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Phenytoin

Classification: C

Drug products: Epanutin®, Fenantoin RPH Pharma, Lehydan®, Phenytoin Sodium Flynn

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. Monitoring of phenytoin concentrations during pregnancy is recommended.
 

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

Additional information

Pharmacokinetics and dosing

A 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) of phenytoin or fosphenytoin and trough phenytoin concentrations were similar between men and women [4].Also, 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 body weight in women that results in higher phenytoin concentration levels [5]. Dose regimens for phenytoin do not need to be adjusted based on patient’s sex, since the more rapid elimination in women counterbalance the generally lower weight that result in higher phenytoin concentration levels [5].

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 patient’s sex does not have a significant effect on binding characteristics of phenytoin to serum proteins in adult patients [6].

Effects

No studies with a clinically relevant sex analysis regarding effects of phenytoin have been found.

Adverse effects

A retrospective analysis (320 men, 343 women) of patients on antiepileptic drug treatment showed fertile women to have a higher risk for skin reactions than men when treated with phenytoin [7].

Reproductive health issues

Enzyme-inducing antiepileptic drugs, such as carbamazepine, phenytoin and phenobarbital, may have potentially negative effects on reproductive endocrine function in men and women. These antiepileptic drugs increase concentrations of sex hormone-binding globulin (SHBG) and thereby reducing the concentrations of unbound biologically active androgens [1-3]. This may result in sexual dysfunction. 

Phenytoin pharmacokinetics is altered during pregnancy resulting in lower plasma concentrations and thus, an increased risk of seizures. For appropriate dose adjustment in pregnant women, monitoring of plasma phenytoin concentrations is recommended [8]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Phenytoin may affect the metabolism of estrogens and progestogens. Thus, the effect of these can be reduced. Additional contraceptive method should be used [9]. Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).

Updated: 2020-04-03

Date of litterature search: 2019-10-11

References

  1. Duncan S, Blacklaw J, Beastall GH, Brodie MJ. Antiepileptic drug therapy and sexual function in men with epilepsy. Epilepsia. 1999;40:197-204. PubMed
  2. Svalheim S, Sveberg L, Mochol M, Taubøll E. Interactions between antiepileptic drugs and hormones. Seizure. 2015;28:12-7. PubMed
  3. Yogarajah M, Mula M. Sexual Dysfunction in Epilepsy and the Role of Anti-Epileptic Drugs. Curr Pharm Des. 2017;23(37):5649-5661. PubMed
  4. 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
  5. 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
  6. 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
  7. Alvestad S, Lydersen S, Brodtkorb E. Rash from antiepileptic drugs: influence by gender, age, and learning disability. Epilepsia. 2007;48:1360-5. PubMed
  8. Phenytek (phenytoin). DailyMed [www]. U.S. National Library of Medicine [updated 2018-02-15, cited 2019-10-14]. länk
  9. Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol. 2003;2:347-56. PubMed
  10. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2019 [cited 2020-03-10.] länk

Authors: Linnéa Karlsson Lind

Reviewed by: Mia von Euler, Carl-Olav Stiller, Diana Rydberg

Approved by: Karin Schenck-Gustafsson