Interactions : אינטראקציות

4.5      Interaction with other medicinal products and other forms of interaction
Note: The prescribing information of concomitant medication should be consulted to identify potential interactions.

•      Effects of other medicinal products on Visabelle

Progestogens including dienogest are metabolized mainly by the cytochrome P450 3A4 system (CYP3A4) located both in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 may affect the progestogen drug metabolism.
An increased clearance of sex hormones due to enzyme induction may reduce the therapeutic effect of Visabelle and may result in undesirable effects e.g., changes in the uterine bleeding profile.

A reduced clearance of sex hormones due to enzyme inhibition may increase the exposure to dienogest and may result in undesirable effects.

-   Substances increasing the clearance of sex hormones (diminished efficacy by enzyme- induction), e.g.: phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing St. John’s wort (Hypericum perforatum).


Enzyme induction can already be observed after a few days of treatment. Maximum enzyme induction is generally seen within a few weeks after cessation of drug therapy enzyme induction may be sustained for about 4 weeks.


The effect of the CYP 3A4 inducer rifampicin was studied in healthy postmenopausal women.
Co-administration of rifampicin with estradiol valerate/dienogest tablets led to significant decreases in steady state concentrations and systemic exposures of dienogest and estradiol. The systemic exposure of dienogest and estradiol at steady state, measured by AUC(0-24h), were decreased by 83% and 44%, respectively.

-    Substances with variable effects on the clearance of sex hormones: When co-administered with sex hormones, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentrations of the progestin. The net effect of these changes may be clinically relevant in some cases.
-   Substances decreasing the clearance of sex hormones (enzyme inhibitors) Dienogest is a substrate of cytochrome P450 (CYP) 3A4.
The clinical relevance of potential interactions with enzyme inhibitors remains unknown.
Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations of dienogest.
Coadministration with the strong CYP3A4 enzyme inhibitor ketoconazole resulted in a 2.9-fold increase of AUC (0-24h) at steady state for dienogest. Concomitant administration of the moderate inhibitor erythromycin increased the AUC (0-24h) of dienogest at steady state by 1.6- fold



•    Effects of Visabelle on other medicinal products
Based on in vitro inhibition studies, a clinically relevant interaction of dienogest with the cytochrome P450 enzyme mediated metabolism of other medication is unlikely.
•     Interaction with food.

A standardized high fat meal did not affect the bioavailability of Visabelle.

•   Laboratory tests
The use of progestogens may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins (e.g. corticosteroid binding globulin and lipid/lipoprotein fractions), parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.