ACTIVELLA (estradiol)
Activella is an estrogen and progestin combination therapy indicated for women with a uterus for the treatment of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. It is also indicated for the prevention of postmenopausal osteoporosis in women at significant risk of bone loss. Limitations of use apply: for vaginal atrophy, topical vaginal products should be considered first; for osteoporosis prevention, non-estrogen medications should be considered first.
How ACTIVELLA Works
Estradiol, the principal intracellular human estrogen, acts by binding to nuclear receptors in estrogen-responsive tissues. It replaces declining estrogen levels in postmenopausal women, modulating the pituitary secretion of gonadotropins (LH and FSH) through a negative feedback mechanism to reduce the elevated levels associated with menopause. The progestin component (norethindrone acetate) opposes the actions of estrogen by decreasing estrogen receptor levels and increasing local metabolism of estrogens, which promotes cellular differentiation and helps protect the endometrium.
Details
- Status
- Discontinued
- First Approved
- 1998-11-18
- Routes
- ORAL
- Dosage Forms
- TABLET
ACTIVELLA Approval History
What ACTIVELLA Treats
3 indicationsACTIVELLA is approved for 3 conditions since its original approval in 1998. These indications span multiple therapeutic areas including oncology, immunology, and more.
- Vasomotor Symptoms
- Vulvar and Vaginal Atrophy
- Osteoporosis
ACTIVELLA Boxed 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 medrox...
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 be
ACTIVELLA Competitive Set
ProThree rings of competition based on shared molecular targets and treated indications.
Direct competitors
Same target(s) AND same indication — head-to-head.
MoA expansion candidates
Same target(s), different indications — where else is this mechanism being explored?
Indication competitors
Same indication, different mechanism — what else might this patient receive?
Filters applied: drops same-active-ingredient (505(b)(2) reformulations), route-mismatch (topical vs systemic), and cross-therapeutic-area matches in same-indication rings.
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3 of 20FDA-approved drugs for similar conditions. Compare mechanisms and indications to understand treatment alternatives.
Clinical Trial Registry
33 trials| Trial | Sponsor ID | Phase | Status | Title |
|---|---|---|---|---|
| NCT05716516 ESTHER | STUDY02001740 NCI-2023-05453 | Ph 2 | recruiting | STUDY02001740;22SCH740: Estradiol For ER+ Advanced Breast Cancer (ESTHER) |
| NCT06005610 GETITRIgHT results posted | A5403 38806 | Ph 2 | terminated | Estradiol Therapy In Transgender Women to Research Interactions With HIV Therapy |
| NCT05457972 | STUDY20220578 | Ph 4 | recruiting | Postpartum Vaginal Estrogen for Breastfeeding Patients |
| NCT04192266 results posted | HSC-MS-23-0497 R33MH111907 | Ph 3 | completed | Estrogen and Fear in PTSD |
| NCT03689543 results posted | 180144 18-M-0144 | Ph 2 | completed | Estrogen Receptor Beta and Mood |
| NCT06253702 | 2023-0548 1R01HL150361-01, EDUC/KINESIOLOGY | Ph 4 | completed | Brain Blood Flow Responses to Stress: Sex Differences |
| NCT02238808 PRESTO | EER001 | Ph 2 | active not recruiting | A Study to See Whether Estrogen Can Slow the Growth of Some ER Positive Breast Cancers |
| NCT05617820 | 71836003 | Ph 3 | completed | Study Comparing Estradiol Vaginal Inserts 4mcg To IMVEXXY ® (Estradiol Vaginal Inerts 4 mcg) In The Treatment Of Dyspareunia in Women With Vulvur and Vaginal Atrophy |
| NCT04225221 results posted | 19-2343 R21MH121726 | Ph 2 | completed | Neurobiology of Bulimia Nervosa |
| NCT04933240 | HM20021901 | Ph 4 | withdrawn | Tamoxifen Versus Estradiol for Unscheduled Bleeding in Etonogestrel Implant Users, a Randomized Pilot Trial |
| NCT01923298 results posted | 13-0477-04 EString | Ph 2 | completed | Estradiol Levels in Patients Treated With Estring |
| NCT03493126 results posted | 2018H0006 | Ph 4 | completed | Vaginal Estrogen on Postpartum Atrophy, Perineal Pain, and Sexual Function |
| NCT02995694 results posted | 71462901 | Ph 3 | completed | A Study Comparing Estradiol Vaginal Cream to Estrace® Cream in Females With Atrophic Vaginitis |
| NCT01441635 results posted | M12-663 | Ph 2 | completed | Safety and Efficacy of Elagolix in Pre-Menopausal Women With Heavy Uterine Bleeding and Uterine Fibroids |
| NCT01895881 EPPA | EPPA - 12101906 | Ph 2 | withdrawn | Estrogen Therapy as Prevention in the Progression of Aneurysm (EPPA) Trial |
| NCT00997893 RISE results posted | 2009-0052 5R01MH083782-05 | Ph 2 | completed | Research Investigation of Soy and Estrogen |
| NCT03848234 | EST-S-01 | Ph 3 | completed | Estradiol Patch as add-on to Antipsychotics in Patients With Schizophrenia, Schizoaffective or Schizophreniform Disorder |
| NCT02455453 results posted | 201411005 5R01CA195450-03 | Ph 2 | completed | Assessment of Functional Status of Estrogen Receptors in Breast Cancer by Positron Emission Tomography |
| NCT01083641 results posted | CO09711 H-2009-0172, NCI-2011-00618 | Ph 2 | terminated | Estrogen for Triple Negative Breast Cancer |
| NCT02255175 PEERS results posted | 13-3572 K12HD001441-15, K23MH105569-01A1 | Ph 4 | completed | Perimenopausal Effects of Estradiol on Reward Responsiveness |
| NCT01942668 REPLENISH results posted | TXC12-05 REPLENISH Trial | Ph 3 | completed | A Safety and Efficacy Study of the Combination Estradiol and Progesterone to Treat Vasomotor Symptoms |
| NCT03479879 | AS1731 | Ph 2, Ph 3 | completed | Estradiol Pretreatment With Misoprostol in Second Trimester Miscarriage |
| NCT01753102 | CLR_10_19 CTRI/2012/09/002983 | Ph 3 | terminated | Efficacy and Safety Of Spil's Estradiol Vaginal Tablet |
| NCT02792153 | IRB00030009 | Ph 1 | withdrawn | Estradiol and Fear Extinction in Anorexia Nervosa (AN) |
| NCT01126801 results posted | 2009p001776 | Ph 2 | terminated | Effects of Estrogen and Hot Flashes on Mood in Postmenopausal Women |
| NCT01308814 PERT results posted | 10-0542 R01MH087619 | Ph 2, Ph 3 | completed | Perimenopausal Estrogen Replacement Therapy Study |
| NCT02253173 REJOICE results posted | TXV14-01 | Ph 3 | completed | Estradiol Vaginal Softgel Capsules in Treating Symptoms of Vulvar and Vaginal Atrophy in Postmenopausal Women |
| NCT02485821 | MS39825273 | Ph 2, Ph 3 | completed | Vaginal Estradiol Pretreatment in Labour Induction With Misoprostol |
| NCT02449902 results posted | TXV13-01 | Ph 2 | completed | TXV13-01 Estradiol Vaginal Softgel Capsules in Treating Postmenopausal Women With Symptoms of Vulvar and Vaginal Atrophy |
| NCT02316249 | NSHS-P001 | Ph 2 | withdrawn | Vaginal Creams to Reduce Vaginal Erosion in Pessary Users |
| NCT01310647 FOLLPRIM | 2009-018009-26 2009-018009-26 | Ph 2 | completed | Antral Follicle Priming Prior to ICSI (Intracytoplasmic Sperm Injection) in Previously Diagnosed Low Responders |
| NCT01065220 | AP13214ONB | Ph 4 | completed | Sex Steroids and the Serotonin Transporter |
| NCT00740194 | 2007/279 | Ph 1, Ph 2 | completed | Reciprocal Influence of Sex Steroid Environment and Adipocyte Function in Men |
Active Pipeline
Ongoing clinical trials by development phase
Key Completed Trials
Completed studies with published results, ranked by significance
Trial Timeline
Full development history with FDA approval milestones
Understanding FDA Approval Types
| Count | Type | What it means |
|---|---|---|
| - | ORIG | Original approval - drug first enters market |
| - | SUPPL - Efficacy | New indication (new disease/condition approved) |
| - | SUPPL - Labeling | Label text changes (warnings, dosing updates) |
| - | SUPPL - Manufacturing | Production changes (new facility) |
| - | SUPPL - Chemistry | Formulation changes (new dosage strength) |
Green lines in the timeline show ORIG and Efficacy approvals - the clinically meaningful milestones.
ACTIVELLA FDA Label Details
Indications & Usage
FDA Label (PDF)ACTIVELLA is indicated for the treatment of Vasomotor Symptoms; Vulvar and Vaginal Atrophy; Osteoporosis.
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), pulm...
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Data Sources
Data sourced from official FDA and NIH databases. Click links to verify on original sources.