Fenytoin
Klassificering: CATC kod: N03AB02
Sammanfattning
Det saknas kontrollerade studier om skillnader mellan könen avseende effekt, säkerhet eller farmakokinetik för fenytoin förutom i samband med graviditet.
Fysiologiska förändringar vid graviditet kan förändra plasmakoncentrationen av fenytoin och därmed kan anfallsfrekvensen hos kvinnan öka. Tätare koncentrationsmätning av fenytoin under graviditet är därför motiverat.
Fenytoin kan påverka metabolismen av p-piller och kompletterande antikonceptiv metod bör användas.
Additional information
Pharmacokinetics and dosing
A randomized controlled trial in healthy subjects (12 men, 12 women) showed that the mean AUC, normalized for the mg/kg phenytoin dose, was about 30% lower in women than men. This might be explained by a more rapid elimination in women. This counterbalance the generally lower weight in women that result in higher phenytoin concentration levels [1]. Another study (39 men, 24 women) found no difference between men and women in phenytoin clearance, distribution volume or half-life. Men and women received the same daily dose (4.8 mg/kg/day) and trough phenytoin concentrations were similar between men and women [2]. Dose regimens for phenytoin do not need to be adjusted based on sex, since the more rapid elimination in women counterbalance the generally lower weight that result in higher phenytoin concentration levels [1].
A study examining binding characteristics of phenytoin to serum proteins in healthy adults (40 men, 40 women) on monotherapy found no sex differences. The affinity of phenytoin to serum proteins was similar in men and women, and sex does not have a significant effect on binding characteristics of phenytoin to serum proteins in adult patients [3].
Phenytoin pharmacokinetics is altered during pregnancy. For appropriate dose adjustment in pregnant women, periodic measurement of plasma phenytoin concentrations may be valuable [4].
Effects
No studies with a clinically relevant sex analysis regarding effects of phenytoin have been found.
Adverse effects
Enzyme-inducing antiepileptic drugs, such as carbamazepine, phenytoin and lamotrigine, can contribute to reproductive disorders among men with epilepsy. These antiepileptic drugs (AEDs) increase SHBG (sex hormone-binding globulin) and thereby decreasing free androgens. This may result in sexual dysfunction, as demonstrated by lower scores on a standardized sexual function questionnaire. A study in 85 men with epilepsy treated with carbamazepine, phenytoin, lamotrigine or no AEDs, showed that 32% had scores below the control group and 24% of men treated with phenytoin had scores below the control group. SHBG was significantly higher in carbamazepine and phenytoin groups than in all other groups. However, most studies evaluating sex steroid hormone profiles in men and women treated with enzyme-inducing AEDs were cross-sectional with limited controls groups [5]. A retrospective analysis analysis (320 men, 343 women) of patients on AED treatment showed fertile women to have a higher risk for skin reactions than men when treated with phenytoin [6].
Reproductive health issues
Phenytoin may affect the metabolism of estrogens and progestogens. Thus, the effect of these can be reduced. Additional contraceptive method should be used [7]. Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Försäljning på recept
Något fler män än kvinnor hämtade ut tabletter/kapslar innehållande fenytoin (ATC-kod N03AB02) på recept i Sverige år 2015, totalt 2 726 män och 2 342 kvinnor. Det motsvarar 0,6 respektive 0,5 personer per tusen invånare. Andelen som hämtat ut läkemedel var högst i åldersgruppen 60 år och äldre hos båda könen. I genomsnitt var tabletter/kapslar innehållande fenytoin 1,4 gånger vanligare hos män [8].
Uppdaterat: 2017-03-28
Litteratursökningsdatum: 2013-02-06
Referenser
- Meyer MC, Straughn AB, Mhatre RM, Shah VP, Chen ML, Williams RL et al. Variability in the bioavailability of phenytoin capsules in males and females. Pharm Res. 2001;18:394-7. PubMed
- Ahn JE, Cloyd JC, Brundage RC, Marino SE, Conway JM, Ramsay RE et al. Phenytoin half-life and clearance during maintenance therapy in adults and elderly patients with epilepsy. Neurology. 2008;71:38-43. PubMed
- Kodama H, Kodama Y, Shinozawa S, Kanemaru R, Todaka K, Mitsuyama Y. No gender effect on binding characteristics of phenytoin to serum proteins in monotherapy for adult patients with epilepsy. Am J Ther. 2000;7:285-9. PubMed
- Phenytoin. DailyMed [www]. US National Library of Medicine. [updated 2010-11-01, cited 2013-02-06]. länk
- Brodie MJ, Mintzer S, Pack AM, Gidal BE, Vecht CJ, Schmidt D. Enzyme induction with antiepileptic drugs: cause for concern?. Epilepsia. 2013;54:11-27. PubMed
- Alvestad S, Lydersen S, Brodtkorb E. Rash from antiepileptic drugs: influence by gender, age, and learning disability. Epilepsia. 2007;48:1360-5. PubMed
- Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol. 2003;2:347-56. PubMed
- Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2015 [cited 2016-04-29] länk
Faktagranskat av: Expertrådet för neurologiska sjukdomar, Ellen Vinge
Godkänt av: Mia von Euler