Tolerability of levetiracetam in elderly patients with CNS disorders

Epilepsy Research 56 (2003) 135–145

Tolerability of levetiracetam in elderly patients with CNS disorders Joyce A. Cramer a,∗ , Ilo E. Leppik b , Katrien De Rue c , Pascal Edrich c , Günter Krämer d a

Department of Psychiatry, Yale University School of Medicine, 950 Campbell Avenue (G7E, Room 7-127), West Haven, CT 06516-2770, USA b MINCEP Epilepsy Care, Department of Neurology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA c UCB Pharma, Brussels, Belgium d Swiss Epilepsy Center, Zürich, Switzerland Received 21 April 2003; received in revised form 12 August 2003; accepted 26 August 2003

Abstract The purpose of this analysis was to compare treatment-emergent adverse events (TEAE) related to use of levetiracetam (LEV) reported by young and elderly patients with anxiety and cognitive disorders, and young epilepsy patients. The LEV database includes reports of TEAE from trials of patients with diagnoses of a cognitive disorder (N = 719), an anxiety disorder (N = 1510), or localization-related epilepsy (N = 1023) who participated in clinical trials lasting up to 16 weeks. Patients were grouped as young (<65 years) or elderly (≥65 years). The most common TEAE occurring most frequently in the LEV-treated groups were abdominal pain, asthenia, headache, anorexia, weight loss, dizziness, insomnia, somnolence, and tremor. The only significant differences in TEAE were seen between young and elderly groups with anxiety disorders (>3% higher for LEV than for placebo-treated patients) in headache (5.2% elderly, −0.9% young, P = 0.041), and tremor (5.2 and −0.5%, respectively, P = 0.022) and between young anxiety patients and young epilepsy patients for somnolence (−0.7 and 5.4%, respectively, P = 0.036). For the other TEAEs there was no evidence for consistent differences between young and elderly patients and between patients with different CNS disorders. Overall, LEV was well tolerated by all patient groups. The favorable adverse event profile suggests that LEV might be suitable for use by elderly patients. © 2003 Elsevier B.V. All rights reserved. Keywords: Levetiracetam; Epilepsy; Anxiety; Cognitive disorder; Adverse event

1. Introduction The development of medications for the treatment of central nervous system (CNS) disorders is based on careful assessment of adverse effects as well as efficacy. In clinical use, it is often the adverse effect profile, rather than lack of efficacy, that limits use ∗ Corresponding author. Tel.: +1-203-937-3894; fax: +1-203-937-3468. E-mail address: [email protected] (J.A. Cramer).

of a drug. Clinical testing usually is performed on populations of young patients who have no medical, neurological, or psychiatric diagnosis other than the disorder being evaluated. Clinical testing of medications in children is encouraged by the possibility of extended patent protection, but no such stimulus is provided for testing in elderly patients. Because the elderly (age≥65 years) are an increasingly large group, clinical trials should include elderly subjects since information regarding adverse events obtained from younger adults may not be applicable. During the clin-

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ical development of levetiracetam (LEV) (Keppra® , UCB Pharma), large numbers of elderly patients were included in studies of cognitive disorders and anxiety. LEV is the S-enantiomer of ␣-ethyl-2-oxo-1-pyrrolidine acetamide and has antiepileptic activity. The mechanism of action of LEV is unknown, but thought to involve an indirect effect on GABAA / glycine inhibitory neurotransmission (through zinc and ␤-carbolines) (Rigo et al., 2002), high-voltageactivated calcium channels (Lukyonetz et al., 2002), and possibly reduced calcium trafficking (Angehagen et al., 2002). Its mechanism of action does not involve GABA, glutamate, serotonin, dopamine, histamine, or other sites which are the targets of many drugs. LEV has been shown to have reversible, saturable, and stereospecific binding to synaptic membrane sites tested including hippocampus, cortex, and cerebellum (Dooley and Plosker, 2000). Phase I studies showed that LEV was well tolerated with a serum half-life of 6–8 h in young healthy volunteers, and 10–11 h in healthy elderly (>65 years). Because studies in subjects with different degrees of renal impairment demonstrated elimination to be directly proportionality to creatinine clearance rates, lower doses are recommended for patients with low creatinine clearance (Keppra package insert, UCB Pharma). Oral absorption is almost 100%, with little effect of food. Its volume of distribution is similar between young and elderly subjects, and binding to plasma proteins is not significant (Patsalos, 2000). Because LEV is not metabolized by hepatic microsomal P450 isoenzymes, it has no known drug interactions and kinetics are linear (Nicolas et al., 1999; Patsalos, 2000). The early clinical trials of LEV were directed at the treatment of cognitive and anxiety disorders. These trials included many elderly subjects. After the effectiveness of LEV in animal models of epilepsy was demonstrated, subsequent clinical trials were performed in persons with epilepsy. Combining safety data from these trials provides a large number of younger adults and elderly in whom treatmentemergent adverse events (TEAE) could be evaluated. LEV is currently approved in Europe and the USA as add-on treatment for adults with localization-related epilepsies. The purpose of this report is to describe the TEAE profile of LEV in young and elderly patients with cognitive disorders, anxiety, and epilepsy.

2. Methods The LEV database was obtained from trials of patients with cognitive disorders (N = 719), anxiety disorders (N = 1510), and localization-related epilepsy (N = 1023) (Table 1). Trials lasted 6–12 weeks for the cognitive disorder patients, 4–12 weeks for the anxiety patients and 16–18 weeks for the epilepsy patients. Trials in cognitive disorders included patients with diagnoses of post-stroke cognitive disorder, post-trauma cognitive disorder, or memory disorder. Placebo-controlled trials in anxiety included patients with or without comorbid depression. Placebo-controlled trials in epilepsy included patients whose seizures were not controlled by stable therapy with one to two available AEDs, requiring adjunctive treatment (add-on LEV or placebo). Epilepsy trials included only 31 patients considered elderly (>65 years). Data from epilepsy trials are presented for the whole cohort considered to be “young” patients. Table 1 describes patient characteristics and LEV doses. A pooled analysis of TEAE from clinical trials was made available by UCB Pharma to the authors for examination of the frequency of TEAE. TEAE are symptoms with onset on or after the first day of study treatment (LEV or placebo) that were spontaneously reported by patients or observed by clinicians, and not present prior to entry into the study. The COSTART (FDA, 1997) dictionary was used to define terms. The percent of patients taking LEV or placebo who reported a TEAE were compared in a series of analyses. The incidences of TEAE observed for placebo were subtracted from those for LEV to demonstrate the effect of LEV over background placebo effect. The time of onset of TEAE was analyzed as onset during the period from day 1 through week 4, and during week 4 through month 3. The severity of each TEAE was based on the report with worst severity for that individual (mild, moderate, severe). The pattern of each TEAE was classified as once; intermittent (the adverse event occurred and resolved more than once in the period); or continuous (the adverse event was present at the same severity for the whole period). The most frequent pattern for an individual was used in the analysis so that each patient was counted only once. A TEAE leading to dose decrease, treatment discontinuation, or

Cognitive disorders (all)

Cognitive disorders (<65 years)

Cognitive disorders (>65 years)

Anxiety disorders (all)

Anxiety disorders (<65 years)

Anxiety disorders (>65 years)

Epilepsy (all)

LEV (N = 394)

PLA (N = 344)

LEV (N = 228)

PLA (N = 191)

LEV (N = 166)

PLA (N = 153)

LEV (N = 1084)

PLA (N = 525)

LEV (N = 987)

PLA (N = 453)

LEV (N = 97)

PLA (N = 72)

LEV (N = 769)a

PLA (N = 439)

Age (years) Mean (S.D.) 60.8 (16.0) Median 63 Minimum to maximum 18–94

59.4 (18.1) 62 17–93

50.5 (12.5) 55 18–64

46.8 (14.0) 51 17–64

74.8 (7.2) 74 65–94

75.0 (7.0) 74 65–93

45.5 (15.9) 44 18–101

47.7 (18.2) 45 18–101

42.1 (11.7) 42 18–64

42.2 (12.2) 43 18–64

80.3 (10.0) 82 65–101

82.5 (9.0) 85 65–101

37.4 (11.3) 37 14–70a

36.9 (11.5) 36 16–69a

Gender Male: N (%)

234 (59)

206 (60)

162 (71)

135 (71)

72 (43)

71 (46)

361 (33)

154 (29)

342 (35)

140 (31)

19 (20)

14 (19)

416 (54)

223 (51)

LEV dose Mean (mg per day) Median Minimum to maximum Mean (mg/kg)d

906 1000 250–1500 12.8

– – – –

962 1000 250–1500 13.1

– – – –

828b 1000 250–1500 12.5

– – – –

516 500 125–1000 7.9

– – – –

527 500 125–1000 8

– – – –

412c 375 250–1000 6.9

– – – –

1975 2000 167–4000 28.2

– – – –

a Patients of all ages were included in the epilepsy cohort because only 31 patients were more than 65 years of age. Patients who participated in crossover studies were eligible to be counted twice, once in the LEV group and once in the placebo (PLA) group. b Cognitive disorder group: elderly mean dose was 14% lower than young mean dose. c Anxiety disorder group: elderly mean dose was 22% lower than young mean dose. d Weight was not available for some patients.

J.A. Cramer et al. / Epilepsy Research 56 (2003) 135–145

Table 1 Demographic characteristics

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early termination from a study was considered a discontinuation for analysis.

3. Statistical analyses Data are presented for patients in each treatment cohort (young and elderly patients with cognition or anxiety disorders, all epilepsy patients). Patients who participated in crossover studies were eligible to be counted twice, once in the LEV group and once in the placebo group. Adverse event terms were included when all the following conditions were met: (a) reported with an incidence >3% in any group, (b) where the incidence is >3% higher than placebo in any LEV group (less than 3% was considered clinically irrelevant), (c) where the attribution of “related to treatment” was more common than “unrelated to treatment” (relationship to study drug was based on the physician’s assessment (related, unrelated) and (d) when self-reported (i.e. not a laboratory test result). The Breslow–Day test was used to compare the treatment effect among disease and age cohorts.

4. Results The largest number of adverse events both by term and by frequency occurred in the elderly anxiety disorder and young epilepsy groups. In contrast, the cognition groups (young and elderly), and the young anxiety group consistently reported fewer TEAE. However, most of the TEAE were reported in equally large numbers by patients receiving placebo or were considered by the investigator to be unrelated to treatment. Using the criteria to select TEAE for review (related to treatment, occurred more often in any LEV-treated group) reduced the terms of interest to: abdominal pain, anorexia, asthenia, dizziness, headache, insomnia, somnolence, tremor, and weight loss. 4.1. Incidence and time of onset The incidence of TEAE in young and elderly patients is shown in Table 2. The most common TEAE in the elderly cognition group was asthenia (7.1% higher than placebo). Somnolence (4.5% higher) and dizziness (3.3% higher) were the only other TEAEs that

were >3% more common in the LEV than placebo groups. In the elderly anxiety group, headache and tremor (5.2% higher), dizziness (4.1% higher), weight loss (4.0% higher), anorexia and abdominal pain (both 3.8% higher), and insomnia (3.0% higher) were the TEAE more common in the LEV than placebo groups. In the younger cognition and anxiety cohorts, the only TEAE (>3%) that appeared more commonly in the LEV than placebo groups was somnolence (young cognition cohort: 6% higher; young anxiety cohort: 5.4% higher). The most common TEAE in the epilepsy group (>3% more common in the LEV than placebo group) was somnolence (6.4% higher than placebo), asthenia (5.6% higher) and dizziness (4.7% higher). The preponderance of adverse events was reported during the first 4 weeks of treatment for all groups (Table 3). 4.2. Severity The severity of TEAE was described as mild, moderate or severe intensity. Table 4 lists the incidences of moderate and severe TEAE to demonstrate differences in patterns of severity among groups. More patients reported “moderate” than “severe” intensity of TEAE. Asthenia, dizziness, and somnolence were more common in the elderly cognitive disorders and younger epilepsy group on LEV than placebo, but most patients reported only moderate problems. No TEAE was notably more often severe among LEV-treated than placebo-treated elderly anxiety or young epilepsy patients. Exceptions include severe somnolence (3.1% LEV versus 0.9% placebo, epilepsy), severe anorexia (2.1% LEV versus 0% placebo, elderly anxiety) and severe weight loss (3.1% LEV versus 0% placebo, elderly anxiety). 4.3. Pattern The pattern of TEAE was described as once, intermittent or continuous. Table 5 lists the incidences of intermittent and continuous TEAE to demonstrate differences in patterns of reporting among group. The elderly cognitive disorders group experienced more continuous asthenia, headache, and somnolence related to LEV than placebo while younger patients experienced more continuous somnolence. The elderly anxiety disorders group experienced more continuous

Abdominal pain Anorexia Asthenia Dizziness Headache∗ Insomnia Somnolence∗∗ Tremor∗∗∗ Weight loss

Cognition (<65 years)

Cognition (>65 years)

Anxiety (<65 years)

Difference Percent Percent (LEV − PLA) PLA LEV (N = 228) (N = 191)

Difference Percent Percent (LEV − PLA) PLA LEV (N = 166) (N = 153)

Percent Percent PLA LEV (N = 987) (N = 453)

Difference (LEV − PLA)

Percent LEV (N = 97)

Anxiety (>65 years) Percent PLA (N = 72)

Epilepsy (all) Difference (LEV − PLA)

Difference Percent Percent (LEV − PLA) PLA LEV (N = 769) (N = 439)

0.9

2.6

−1.7

1.2

1.3

−0.1

2.2

3.3

−1.1

5.2

1.4

3.8

3.9

4.6

−0.7

0.4 14.5 7.5 12.7 3.5 14.9 0 0

1 13.6 4.7 12 6.3 8.9 0 0

−0.6 0.9 2.8 0.7 −2.8 6 0 0

1.8 16.9 7.2 7.2 1.8 7.8 0 0

1.3 9.8 3.9 5.9 1.3 3.3 0 0

0.5 7.1 3.3 1.3 0.5 4.5 0 0

0.5 5.1 4.4 6.4 2.2 6.9 0.4 0.5

0.4 3.1 3.1 7.3 1.5 1.5 0.9 0.2

0.1 2 1.3 −0.9 0.7 5.4 −0.5 0.3

5.2 3.1 4.1 5.2 7.2 2.1 5.2 8.2

1.4 2.8 0 0 4.2 2.8 0 4.2

3.8 0.3 4.1 5.2 3 −0.7 5.2 4

2.5 14.7 8.8 13.7 3.1 14.8 1.8 0.5

1.8 9.1 4.1 13.4 2.5 8.4 1.6 0.9

0.7 5.6 4.7 0.3 0.6 6.4 0.2 −0.4

a Patients who participated in crossover studies were eligible to be counted twice, once in the LEV group and once in the placebo group. ∗ Headache: P = 0.041 for LEV − PLA difference between age groups (<65 years vs. ≥65 years, anxiety). ∗∗ Somnolence: P = 0.036 for LEV − PLA difference between anxiety <65 years and epilepsy all groups. ∗∗∗ Tremor: P = 0.022 for LEV − PLA difference between age groups (<65 years vs. ≥65 years, anxiety).

J.A. Cramer et al. / Epilepsy Research 56 (2003) 135–145

Table 2 Difference between LEV and placebo (PLA) incidence reported by more than 3% of patientsa

139

140

Table 3 Onset of first report of an adverse event among patients receiving LEV or placebo (PLA)

Abdominal pain Anorexia Asthenia Dizziness Headache Insomnia Somnolence Tremor Weight loss

Cognition (<65 years)

Cognition (≥65 years)

Cognition (≥65 years)

Anxiety (<65 years)

LEV

PLA

LEV

PLA

LEV

1 day to ≤4 weeks (N = 228)

>4 weeks to ≤3 months (N = 206)

1 day to ≤4 weeks (N = 191)

>4 weeks to ≤3 months (N = 173)

1 day to ≤4 weeks (N = 166)

>4 weeks to ≤3 months (N = 152)

1 day to ≤4 weeks (N = 153)

>4 weeks to ≤3 months (N = 142)

1 day to ≤4 weeks (N = 987)

>4 weeks to ≤3 months (N = 629)

0.9 0.4 13.2 6.6 11 2.2 14.5 0 0

0 0 1.5 0 1.9 1 0.5 0 0

2.1 1 11 4.2 9.4 6.3 7.9 0 0

0.6 0 1.7 0.6 2.9 0 1.2 0 0

1.2 1.2 16.3 7.2 6.6 1.2 7.8 0 0

0 0.7 0.7 0 0.7 0.7 0 0 0

1.3 1.3 9.2 3.9 5.9 1.3 2.6 0 0

0 0 0 0 0 0 0.7 0 0

1.4 0.5 4.5 4.1 5.3 1.5 6.3 0.3 0.5

1.3 0 1 0.3 1.7 1.1 0.6 0.2 0

Anxiety (<65 years)

Anxiety (≥65 years)

Anxiety (≥65 years)

Epilepsy (all)

Epilepsy (all)

PLA

LEV

PLA

LEV

PLA

1 day to ≤4 weeks (N = 453)

>4 weeks to ≤3 months (N = 310)

1 day to ≤4 weeks (N = 97)

>4 weeks to ≤3 months (N = 76)

1 day to ≤4 weeks (N = 72)

>4 weeks to ≤3 months (N = 65 years)

1 day to ≤4 weeks (N = 769)

>4 weeks to ≤3 months (N = 732)

1 day to ≤4 weeks (N = 439)

>4 weeks to ≤3 months (N = 426)

2.9 0.4 2.2 2.9 6.2 1.3 1.5 0.7 0

0.6 0 1.3 0.3 1.6 0.3 0 0.3 0.3

4.1 4.1 1 4.1 4.1 7.2 1 3.1 1

1.3 1.3 2.6 0 1.3 0 1.3 2.6 9.2

1.4 1.4 1.4 0 0 2.8 0 0 0

0 0 1.5 0 0 1.5 3.1 0 4.6

1.4 1.3 9 4.8 7.5 1.4 11.7 0.5 0.1

1.2 0.8 3.4 3.6 3.8 1.1 1.8 0.8 0.3

2.5 0.5 4.3 1.4 8.2 0.7 4.1 0.5 0.2

1.6 1.2 3.1 1.6 4 1.2 2.8 0.5 0.7

J.A. Cramer et al. / Epilepsy Research 56 (2003) 135–145

Abdominal pain Anorexia Asthenia Dizziness Headache Insomnia Somnolence Tremor Weight loss

Cognition (<65 years)

Abdominal pain Anorexia Asthenia Dizziness∗ Headache Insomnia Somnolence Tremor Weight loss∗∗

Cognition (<65 years)

Cognition (<65 years)

Cognition (≥65 years)

Cognition (≥65 years)

Anxiety (<65 years)

Anxiety (<65 years)

Anxiety (≥65 years)

Anxiety (≥65 years)

Epilepsy (all)

LEV (N= 228)

PLA (N= 191)

LEV (N= 166)

PLA (N= 153)

LEV (N= 987)

PLA (N= 453)

LEV (N= 97)

PLA (N= 72)

LEV (N= 769)

MOD

SEV

MOD

SEV

MOD

SEV

MOD

SEV

MOD

SEV

MOD

SEV

MOD

SEV

MOD

SEV

MOD

SEV

MOD

SEV

0.4 0 1.3 0.9 0.9 0.9 1.8 0 0

0 0 1.3 0.4 0.9 0 2.2 0 0

0.5 0 0.5 0.5 1.6 0.5 1 0 0

0 0 1 0 0 0.5 1 0 0

0 0.6 6.6 2.4 1.2 0 3.6 0 0

0 0 1.2 0 0 0 0 0 0

0 0 3.9 2 0.7 0.7 0.7 0 0

0 0 0 0.7 0.7 0 0 0 0

1.1 0.2 1.6 1.6 3.5 1.1 2.7 0.2 0.2

0.4 0.1 0.9 1.2 1.2 0.7 1.6 0 0

2 0.2 1.1 1.1 2.6 0.9 0.4 0.4 0

0.2 0 0.4 1.3 1.1 0.2 0.2 0.2 0

2.1 2.1 1 1 2.1 3.1 2.1 1 2.1

0 2.1 1 1 1 3.1 0 1 3.1

1.4 0 0 0 0 1.4 1.4 0 4.2

0 0 1.4 0 0 1.4 0 0 0

2 0.5 6.2 3.8 5.7 1.4 6.9 0.4 0

0 0.1 1.6 0.7 1.7 0.4 3.1 0.1 0

0.5 0.5 3 1.6 5.7 1.1 2.7 0.2 0.7

0.2 0 0.5 0 2.1 0.5 0.9 0 0.2

MOD: moderate, SEV: severe, PLA: placebo. ∗ Dizziness: P = 0.032 for difference between cognition (≥65 years) and epilepsy (all) groups (LEV vs. PLA). ∗∗ Weight Loss: P = 0.031 for difference between anxiety (≥65 years) and epilepsy (all) groups (LEV vs. PLA).

Epilepsy (all) PLA (N= 439)

J.A. Cramer et al. / Epilepsy Research 56 (2003) 135–145

Table 4 Incidence of adverse events with maximum intensity reported as moderate or severe

141

142

Table 5 Pattern of adverse events reported as intermittent or continuous while receiving LEV or placebo (PLA) Cognition (<65 years)

Abdominal pain Anorexia Asthenia Dizziness Headache Insomnia Somnolence Tremor Weight loss

Cognition (>65 years) PLA (N= 191)

LEV (N= 166)

LEV (N= 987)

PLA (N= 453)

Intermittent

Continuous

Intermittent

Continuous

Intermittent

Continuous

Intermittent

Continuous

Intermittent

Continuous

Intermittent

Continuous

0 0 4.4 2.6 2.2 0 4.4 0 0

0.4 0.4 3.9 1.8 2.6 0.4 5.3 0 0

0 0 2.1 1 2.1 1 1 0 0

1 0 2.6 0 2.6 1 2.6 0 0

0 0.6 3.6 3 1.2 0.6 1.2 0 0

0 0 7.2 0.6 2.4 0.6 3.6 0 0

0 0.7 3.9 2 1.3 0 2 0 0

0 0.7 3.9 0 0 0.7 0 0 0

0.9 0.1 1.2 1.1 2.1 0.7 1.8 0 0

0.9 0.3 3 2.1 2.5 1.3 4.2 0.2 0.4

2.2 0.2 0.4 0.4 2.6 0.2 0.7 0.2 0

0.7 0 2.2 1.8 2 0.9 0.9 0.7 0.2

Anxiety (>65 years) LEV (N= 97)

Abdominal pain Anorexia Asthenia Dizziness Headache Insomnia Somnolence Tremor Weight loss

Anxiety (<65 years) PLA (N= 153)

Epilepsy (all) PLA (N= 72)

LEV (N= 769)

PLA (N= 439)

Intermittent

Continuous

Intermittent

Continuous

Intermittent

Continuous

Intermittent

Continuous

2.1 1 0 0 2.1 1 1 1 0

3.1 4.1 3.1 1 2.1 6.2 1 2.1 7.2

1.4 0 0 0 0 2.8 1.4 0 0

0 1.4 2.8 0 0 1.4 1.4 0 4.2

1.3 1.3 5.5 4.9 7.4 1.4 6.1 1 0.3

1.3 0.9 7.9 2.1 2 1.6 7.7 0.5 0.3

2.7 0.9 5.7 2.1 6.8 1.6 4.1 0.7 0

0.7 0.9 3.4 1.1 1.6 0.7 3.9 0.7 0.9

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LEV (N= 228)

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abdominal pain, anorexia, insomnia, tremor, and weight loss than younger patients. Younger anxiety patients experienced more continuous somnolence as compared to the elderly patients. The young epilepsy group experienced more continuous asthenia and somnolence related to LEV.

5. Events leading to dose reduction or discontinuation The most common TEAE leading to a dose reduction or discontinuation of treatment with LEV or placebo included asthenia, headache, nausea, dizziness, somnolence, abdominal pain, and tremor. The proportion of LEV and placebo-treated patients discontinuing was low, exceeding 2% difference between LEV groups and placebo groups (more frequent in LEV as compared to placebo) only for somnolence (all young LEV-treated groups), dizziness (both elderly LEV-treated groups), tremor (elderly LEVtreated anxiety patients only), and asthenia (elderly LEV-treated cognition group).

6. Discussion These data demonstrate that LEV was well tolerated by elderly patients, as well as young patients with various CNS disorders. The LEV early clinical development program fortuitously included enough patients more than 65 years of age to make these comparisons. In contrast the LEV epilepsy development program included few elderly patients because the most common patients enrolled in clinical trials at epilepsy centers are younger. The information available from studies in cognitive and anxiety disorders provides a window on the types of adverse events that might be more common among elderly than young patients. Mean LEV doses were 14 and 22% lower for elderly cognitive and anxiety disorder groups, as compared to young. However, reduced renal clearance in elderly patients probably produced similar plasma levels in young and elderly patients. The differences in TEAE demonstrate that the doses tested were adequate to elicit adverse events. Overall, elderly anxiety and epilepsy patients had the highest incidences of TEAE, whereas those with

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cognitive disorders and young anxiety patients had the lowest incidences of TEAE. There were parallels between the types of TEAE occurring with a difference of 3% or more between LEV and placebo in the elderly cognitive disorders and epilepsy groups (asthenia, dizziness, and somnolence). In contrast, the elderly anxiety disorders group reported a different TEAE profile (rates of more than 3% difference between LEV and placebo: abdominal pain, anorexia, dizziness, headache, insomnia, tremor, and weight loss). Insomnia in elderly anxiety patients is in contrast with somnolence in other groups. This difference suggests that the underlying disorder may play a role in the type of TEAE. Both young anxiety and cognitive disorder groups experienced fewer TEAE than the epilepsy group, which was a mostly younger population. However, all of the epilepsy patients were receiving at least one other antiepileptic drug that may have contributed to this finding. The increasing number of people over the age of 65 years has focused attention on the need for information specific to the elderly population. Longevity also has increased the likelihood that a person will develop a CNS disorder. Renal function may decrease by half, with a linear decay in creatinine clearance that affects drugs with renal elimination (Rowe et al., 1976). Lower plasma protein concentrations also affect drug binding. Elderly patients generally should receive lower than usual doses to avoid toxicity because of these hepato-renal changes and interactions with other drugs (Lackner et al., 1998; Leppik, 2001; Woodhouse and Wynne, 1988). Changes in neuronal number and function also could affect drug binding to receptor sites. Any or all of these factors could be important in the pharmacokinetic or pharmacodynamic effect of a drug for elderly patients (Feely and Coakley, 1990). Although few studies of antiepileptic drugs have been performed with patients more than 65 years of age, the increased incidence of seizure disorders in this population requires a better understanding of drug therapy (Leppik and Worff, 1997; Cloyd et al., 1994). LEV does not induce or inhibit the metabolism of other drugs, auto-induce, or is induced by other drugs (Browne et al., 2000; Coupez et al., 2003; Levy et al., 2001; Ragueneau-Majlessi et al., 2001). This is an important issue for elderly patients who often take multiple other drugs (Krämer, 2001; Sirven et al., 1999). Age-related slowing of creatinine

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clearance should be considered when dosing LEV. In one recent report, the mean dose was 23 mg/kg per day for ≤65 years compared to 35.3 mg/kg per day for 19- to 64-year-old patients to achieve acceptable clinical results (Leppik et al., 2002). Age-related decreases in plasma albumin and protein are not an issue because LEV does not bind to plasma proteins. Doses for young epilepsy patients were much higher than for all patients with cognitive and anxiety disorders because of protocol designs. This difference would have affected the incidence of TEAE. However, the comparisons between young and elderly patients with cognitive and anxiety disorders were the main focus of these analyses. The data for young epilepsy patients were presented for perspective because there was no elderly cohort of comparison. Lower LEV doses (14–22% lower) for elderly than young patients were attributable to differences in clearance. Partial seizures with or without generalization are considered localization-related epilepsy, signifying that there is a presumed focus of brain damage. Cognitive disorders could have been caused by head trauma, stroke, another focal lesion, age-related atrophy, or other problems. Despite the diverse etiologies for the cognitive disorders cohort, their TEAE profile was similar to the epilepsy cohort. In contrast, anxiety disorders are not thought to be caused by a focal lesion. Patients enrolled in trials would have met criteria for the diagnosis of anxiety alone, precluding the possibility that their anxiety was secondary to another CNS disorder. Both LEV and placebo-treated anxiety patients reported a wider range of TEAE than the cognitive disorder groups, even with lower mean LEV doses. Their experiences were similar to epilepsy patients except that they used LEV in monotherapy whereas epilepsy patients used LEV as an add-on drug. The lack of adverse effects that might be expected in elderly patients was notable. Patients with a cognitive or anxiety disorder might be expected to experience increased confusion, hostility, emotional lability, or nervousness when a CNS-active medication is initiated. Absence of these problems further confirms the low impact of LEV on patients with brain disorders (Krämer, 2001; Krämer and Edrich, 2002). Patients with an anxiety disorder exhibited a different pattern of TEAE than the other cohorts. The anxious elderly group might have been concerned about overdose with medications. Anti-anxiety

medications commonly cause somnolence, asthenia, headache, and insomnia in elderly patients (Figgitt and McClellan, 2000; Rickels et al., 2000; Small and Bystritsky, 1997). Patients with cognitive disorders reported few TEAE, perhaps because the cognitive deficits blunted their concerns. LEV has previously been shown to have a low adverse event profile compared to other antiepileptic drugs (Cramer et al., 2001). Adverse effects related to levetiracetam in an elderly epilepsy population were compiled during a community-based open-label study (Keeper trial) (Ferrendelli et al., 2003). The types of adverse events reported by 78 patients aged ≥65 years did not differ from the overall evaluation of 1030 adults enrolled. The most common TEAE were somnolence (17%) and dizziness (9%). Dosing patterns for patients treated in community practice were lower than in clinical trials, with 52.6% of patients receiving a maximum daily dose of 1000 mg per day, and the remaining patients split evenly between maximum daily doses of 2000 and 3000 mg per day. In post-marketing experience in the treatment of epilepsy, adverse events have been the most common reason for the discontinuation of LEV, constituting approximately 6% in one series (White et al., in press). The behavioral effects that are common to all antiepileptic drugs were more common in the epilepsy population than the cognitive and anxiety disorder populations (Cramer et al., 2003). The result of this analysis of a large population of patients with various CNS disorders demonstrates that LEV has a favorable adverse effect profile in both young and elderly. This, in conjunction with its favorable pharmacokinetic and pharmacodynamic profile of linear kinetics, lack of hepatic induction or inhibition, and insignificant protein binding, makes it an easy and safe drug to use in the elderly.

Acknowledgements The project was supported by UCB Pharma who provided open access to all data.

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