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The following serious adverse reactions are discussed elsewhere in the labeling:

  • Cardiovascular Disorders [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
  • Malignant Neoplasms [see BOXED WARNING, WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions reported with Activella 1 mg/0.5 mg by investigators in the Phase 3 studies regardless of causality assessment are shown in Table 1.

TABLE 1 : ALL TREATMENT-EMERGENT ADVERSE REACTIONS REGARDLESS OF RELATIONSHIP REPORTED AT A FREQUENCY OF ≥ 5 PERCENT WITH ACTIVELLA 1 MG/0.5 MG

  Endometrial Hyperplasia Study (12-Months) Vasomotor Symptoms Study (3-Months) Osteoporosis Study (2-Years)
Activella1 mg/0.5 mg
(n=295)
1 mg E2
(n=296)
Activella1 mg/0.5 mg
(n=29)
Placebo
(n=34)
Activella1 mg/0.5 mg
(n=47)
Placebo (n=48)
Body as a Whole
  Back Pain 6% 5% 3% 3% 6% 4%
  Headache 16% 16% 17% 18% 11% 6%
Digestive System
  Nausea 3% 5% 10% 0% 11% 0%
  Gastroenteritis 2% 2% 0% 0% 6% 4%
Nervous System
  Insomnia 6% 4% 3% 3% 0% 8%
  Emotional Lability 1% 1% 0% 0% 6% 0%
Respiratory System
  Upper Respiratory 18% 15% 10% 6% 15% 19%
Tract Infection
  Sinusitis 7% 11% 7% 0% 15% 10%
Metabolic and Nutritional
  Weight Increase 0% 0% 0% 0% 9% 6%
Urogenital System
  Breast Pain 24% 10% 21% 0% 17% 8%
  Post-Menopausal Bleeding 5% 15% 10% 3% 11% 0%
  Uterine Fibroid 5% 4% 0% 0% 4% 8%
  Ovarian Cyst 3% 2% 7% 0% 0% 8%
Resistance Mechanism
  Infection Viral 4% 6% 0% 3% 6% 6%
  Moniliasis Genital 4% 7% 0% 0% 6% 0%
Secondary Terms
  Injury Accidental 4% 3% 3% 0% 17%* 4%*
  Other Events 2% 3% 3% 0% 6% 4%
* including one upper extremity fracture in each group

Adverse reactions reported with Activella 0.5 mg/0.1 mg by investigators during the Phase 3 study regardless of causality assessment are shown in Table 2.

TABLE 2 : ALL TREATMENT-EMERGENT ADVERSE REACTIONS REGARDLESS OF RELATIONSHIP REPORTED AT A FREQUENCY OF ≥ 5 PERCENT WITH ACTIVELLA 0.5 MG/0.1 MG

  Activella 0.5 mg/0.1 mg
(n=194)
Placebo
(n=200)
Body as a Whole
  Back Pain 10% 4%
  Headache 22% 19%
  Pain in extremity 5% 4%
Digestive System
  Nausea 5% 4%
  Diarrhea 6% 6%
Respiratory System
  Nasopharyngitis 21% 18%
  Urogenital System Endometrial thickening 10% 4%
  Vaginal hemorrhage 26% 12%

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Activella. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Genitourinary System

Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; pre-menstrual-like syndrome; cystitis-like syndrome; ovarian cancer; endometrial hyperplasia; endometrial cancer.

Breast

Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.

Cardiovascular

Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction, stroke; increase in blood pressure.

Gastrointestinal

Nausea, vomiting; changes in appetite; cholestatic jaundice; abdominal pain/cramps, flatulence, bloating; increased incidence of gallbladder disease and pancreatitis.

Skin

Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; seborrhea; hirsutism; itching; skin rash; pruritus.

Eyes

Retinal vascular thrombosis, intolerance to contact lenses.

Central Nervous System

Headache; migraine; dizziness; mental depression; chorea; insomnia; nervousness; mood disturbances; irritability; exacerbation of epilepsy; dementia.

Miscellaneous

Increase or decrease in weight; edema; leg cramps; changes in libido; fatigue; exacerbation of asthma; increased triglycerides; hypersensitivity; anaphylactoid/anaphylactic reactions.