Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.

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, women taking Belara should switch to
13 a different method of contraception (e.g. a progestogen-only contraceptive or a non-hormonal method) before starting treatment with the combination drug regimens. Belara can be started again two weeks after the end of treatment with these combination drug regimens.

Pharmacokinetic interactions

Effects of other medicines on Belara film-coated tablets
Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.

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

Short-term treatment
Women on treatment with enzyme inducing drugs should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method must be used during the whole time of the concomitant drug therapy and for 28 days after its discontinuation. If the drug therapy runs beyond the end of the tablets in the COC pack, the next COC pack should be started right after the previous one without the usual tablet-free interval.

Long-term treatment
In women on long-term treatment with enzyme-inducing active ingredients, another reliable, non- hormonal, method of contraception is recommended.

The following interactions have been reported in the literature:

Active ingredients increasing the clearance of COCs (diminished efficacy of COCs due to enzyme- induction), e.g.:

Barbiturates, bosentan, carbamazepine, barbexaclone, phenytoin, primidone, modafinil, rifampicin, rifabutin, and HIV medication ritonavir, nevirapine and efavirenz and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John's-wort (Hypericum perforatum).

The following medicines/agents may reduce serum concentrations of ethinylestradiol:
• any medicine that increases gastrointestinal motility (e.g. metoclopramide) or reduces absorption (e.g. activated charcoal).

Active ingredients with variable effects on the clearance of COCs:

When co-administered with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentrations of oestrogen or progestins. The net effect of these changes may be clinically relevant in some cases.

Therefore, the prescribing information of concomitant HIV/HCV medications should be reviewed to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier contraceptive method should be used by women on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.

The following medicines/agents may increase serum concentrations of ethinylestradiol: 14
•    active ingredients that inhibit the sulphation of ethinylestradiol in the intestinal wall, such as ascorbic acid or paracetamol;
•    atorvastatin (increases ethinylestradiol AUC by 20%);
•    drugs that inhibit liver microsomal enzymes, such as imidazole-type antifungals (e.g.
fluconazole), indinavir or troleandomycin.

Effects of Belara film-coated tablets on other medicinal products
• Inhibition of hepatic microsomal enzymes and consequent increase in serum concentrations of certain drugs such as diazepam (and other benzodiazepines metabolized by hydroxylation), cyclosporine, theophylline and prednisolone;
• Induction of glucuronidation in the liver and consequent reduction of serum concentrations of certain drugs such as lamotrigine, clofibrate, paracetamol, morphine and lorazepam.

Because of the effects on glucose tolerance, the insulin requirement or the dose of oral antidiabetics required may be modified (see section 4.4).

This may also apply to medicines you have taken recently.

The prescribing information of such medicines should be reviewed to see if there are any possible interactions with Belara.

Laboratory tests
The use of contraceptive steroids may influence the results of certain laboratory tests (such as liver, thyroid, adrenal and renal function tests), blood levels of (carrier) proteins (e.g. corticosteroid-binding globulins), and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.