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4.4 Special warnings and precautions for use
Ovarian cancer is much rarer than breast cancer.
Long-term (at least 5-10 years) use of oestrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see section 4.8). Some studies including the WHI trial suggest that the long-term use of combined HRT may confer a similar, or slightly smaller risk.
Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.
Some other studies, including the WHI trial, suggest that use of combined HRTs may be associated with a similar or slightly smaller risk (see section 4.8).
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:
Effects of other medicinal products on Angeliq
Substances increasing the clearance of
HRTssex hormones (diminished efficacy of HRTs by enzyme-induction):
The metabolism of oestrogens (and progestogens) may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g.
phenobarbital,barbiturates, phenytoin, primidone, carbama ez aepine,) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz) and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John's Wort (hypericum perforatum).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Oxcarbazepine, topiramte, felbamate, griseofulvin and Hherbal preparations containing St. John’s wort (Hypericum perforatum) may induce the metabolism of oestrogens (and progestogens).
Clinically, an increased metabolism of oestrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.
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.
Substances with variable effects on the clearance of
When co-administered with
HRTssex hormones, many combinations of HIV/ HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentrations of oestrogen or progestins or both. The net effect of these These changes may be clinically relevant in some cases.
Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations.
Substances decreasing the clearance of
HRTs–sex hormones (enzyme inhibitors)
Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole,
fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit 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 fold (90%CI: 2.08, 2.54). No change was observed for oestradiol, although the AUC(0 24h) of its less potent metabolite oestrone increased 1.39-fold (90%CI: 1.27, 1.52).
Other forms of interaction
The use of sex 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. sex hormone binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the
reference normal laboratory range. Glucose tolerance was not compromised by the use of Angeliq. Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid activity.
Long term use Use of oestrogen-only and or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see Section 4.4). In the million Women Study 5 years of HRT resulted in 1 extra case per 2500 users.
A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.
10. DATE OF REVISION OF THE TEXT
May 2015October 2016