ANGELIQ- drospirenone and estradiol tablet, film coated

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

ESTRADIOL (UNII: 4TI98Z838E) (ESTRADIOL - UNII:4TI98Z838E), DROSPIRENONE (UNII: N295J34A25) (DROSPIRENONE - UNII:N295J34A25)

Available from:

Bayer HealthCare Pharmaceuticals Inc.

INN (International Name):

ESTRADIOL

Composition:

ESTRADIOL 1 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Angeliq is contraindicated in women with any of the following conditions: Angeliq is not indicated for use in pregnancy. There are no data with the use of Angeliq in pregnant women, however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies or limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy. In reproduction studies in rats, rabbits and monkeys with oral administration of DRSP either as single compound or in combination with EE, no non-genital teratogenicity was observed. Adverse developmental outcomes like an increase in fetal mortality and a retardation of fetal maturation were seen in rats and rabbits at exposures to DRSP exceeding the human exposure by a factor of >15 (in rats) or >60 (rabbits). Related to the antiandrogenic activity of drospirenone, a feminization of male fetuses and an impairment of male fertility was observed in rats (>150 times the human exposure to drospirenone) but not in monkeys (at up to more than 300 times the human exposure to drospirenone). Due to the large safety margins observed in the animal studies only a low likelihood of an increased risk for human pregnancy was concluded (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. In an embryo-fetal toxicity study in pregnant rats, DRSP was given from day 6 to 15 of gestation orally at doses of 5, 15 and 45 mg/kg/day, more than 60 times the human exposure starting from the low dose based on AUC of DRSP. A slight increase in postimplantational loss and a slight increase in retardation of fetal development (e.g. delayed ossification of bones of the feet) was seen in the two higher doses. No teratogenicity was observed in rats. In an embryo-fetal study in rabbits, DRSP was given from day 6 to 18 of gestation orally at doses of 10, 30 and 100 mg/kg/day, about 20, 60 and 250 times the human exposure based on AUC. This resulted in a retardation of fetal development (delayed ossification of small bones, multiple fusions of ribs) at the high dose only and in an increase in fetal loss from the mid dose level. No compound-related teratogenicity was seen in rabbits. In a further embryo-fetal toxicity study in pregnant rats, DRSP was orally administered in combination with ethinyl estradiol (100:1) from day 6 to 17 of gestation at doses of 1, 3 and 10 mg/kg/day DRSP, at about 1, 3 and 23 times the human exposure to DRSP on basis of AUC. Maternal toxicity (decreased body weight gain and food consumption) was seen starting at the low dose and an increase of early resorptions at the high dose level. Skeletal variations and retardations were seen in fetuses at the high dose. No malformed fetuses and no effect on the external genitalia of the fetuses were observed. DRSP was administered with ethinyl estradiol (100:1) orally to pregnant rats during late pregnancy from day 14 to 21 of gestation (the period of genital development) at doses of 5, 15 and 45 mg/kg of DRSP, more than 60 times the human exposure starting from the low dose based on AUC of DRSP. Maternal toxicity (decreased body weight gain) and fetal retardation (decreased fetal body weights) were seen starting at the low dose. There was a dose dependent increase in feminization of male rat fetuses starting at the mid dose level (that is, >150 times the human exposure to DRSP). DRSP was administered with ethinyl estradiol (100:1) orally to pregnant cynomolgus monkeys at doses up to 10 mg/kg DRSP, more than 300 times the human exposure based on AUC from day 20 to 90 of gestation. A dose-dependent increase of abortions was observed. No teratogenic or feminization effects were seen in any dose group. DRSP was administered with ethinyl estradiol (100:1) in a peri-postnatal study in rats from day 6 to 16 of gestation and day 1 to 22 postpartum at doses of 5, 15 and 45 mg/kg; more than 60 times the human exposure starting from the low dose based on AUC of DRSP. There was a dose dependent delay in fetal development and an increase in mortality of the F1-generation during the lactational phase. Fertility was impaired in the male offspring at the high dose level. Estrogens plus progestogens are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. After administration of an oral contraceptive containing DRSP about 0.02% of the DRSP dose was excreted into the breast milk of postpartum women within 24 hours. This results in a maximal daily dose of about 3 mcg DRSP in an infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Angeliq and any potential adverse effects on the breastfed infant from Angeliq or from the underlying maternal condition. Angeliq is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Angeliq to determine whether those over 65 years of age differ from younger women in their response to Angeliq. In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions (5.1, 5.3) and Clinical Studies (14.4)] . In the WHI estrogen-alone substudy (daily CE [0.625 mg] versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Warnings and Precautions (5.1) and Clinical Studies (14.4)] . In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions (5.4), and Clinical Studies (14.5)] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Warnings and Precautions (5.4), and Clinical Studies (14.5)]. Angeliq is contraindicated in patients with renal impairment because of the risk of hyperkalemia [see Contraindications (4), Warnings and Precautions (5.2 )  and Clinical Pharmacology (12.3)]. Angeliq is contraindicated in patients with hepatic impairment because of the risk of increased DRSP exposure and subsequent hyperkalemia [see Contraindications (4), Warnings and Precautions (5.10)   and Clinical Pharmacology (12.3)]. Angeliq is contraindicated in patients with adrenal insufficiency because of the risk of hyperkalemia [see Contraindications (4) and Warnings and Precautions (5.2)].

Product summary:

Angeliq is supplied in packages of three blister packs: Angeliq 0.25 mg DRSP/0.5 mg E2 tablets are available as round, biconvex yellow film-coated tablets embossed with "EL" inside a hexagon. 3 blisters of 28 tablets NDC 50419-482-03 Angeliq 0.5 mg DRSP/1 mg E2 tablets are available as round, biconvex pink film-coated tablets embossed with "CK" inside a hexagon. 3 blisters of 28 tablets NDC 50419-483-03 Store at 20° to 25° C (68 to 77° F); excursions permitted to 15°–30° C (59°–86° F) [see USP Controlled Room Temperature].

Authorization status:

New Drug Application

Summary of Product characteristics

ANGELIQ- DROSPIRENONE AND ESTRADIOL TABLET, FILM COATED
BAYER HEALTHCARE PHARMACEUTICALS INC.
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
ANGELIQ SAFELY AND
EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR ANGELIQ.
ANGELIQ (DROSPIRENONE AND ESTRADIOL) TABLETS, FOR ORAL USE
INITIAL U.S. APPROVAL: 2005
WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA BREAST CANCER,
AND
ENDOMETRIAL CANCER
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING_
ESTROGEN PLUS PROGESTIN THERAPY
•
•
•
•
•
•
•
DO NOT USE ESTROGEN-ALONE THERAPY FOR THE PREVENTION OF CARDIOVASCULAR
DISEASE OR
DEMENTIA (5.1), 5.4)
RECENT MAJOR CHANGES
Boxed Warning 10/2023
Warnings and Precautions (5.3) MM/YYYY
INDICATIONS AND USAGE
Angeliq is a combination of an estrogen and progestin indicated in a
woman with a uterus for the
treatment of:
•
•
Use estrogen, alone or in combination with a progestogen, at the
lowest effective dose and the shortest
duration consistent with treatment goals and risks for the individual
woman. Re-evaluate postmenopausal
women periodically as clinically appropriate to determine whether
treatment is still necessary.
DOSAGE AND ADMINISTRATION
•
•
THE WOMEN’S HEALTH INITIATIVE (WHI) ESTROGEN PLUS PROGESTIN SUBSTUDY
REPORTED
INCREASED RISKS OF PULMONARY EMBOLISM (PE), DEEP VEIN THROMBOSIS
(DVT), STROKE,
AND MYOCARDIAL INFARCTION (MI) (5.1)
THE WHI ESTROGEN PLUS PROGESTIN SUBSTUDY REPORTED INCREASED RISKS OF
INVASIVE
BREAST CANCER (5.2)
THE WHI MEMORY STUDY (WHIMS) ESTROGEN PLUS PROGESTIN ANCILLARY STUDY
OF WHI
REPORTED AN INCREASED RISK OF PROBABLE DEMENTIA IN POSTMENOPAUSAL
WOMEN 65
YEARS OF AGE AND OLDER (5.4)
DO NOT USE ESTROGEN PLUS PROGESTOGEN THERAPY FOR THE PREVENTION OF
CARDIOVASCULAR DISEASE OR DEMENTIA (5.1), 5.4)
ESTROGEN-ALONE THERAPY
THERE IS AN INCREASED RISK OF ENDOMETRIAL CANCER IN A WOMAN WITH A
UTERUS WHO
USES UNOPPOSED ESTROGENS (5.3)
THE WHI ESTROGEN-ALONE SUBSTUDY REPORTED INCREASED RISKS OF STROKE AND
DVT (