Does St John´s wort interact with carbamazepine and thereby increase the risk of unexpected seizure

Fråga: Does St John´s wort interact with carbamazepine and thereby increase the risk of unexpected seizures?

A 16-year-old male patient with autism, epilepsy and developmental disorder is under care at an anthroposophy nursing home. He is currently treated with carbamazepine 1000mg daily for epilepsy. During the autumn 2000 treatment with St John´s wort was initiated for depression and soon thereafter the patient suffered from unexpected seizures.

There was no dose change of carbamazepine at that time. However plasma levels were not measured. Treatment with St John´s wort ceased and the patient´s epilepsy was stabilised.

Sammanfattning: St John´s wort is a non-selective inducer of the metabolising cytochrome P450 enzymes. No previous reports of interactions between carbamazepine and St John´s wort have been published. Carbamazepine is metabolised by CYP3A4 and both carbamazepine and St John´s wort are inducers of the same enzyme. This, together with the fact that the seizures were well-controlled before the addition of St John´s wort and after its withdrawal strongly suggests a causal relationship. The Swedish medical product agency recommends that all concomitant medication with St John´s wort should be avoided.

Svar: St John´s wort is a non-selective inducer of the cytochrome P450 enzymes and there are several clinical reports of pharmacokinetic interactions between St John´s wort and drugs metabolised by these enzymes (1-5). Pharmacokinetic interactions, due to induction of cytochrome P450 isoenzyme CYP3A4, have been documented for concurrent use of St John´s wort and oral contraceptives (1-3,5), cyclosporine (1,4,5) or indinavir (1,6).

St John´s wort consists of several (7) alkaloids with hypericum and hyperforin being the most pharmacologically active agents. An in vitro study has shown that hyperforin is a potent ligand for the pregnane X receptor, an orphan nuclear receptor that regulates the expression of the CYP3A4 enzyme. A marked induction of CYP3A4 expression was seen after treatment of human hepatocytes with St John´s wort extract. This study further supports that St John´s wort extract is likely to interact with drugs metabolised via this pathway. It also suggests that hypericum might not be the only alkaloid in St John´s wort extract responsible for induction of cytochrome P450 enzymes (8).

Carbamazepine is extensively metabolised in the liver by CYP3A4 and can also induce the same enzyme (9,10). No previous report of interactions between carbamazepine and St John´s wort has been documented. There is a potential risk of a pharmacokinetic drug interaction since both drugs affect CYP3A4. It is plausible to assume that the unexpected seizures have been caused by an induction of CYP3A4 of both St John´s wort and carbamazepine, leading to an increased metabolism of carbamazepine and result in a lower concentration of the latter. Unfortunately, plasma concentration of carbamazepine was not measured at that time. There is no known pharmacodynamic interaction on receptor or transduction levels. The Swedish medical product agency recommends that all concomitant medication with St John´s wort should be avoided (11).

We recommend that this case be reported to the Regional Center of the Swedish Adverse Reactions Advisory Committee (SADRAC). 1 FASS 2000 (The Swedish catalogue of approved medical products), interactions chapter

2 Drugline no 17086 (year 2000)
3 Drugline no 16596 (year 2000)
4 Fugh-Berman A. Herb-drug interactions. The Lancet 2000; 355: 134-8

5 Yue Q Y, Bergquist C. Johannesört kan ge oönskade interaktioner med många viktiga läkemedel. Information från läkemedelsverket 1999 (http://www.mpa.se/observanda/obs99/johannesort.shtml; cited 20000505) 6 Yue Q Y, Bergquist C, Gerden B. Ytterligare information om interaktioner mellan Johannesört och andra läkemedel 2000 (http://www.mpa.se/bivekrningar/biv00/johannesort0405.shtml; cited 20000505) 7 Naturläkemedel 2000. Stockholm: Hälsokostrådets Förlag 1999; 200-201 8 Moore L B, Goodwin B, Jones S A, Wisely G B, Serbjit-Singh C, Willson T M, Collins J L, Kliewer S A. St John´s wort induces hepatic drug metabolism through activiation of the pregnane X receptor. PNAS 2000; 97: 7500-2 9 Drugline no 17221 (year 2000) 10 Drugline no 13975 (year 1996) 11 Yue Q Y, Ahlqvist R. Johannesörtpreparat skall inte användas tillsammmans med andra läkemedel 2000 (http://www.mpa.se/observanda/obs00/johannesort.shtlm; cited 20000505)