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 identif y potential interactions:

Ef f ects of other medicinal products on Angeliq

Substances increasing the clearance of sex hormones (diminished efficacy by enzyme- induction):

The metabolism of oestrogens (and progestogens) may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specif ically cytochrome P450 enzymes, such as anticonvulsants (e.g. barbiturates, phenytoin, primiodine, carbamazapine) and anti-inf ectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz) and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John's Wort (hypericum perf oratum).


Clinically, an increased metabolism of oestrogens and progestogens may lead to decreased ef f ect and changes in the uterine bleeding prof ile.
Enzyme induction can already be observed af ter a f ew days of treatment. Maximal enzyme induction is generally seen within a f ew weeks. Af ter the cessation of drug therapy enzyme induction may be sustained f or about 4 weeks.

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 oestrogen or progestins. The net ef fect of these changes may be clinically relevant in some cases.
Theref ore, the prescribing inf ormation of concomitant HIV/HCV medications should be consulted to identif y potential interactions and any related recommendations.

Substances decreasing the clearance of sex hormones (enzyme inhibitors): 
Strong and moderate CYP3A4 inhibitors such as azole antif ungals (e.g. f luconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapef ruit juice can increase plasma concentrations of the progestin or the oestrogen or both. In a multiple dose study with a drospirenone (3 mg/day) / oestradiol (1.5 mg/day) combination, co-administration of the strong CYP3A4 inhibitor ketoconazole for 10 days increased the AUC(0 24h) of drospirenone 2.30 f old (90%CI: 2.08, 2.54). No change was observed f or oestradiol, although the AUC(0 24h) of its less potent metabolite oestrone increased 1.39-f old (90%CI: 1.27, 1.52).

Ef f ect of Angeliq on other medicinal products

In vitro, drospirenone is capable to inhibit weakly to moderately the cytochrome P450 enzymes CYP1A1, CYP2C9, CYP2C19 and CYP3A4.

Based on in vivo interaction studies in f emale volunteers using omeprazole, simvastatin, or midazolam as marker substrate, a clinically relevant interaction of drospirenone at doses of 3 mg with the cytochrome P450 enzyme mediated metabolism of other drugs is unlikely.

Concomitant use of Angeliq and either NSAIDs or ACE inhibitors / angiotensin II receptor antagonists is unlikely to increase serum potassium. However, concomitant use of all these three types of medications together may cause a small increase in serum potassium, which is more pronounced in diabetic women.

Hypertensive women treated with Angeliq and antihypertensive medications may experience an additional decrease in blood pressure (see section 4.4).

Ef f ect of HRT with oestrogens on other medicinal products

Hormone contraceptives containing oestrogens have been shown to signif icantly 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.


Other 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 oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted f or 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).


Laboratory tests
The use of sex steroids may inf luence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal f unction, plasma levels of (carrier) proteins, e.g. sex hormone binding globulin and lipid/lipoprotein f ractions, parameters of carbohydrate metabolism and parameters of coagulation and f ibrinolysis. Changes generally remain within the normal laboratory range. Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid activity.