Label: ACTIVELLA- estradiol/norethindrone acetate tablet, film coated
- NDC Code(s): 60846-231-01, 60846-232-01
- Packager: Amneal Pharmaceuticals LLC
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: None
- Marketing Status: New Drug Application
Drug Label Information
Updated November 30, 2023
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ACTIVELLA safely and effectively. See full prescribing information for ACTIVELLA. ACTIVELLA® (estradiol/norethindrone acetate ...
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Table of ContentsTable of Contents
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BOXED WARNING
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WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and ENDOMETRIAL CANCER
Estrogen Plus Progestin Therapy
Cardiovascular Disorders and Probable Dementia
The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogen (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)].
The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6)].
Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)].
Breast Cancer
The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.5)].
Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile.
Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Estrogen-Alone Therapy
Endometrial Cancer
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)].
Cardiovascular Disorders and Probable Dementia
The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)].
The WHIMS estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6)].
Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)].
Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile.
Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
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1 INDICATIONS AND USAGEActivella is indicated for: 1.1 Treatment of - Moderate to Severe Vasomotor Symptoms due to Menopause - 1.2 Treatment of - Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to ...
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2 DOSAGE AND ADMINISTRATIONUse 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. Reevaluate ...
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3 DOSAGE FORMS AND STRENGTHSActivella is available in two strengths: Activella 1 mg/ 0.5 mg contains 1 mg of estradiol and 0.5 mg of norethindrone acetate. The tablets are white, round, biconvex, film-coated tablets ...
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4 CONTRAINDICATIONSActivella is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.2)] Breast cancer or history of breast ...
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5 WARNINGS AND PRECAUTIONS5.1 Cardiovascular Disorders - Increased risks of PE, DVT, stroke and MI are reported with estrogen plus progestin therapy. Increased risks of stroke and DVT are reported with estrogen-alone ...
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6 ADVERSE REACTIONSThe following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)] Malignant Neoplasms [see Boxed ...
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7 DRUG INTERACTIONSCo-administration of estradiol with norethindrone acetate did not elicit any apparent influence on the pharmacokinetics of norethindrone acetate. Similarly, no relevant interaction of ...
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8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy - Risk Summary - Activella is not indicated for use in pregnancy. There are no data with the use of Activella in pregnant women; however, epidemiologic studies and meta-analyses ...
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10 OVERDOSAGEOverdosage of estrogen plus progestogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose ...
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11 DESCRIPTIONActivella 1 mg/0.5 mg is a single tablet for oral administration containing 1 mg of estradiol and 0.5 mg of norethindrone acetate and the following excipients: lactose monohydrate, starch (corn) ...
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12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action - Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although ...
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13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas ...
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14 CLINICAL STUDIES14.1 Effects on Vasomotor Symptoms in Postmenopausal Women - In a 12-week randomized clinical trial involving 92 subjects, Activella 1 mg/0.5 mg was compared to 1 mg of estradiol and to placebo ...
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15 REFERENCES1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477. 2. Hsia J, et al. Conjugated ...
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16 HOW SUPPLIED/STORAGE AND HANDLING16.1 - How Supplied - Activella (estradiol/norethindrone acetate) tablets, 1 mg/0.5 mg are available as white, round, biconvex, film-coated tablets, debossed with “ALH” on the one side and plain ...
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17 PATIENT COUNSELING INFORMATIONAdvise women to read the FDA-approved patient labeling (Patient Information) Vaginal Bleeding - Inform postmenopausal women to report any vaginal bleeding to their healthcare provider as soon as ...
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PATIENT INFORMATIONActivella® (AK-ti-vel-la) (estradiol/norethindrone acetate) tablets, for oral use - Read this Patient Information before you start using ACTIVELLA and each time you get a refill. There may be ...
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INGREDIENTS AND APPEARANCEProduct Information