Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction

Interactions between ethinylestradiol (EE) and other substances may lead to decreased or increased serum EE concentrations.

Decreased EE serum concentrations may cause an increased incidence of breakthrough bleeding and menstrual irregularities and may possibly reduce efficacy of the CHC.

During concomitant use of EE-containing products and substances that may lead to decreased EE serum concentrations, it is recommended that a non-hormonal back-up method of birth control (such as condoms and spermicide) be used in addition to the regular intake of Minulet.
In the case of prolonged use of such substances CHCs should not be considered the primary contraceptive.

Examples of substances that may decrease serum EE concentrations:

-      Any substance that reduces gastrointestinal transit time and, therefore, EE absorption 
-      Substances that induce hepatic microsomal enzymes, such as carbamazepine, oxycarbamazepine, rifampicin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, griseofulvin, topiramate modafinil, dexamethasone, some protease inhibitors


-      St. John’s wort: Breakthrough bleeding and unintended pregnancies have been reported in women taking CHCs and St. John’s wort (Hypericum perforatum). St. John’s wort may induce microsomal enzymes, which theoretically may result in reduced clinical efficacy of CHCs. The inducing effect may persist for at least 2 weeks after cessation of treatment with St. John’s wort. If CHCs and St. John’s wort are used concomitantly, a non-hormonal backup method of birth control is recommended

After discontinuation of substances that may lead to decreased EE serum concentrations, use of a non-hormonal back-up method is recommended for at least 7 days. Longer use of a back- up method is advisable after discontinuation of substances that have led to induction of hepatic microsomal enzymes, resulting in decreased EE serum concentrations Maximal enzyme induction is generally not seen for 2-3 weeks but may then be sustained for at least 4 weeks after the cessation of drug therapy.
Examples of substances that may increase serum EE concentrations:

-      Atorvastatin

-      Competitive inhibitors for sulfation in the gastrointestinal wall, such as ascorbic acid (vitamin C) and paracetamol

-      Substances that inhibit cytochrome P450 3A4 isoenzymes, such as indinavir, fluconazole and troleandomycin

Troleandomycin may increase the risk of intrahepatic cholestasis during co-administration with CHCs.

EE may interfere with the metabolism of other drugs by inhibiting hepatic microsomal enzymes, or by inducing hepatic drug conjugation, particularly glucuronidation. Accordingly, plasma and tissue concentrations may either be increased (e.g. ciclosporin theophylline, corticosteroids) or decreased (e.g. lamotrigine).

In patients treated with flunarizine, use of oral contraceptives has been reported to increase the risk of galactorrhea.

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

LABORATORY TESTS
The use of contraceptive steroids 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.

In women on chronic treatment with hepatic enzyme inducing medications, CHCs are not recommended unless other more appropriate methods are not available or acceptable.

Pharmacodynamic interactions

During clinical trials with patients treated for hepatitis C virus infections (HCV) with medicinal products containing ombitasvir/paritaprevir/ritonavir, 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, Minulet users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with thes combination drug regimens. Minulet can be restarted 2 weeks following completion of treatment with these combination drug regimens.