In clinical studies in male volunteers doses up to 100 mg of drospirenone were well tolerated. Based on general experience with combined oral contraceptives, symptoms that may possibly occur are nausea and vomiting and - in young girls and some women - vaginal bleeding. There are no specific antidotes, and, therefore, treatment should be symptomatic
5 years
Not applicable.
Tablet core:
Lactose monohydrate
Maize starch
Pregelatinised maize starch
Povidone
Magnesium stearate (E470b)
Film-coating material:
Hypromellose (E464)
Macrogol 6000
Talc (E553b)
Titanium dioxide (E171)
Ferric oxide, red (E172)
Animal studies with oestradiol and drospirenone have shown expected oestrogenic and gestagenic effects. There are no preclinical data of relevance to the prescriber that are additional to those already included in other sections of the SPC.
Pharmacotherapeutic group: progestogens and estrogens, combinations. ATC code: G03FA17
Oestradiol
Angeliq contains synthetic 17ß-oestradiol, which is chemically and biologically identical to endogenous human oestradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss following menopause or ovariectomy.
Drospirenone
Drospirenone is a synthetic progestogen.
As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen reduces, but does not eliminate the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
Drospirenone displays aldosterone antagonist activity. Therefore, increases in sodium and water excretion and decreases in potassium excretion may be observed.
In animal studies, drospirenone has no oestrogenic, glucocorticoid or antiglucocorticoid activity.
Clinical trial information
- Relief of oestrogen-deficiency symptoms and bleeding patterns
Relief of menopausal symptoms was achieved during the first few weeks of treatment.
Amenorrhea was seen in 73% of the women during months 10-12 of treatment. Breakthrough bleeding and /or spotting appeared in 59% of the women during the first three months of treatment and in 27% during months 10-12 of treatment.
- Prevention of osteoporosis
Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass.
The effect of oestrogen on the bone mineral density is dose-dependent. Protection appears to be effective as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.
Evidence from WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestogen - given to predominantly healthy women - reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.
After 2 years of treatment with Angeliq, the increase in hip bone mineral density (BMD) was 3.96 +/- 3.15% (mean +/- SD) in osteopenic patients and 2.78 +/- 1.89% (mean +/- SD) in non-osteopenic patients. The percentage of women who maintained or gained BMD in hip zone during treatment was 94.4% in osteopenic patients and 96.4% in non-osteopenic patients.
Angeliq also had an effect on lumbar spine BMD. The increase after 2 years was 5.61 +/- 3.34% (mean +/- SD) in osteopenic women and 4.92+/- 3.02% (mean +/- SD) in non-osteopenic women. The percentage of osteopenic women who maintained or gained BMD in lumbar zone during treatment was 100% , whereas this percentage was 96.4% in non-osteopenic women.
- Antimineralocorticoid activity
DRSP has aldosterone antagonistic properties that can result in a decrease in blood pressure in hypertensive women. In a double-blind placebo-controlled trial hypertensive postmenopausal women treated with Angeliq (n=123) for 8 weeks experienced a significant decrease in systolic/diastolic blood pressure values (office cuff versus baseline -12/-9 mm Hg, corrected for placebo effect -3/-4 mm Hg; 24h ambulatory blood pressure measurement versus baseline -5/—3 mm Hg, corrected for placebo effect -3/-2 mm Hg).
Angeliq should not be used to treat hypertension. Women with hypertension should be treated according to hypertension guidelines.
Drospirenone
- Absorption
After oral administration drospirenone is rapidly and completely absorbed. With a single administration, peak serum levels of approx. 21.9 ng/ml are reached about 1 hour after ingestion. After repeated administration, a maximum steady-state concentration of 35.9 ng/ml is reached after about 10 days. The absolute bioavailability is between 76 and 85%. Concomitant ingestion of food had no influence on the bioavailability.
- Distribution
After oral administration, serum drospirenone levels decrease in two phases which are characterised by a mean terminal half-life of about 35-39 hours. Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Only 3-5% of the total serum drug concentrations are present as free steroid. The mean apparent volume of distribution of drospirenone is 3.7-4.2 l/kg.
- Biotransformation
Drospirenone is extensively metabolized after oral administration. The major metabolites in plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulphate, formed by reduction and subsequent sulfatation. Both major metabolites are pharmacologically inactive. Drospirenone is also subject to oxidative metabolism catalysed by CYP3A4.
- Elimination
The metabolic clearance rate of drospirenone in serum is 1.2-1.5 ml/min/kg showing an intersubject variability of about 25%. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the faeces and urine at an excretion ratio of about 1.2 to 1.4. The half-life of metabolite excretion with the urine and faeces is about 40 hours.
- Steady-state conditions and linearity
Following daily oral administration of Angeliq, drospirenone concentrations reached a steady-state after about 10 days. Serum drospirenone levels accumulated by a factor of about 2 to 3 as a consequence of the ratio of terminal half-life and dosing interval. At steady-state, mean serum levels of drospirenone fluctuate in the range of 14-36 ng/ml after administration of Angeliq. Pharmacokinetics of drospirenone are dose-proportional within the dose range of 1 to 4 mg.
Oestradiol
- Absorption
Following oral administration, oestradiol is rapidly and completely absorbed. During the absorption and the first liver passage, oestradiol undergoes extensive metabolism, thus reducing the absolute bioavailability of oestrogen after oral administration to about 5% of the dose. Maximum concentrations of about 22 pg/ml were reached 6-8 hours after single oral administration of Angeliq. The intake of food had no influence on the bioavailability of oestradiol as compared to drug intake on an empty stomach.
- Distribution
Following oral administration of Angeliq only gradually changing serum levels of oestradiol are observed within an administration interval of 24 hours. Because of the large circulating pool of oestrogen sulphates and glucuronides on the one hand and the enterohepatic recirculation on the other hand, the terminal half-life of oestradiol represents a composite parameter that is dependent on all of these processes and is in the range of about 13-20 hours after oral administration.
Oestradiol is bound non-specifically to serum albumin and specifically to SHBG. Only about 1-2% of the circulating oestradiol is present as free steroid, 40-45% is bound to SHBG. The apparent volume of distribution of oestradiol after single intravenous administration is about 1 l/kg.
- Biotransformation
Oestradiol is rapidly metabolized, and besides oestrone and oestrone sulphate, a large number of other metabolites and conjugates are formed. Oestrone and oestriol are known as pharmacologically active metabolites of oestradiol; only oestrone occurs in relevant concentrations in plasma. Oestrone reaches about 6-fold higher serum levels than oestradiol. The serum levels of the oestrone conjugates are about 26-times higher than the corresponding concentrations of free oestrone.
- Elimination
The metabolic clearance has been found to be about 30 ml/min/kg. The metabolites of oestradiol are excreted via urine and bile with a half-life of about 1 day.
- Steady-state conditions and linearity
Following daily oral administration of Angeliq, oestradiol concentrations reached a steady-state after about five days. Serum oestradiol levels accumulate approx. 2-fold. Orally administered oestradiol induces the formation of SHBG which influences the distribution with respect to the serum proteins, causing an increase of the SHBG-bound fraction and a decrease in the albumin-bound and unbound fraction indicating non-linearity of the pharmacokinetics of oestradiol after ingestion of Angeliq. With a dosing interval of 24 hours, mean steady-state serum levels of oestradiol fluctuate in the range of 20-43 pg/ml following administration of Angeliq. Pharmacokinetics of oestradiol are dose-proportional at doses of 1 and 2 mg.
Special populations
- Hepatic impairment
The pharmacokinetics of a single oral dose of 3 mg DRSP in combination with 1 mg oestradiol (E2) was evaluated in 10 female patients with moderate hepatic impairment (Child Pugh B) and 10 healthy female subjects matched for age, weight, and smoking history. Mean serum DRSP concentration-time profiles were comparable in both groups of women during the absorption/ distribution phases with similar Cmax and tmax values, suggesting that the rate of absorption was not affected by the hepatic impairment. The mean terminal half-life was about 1.8-times greater and an about 50% decrease in apparent oral clearance (CL/f) was seen in volunteers with moderate hepatic impairment as compared to those with normal liver function.
- Renal Impairment
The effect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily for 14 days) were investigated in female subjects with normal renal function and mild and moderate renal impairment. At steady-state of DRSP treatment, serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50-80 ml/min) were comparable to those in the group with normal renal function (CLcr, > 80 ml/min). The serum DRSP levels were on average 37% higher in the group with moderate renal impairment (CLcr, 30-50 ml/min) compared to those in the group with normal renal function. Linear regression analysis of the DRSP AUC(0-24 hours) values in relation to the creatinine clearance revealed a 3.5% increase with a 10 ml/min reduction of creatinine clearance. This slight increase is not expected to be of clinical relevance.
31/08/2017
Bayer plc
400 South Oak Way
Reading, RG2 6AD
This medicinal product does not require any special storage conditions.
Transparent polyvinyl film (250 µm) / aluminium foil (20 µm) blisters of 28 tablets with imprinted week days.
The pack sizes are 1x28 tablets and 3x28 tablets.
Not all pack sizes may be marketed.
PL 00010/0518
No special requirements.
1st May 2008
