`>1
`
`3
`0.8
`
`2
`0.5
`
`5
`1.4
`
`3
`0.8
`
`3
`0.8
`
`2
`0.5
`
`5
`1.4
`
`>0.1
`
`>0.1
`
`>1
`
`N/A
`
`>0.01
`
`>1
`
`>1
`
`7
`11.3
`
`>1
`
`>0.1
`
`N/A
`
`>0.1
`
`3
`4.5
`
`3
`4.5
`
`9
`13.2
`
`N/A
`
`>1
`
`>1
`
`>0.1
`
`1
`1.6
`
`1
`1.6
`
`1
`1.6
`
`N/A
`
`N/A
`
`>1
`
`>0.1
`
`1
`1.5
`
`1
`1.5
`
`>1
`
`>10
`
`2
`1.1
`
`1
`0.6
`
`67
`37.0
`
`3
`1.7
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`>1
`
`N/A
`
`>1
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`>1
`
`1
`5.9
`
`10
`58.8
`
`1
`5.9
`
`N/A
`
`>0.1
`
`>1
`
`N/A
`
`>1
`
`>1
`
`>0.1
`
`3
`2.9
`
`3
`2.9
`
`4
`3.9
`
`Metabolism and nutrition disorders
`Weight gain
`N
`% (cid:9)
`Weight loss
`9
`N (cid:9)
`>10
`% (cid:9)
`8.2 (cid:9)
`Decreased appetite/anorexia
`5
`N (cid:9)
`% (cid:9)
`4.5 (cid:9)
`Hypokalemia
`11
`N (cid:9)
`% (cid:9)
`10.1 (cid:9)
`Hyponatremia
`N
`N/A
`% (cid:9)
`Psychiatric disorders
`Sleep disturbance/insomnia
`N
`>1
`% (cid:9)
`Nervousness/agitation
`1
`N (cid:9)
`% (cid:9)
`0.9 (cid:9)
`Irritability
`2
`N (cid:9)
`>1
`% (cid:9)
`1.8 (cid:9)
`Aggressive reaction
`2
`N (cid:9)
`% (cid:9)
`1.8 (cid:9)
`Anxiety
`N
`>1
`% (cid:9)
`Listlessness/apathy
`2
`N
`0.5
`% (cid:9)
`>0.1
`Mood swings/depressed mood
`2
`8
`N (cid:9)
`% (cid:9)
`1.8 (cid:9)
`2.2
`Confusion
`N
`% (cid:9)
`Suicidal ideation
`N (cid:9)
`1
`>0.1
`% (cid:9)
`0.9 (cid:9)
`Nervous system disorders
`Fatigue/tiredness
`5
`N (cid:9)
`% (cid:9)
`4.5 (cid:9)
`Dizziness
`5
`N (cid:9)
`% (cid:9)
`4.5 (cid:9)
`
`10
`2.7
`
`11
`3.0
`
`4
`1.1
`
`2
`0.5
`
`4
`1.1
`
`25
`6.8
`
`23
`6.3
`
`>1
`
`>1
`
`>1
`
`N/A
`
`>1
`
`>0.1
`
`>1
`
`>10
`
`>1
`
`>1
`
`>0.1
`
`N/A
`
`N/A
`
`>0.1
`
`>1
`
`N/A
`
`>10
`
`>1
`
`1
`1.6
`
`1
`1.6
`
`1
`1.6
`
`5
`8.1
`
`7
`11.3
`
`2
`3.0
`
`3
`4.5
`
`6
`9.0
`
`5
`7.5
`
`>10
`
`>0.1
`
`>1
`
`N/A
`
`>10
`
`>10
`
`>0.1
`
`>10
`
`>10
`
`1
`0.6
`
`2
`1.1
`
`1
`0.6
`
`1
`0.6
`
`1
`0.6
`
`1
`0.6
`
`12
`6.6
`
`24
`13.3
`
`N/A
`
`N/A
`
`N/A
`
`>1
`
`>1
`
`>1
`
`N/A
`
`>10
`
`>10
`
`1
`5.9
`
`>0.1
`
`>1
`
`>0.1
`
`N/A
`
`N/A
`
`>I
`
`>1
`
`>0.1
`
`N/A
`
`N/A
`
`>0.1
`
`>0.1
`
`>0.1
`
`>0.1
`
`N/A
`
`>1
`
`>10
`
`2
`11.8
`
`5
`29.4
`
`>10
`
`>10
`
`A Adis
`
`1
`1.0
`
`2
`1.9
`
`1
`1.0
`
`6
`5.8
`
`25
`24.3
`
`>1
`
`>10
`
`>1
`
`>10
`
`>10
`
`Page 00007
`
`

`
`216
`
`Table 4 continued
`
`A. Hilgers, M. Schaefer
`
`TPM
`
`LEV
`
`PGB
`
`ZNS
`
`OXC(ER)
`
`LCM
`
`ESL
`
`Obs. (cid:9)
`
`SmPC
`
`Obs.
`
`SmPC
`
`Obs.
`
`SmPC
`
`Obs.
`
`SmPC
`
`Obs.
`
`SmPC
`
`Obs.
`
`SmPC
`
`Obs.
`
`SmPC
`
`>1
`
`5
`8.1
`
`3
`4.8
`
`2
`3.2
`
`2
`3.2
`
`10
`2.7
`
`17
`4.6
`
`11
`3.0
`
`4
`1.1
`
`N/A
`
`>1
`
`>1
`
`>0.1
`
`>0.1
`
`N/A
`
`N/A
`
`2
`3.0
`
`2
`3.0
`
`2
`3.0
`
`2
`3.0
`
`6
`9.0
`
`3
`4.4
`
`>0.1
`
`>1
`
`>1
`
`>1
`
`>1
`
`>0.1
`
`>0.1
`
`>1
`
`>1
`
`>10
`
`>1
`
`>10
`
`>1
`
`>1
`
`13
`7.2
`
`3
`1.7
`
`12
`6.6
`
`2
`1.1
`
`3
`1.7
`
`4
`2.2
`
`>1
`
`>1
`
`>1
`
`>1
`
`>1
`
`N/A
`
`N/A
`
`19
`18.4
`
`8
`7.8
`
`11
`10.7
`
`1
`1.0
`
`2
`1.9
`
`2
`1.9
`
`4
`3.9
`
`>1
`
`>1
`
`>1
`
`>1
`
`>1
`
`> 1
`
`>1
`
`4
`23.5
`
`1
`5.9
`
`2
`11.8
`
`>0.1
`
`>1
`
`>1
`
`>1
`
`>0.1
`
`>0.1
`
`N/A
`
`Nystagmus
`4
`N (cid:9)
`% (cid:9)
`3.6 (cid:9)
`Tremor
`2
`N (cid:9)
`>1
`1.8 (cid:9)
`% (cid:9)
`Balance disorder/ataxia
`10
`3
`N (cid:9)
`2.7
`>1
`% (cid:9)
`2.7 (cid:9)
`Disturbance in concentration/attention
`16
`3
`N (cid:9)
`>1
`0.8
`% (cid:9)
`14.7 (cid:9)
`Memory impairment
`25
`N (cid:9)
`>1
`% (cid:9)
`22.9 (cid:9)
`Disturbance of speech
`31
`N (cid:9)
`>1
`% (cid:9)
`28.4 (cid:9)
`Mental slowing/bradyphrenia
`N (cid:9)
`17
`% (cid:9)
`15.6 (cid:9)
`Headache
`N (cid:9)
`1
`% (cid:9)
`0.9 (cid:9)
`Dysgeusia
`N
`% (cid:9)
`Paresthesia
`3
`N (cid:9)
`% (cid:9)
`2.7 (cid:9)
`Eye disorders
`Blurred vision/diplopia
`6
`N (cid:9)
`% (cid:9)
`5.5 (cid:9)
`Ear and labyrinth disorders
`Tinnitus
`1
`N (cid:9)
`>1
`0.9 (cid:9)
`% (cid:9)
`Gastro-intestinal disorders
`Nausea/vomiting
`3
`N (cid:9)
`% (cid:9)
`2.7 (cid:9)
`Diarrhea
`N (cid:9)
`1
`% (cid:9)
`0.9 (cid:9)
`Obstipation
`N (cid:9)
`1
`% (cid:9)
`0.9 (cid:9)
`flatulence
`N
`% (cid:9)
`
`10
`2.7
`
`6
`1.6
`
`1
`0.3
`
`2
`0.5
`
`13
`3.5
`
`1
`0.3
`
`4
`1.1
`
`I
`0.3
`
`1
`1.6
`
`1
`1.6
`
`1
`1.6
`
`>10
`
`N/A
`
`N/A
`
`>0.1
`
`5
`8.1
`
`>10
`
`>0.1
`
`>1
`
`>1
`
`8
`11.9
`
`4
`2.2
`
`7
`3.9
`
`N/A
`
`N/A
`
`> 1
`
`>10
`
`N/A
`
`N/A
`
`4
`3.9
`
`>10
`
`N/A
`
`>1
`
`1
`5.9
`
`>1
`
`N/A
`
`>0.1
`
`5
`7.5
`
`>10
`
`23
`12.6
`
`>10
`
`17
`16.5
`
`>10
`
`4
`23.5
`
`>1
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`>1
`
`>0.1
`
`1
`1.6
`
`1
`1.6
`
`>1
`
`>1
`
`>1
`
`>1
`
`>1
`
`>1
`
`N/A
`
`N/A
`
`>1
`
`>1
`
`>1
`
`N/A
`
`13
`7.2
`
`4
`2.2
`
`1
`0.6
`
`>10
`
`>1
`
`>1
`
`N/A
`
`2
`3.0
`
`15
`14.6
`
`>10
`
`2
`11.8
`
`1
`1.0
`
`2
`1.9
`
`4
`3.9
`
`>1
`
`>1
`
`>1
`
`>1
`
`>1
`
`>0.1
`
`>0.1
`
`>1
`
`N/A
`
`>1
`
`>10
`
`>1
`
`>10
`
`>10
`
`>1
`
`>0.1
`
`A Adis
`
`Page 00008
`
`

`
`Systematic ADR Monitoring in Epilepsy Therapy Using Routine Clinical Data (cid:9)
`
`217
`
`Table 4 continued
`
`TPM (cid:9)
`
`LEV
`
`PGB (cid:9)
`
`ZNS
`
`OXC(ER)
`
`LCM (cid:9)
`
`ESL
`
`Obs. SmPC Obs. SmPC Obs. SmPC Obs. SmPC Obs. SmPC Obs. SmPC Obs. SmPC
`
`Hepatobiliary disorders
`Increase in liver enzymes
`N
`
`6
`>0.1
`>0.1
`1.6
`Skin and subcutaneous tissue disorders
`Hypersensitivity/pruritus
`N
`
`2
`0.5
`
`2
`0.5
`
`1
`0.3
`
`>1
`
`Alopecia
`1
`N (cid:9)
`>1
`% (cid:9)
`0.9 (cid:9)
`Musculoskeletal disorders
`Myoclonia
`N
`
`>1
`General disorders
`Peripheral edema
`N
`
`1
`1.6
`
`>0.1
`
`2
`3.0
`
`>1
`
`>0.01
`
`>0.1
`
`>0.01
`
`N/A
`
`N/A
`
`>0.1
`
`1
`1.5
`
`N/A
`
`6
`3.3
`
`1
`0.6
`
`2
`1.1
`
`2
`1.1
`
`2
`1.1
`
`183
`100
`
`>0.1
`
`>0.001
`
`>1
`
`2
`1.9
`
`1
`1.0
`
`1
`1.0
`
`>0.1
`
`2
`11.8
`
`>0.1
`
`>1
`
`>0.1
`
`N/A
`
`>0.1
`
`N/A
`
`>1
`
`N/A
`
`N/A
`
`N/A
`
`102
`100
`
`>0.1
`
`1
`5.9
`
`17
`100
`
`N/A
`
`N/A
`
`Total
`N (cid:9)
`% (cid:9)
`
`109
`100
`
`367
`100
`
`4
`6.5
`
`61
`100
`
`>1
`
`>1
`
`68
`100
`
`ADR adverse drug reaction, ESL eslicarbazepine, LCM lacosamide, LEV levetiracetam, N/A not available, Obs. observed, OXC(ER) oxcarbazepine
`extended-release formulation, PGB pregabalin, SmPC Summary of Product Characteristics, TPM topiramate, ZNS zonisamide
`
`4 Discussion
`
`4.1 AED Usage and ADR Incidence
`
`Of the various AEDs of interest in this survey, OXC(ER)
`and LEV were most frequently used. To our knowledge, no
`study has so far investigated this selection of newer AEDs,
`but there are three different papers reporting on the nation-
`wide prescription patterns of AEDs in Italy (data included
`until 2007), Norway (until 2009) and Germany (until 2010)
`[13, 29, 30]. Extracting the data related to the AEDs
`focused on in this survey also reveals the tendency towards
`LEV being the most frequently used, followed by
`OXC(ER), TPM, ZNS and PGB. LCM and ESL were the
`most recently approved AEDs, which is why no reliable
`data were available.
`With regard to every first documented observation per
`patient in this evaluation, almost 90 % were on polyther-
`apy. Compared with the studies of Canevini et al. and
`Malerba et al. in which 22.5 and 21 %, respectively, of
`drug refractory patients were being managed on a single
`AED [30, 31], a proportion of 10.1 % is small. However, in
`our survey only patients recently admitted to in-house
`treatment were included, for whom, other than severe
`epilepsy, the need for a complex therapy management,
`
`including administration of antiepileptic medication for
`acute use and the change in therapy by gradual cross-over
`of AEDs, can be assumed. By considering the calculated
`mean data for the length of stay, number of concomitant
`AEDs and AED load, defined as the sum of DDDs
`(Table 1), this assumption can be substantiated.
`It is still a matter of debate if antiepileptic polymedi-
`cation compared with monotherapy is generally associated
`with more frequent ADRs. The correlation between AED
`toxicity and total drug load rather than the number of
`concomitant AEDs is also still under discussion [31-34]. In
`this survey, both factors were significantly associated with
`a more frequent occurrence of ADRs, whilst also both were
`strongly correlated with each other. However, in view of
`the numerical extent of association, the total number of
`AEDs seemed to be of greater impact. The reasons for this
`can be manifold, including the absence of a rigid dosing
`scheme, a gradual cross-over of AEDs, and the value of
`DDD as an imperfect measure of drug exposure itself [15,
`31, 35]. Testing for serum concentration-dependent toler-
`ability was also considered for this survey, but ultimately
`rejected as therapeutic drug monitoring of the newer AEDs
`often was applied in selected cases only [36] and, therefore,
`corresponding serum concentrations were not available in
`every documented d