The Pharmacovigilance Risk Assessment Committee (PRAC), based on the analysis of Periodic Safety Update Reports (PSURs) for medicinal products containing valproates (see the original text), made the following conclusions.
Given the available literature data and data from spontaneous reports on eye malformations resulting from in utero exposure, PRAC considers the causal relationship between the use of medicinal products containing valproate and eye malformations to be established. 23 cases of retinal fold/rosette-like retina/coloboma and retinal coloboma were reported in children exposed to valproate in utero. All cases were serious. In most cases valproate was used as monotherapy and the daily dose used by the mothers did not exceed the therapeutic dose range. In 22 of 23 (95,7%) cases, associated congenital malformations were reported, including fetal anticonvulsant syndrome in 13. The 23 cases described indicate that 18 cases occurred in children with facial dysmorphism/dysmorphism. PRAC concluded that the instructions for medical use of medicinal products containing valproate should be amended accordingly.
In addition, in view of the available data, including 2 cases in which serum valproate levels and lack of seizure control were reported when valproate was administered to patients on hemodialysis, the PRAC considers the cumulative evidence sufficient to include in the section “Method of administration and doses” of the instructions for medical use a warning that patients with end-stage renal failure on hemodialysis may experience a lack of therapeutic effect.
The Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) agrees with the PRAC scientific conclusions.
Based on the scientific conclusions, the CMDh considers that the benefit/risk balance of medicinal products containing valproates remains unchanged, taking into account the proposed amendments to the instructions for medical use.
Amendments to be included in the relevant sections of the package insert (new text underlined in bold, deleted text struck through).
Section “Use during pregnancy or breastfeeding. Pregnancy. Breastfeeding period. Fertility”
Intrauterine exposure to valproates may also lead to hearing impairment or deafness due to malformations of the ear and/or nose (secondary effect) and/or a direct toxic effect on hearing function. The cases describe both unilateral and bilateral deafness or hearing impairment. The outcomes were not known in all cases. In most cases with a known outcome, recovery did not occur.
Intrauterine exposure to valproates may lead to eye malformations (including colobomas, microphthalmia), which have been reported in combination with other congenital malformations. These eye malformations may affect vision.
Section "Posology and method of administration"
In patients with renal impairment
Patients with renal impairment may require a dose reduction, or patients on hemodialysis may require a dose increase. [active substance] is dialyzable (see section “Overdose”). The dose should be adjusted according to the clinical monitoring of the patient (see section “Special warnings and precautions for use”).
Preclinical safety data
In repeat-dose toxicity studies, testicular degeneration/atrophy or abnormalities of spermatogenesis and decreased testicular weight were reported in adult rats and dogs after oral administration at doses of 1250 mg/kg/day and 150 mg/kg/day, respectively.
In juvenile rats, a decrease in testicular weight was observed only at doses exceeding the maximum tolerated dose (from 240 mg/kg/day intraperitoneally or intravenously) without associated histopathological changes. At tolerated doses (up to 90 mg/kg/day), no effect on male reproductive organs was noted. Based on these data, the effect on the testes of juvenile animals was not considered more pronounced than in adults. The result of testicular sensitivity to the effect of valproates for the pediatric population is unknown.
In a fertility study in rats, valproate at doses up to 350 mg/kg/day did not affect male reproductive function. However, male infertility has been identified as an adverse reaction in humans (see the sections “Use during pregnancy or breastfeeding. Pregnancy. Breastfeeding. Fertility” and “Adverse reactions”).
Перелік лікарських засобів, що містять вальпроат (valproate) і дозволені до медичного застосування в Україні (за даними Державного реєстру лікарських засобів України станом на 06.12.2021).
To analyze the published information, the applicant must use the original text available at the linkhttps://www.ema.europa.eu/en/documents/psusa/valproic-acid-sodium-valproate-valproate-pivoxil-valproate-semisodium-valpriomide-valproate-bismuth_en-0.pdf
