Drug · FAERS side-effect profile with label screen

Estradiol and Norethindrone side effects: what 369 FDA adverse event reports show

Estradiol And Norethindrone Acetate · 7 reaction terms · 67 drug–reaction co-reports · data 2026-09-14

Drug class

Estrogen

FDA label (Established Pharmacologic Class) of the closest related product

Label matched

Estradiol (Estradiol)

closest FDA label found for this product string; brand list suppressed because the label is a related product, not an exact match

Who reports

369 reports · 43% serious · 6 with death outcome · 99% female

openFDA FAERS counts, all years, deduplication not applied

Used for

Estradiol transdermal system is indicated for: Estradiol transdermal system is an estrogen indicated for: Treatment of moderate to severe vasomotor symptoms due to menopause (1.1) Treatment of moderate to severe symptoms of vulvar and vaginal atrophy d.

FDA label, Indications and Usage

What it is

Estradiol transdermal system, USP contains estradiol, USP in a multipolymeric adhesive. The system is designed to release estradiol, USP continuously upon application to intact skin. Five dosa.

FDA label, Description section

Boxed warning

ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, and BREAST CANCER Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.

FDA label

How to read this page. FAERS is a spontaneous-reporting system: counts are not incidence rates and a signal is not proof of causation. Each reaction below is run through an automated screen — is the term in the FDA label (known), in the indications (the disease being treated), an administrative/coding term, or none of these (unlabeled)? That screen is mechanical text matching, not a causality assessment. The 30 hand-written Bradford Hill assessments are on the causality assessment page. Not medical advice.

Causality screen of the 6 strongest signals

Labeled — boxed warning 1Labeled adverse reaction 2Labeled (related wording) 1Not in label — unassessed 2

What the badges mean

Labeled — boxed warning The term (or its clinical synonym) appears in the FDA boxed warning: causality is regulator-recognised and considered serious.
Labeled adverse reaction The exact term appears in the label's warnings or adverse-reactions sections: a known, expected effect. The FAERS signal confirms the label rather than discovering anything.
Labeled (related wording) The label describes this effect under different wording (e.g. 'neutropenia' for 'neutrophil count decreased'). Treated as known.
Not in label — unassessed Not found in the label text, not an artifact pattern. This is a genuine candidate for a formal causality assessment (Bradford Hill / WHO-UMC); it has NOT had one here.

Strongest disproportionality signals

Flagged terms (PRR ≥ 2, χ² ≥ 4, n ≥ 10), ranked by PRR; infinite PRRs (no comparator reports) excluded. The EBGM column is a second, shrinkage-based estimate (MGPS) with its 5th percentile EB05 and the BCPNN IC025; a pair flagged by PRR alone is marked PRR-only and should be read as fragile. The strata column recomputes the PRR on serious reports only and flags pairs whose reports are unusually skewed by sex or come mostly from consumers rather than clinicians. 1 further terms are in the interactive explorer. Reaction links open the term's cross-drug page.

Show: hide coding/lab/outcome terms hide indication terms unlabeled only hide PRR-only

Reaction	Reports	PRR 95% CI · ROR · χ²/p	EBGM EB05 · IC025	Label screen	Serious-only & strata	Trial cross-check
Breast pain	5	26.5 11.1–63.4ROR 26.9 · χ² 99 / p 2e-23	22.4 EB05 7.6 · IC025 +1.4 3/3 methods agree	Labeled (related wording) related wording	serious n=3	no trial data cached
Metrorrhagia	7	22.9 11.0–47.7ROR 23.3 · χ² 125 / p 2e-29	20.7 EB05 9.2 · IC025 +1.9 3/3 methods agree	Not in label — unassessed	serious n=4	no trial data cached
Hot flush (hot flashes)	25	18.7 12.8–27.4ROR 20.0 · χ² 404 / p 4e-90	18.4 EB05 13.0 · IC025 +3.1 3/3 methods agree	Labeled adverse reaction exact term	serious PRR 18.0	no trial data cached
Vaginal haemorrhage	11	14.6 8.2–26.1ROR 15.0 · χ² 126 / p 1e-29	13.1 EB05 6.8 · IC025 +2.2 3/3 methods agree	Labeled adverse reaction exact term	serious PRR 22.6	no trial data cached
Breast cancer	10	6.0 3.3–11.1ROR 6.1 · χ² 37 / p 6e-10	4.8 EB05 2.8 · IC025 +1.2 3/3 methods agree	Labeled — boxed warning exact term	serious PRR 8.1	no trial data cached
Dermatitis atopic	5	5.7 2.4–13.5ROR 5.7 · χ² 15 / p 6e-5	4.0 EB05 1.9 · IC025 +0.4	Not in label — unassessed	–	no trial data cached

Trial evidence (ClinicalTrials.gov)

Trial cross-check not yet run for this drug (ClinicalTrials.gov pull covers the 800 most-reported drugs first).

Most frequently reported reactions

By raw co-report count, regardless of disproportionality. Common terms here are often the illness itself or generic outcomes.

Reaction	Reports	PRR 95% CI · ROR · χ²/p	EBGM EB05 · IC025	Label screen	Serious-only & strata	Trial cross-check
Hot flush (hot flashes)	25	18.7 12.8–27.4ROR 20.0 · χ² 404 / p 4e-90	18.4 EB05 13.0 · IC025 +3.1 3/3 methods agree	Labeled adverse reaction exact term	serious PRR 18.0	no trial data cached
Vaginal haemorrhage	11	14.6 8.2–26.1ROR 15.0 · χ² 126 / p 1e-29	13.1 EB05 6.8 · IC025 +2.2 3/3 methods agree	Labeled adverse reaction exact term	serious PRR 22.6	no trial data cached
Breast cancer	10	6.0 3.3–11.1ROR 6.1 · χ² 37 / p 6e-10	4.8 EB05 2.8 · IC025 +1.2 3/3 methods agree	Labeled — boxed warning exact term	serious PRR 8.1	no trial data cached
Metrorrhagia	7	22.9 11.0–47.7ROR 23.3 · χ² 125 / p 2e-29	20.7 EB05 9.2 · IC025 +1.9 3/3 methods agree	Not in label — unassessed	serious n=4	no trial data cached
Dermatitis atopic	5	5.7 2.4–13.5ROR 5.7 · χ² 15 / p 6e-5	4.0 EB05 1.9 · IC025 +0.4	Not in label — unassessed	–	no trial data cached
Breast pain	5	26.5 11.1–63.4ROR 26.9 · χ² 99 / p 2e-23	22.4 EB05 7.6 · IC025 +1.4 3/3 methods agree	Labeled (related wording) related wording	serious n=3	no trial data cached
Menstruation irregular	4	8.5 3.2–22.6ROR 8.6 · χ² 20 / p 5e-6	5.0 EB05 2.1 · IC025 +0.4 3/3 methods agree	Not in label — unassessed	serious n=1	no trial data cached

Unlabeled candidate signals

Every screened signal with n ≥ 20 was either labeled, an indication term, or an artifact pattern — no unlabeled candidate stood out in the top signals.

✓ A hand-written Bradford Hill causality assessment exists for this drug: Drospirenone/ethinyl estradiol ↔ Pulmonary embolism (venous thromboembolism).

Want to assess one of these properly? The runbook describes the Bradford Hill / trial-evidence workflow used on the assessment page, and handoff_top1000_signals.csv lists the strongest unassessed pairs across all drugs.

Common questions

What are the most reported side effects of Estradiol and Norethindrone?

In FDA FAERS, the most frequently co-reported reaction terms for Estradiol and Norethindrone are hot flush, vaginal haemorrhage, breast cancer, metrorrhagia, dermatitis atopic, breast pain. These are report counts, not rates: FAERS has no denominator, reporting is voluntary and uneven, and a term can be reported because of the illness being treated rather than the drug.

Does Estradiol and Norethindrone have an FDA boxed warning?

Yes. The current FDA label carries a boxed warning: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, and BREAST CANCER Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.

Do FAERS signals prove that Estradiol and Norethindrone causes these side effects?

No. A disproportionality signal (PRR, ROR) means a reaction is reported more often with this drug than with others in the database. That can reflect a real effect, but also the disease being treated, stimulated reporting after news or litigation, co-medications, or how reports are coded. Causality needs temporality, dose-response, biological plausibility, consistency across data sources and, ideally, trial or cohort evidence. This page screens each term against the FDA label and ClinicalTrials.gov results; it does not establish causation.

Sources & methods

FDA label via openFDA (set ID 0500ee9b-bf4a-4432-9afe-20a7d60a6fe5, effective 20240514; matched on openfda.generic_name.exact:"ESTRADIOL")
Bayesian shrinkage measures computed offline over all 1,317,300 cached pairs: BCPNN information component (IC, with Norén closed-form IC025) and MGPS empirical-Bayes geometric mean (EBGM, EB05) with a two-component gamma prior fitted by maximum marginal likelihood (α₁=0.57, β₁=0.02, α₂=1.42, β₂=0.70, w=0.17); unstratified
FAERS pair statistics from the OpenPV build of 2026-09-14 (openFDA count= aggregation, field patient.drug.openfda.generic_name.exact, 7 reaction terms, min 3 co-reports); PRR/ROR with 95% CI, chi-square with Yates correction
Serious-only and stratified counts (serious:1, patient.patientsex, primarysource.qualification) from openFDA count queries; serious-only PRR uses the drug serious report total and the term global serious total (N_serious=11,882,979); strata shown only when n ≥ 20
Seriousness and sex counts from openFDA count=serious, patient.patientsex, seriousnessdeath

Page generated 2026-10-08. Label and PubChem text are retrieved automatically and may lag the current label; always check the current prescribing information. OpenPV is a beta research tool of the Open Source Medicine Foundation.