Interactions : אינטראקציות

4.5. Interaction with other medicinal products and other forms of interaction
Interactions between ethinyloestradiol and other drugs can cause a decrease or increase in plasma levels of ethinyloestradiol.

The decrease in plasma levels of ethinyloestradiol can increase the incidence of intermenstrual bleeding and menstrual irregularities and may reduce the efficacy of the oral contraceptive. During concomitant use of substances that may lead to decreased ethyniestradiol serum concentrations, it is recommended that an additional non-hormonal, mechanical method of contraception (condoms, spermicides etc.) be used. Another method of contraception should be considered in the case of prolonged usage of these drugs.

After the discontinuation of drugs capable of reducing serum concentrations of ethinyloestradiol, it is recommended that an additional non-hormonal, mechanical method of contraception (condoms, spermicides etc.) be used for at least seven days. In the case of treatment with hepatic enzyme inducers, these measures must be observed for longer. It can actually take several weeks until the induction of enzymes has completely stopped, depending on the dose administered, the duration of treatment and the levels of elimination of the inducer.

Contraindicated association
An interaction has been observed between oral contraceptives and St. John's Wort (Hypericum perforatum). This interaction is probably due to an induction of certain cytochrome P450 isoenzymes by Hypericum perforatum. St. John's Wort (Hypericum perforatum) should therefore not be used at the same time as oral contraceptives.

Non-recommended associations
Decrease in plasma levels of ethinylestradiol:
- any drug capable of reducing gastrointestinal transit time.
- enzyme inducers: anticonvulsants (barbiturates, phenytoin, primidone, carbamazepine, topiramate, felbamate), dexamethasone, phenylbutazone, rifabutin, rifampicin, griseofulvin.

Reduction in contraceptive efficacy through an increase in hepatic metabolism during treatment and one cycle after ending treatment.
-   ritonavir (probably by induction of hepatic enzymes)
-   modafinil: risk of reduction in contraceptive efficacy during treatment and one cycle after ending treatment with modafinil.
-   Probably also oxcarbazepine and nevirapine

Increase in plasma levels of ethinylestradiol:
- atorvastatin
- ascorbic acid and paracetamol
- drugs that inhibit cytochrome P450 3A4 isoenzymes such as indinavir, fluconazole, voriconazole, troleandomycin (which can increase the risk of intrahepatic cholestasis during concomitant administration of oral CHCs), ketoconazole and itraconazole.

Others
Oral antidiabetic or insulin requirements can be modified by the effect of oral contraceptives on glucose tolerance.

Oral contraceptives can influence the metabolism of other drugs by inhibiting hepatic microsomal enzymes, or by inducing hepatic drug conjugation, particularly glucuronidation or by other mechanisms. Tissue or plasma concentrations of these drugs may be reduced (e.g. lamotrigine, levothyroxine, valproate) or increased (for example theophylline, ciclosporin, corticosteroids, oral anticoagulants), but the clinical significance is not always clear.

In patients treated with flunarizine: risk of galactorrhoea through the flunarizine-induced increase in sensitivity of breast tissue to prolactin.

The Summary of Product Characteristics (section "Interactions") should be consulted for all concomitant medication.

Pharmacodynamic interactions
During clinical trials with patients treated for hepatitis C virus infections (HCV) with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequently in women using ethinylestradiol containing medications such as combined hormonal contraceptives (CHCs). Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs (see section 4.3).

Therefore, Harmonet® users must switch to an alternative method of contraception (e.g., progestagen- only contraception or non-hormonal methods) prior to starting therapy with these combination drug regimens. Harmonet® can be restarted 2 weeks following completion of treatment with these combination drug regimens.