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Karbamazepin

Klassificering: C

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

ATC kod: N03AF01

Substanser: karbamazepin

Sammanfattning

Karbamazepin kan ha negativa, men vanligen reversibla, effekter på könshormonfunktion hos både kvinnor och män. En del kvinnor med långtidsbehandling kan få menstruella störningar.

Karbamazepin kan påverka metabolismen av p-piller och kompletterande antikonceptiv metod bör användas. Under graviditet är obunden koncentration av karbamazepin väsentligen oförändrad, medan total plasmakoncentration kan minska. Detta brukar dock inte vara kliniskt relevant. Gravida kvinnor bör ordineras lägsta möjliga dosering som ger anfallskontroll.

En studie har visat att karbamazepin ökar koncentrationen av HDL- och LDL-kolesterol hos både kvinnor och män, möjligen kan ökningen var större hos kvinnor.

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 [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) [5]. 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) [4]. However, other studies have not found significant differences in clearance between men/boys and women/girls [4].

Effects

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

Adverse effects

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%) [6]. 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 [7].

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 [8]. 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 [9].

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 [10].

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.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 [11].

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 [15].

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Försäljning på recept

Fler män än kvinnor hämtade ut läkemedel innehållande karbamazepin (ATC-kod N03AF01) på recept i Sverige år 2019, totalt 14 421 män och 12 074 kvinnor. Det motsvarar 2,8 respektive 2,4 personer per tusen invånare. Andelen som hämtat ut var högst i åldersgruppen 75 år och äldre hos båda könen. I genomsnitt var läkemedel innehållande karbamazepin 1,4 gånger vanligare hos män [16].

Uppdaterat: 2020-04-06

Litteratursökningsdatum: 2019-09-20

Referenser

  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. 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
  5. 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
  6. 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
  7. Yamamoto Y, Terada K, Takahashi Y, Imai K, Kagawa Y, Inoue Y. Influence of antiepileptic drugs on serum lipid levels in adult epilepsy patients. Epilepsy Res. 2016;127:101-106. 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. Berghuis B, van der Palen J, de Haan GJ, Lindhout D, Koeleman BPC, Sander JW et al. Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy. Epilepsia. 2017;58(7):1227-1233. PubMed
  10. Alvestad S, Lydersen S, Brodtkorb E. Rash from antiepileptic drugs: influence by gender, age, and learning disability. Epilepsia. 2007;48:1360-5. PubMed
  11. 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
  12. 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
  13. Ocek L, Tarhan H, Uludağ FI, Sarıteke A, Köse C, Colak A et al. Evaluation of sex hormones and sperm parameters in male epileptic patients. Acta Neurol Scand. 2018;137(4):409-416. PubMed
  14. Asadi-Pooya A, Farazdaghi M, Ashjazadeh N. Effects of carbamazepine on semen parameters in men with newly diagnosed epilepsy. Iran J Neurol. 2015;14(3):168-70. PubMed
  15. Wu D, Chen L, Ji F, Si Y, Sun H. The effects of oxcarbazepine, levetiracetam, and lamotrigine on semen quality, sexual function, and sex hormones in male adults with epilepsy. Epilepsia. 2018;59(7):1344-1350. PubMed
  16. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2019 [cited 2020-03-10.] länk

Författare: Linnéa Karlsson Lind

Faktagranskat av: Mia von Euler, Carl-Olav Stiller, Diana Rydberg

Godkänt av: Karin Schenck-Gustafsson