Angeliq

ANGELIQ — estradiol and drospirenone tablet, film coated
Physicians Total Care, Inc.

Rx only

PRESCRIBING INFORMATION

Boxed Warnings

Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. (See WARNINGS, Cardiovascular disorders and Dementia.) The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated equine estrogens (CE 0.625mg) combined with medroxyprogesterone acetate (MPA 2.5mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical Studies and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer.) The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with conjugated estrogens alone and during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.) Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials, and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Description

ANGELIQ TABLETS provide a hormone regimen consisting of film coated tablets each containing 0.5 mg of drospirenone and 1 mg of estradiol. The inactive ingredients are lactose monohydrate NF, corn starch NF, modified starch NF, povidone 25000 USP, magnesium stearate NF, hydroxylpropylmethyl cellulose USP, macrogol 6000 NF, talc USP, titanium dioxide USP, and ferric oxide pigment NF.

Drospirenone, (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3´,4´,6, 6a,7,8,9,10,11,12,13,14,15,15a,16-hexadecahydro-10,13-dimethylspiro-[ 17H-dicyclopropa[6,7:15,16]cyclopenta[a]phenanthrene- 17,2´(5H)-furan]-3,5´(2H)-dione (CAS) is a synthetic progestational compound and has a molecular weight of 366.5 and a molecular formula of C24 H30 O3 .

Estradiol USP, (Estra-1,3,5(10)-triene-3,17-diol,17ß), has a molecular weight of 272.39 and the molecular formula is C18 H24 O2 . The structural formulas are as follows:

structural formula
(click image for full-size original)

Clinical Pharmacology

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol (E2) is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These will vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), through a negative feedback mechanism.

Drospirenone (DRSP) is a synthetic progestin and spironolactone analog with antimineralocorticoid activity. In animals and in vitro , drospirenone has antiandrogenic activity, but no glucocorticoid, antiglucocorticoid, estrogenic, or androgenic activity. Progestins counter estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.

Pharmacokinetics

Absorption

Serum concentrations of DRSP reach peak levels approximately 1 hour after administration of ANGELIQ and mean absolute bioavailability of DRSP ranges from 76–85%. Following oral administration, peak serum estradiol concentrations are typically reached 6–8 hours after dosing with ANGELIQ. The oral relative bioavailability of estradiol and DRSP following administration of ANGELIQ is 107% and 102%, respectively when compared to a combination oral suspension.

The pharmacokinetics of DRSP are dose proportional within the dose range of 0.5–4 mg. Following daily dosing of ANGELIQ, steady state DRSP concentrations were observed after 10 days. Mean accumulation ratios for estradiol and DRSP were 1.9 and 2.4, respectively. Mean concentrations at 2 hours for DRSP ranged between 5.9 and 6.7 ng/mL after treatment with ANGELIQ for 365 days. Mean steady state serum DRSP and E2 concentrations are shown in Figure 1, and a summary of primary pharmacokinetic parameters following the administration of 1mg E2/1mg DRSP for 28 days is presented in Table 1.

Figure 1
(click image for full-size original)

Figure 1: Mean steady state serum drospirenone and estradiol concentrations following daily oral administration of 1 mg E2/0.5 mg DRSP1 1 DRSP levels are simulated based on data obtained after oral administration of 1 mg DRSP/1 mg Estradiol

Table 1: Mean Steady State Pharmacokinetic Parameters of Tablets Containing Drospirenone (1 mg) and Estradiol (1 mg)
*
SD = standard deviation.
Cmax = Maximum serum concentration,
tmax = time of maximum serum concentration,
§
AUC = area under the curve
t1/2 = half-life,

Drospirenone (Mean** ± SD *)

Dose

No. of

Subjects

Cmax

(ng/mL)

tmax

(h)

Median

(range)

AUC§

(0–24h)

(ng•h/mL)

t1/2

(h)

1mg E2/1mg

DRSP

1418.3±5.551.0 (1.0–2.0)208±8342.3±21.3
Estradiol (Mean ± SD *)
Dose

No. of

Subjects

Cmax

(pg/mL)

tmax

(h)

Median

(range)

AUC§

(0–24h)

(pg•h/mL)

t1/2

(h)

1mg E2/1mg

DRSP

1443.8±10.02.5(0.5–12.0)665±178NA

Estrone (Mean ± SD *)

Dose

No. of

Subjects

Cmax

(pg/mL)

tmax

(h)

Median

(range)

AUC§

(0–24h)

(pg•h/mL)

t1/2

(h)

1mg E2/1mg

14245±50.64.0 (3.06.0)3814±115923±6.2

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