Drug · FAERS side-effect profile with label screen

Estradiol and Norethindrone side effects: what 1,920 FDA adverse event reports show

Estradiol/Norethindrone Acetate · 73 reaction terms · 1,237 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

1,920 reports · 75% serious · 37 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 28 strongest signals

Labeled — boxed warning 1Labeled adverse reaction 3Labeled (related wording) 4Reporting / coding artifact 3Lab value / disease marker 6Not in label — unassessed 11

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.
Reporting / coding artifact An administrative, monitoring or exposure term (product issue, off-label use, 'test normal', overdose...). Not a biological reaction; a high PRR here reflects how reports are coded.
Lab value / disease marker A laboratory result, investigation or disease-activity marker (antibody positive, CRP abnormal, swollen joint count) not described in the label. These usually mirror the monitored disease or testing protocol rather than a drug effect; not screened further.
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. 45 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 cancer female	191	78.1 68.2–89.4ROR 86.6 · χ² 14,375 / p <1e-300	77.0 EB05 68.2 · IC025 +5.8 3/3 methods agree	Not in label — unassessed	serious PRR 59.4	no trial data cached
Breast cancer metastatic	44	45.0 33.6–60.3ROR 46.0 · χ² 1,841 / p <1e-300	44.0 EB05 34.1 · IC025 +4.4 3/3 methods agree	Labeled (related wording) related wording	serious PRR 35.2 · 96% consumer	no trial data cached
Breast cancer	281	32.7 29.4–36.5ROR 38.2 · χ² 8,623 / p <1e-300	32.6 EB05 29.5 · IC025 +4.8 3/3 methods agree	Labeled — boxed warning exact term	serious PRR 25.0 · 88% consumer	no trial data cached
Bursitis	20	18.1 11.7–28.0ROR 18.3 · χ² 306 / p 6e-69	17.7 EB05 11.8 · IC025 +2.9 3/3 methods agree	Not in label — unassessed	serious PRR 16.4	no trial data cached
Body temperature decreased	16	17.6 10.8–28.7ROR 17.8 · χ² 234 / p 3e-53	17.0 EB05 10.6 · IC025 +2.7 3/3 methods agree	Lab value / disease marker	serious PRR 15.0	no trial data cached
Brain fog	20	15.0 9.7–23.2ROR 15.1 · χ² 247 / p 5e-56	14.4 EB05 9.4 · IC025 +2.7 3/3 methods agree	Not in label — unassessed	serious PRR 22.2	no trial data cached
Hypokinesia	17	12.8 8.0–20.5ROR 12.9 · χ² 173 / p 8e-40	11.8 EB05 7.2 · IC025 +2.4 3/3 methods agree	Not in label — unassessed	serious PRR 12.6	no trial data cached
Bone density decreased	32	11.0 7.8–15.6ROR 11.2 · χ² 282 / p 1e-63	10.5 EB05 7.5 · IC025 +2.7 3/3 methods agree	Lab value / disease marker	serious PRR 0.3 · 100% clinician	no trial data cached
Menorrhagia (heavy periods)	20	11.0 7.1–17.0ROR 11.1 · χ² 171 / p 2e-39	10.0 EB05 6.5 · IC025 +2.4 3/3 methods agree	Not in label — unassessed	serious PRR 17.1	no trial data cached
Blood pressure systolic increased	19	10.6 6.8–16.6ROR 10.7 · χ² 156 / p 5e-36	9.5 EB05 6.1 · IC025 +2.3 3/3 methods agree	Lab value / disease marker	serious PRR 8.9	no trial data cached
Middle insomnia	18	10.6 6.7–16.8ROR 10.7 · χ² 147 / p 5e-34	9.4 EB05 6.0 · IC025 +2.3 3/3 methods agree	Not in label — unassessed	serious PRR 13.8	no trial data cached
Breast pain	10	10.3 5.5–19.0ROR 10.3 · χ² 74 / p 3e-18	8.2 EB05 4.3 · IC025 +1.8 3/3 methods agree	Labeled (related wording) related wording	serious n=10	no trial data cached
Product administration error	18	9.9 6.2–15.6ROR 9.9 · χ² 135 / p 2e-31	8.7 EB05 5.5 · IC025 +2.2 3/3 methods agree	Reporting / coding artifact	serious PRR 17.5	no trial data cached
Vaginal haemorrhage	35	9.0 6.5–12.5ROR 9.1 · χ² 241 / p 1e-54	8.4 EB05 6.2 · IC025 +2.4 3/3 methods agree	Labeled adverse reaction exact term	serious PRR 10.8	no trial data cached
Abnormal dreams	21	8.3 5.4–12.6ROR 8.3 · χ² 127 / p 1e-29	7.3 EB05 4.9 · IC025 +2.1 3/3 methods agree	Not in label — unassessed	serious PRR 11.6 · 90% consumer	no trial data cached
Abdominal pain lower	18	7.8 4.9–12.3ROR 7.8 · χ² 99 / p 1e-23	6.7 EB05 4.4 · IC025 +1.9 3/3 methods agree	Labeled (related wording) related wording	serious PRR 9.0	no trial data cached
Hot flush (hot flashes)	51	7.4 5.6–9.7ROR 7.6 · χ² 276 / p 2e-62	7.0 EB05 5.5 · IC025 +2.3 3/3 methods agree	Labeled adverse reaction exact term	serious PRR 8.8 · 74% consumer	no trial data cached
Heart rate decreased	23	7.1 4.7–10.7ROR 7.2 · χ² 115 / p 4e-27	6.4 EB05 4.4 · IC025 +2.0 3/3 methods agree	Lab value / disease marker	serious PRR 6.5	no trial data cached
Blood potassium decreased	19	6.9 4.4–10.8ROR 7.0 · χ² 90 / p 1e-21	6.0 EB05 4.0 · IC025 +1.8 3/3 methods agree	Lab value / disease marker	serious PRR 6.4	no trial data cached
Joint injury	11	5.6 3.1–10.1ROR 5.6 · χ² 37 / p 5e-10	4.6 EB05 2.8 · IC025 +1.2 3/3 methods agree	Not in label — unassessed	serious PRR 5.1	no trial data cached
Poor quality sleep	11	5.6 3.1–10.1ROR 5.6 · χ² 37 / p 5e-10	4.6 EB05 2.8 · IC025 +1.2 3/3 methods agree	Reporting / coding artifact	serious PRR 6.5	no trial data cached
Tooth disorder	10	4.9 2.6–9.1ROR 4.9 · χ² 27 / p 9e-8	4.1 EB05 2.4 · IC025 +1.0 3/3 methods agree	Not in label — unassessed	serious PRR 6.5	no trial data cached
Blood pressure fluctuation	10	4.5 2.4–8.4ROR 4.6 · χ² 24 / p 4e-7	3.8 EB05 2.3 · IC025 +0.9 3/3 methods agree	Lab value / disease marker	serious PRR 4.4	no trial data cached
Needle issue	11	4.2 2.3–7.6ROR 4.2 · χ² 24 / p 5e-7	3.6 EB05 2.2 · IC025 +0.9 3/3 methods agree	Not in label — unassessed	serious n=11	no trial data cached
Lip swelling	12	3.9 2.2–6.9ROR 4.0 · χ² 24 / p 6e-7	3.5 EB05 2.2 · IC025 +0.8 3/3 methods agree	Labeled (related wording) related wording	serious PRR 4.8	no trial data cached
Angioedema (deep swelling of face/throat)	13	3.2 1.9–5.5ROR 3.2 · χ² 18 / p 1e-5	3.0 EB05 1.9 · IC025 +0.6	Labeled adverse reaction exact term	serious PRR 2.6	no trial data cached
Acne	18	2.6 1.6–4.1ROR 2.6 · χ² 16 / p 3e-5	2.5 EB05 1.7 · IC025 +0.5	Not in label — unassessed	serious PRR 9.8	no trial data cached
Product substitution issue	13	2.5 1.4–4.2ROR 2.5 · χ² 10 / p 8e-4	2.3 EB05 1.5 · IC025 +0.3	Reporting / coding artifact	serious PRR 1.9	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
Breast cancer	281	32.7 29.4–36.5ROR 38.2 · χ² 8,623 / p <1e-300	32.6 EB05 29.5 · IC025 +4.8 3/3 methods agree	Labeled — boxed warning exact term	serious PRR 25.0 · 88% consumer	no trial data cached
Breast cancer female	191	78.1 68.2–89.4ROR 86.6 · χ² 14,375 / p <1e-300	77.0 EB05 68.2 · IC025 +5.8 3/3 methods agree	Not in label — unassessed	serious PRR 59.4	no trial data cached
Hot flush (hot flashes)	51	7.4 5.6–9.7ROR 7.6 · χ² 276 / p 2e-62	7.0 EB05 5.5 · IC025 +2.3 3/3 methods agree	Labeled adverse reaction exact term	serious PRR 8.8 · 74% consumer	no trial data cached
Breast cancer metastatic	44	45.0 33.6–60.3ROR 46.0 · χ² 1,841 / p <1e-300	44.0 EB05 34.1 · IC025 +4.4 3/3 methods agree	Labeled (related wording) related wording	serious PRR 35.2 · 96% consumer	no trial data cached
Vaginal haemorrhage	35	9.0 6.5–12.5ROR 9.1 · χ² 241 / p 1e-54	8.4 EB05 6.2 · IC025 +2.4 3/3 methods agree	Labeled adverse reaction exact term	serious PRR 10.8	no trial data cached
Bone density decreased	32	11.0 7.8–15.6ROR 11.2 · χ² 282 / p 1e-63	10.5 EB05 7.5 · IC025 +2.7 3/3 methods agree	Lab value / disease marker	serious PRR 0.3 · 100% clinician	no trial data cached
Heart rate decreased	23	7.1 4.7–10.7ROR 7.2 · χ² 115 / p 4e-27	6.4 EB05 4.4 · IC025 +2.0 3/3 methods agree	Lab value / disease marker	serious PRR 6.5	no trial data cached
Abnormal dreams	21	8.3 5.4–12.6ROR 8.3 · χ² 127 / p 1e-29	7.3 EB05 4.9 · IC025 +2.1 3/3 methods agree	Not in label — unassessed	serious PRR 11.6 · 90% consumer	no trial data cached
Menorrhagia (heavy periods)	20	11.0 7.1–17.0ROR 11.1 · χ² 171 / p 2e-39	10.0 EB05 6.5 · IC025 +2.4 3/3 methods agree	Not in label — unassessed	serious PRR 17.1	no trial data cached
Brain fog	20	15.0 9.7–23.2ROR 15.1 · χ² 247 / p 5e-56	14.4 EB05 9.4 · IC025 +2.7 3/3 methods agree	Not in label — unassessed	serious PRR 22.2	no trial data cached
Bursitis	20	18.1 11.7–28.0ROR 18.3 · χ² 306 / p 6e-69	17.7 EB05 11.8 · IC025 +2.9 3/3 methods agree	Not in label — unassessed	serious PRR 16.4	no trial data cached
Blood potassium decreased	19	6.9 4.4–10.8ROR 7.0 · χ² 90 / p 1e-21	6.0 EB05 4.0 · IC025 +1.8 3/3 methods agree	Lab value / disease marker	serious PRR 6.4	no trial data cached
Blood pressure systolic increased	19	10.6 6.8–16.6ROR 10.7 · χ² 156 / p 5e-36	9.5 EB05 6.1 · IC025 +2.3 3/3 methods agree	Lab value / disease marker	serious PRR 8.9	no trial data cached
Acne	18	2.6 1.6–4.1ROR 2.6 · χ² 16 / p 3e-5	2.5 EB05 1.7 · IC025 +0.5	Not in label — unassessed	serious PRR 9.8	no trial data cached
Abdominal pain lower	18	7.8 4.9–12.3ROR 7.8 · χ² 99 / p 1e-23	6.7 EB05 4.4 · IC025 +1.9 3/3 methods agree	Labeled (related wording) related wording	serious PRR 9.0	no trial data cached

Unlabeled candidate signals

These flagged terms were not found in the FDA label text and do not match an artifact pattern. They are the pairs that would merit a structured assessment (temporality, dose-response, biological plausibility, consistency across databases, trial or cohort evidence). The screen has not done that; string-matching misses label wording, and a strong PRR can still be stimulated reporting, co-medication, or the disease itself.

Breast cancer female — n=191, PRR 78.1
Bursitis — n=20, PRR 18.1
Brain fog — n=20, PRR 15.0
Menorrhagia — n=20, PRR 11.0
Abnormal dreams — n=21, PRR 8.3

✓ 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 breast cancer, breast cancer female, hot flush, breast cancer metastatic, vaginal haemorrhage, bone density decreased. 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, 73 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.