WC500169468

Administrative details:
EPITT 17956 – New signal
Leading MS: DE
MAH(s): Sanofi- Aventis, Neuraxpharm Arzneimittel GmbH, various
Background
Valproate is a well-known anti-epileptic substance. In most EU Member States nationally authorised
medicines containing valproate (as valproic acid, sodium valproate and, valproate semisodium) are
also authorised for the treatment of patients with bipolar disorder. In some Member States valproatecontaining
medicines are also approved for the prophylactic treatment of migraine.
A signal of mitochondrial toxicity in association with valproate had been received by the German
Agency from a MAH of generic valproate-containing products. The signal included 10 case reports
identified in the literature describing a temporal association between the administration of valproate
and the unmasking of mitochondrial disorders (MID) or aggravation of symptoms in patients suffering
from MIDs. DE confirmed that the signal needed initial analysis and prioritisation by the PRAC.
Discussion
MIDs are predominantly but not exclusively due to dysfunction of the respiratory chain, which is more
frequently inherited than acquired. Epilepsy is a frequent central nervous system (CNS) manifestation
of MIDs.
Comparative studies of the safety of antiepileptic drugs revealed that adverse effects on the
respiratory chain and other mitochondrial functions or structures differ between the most commonly
used drugs. In these studies, valproate was the compound with the greatest potential to interfere with
mitochondrial pathways. This suggested that valproic acid should only be the last option to treat
epilepsy in patients with MID. The PRAC acknowledged that the current product information did not
include warnings/contraindications for use of valproic acid in patients with MIDs and concluded that
further investigation was warranted.
The PRAC appointed Martin Huber (DE) as Rapporteur for the signal.
Summary of recommendation(s)
The MAH for the innovator valproate medicines (Depakine, Epilim) should submit within 90
days to the PRAC Rapporteur a review of mitochondrial toxicity following the administration of
valproate and the MAH should propose wording to be included in the product information as
appropriate.
A 60-day timetable was recommended for the assessment of this review leading to a further
PRAC recommendation.
4.3. Signals follow-up and prioritisation
4.3.1. Azithromycin (NAP)
Signal of potentially fatal heart events
Regulatory details:
PRAC Rapporteur: Terhi Lehtinen (FI)
Administrative details:
EPITT 16156 – Follow up October 2013
Pharmacovigilance Risk Assessment Committee (PRAC)
EMA/PRAC/324055/2014 Page 21/73