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Carbamazepine

Classification: C

Drug products: Carbamazepine Essential Pharma, Hermolepsin®, Hermolepsin® Retard®, Tegretal Retard, Tegretol, Tegretol Retard, Tegretol®, Tegretol® Retard, Trimonil retard

ATC code: N03AF01

Substances: carbamazepine

Summary

Carbamazepine may have negative effects on sex hormonal function in both men and women. Menstrual disturbances may occur in women on long term treatment.

One study has shown increased HDL leves in both men and women but more pronounced in women.

Carbamazepine induces metabolism of oral contraceptives and additional anticonceptive method should be used. During pregnancy, the unbound concentration of carbamazepine usually remains unchanged while the total plasma concentration may decrease. This is usually not of clinical significance. Pregnant women should use the lowest effective dose.

Additional information

Pharmacokinetics and dosing

Pharmacokinetic studies have shown men/boys to have a lower clearance and a longer half-life of carbamazepine compared to women/girls [1, 2]. In one study, men had lower clearance than women (0.039 vs. 0.049 L/h/kg) and a longer half-life than women (22.7 vs. 17.5 h) [2]. A significant difference in clearance have also been found in children (0.108 L/h/kg in boys vs. 0.72 L/h/kg in girls) [1]. However, other studies have not found significant differences in clearance between men/boys and women/girls [1].

Effects

No studies with a clincally relevant sex analysis regarding the effects of carbamazepine have been found.

Adverse effects

A comparative study found that HDL cholesterol concentration increased in both women and men taking carbamazepine. The increase was more pronounced in women. The HDL cholesterol levels in women were 27% higher than in healthy female controls. The increase of HDL cholesterol was less in men, 16% compared with healthy male controls. In healthy subjects, HDL cholesterol is higher in women than in men [3].

Carbamazepine treatment may have potentially negative effects on reproductive endocrine function in men and women. Several studies have shown that carbamazepine increased concentrations of sex hormone-binding globulin (SHBG), thus reducing unbound biologically active testosterone concentrations [4-6]. Carbamazepine is also an enzyme-inducing drug and may enhance the metabolism of sex hormones. However, these changes may be reversible. In a randomized controlled trial, withdrawal of medication three months after intervention resulted in statistically significant increases in total testosterone serum levels in both sexes, as compared to men and women in the non-withdrawal group. Women also demonstrated a significant increase in estradiol/SHBG ratio after withdrawal. These findings might explain the menstrual disorders that occur in some women after long-term treatment, due to low estradiol/SHBG ratio. It is suggested that men taking carbamazepine could have their sexual function improved by withdrawal of the agent. Likewise, withdrawal of carbamazepine in women would reduce menstrual disturbances [4]. There is one study indicating that treatment with carbamazepine (as well as oxcarbazepine and valproic acid) is associated with sperm abnormalities in men with epilepsy. The clinical relevance of this finding is unclear [7].

Carbamazepine can induce hyponatremia and female sex may have played a role in the development of hyponatremia. A suggested explanation to this might be sex-related differences in the mechanisms of sodium transport [8].

A retrospective analysis of patients on AED treatment showed fertile women to have a higher risk for skin reactions than men when treated with carbamazepine [9].

Drug interactions

Carbamazepine has an enzyme-inducing potential and can reduce plasma concentrations of estrogens and progestogens used in oral contraceptives. The effect of hormone therapy may be compromised [10]. Swedish users, please consult Janusmed Interactions(Janusmed interaktioner).

Birth defects

Swedish users, please consult Janusmed Drugs and Birth Defects(Janusmed fosterpåverkan).

Updated: 2017-03-28

Date of litterature search: 2013-02-07

References

  1. Liu H, Delgado MR. Influence of sex, age, weight, and carbamazepine dose on serum concentrations, concentration ratios, and level/dose ratios of carbamazepine and its metabolites. Ther Drug Monit. 1994;16:469-76. PubMed
  2. Marino SE, Birnbaum AK, Leppik IE, Conway JM, Musib LC, Brundage RC et al. Steady-state carbamazepine pharmacokinetics following oral and stable-labeled intravenous administration in epilepsy patients: effects of race and sex. Clin Pharmacol Ther. 2012;91:483-8. PubMed
  3. Sudhop T, Bauer J, Elger CE, von Bergmann K. Increased high-density lipoprotein cholesterol in patients with epilepsy treated with carbamazepine: a gender-related study. Epilepsia. 1999;40:480-4. PubMed
  4. Lossius MI, Taubøll E, Mowinckel P, Mørkrid L, Gjerstad L. Reversible effects of antiepileptic drugs on reproductive endocrine function in men and women with epilepsy--a prospective randomized double-blind withdrawal study. Epilepsia. 2007;48:1875-82. PubMed
  5. Herzog AG, Drislane FW, Schomer DL, Pennell PB, Bromfield EB, Dworetzky BA et al. Differential effects of antiepileptic drugs on sexual function and hormones in men with epilepsy. Neurology. 2005;65:1016-20. PubMed
  6. Duncan S, Blacklaw J, Beastall GH, Brodie MJ. Antiepileptic drug therapy and sexual function in men with epilepsy. Epilepsia. 1999;40:197-204. PubMed
  7. 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. PubMed
  8. Grikiniene J, Volbekas V, Stakisaitis D. Gender differences of sodium metabolism and hyponatremia as an adverse drug effect. Medicina (Kaunas). 2004;40:935-42. PubMed
  9. Alvestad S, Lydersen S, Brodtkorb E. Rash from antiepileptic drugs: influence by gender, age, and learning disability. Epilepsia. 2007;48:1360-5. PubMed
  10. Carbamazepine. DailyMed [www]. US National Library of Medicine. [updated 2013-03-01, cited 2013-02-07]. länk
  11. 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