(1, 2)

Assessing the efficacy and tolerability of: High completion rate at 1 year
Levetiracetam (LEV), Completion rate at 1 year :
Levetiracetam (n=841) 76%
Depakine® (VPA-ER), Classical AEDs (n=847) 74%
Controlled-release carbamazepine (CBZ-CR),
as monotherapy in patients with newly Hazard ratios for time to withdrawal
LEV (n=841)
vs classical AEDs (n=847)
Primary endpoint
HR (95% CI) p
0.90 (0.74-1.08) 0.258

diagnosed partial or generalized epilepsy LEV (n=349)

vs Depakine® (n=347)
LEV (n=492)
1.03 (0.75-1.41)

0.84 (0.66-1.07)
0.882

0.161
vs CBZ-CR (n=500)

Methods
Open-label, randomized, parallel-group, 52-week trial. By randomization, patients were allocated to best recommended treatment. Initial target
doses: extended-release sodium valproate, 1000 mg/day, controlled-release carbamazepine, 600 mg/day and levetiracetam, 1000 mg/day.
Patients’characteristics levetiracetam vs Depakine®
• 1688 patients (≥16 years old) with ≥ 2 unprovoked seizures
in the past 2 years and ≥ 1 in the last 6 months (ITT population)

Cumulative % of patients continuously present in the trial

• Patients experienced a median of 3 seizures in the last 2 years
• Median epilepsy duration of 0.9 years LEV (n=349)

Depakine® (n=347)
LEV/VPA-ER group LEV/CBZ-CR group
Classical
Seizure type LEV
AEDs LEV VPA-ER LEV CBZ-CR
n (%) (n=841) HR (95 % CI)=1.03 (0.75-1.41); p= 0.882
(n=847) (n=349) (n=347) (n=492) (n=500)

Partial-onset only 517 (61.5) 531 (62.7) 99 (28.4) 91 (26.2) 418 (85.0) 440 (88.0)

Primary generalized 272 (32.3) 272 (32.1) 226 (64.8) 232 (66.9) 46 (9.4) 40 (8.0)

Partial-onset
25 (3.0) 18 (2.1) 9 (2.6) 10 (2.9) 16 (3.3) 8 (1.6)
and primary generalized

Partial-onset + unclassified 1 (0.1) 0 1 (0.3) 0 0 0

Unclassified only 18 (2.1) 18 (2.1) 11 (3.2) 11 (3.2) 7 (1.4) 7 (1.4)

Unknown 8 (1.0) 8 (0.9) 3 (0.9) 3 (0.9) 5 (1.0) 5 (1.0) 0 50 100 150 200 250 300 350 400
Days
Primary endpoint Calculated from time of randomization. HR= hazards ratio; CI= confidence interval
Time to withdrawal from study medication: levetiracetam vs classical antiepileptic drugs (extended-release sodium valproate Denotes censored values are not represented
and controlled-release carbamazepine).
Main secondary variables
Time to withdrawal from study medication: levetiracetam vs extended-release sodium valproate and levetiracetam vs controlled-release
carbamazepine, time to first seizure, seizure freedom at 6 and 12 months, safety and tolerability parameters: treatment-emergent adverse
events, vital signs, body weight, physical and neurological examinations.
 (1, 2)

1 patient out of 3 is seizure-free after 1 year Low discontinuation rates at 1 year

levetiracetam vs Depakine® levetiracetam vs Depakine®
100
30
LEV (n=349) LEV (n=349)
Depakine® (n=347) Depakine® (n=347)
80 No statistically significant difference in seizure 25 No statistically significant difference
freedom rates at 6 and 12 months

20
60 59.1
Patients (%)

54.7

Patients (%)
15 13.8
12.9
40
32.4 33.7
10

20 6.3
Seizure-freedom rates at 6 months (no statistically significant difference) Reasons for discontinuation
LEV (n=841) 51.2 % vs classical AEDs (n=847) 53.0 % 5 4.6
3.5 Discontinuation rates due to lack of efficacy
LEV (n=492) 48.8 % vs CBZ-CR (n=500) 48.8 % 2.6 (no statistically significant difference)
Seizure-freedom rates at 12 months (no statistically significant difference) LEV (n=841) 4.2 % vs classical AEDs (n=847) 3.0 %
0
6 months 12 months LEV (n=841) 28.3 % vs classical AEDs (n=847) 26.6 % 0 LEV (n=492) 5.3 % vs CBZ-CR (n=500) 2.6 %
LEV (n=492) 25.4 % vs CBZ-CR (n=500) 21.6 % Lack of efficacy AEs* O
Other
h Discontinuation rates due to adverse events
(no statistically significant difference)
* AEs= adverse events
LEV (n=841) 8.4 % vs classical AEDs (n=847) 13.0 %
Time to first seizure significantly longer LEV (n=492) 10.0 % vs CBZ-CR (n=500) 18.8 %

with classical AEDs: Depakine®/CBZ-CR Comparable safety profile

levetiracetam vs classical AEDs
Controlled-release
Levetiracetam Depakine®
Cumulative % of patients continuously seizure free

carbamazepine
(n=835) (n=342)
LEV (n=841) (n=499)

Classical AEDs (n=847) ≥ 1 Treatment-Emergent

45.6 % 45.9 % 52.3 %
Adverse Events (TEAEs)*
HR= hazards ratio
Most frequently reported TEAEs (> 10 %)
Headache 19.3 % 17.0 % 22.4 %
Fatigue 14.4 % 11.4 % 19.0 %
HR (95 % CI)=1.20 (1.03-1.39); p=0.022 Weight increase 5.6 % 19.0 % 6.6 %
Dizziness 8.1 % 5.3 % 10.4 %

* Considered to be related to the study group

0 50 100 150 200 250 300 350 400

Days Time to first seizure
Denotes censored values are not represented (no statistically significant difference)
LEV (n=349) vs Depakine® (n=347),
HR (95% CI) = 1.19 (0.93-1.54)
LEV (n=492) vs CBZ-CR (n=500),
HR (95% CI) = 1.20 (0.99-1.46)
 Please
price in insert daily
your c
Abbreviated Prescribing Information
ountry
1. NAME AND PRESENTATION: Depakine Chronosphere / Epilim Chronosphere / Ergenyl Chronosphere / Micropakine
And much less expensive! LP 1000, 750, 500, 250, 100, 50 granules in sachet, containing sodium valproate and valproic acid corresponding
to 1000, 750, 500, 250, 100 and 50 mg sodium valproate respectively.
Depakine® 1000 mg xx € per day 2. THERAPEUTIC INDICATIONS: either in monotherapy or in combination with other antiepileptic drugs: Treatment
levetiracetam 1000 mg yy € per day of generalized epilepsy clonic, tonic, tonic-clonic, absence, myoclonic, atonic seizures; Lennox-Gastaut syndrome;
partial epilepsy; partial seizures with or without secondary generalization.

Prescriber Guide 3. DOSAGE AND ADMINISTRATION: Epilepsy: - Initiation should start at 600 mg and be increased by successive dose
Simplicity and flexibility levels at 2-3 day intervals - Substitution or addition should be progressive. Dosage ranging for adults and children
over 20 kg: from 20 to 30 mg/kg. For children under 20 kg: 20 mg/kg. See full SmPC.
Easy to initiate for you and your patients 4. CONTRA-INDICATIONS: Hypersensitivity to sodium valproate, acute liver disease, personal or family history
to severe hepatitis, especially drug related, porphyria.
Once-daily dosing 5. SPECIAL WARNINGS AND PRECAUTIONS FOR USE: Liver function tests should be carried out before therapy, and
periodically during the first 6 months. Blood tests are recommended prior to initiation of therapy or before surgery,
Flexible and in case of spontaneous bruising or bleeding. - Renal insufficiency, may need to decrease dosage. See full SmPC.

No blood monitoring required 6. DRUG INTERACTIONS: - Possible potentiation of the effect of other psychotropic drugs: antipsychotics, MAOI,
antidepressant and benzodiazepine. - Decrease or increase of plasma concentration of valproate or other drugs:
Please
in
availab sert locally
phenobarbital, primidone, phenytoine, carbamazepine, lamotrigine, felbamate, zidovudine, vitamin K-dependent
No interactions with oral contraceptive(10)
le form
ulatio
anticoagulants, telozolomide, antiepileptics with enzyme inducing effect, felbamate, mefloquine, chloroquine, highly
and pa
ckshot n
protein bound agents (aspirin), cimetidine, erythromycin, carbapenem antibiotics, colestyramine – See full SmPC.
7. PREGNANCY AND LACTATION: Adequate counseling to all women with epilepsy of child bearing potential.
For details see full SmPC. Low concentration of valproate in breast milk, but lactation is not contra-indicated.

Chronosphere
8. EFFECT ON ABILITY TO DRIVE AND USE MACHINES: risk of somnolence.

Tablets pack shot Syrup pack shot I.V. pack shot

pack shot
9. UNDESIRABLE EFFECTS: congenital and familial genetic disorders, increased liver enzymes, nausea, gastralgia,
diarrhoea, thrombocytopenia. For rare and very rare side effects see full SmPC.
10. OVERDOSAGE: symptomatic management in hospital. Haemodialysis is possible.
11. PHARMACODYNAMIC PROPERTIES: Antiepileptic (ATC code: NO3AG01).
12. MARKETING AUTHORIZATION HOLDER: Sanofi-aventis Guildford Surrey GU1 4YS UK.
Tablets Syrup I.V. Chronosphere

Woman of childbearing potential(10): Abbreviated Prescribing Information based on the UK SmPC as of June 2007.
Always refer to the full Summary of Product Characteristics (SmPC) before prescribing.
Valproate may be appropriate for women of childbearing potential after a careful evaluation of the benefit/risk ratio
related to pregnancy. (See prescribing information for more details)(10)

Dosage
References:
Initial daily dosage Targeted daily dosage Infants and children

From 10 to 15 mg/kg From 20 to 30 mg/kg* 30 mg/kg* (1) Pohlmann-Eden B et al. Poster presented at the 62nd Annual Meeting of the American Epilepsy Society,
2nd Biennial North American Regional Epilepsy Congress, December 5-9, 2008; Seattle, WA.
Depakine® should be increased gradually every 2 or 3 days in order to reach the optimal (2) Pohlmann-Eden B et al. Epilepsia 2008; 49 (suppl. 7): 448-9. (abstract).
Monotherapy dosage within a week
http://www3.interscience.wiley.com/cgi-bin/fulltext/121481280/PDFSTART
Depakine® should be introduced progressively in order to reach the optimal dosage within 2 http://www.clinicaltrials.gov/ct2/show/NCT00175903
Add-on therapy weeks; the other antiepileptic drug can be tapered according to the seizure control achieved
(3) Marson AG, Al-Kharusi AM, Alwaidh M, et al. Lancet. 2007; 369(9566): 1016-1026.
Switching from a previous (4) Perucca E. CNS Drugs 2002, 16(10): 695-714.
Maintain the same daily dose
valproate formulation
(5) Jedrzejczak J, Kuncikova M, Magureanu S. Eur J Neurol 2008, 15: 66-72.
* In some patients, dosage can be adjusted upwards without exceeding 60 mg/kg/day.
(6) Guerrini R. Pediatr Drugs 2006, 8(2): 113-129.
(7) Aldenkamp A, Vigevano F, Arzimanoglou A et al. Acta Neurol Scand 2006, 114 (suppl. 184) 1-13.

EUR.VPA 09.02.01 -
(8) Ben-Menachem E, Schmitz B, Tomson T et al. Acta Neurol Scand 2006, 114 (suppl. 184) 14-27.
(9) Perucca E, Aldenkamp A, Tallis R et al. Acta Neurol Scand 2006, 114 (suppl. 184) 28-37.
(10) Summary of Product Characteristics.