Interactions : אינטראקציות

4.5    Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
The efficacy of estrogens and progestogens might be impaired:
• The metabolism of estrogens and progestogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically the P450 enzymes 2B6, 3A4, 3A5, 3A7, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamezapin) and anti-infectives (e.g.
rifampicin, rifabutin, nevirapine, efavirenz).
• Ritonavir and nelfinavir, although known as strong inhibitors of CYP450 3A4, A5, A7, by contrast exhibit inducing properties when used concomitantly with steroid hormones.
• Herbal preparations containing St John’s Wort (Hypericum perforatum) may induce the metabolism of estrogens and progestogens via the CYP450 3A4 pathway.
• Clinically an increased metabolism of estrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.


Effect of HRT with estrogens on other medicinal products
Hormone contraceptives containing estrogens have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both medicinal products together.

Pharmacodynamic interactions
During     clinical   trials    with    the   HCV      combination     drug     regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Women using medicinal products containing estrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of women taking these other estrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen with glecaprevir/pibrentasvir (see section 4.4).
Estrogens might interfere with the metabolism of other drugs:
Estrogens per se may inhibit CYP450 drug-metabolising enzymes via competitive inhibition. This is in particular to be considered for substrates with a narrow therapeutic index, such as:
- tacrolimus and cyclosporine A (CYP450 3A4, 3A3)
- fentanyl (CYP450 3A4)
- theophylline (CYP450 1A2).
Clinically this may lead to an increased plasma level of the affected substances up to toxic concentrations. Thus, careful drug monitoring for an extended period of time might be indicated and a dosage decrease of tacrolimus, fentanyl, cyclosporin A and theophylline may be necessary.