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Phenytoin

Classification: C

Drug products: Epanutin®, Fenantoin Meda, Lehydan®

ATC code: N03AB02

Substances: phenytoin, phenytoin sodium

Summary

Randomized controlled studies on differences between men and women in efficacy, safety, or pharmacokinetics of phenytoin are lacking except for studies in pregnant women.

Physiological changes during pregnancy may alter plasma concentrations of phenytoin and thus the seizure frequency can increase.

Phenytoin can affect the metabolism of oral contraceptives and additional contraception should be used.

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).

Updated: 2017-03-28

Date of litterature search: 2013-02-06

References

  1. 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
  2. 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
  3. 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
  4. Phenytoin. DailyMed [www]. US National Library of Medicine. [updated 2010-11-01, cited 2013-02-06]. länk
  5. 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
  6. Alvestad S, Lydersen S, Brodtkorb E. Rash from antiepileptic drugs: influence by gender, age, and learning disability. Epilepsia. 2007;48:1360-5. PubMed
  7. Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol. 2003;2:347-56. PubMed
  8. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2015 [cited 2016-04-29] länk

Authors: Linnéa Karlsson Lind, Desirée Loikas

Reviewed by: Expertrådet för neurologiska sjukdomar, Ellen Vinge

Approved by: Mia von Euler