1/23/2025

Janusmed kön och genus

Janusmed kön och genus – Orfiril

Janusmed kön och genus är ett kunskapsstöd som tillhandahåller information om köns- och genusaspekter på läkemedelsbehandling. Kunskapsstödet är avsedd främst för hälso- och sjukvårdspersonal. Texterna är generella och ska inte ses som behandlingsriktlinjer. Det är alltid behandlande läkare som ansvarar för patientens medicinering.

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Valproinsyra

Valproinsyra

Klass : C!

Produkter

Absenor, Absenor Depot, Convulex, Delepsine, Depakine, Depakine Retard......

Absenor, Absenor Depot, Convulex, Delepsine, Depakine, Depakine Retard, Deprakine, Ergenyl, Ergenyl 300mg/ml Lösung, Ergenyl Retard, Ergenyl chrono, Ergenyl intravenös, Orfiril, Orfiril long, Valproinsyra Ebb, valproat-biomo
ATC-koder

N03AG01

N03AG01
Substanser

natriumvalproat, valproinsyra

natriumvalproat, valproinsyra
Sammanfattning

Valproinsyra ska undvikas till flickor och kvinnor som kan tänkas bli gravida om inte villkoren i graviditetspreventionsprogrammet uppfylls. Andra behandlingsalternativ ska då övervägas.

Valproinsyra kan orsaka fosterskador och neuropsykiatrisk funktionsnedsättning hos barn som exponerats under graviditet. Av denna anledning är valproinsyra kontraindicerat under graviditet vid behandling av bipolär sjukdom. Valproinsyra är kontraindicerat under graviditet vid behandling av epilepsi om andra lämpliga behandlingsalternativ finns. För mer information, se kunskapsstödet Janusmed fosterpåverkan.

Valproinsyra kan öka risken för neuropsykiatrisk funktionsnedsättning hos barn till män som behandlats med valproinsyra under 3 månader före konception. Därför rekommenderas försiktighetsåtgärder vid behandling med valproinsyra hos män.

Kvinnor, framförallt flickor som passerat puberteten, tycks vara mer benägna till viktökning vid behandling med valproinsyra jämfört med pojkar/män. Hos kvinnor som behandlas med valproinsyra är det vanligt med störningar av hormonbalansen, som vid polycystiskt......

Valproinsyra ska undvikas till flickor och kvinnor som kan tänkas bli gravida om inte villkoren i graviditetspreventionsprogrammet uppfylls. Andra behandlingsalternativ ska då övervägas. Valproinsyra kan orsaka fosterskador och neuropsykiatrisk funktionsnedsättning hos barn som exponerats under graviditet. Av denna anledning är valproinsyra kontraindicerat under graviditet vid behandling av bipolär sjukdom. Valproinsyra är kontraindicerat under graviditet vid behandling av epilepsi om andra lämpliga behandlingsalternativ finns. För mer information, se kunskapsstödet Janusmed fosterpåverkan. Valproinsyra kan öka risken för neuropsykiatrisk funktionsnedsättning hos barn till män som behandlats med valproinsyra under 3 månader före konception. Därför rekommenderas försiktighetsåtgärder vid behandling med valproinsyra hos män. Kvinnor, framförallt flickor som passerat puberteten, tycks vara mer benägna till viktökning vid behandling med valproinsyra jämfört med pojkar/män. Hos kvinnor som behandlas med valproinsyra är det vanligt med störningar av hormonbalansen, som vid polycystiskt ovariesyndrom och hyperandrogenism. Dessa tillstånd kan leda till minskad fertilitet. Valproinsyra bör undvikas i dessa grupper med tanke på fosterriskerna.
Background

Pharmacokinetics and dosing
A small single dose pharmacokinetic study showed women, particularly women without contraceptive treatment, to have higher valproic acid exposure than men. The reason being that hepatic reabsorption was twice that in men (46% vs. 22%) [1]. Another study showed men to have a larger distribution volume than women even though the differences were mainly attributed to weight [2]. A study based on therapeutic drug monitoring data showed that women and patients over 65 years had lower daily dose and higher mean dose-adjusted serum concentrations of valproic acid, compared to men and younger patients. The authors suggest that women over 65 years would require 30-50% lower daily dose to achieve therapeutic serum concentrations comparable to younger men [3].

No studies with a clinically relevant sex analysis regarding the dosing of valproic acid have been found. The producer does not recommend different dosing in men and women [4, 5].

During pregnancy, total concentrations of valproic acid have been reported to fall in late pregnancy by up to 40% compared with......

# Pharmacokinetics and dosing A small single dose pharmacokinetic study showed women, particularly women without contraceptive treatment, to have higher valproic acid exposure than men. The reason being that hepatic reabsorption was twice that in men (46% vs. 22%) [1]. Another study showed men to have a larger distribution volume than women even though the differences were mainly attributed to weight [2]. A study based on therapeutic drug monitoring data showed that women and patients over 65 years had lower daily dose and higher mean dose-adjusted serum concentrations of valproic acid, compared to men and younger patients. The authors suggest that women over 65 years would require 30-50% lower daily dose to achieve therapeutic serum concentrations comparable to younger men [3]. No studies with a clinically relevant sex analysis regarding the dosing of valproic acid have been found. The producer does not recommend different dosing in men and women [4, 5]. During pregnancy, total concentrations of valproic acid have been reported to fall in late pregnancy by up to 40% compared with before pregnancy [6]. # Effects No controlled studies with a clinically relevant sex analysis regarding the effects of valproic acid have been found. # Adverse effects Women seem to be more prone to weight gain during valproic acid monotherapy than men. Several studies report that the increase in body weight appears to occur most frequently in post-pubertal girls. The underlying mechanism of induced weight gain by valproic acid is still unclear and various hypotheses have been suggested: dysregulation of the hypothalamic system, effect on adipokine levels, insulin and leptin resistances. It is most likely to be multifactorial [7]. A retrospective Japanese study in children with epilepsy (51 boys, 34 girls) showed that girls with loss-of-function CYP2C19 polymorphism were at risk for becoming overweight during valproic acid treatment, while no such association was observed in boys [8]. Patient’s sex can be a risk factor for hyperammonemia from valproic acid treatment. Some studies report that female sex is a risk factor [9, 10], while other studies report that male sex is a risk factor [11]. However, the number of included men and women varied between studies and other factors could explain the findings, such as differences in body weight [11]. # Reproductive health issues Valproic acid can cause fetal harm and long-term development disorders in children when administered to a pregnant woman. Swedish users, please consult Janusmed Drugs and Birth Defects (Janusmed fosterpåverkan). Valproic acid is contraindicated during pregnancy in epilepsy unless no other treatment alternatives are insufficient, and contraindicated during pregnancy in bipolar disorder. Valproic acid is contraindicated in girls and women of childbearing potential unless the terms of a special pregnancy prevention program are followed. For more information see product information for valproic acid containing products [4, 5, 12]. Valproic acid may increase the risk of neurodevelopmental disorders in children if the father is treated with valproic acid during the 3 months before conception. Therefore, precautionary measures are recommended by the EMA when treating men with valproic acid [13]. A review confirms that valproic acid in women is associated with reproductive endocrine disorders, such as PCO (Polycystic Ovarian Syndrome), high serum concentrations of testosterone and androstenedione, increased LH levels and LH/FSH ratio, and amenorrhea. These abnormalities were especially common among women who had gained weight during valproic acid therapy. PCO and hyperandrogenism seemed to be common if valproic acid was initiated before the age of 20 years. The mechanism behind this is unclear. The endocrine effects of valproic acid may be reversible after the medication is discontinued [14]. There are studies indicating that treatment with valproic acid (as well as carbamazepine and oxcarbazepine) is associated with sperm abnormalities in men with epilepsy. The clinical relevance of this finding is unclear [15, 16].
Försäljning på recept

Fler män än kvinnor hämtade ut läkemedel innehållande valproinsyra (ATC-kod N03AG01) på recept i Sverige år 2022, totalt 13 896 män och 9 415 kvinnor. Det motsvarar 2,6 respektive 1,8 personer per tusen invånare. Andelen som hämtat ut läkemedel var högst i åldersgruppen 55-59 år hos båda könen. I genomsnitt var läkemedel innehållande valproinsyra 1,6 gånger vanligare hos män [17].
Referenser
  1. Ibarra M, Vázquez M, Fagiolino P, Derendorf H. Sex related differences on valproic acid pharmacokinetics after oral single dose. J Pharmacokinet Pharmacodyn. 2013;40:479-86.
  2. Park HM, Kang SS, Lee YB, Shin DJ, Kim ON, Lee SB et al. Population pharmacokinetics of intravenous valproic acid in Korean patients. J Clin Pharm Ther. 2002;27:419-25.
  3. Smith RL, Haslemo T, Refsum H, Molden E. Impact of age, gender and CYP2C9/2C19 genotypes on dose-adjusted steady-state serum concentrations of valproic acid-a large-scale study based on naturalistic therapeutic drug monitoring data. Eur J Clin Pharmacol. 2016;72(9):1099-104.
  4. Absenor (valproic acid). Summary of Product Characteristics. Swedish Medical Products Agency; 2018.
  5. Ergenyl (valproic acid). Summary of Product Characteristics. Swedish Medical Products Agency; 2018.
  6. Tomson T, Landmark CJ, Battino D. Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications. Epilepsia. 2013;54:405-14.
  7. Verrotti A, D'Egidio C, Mohn A, Coppola G, Chiarelli F. Weight gain following treatment with valproic acid: pathogenetic mechanisms and clinical implications. Obes Rev. 2011;12:e32-43.
  8. Noai M, Soraoka H, Kajiwara A, Tanamachi Y, Oniki K, Nakagawa K et al. Cytochrome P450 2C19 polymorphisms and valproic acid-induced weight gain. Acta Neurol Scand. 2016;133(3):216-23.
  9. Yamamoto Y, Takahashi Y, Imai K, Mishima N, Yazawa R, Inoue K et al. Risk factors for hyperammonemia in pediatric patients with epilepsy. Epilepsia. 2013;54(6):983-9.
  10. Yamamoto Y, Takahashi Y, Suzuki E, Mishima N, Inoue K, Itoh K et al. Risk factors for hyperammonemia associated with valproic acid therapy in adult epilepsy patients. Epilepsy Res. 2012;101(3):202-9.
  11. Tseng YL, Huang CR, Lin CH, Lu YT, Lu CH, Chen NC et al. Risk factors of hyperammonemia in patients with epilepsy under valproic acid therapy. Medicine (Baltimore). 2014;93(11):e66.
  12. Läkemedelsverket. Valproat: Nya användningsbegränsningar; implementering av graviditetspreventionsprogrammet. Läkemedelsverket [www]. [cited 2018-09-28].
  13. Potential risk of neurodevelopmental disorders in children born to men treated with valproate medicines: PRAC recommends precautionary measures. European Medicines Agency (EMA) [www]. [updated 2024-01-12, cited 2024-01-19].
  14. Verrotti A, D'Egidio C, Mohn A, Coppola G, Parisi P, Chiarelli F. Antiepileptic drugs, sex hormones, and PCOS. Epilepsia. 2011;52:199-211.
  15. Isojärvi JI, Löfgren E, Juntunen KS, Pakarinen AJ, Päivänsalo M, Rautakorpi I et al. Effect of epilepsy and antiepileptic drugs on male reproductive health. Neurology. 2004;62:247-53.
  16. Ocek L, Tarhan H, Uludağ FI, Sarıteke A, Köse C, Colak A et al. Evaluation of sex hormones and sperm parameters in male epileptic patients. Acta Neurol Scand. 2018;137(4):409-416.
  17. Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2022 [cited 2023-03-02.]
Uppdaterat

Litteratursökningsdatum: 1/19/2024

Litteratursökningsdatum: 1/19/2024
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