Drug products: Carbamazepine Essential Pharma, Hermolepsin®, Hermolepsin® Retard®, Tegretal Retard, Tegretol, Tegretol Retard, Tegretol®, Tegretol® Retard, Trimonil retard
ATC code: N03AF01
Carbamazepine may have negative effects on sex hormonal function in both men and women. Menstrual disturbances may occur in women on long term treatment.
Carbamazepine induces metabolism of oral contraceptives and additional contraceptive 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.
One study has shown increased HDL and LDL levels in both men and women, the increase may be more pronounced in women.
Pharmacokinetic studies have shown men/boys to have a lower clearance and a longer half-life of carbamazepine compared to women/girls [4, 5]. In one study (45 men, 47 women), 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) . A significant difference in clearance have also been found in children (0.108 L/h/kg in boys vs. 0.072 L/h/kg in girls) (25 boys, 30 girls) . However, other studies have not found significant differences in clearance between men/boys and women/girls .
No studies with a clinically relevant sex analysis regarding the effects of carbamazepine have been found.
In healthy individuals, HDL cholesterol is higher in women than in men. A comparative study (71 men, 56 women) found that HDL cholesterol concentrations increased in both women and men taking carbamazepine. The increase was more pronounced in women; compared to healthy controls the HDL cholesterol levels in women were 27% higher than in healthy female controls. The increase of HDL cholesterol was less in men, 16% higher in men treated with carbamazepine compared with healthy male controls. Also LDL cholesterol increased more in women than in men (+38% vs. +17%) . Another study showed that elevated non-HDL cholesterol in patients treated with either carbamazepine, phenytoin or phenobarbital (1824 men, 1390 women) was associated with male sex, increasing age and increasing BMI .
Carbamazepine can induce hyponatremia and women may be at higher risk than men of developing hyponatremia. A suggested explanation to this is that there are sex-related differences in the mechanisms of sodium transport . In contrast to the previous finding, a register-based study in epilepsy patients (292 men, 1132 women) showed no significant sex difference in frequency of hyponatremia (≤134 mEq/L) in carbamazepine-treated men and women .
A retrospective analysis of patients on antiepileptic drug treatment showed fertile women to have a higher risk for skin reactions than men when treated with carbamazepine .
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.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 .
The plasma concentrations of estrogens and progestogens may be decreased by coadministration of carbamazepine. The effect of hormone therapy may therefore be impaired. Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).
There are studies indicating that treatment with carbamazepine (as well as oxcarbazepine and valproic acid) is associated with sperm abnormalities in men with epilepsy [2, 12-14]. The clinical relevance of this finding is unclear. However, it is possible that the epilepsy itself affect the sperm quality, since decreased levels have been seen in men with epilepsy even before antiepileptic drug treatment .
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2019-09-20
Reviewed by: Mia von Euler, Carl-Olav Stiller, Diana Rydberg
Approved by: Karin Schenck-Gustafsson