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Phenobarbital

Classification: A

Drug products: Fenemal Meda, Fenobarbital APL, Luminal

ATC code: N03AA02

Substances: phenobarbital, phenobarbital sodium

Summary

One study has shown that men treated with phenobarbital had higher prolactin levels compared to healthy men.

Phenobarbital increases the metabolism of oral contraceptives and additional contraception should be used. During pregnancy, serum concentration of phenobarbital decreases 50-55% and even more up to 70% in primidon derived phenobarbital.

Additional information

Pharmacokinetics and dosing

Several studies have shown that patient’s sex does not significantly improve the estimate of phenobarbital clearance, neither in neonatal, infants or elderly [4, 5]. A review article on clinical pharmacokinetics in pediatric patients concludes that no sex differences on phenobarbital C/D ratios (ratio between plasma concentrations and dose/kg) were found [6].

Effects

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

Adverse effects

A study evaluated prolactin secretion in patients with partial or generalized epilepsy (78 men, 56 women; aged 13-60 years) treated with phenobarbital alone or in combination with either phenytoin or benzodiazepines. An increase in baseline prolactin values was observed in men in all treatment groups, but not in women, compared with healthy controls [7]. Abnormal prolactin levels may be associated with sexual dysfunction [8].

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. 

Concurrent administration of phenobarbital and oral contraceptives may decrease the effect of estradiol. Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).

In pregnant women, the concentration of phenobarbital is decreased up to 50-55%. The lowered serum concentration is even more pronounced in primidone derived phenobarbital, up to 70% [9]. This may necessitate dose adjustments and therapeutic drug monitoring. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Updated: 2020-04-03

Date of litterature search: 2019-08-28

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. Messina S, Battino D, Croci D, Mamoli D, Ratti S, Perucca E. Phenobarbital pharmacokinetics in old age: a case-matched evaluation based on therapeutic drug monitoring data. Epilepsia. 2005;46:372-7. PubMed
  5. Yukawa M, Yukawa E, Suematsu F, Takiguchi T, Ikeda H, Aki H et al. Population pharmacokinetics of phenobarbital by mixed effect modelling using routine clinical pharmacokinetic data in Japanese neonates and infants: an update. J Clin Pharm Ther. 2011;36:704-10. PubMed
  6. Battino D, Estienne M, Avanzini G. Clinical pharmacokinetics of antiepileptic drugs in paediatric patients Part I: Phenobarbital, primidone, valproic acid, ethosuximide and mesuximide. Clin Pharmacokinet. 1995;29:257-86. PubMed
  7. Bonuccelli U, Murialdo G, Rossi G, Bonura ML, Polleri A, Murri L. Prolactin secretion in epileptic subjects treated with phenobarbital: sex differences and circadian periodicity. Epilepsia. 1986;27:142-8. PubMed
  8. Calafato MS, Austin-Zimmerman I, Thygesen JH, Sairam M, Metastasio A, Marston L et al. The effect of CYP2D6 variation on antipsychotic-induced hyperprolactinaemia: a systematic review and meta-analysis. Pharmacogenomics J. 2020. PubMed
  9. Tomson T, Landmark CJ, Battino D. Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications. Epilepsia. 2013;54:405-14. 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