Drug · FAERS side-effect profile with label screen

Estradiol and Levonorgestrel side effects: what 2,021 FDA adverse event reports show

Estradiol And Levonorgestrel · 50 reaction terms · 3,228 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

2,021 reports · 12% serious · 1 with death outcome · 100% 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 36 strongest signals

Labeled adverse reaction 4Labeled (related wording) 7Reporting / coding artifact 19Not in label — unassessed 6

What the badges mean

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.
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. 14 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
Product adhesion issue	668	199.3 187.1–212.2ROR 297.2 · χ² 129,287 / p <1e-300	194.4 EB05 182.3 · IC025 +7.3 3/3 methods agree	Reporting / coding artifact	serious n=66	no trial data cached
Product physical issue	329	174.2 157.6–192.4ROR 207.8 · χ² 55,575 / p <1e-300	169.6 EB05 154.7 · IC025 +6.9 3/3 methods agree	Reporting / coding artifact	serious n=26	no trial data cached
Device adhesion issue	245	169.9 150.9–191.2ROR 193.2 · χ² 40,324 / p <1e-300	165.0 EB05 148.4 · IC025 +6.8 3/3 methods agree	Reporting / coding artifact	serious n=17 · 87% consumer	no trial data cached
Application site rash	189	144.1 125.7–165.2ROR 158.8 · χ² 26,360 / p <1e-300	140.1 EB05 124.1 · IC025 +6.5 3/3 methods agree	Labeled (related wording) related wording	serious n=3 · 79% consumer	no trial data cached
Application site irritation	89	74.7 60.9–91.6ROR 78.1 · χ² 6,358 / p <1e-300	73.1 EB05 61.2 · IC025 +5.4 3/3 methods agree	Labeled adverse reaction exact term	serious n=7 · 77% consumer	no trial data cached
Application site pruritus	107	49.1 40.8–59.1ROR 51.8 · χ² 4,980 / p <1e-300	48.5 EB05 41.3 · IC025 +5.0 3/3 methods agree	Labeled (related wording) related wording	serious n=4 · 78% consumer	no trial data cached
Application site erythema	98	38.8 32.0–47.1ROR 40.7 · χ² 3,560 / p <1e-300	38.4 EB05 32.4 · IC025 +4.7 3/3 methods agree	Labeled adverse reaction exact term	serious n=4 · 75% consumer	no trial data cached
Hot flush (hot flashes)	226	31.2 27.6–35.3ROR 35.0 · χ² 6,579 / p <1e-300	31.0 EB05 27.8 · IC025 +4.6 3/3 methods agree	Labeled adverse reaction exact term	serious PRR 27.6 · 70% consumer	no trial data cached
Metrorrhagia	51	30.7 23.4–40.2ROR 31.4 · χ² 1,432 / p <1e-300	30.3 EB05 23.9 · IC025 +4.1 3/3 methods agree	Not in label — unassessed	serious n=2 · 84% consumer	no trial data cached
Genital haemorrhage	31	24.9 17.6–35.3ROR 25.3 · χ² 687 / p 1e-151	24.5 EB05 18.1 · IC025 +3.6 3/3 methods agree	Labeled (related wording) related wording	serious PRR 88.1 · 81% consumer	no trial data cached
Device breakage	92	24.4 19.9–29.7ROR 25.5 · χ² 2,036 / p <1e-300	24.2 EB05 20.3 · IC025 +4.1 3/3 methods agree	Reporting / coding artifact	serious PRR 12.9	no trial data cached
Device use issue	30	18.0 12.6–25.7ROR 18.3 · χ² 465 / p 2e-103	17.7 EB05 12.9 · IC025 +3.2 3/3 methods agree	Reporting / coding artifact	80% consumer	no trial data cached
Vaginal haemorrhage	73	17.8 14.2–22.3ROR 18.4 · χ² 1,142 / p 1e-250	17.7 EB05 14.5 · IC025 +3.6 3/3 methods agree	Labeled adverse reaction exact term	serious PRR 50.1 · 79% consumer	no trial data cached
Wrong technique in device usage process	71	16.1 12.8–20.3ROR 16.7 · χ² 993 / p 2e-218	16.0 EB05 13.1 · IC025 +3.5 3/3 methods agree	Reporting / coding artifact	serious n=8 · 82% consumer	no trial data cached
Device defective	25	16.1 10.9–23.7ROR 16.2 · χ² 338 / p 1e-75	15.7 EB05 10.9 · IC025 +3.0 3/3 methods agree	Reporting / coding artifact	serious n=4 · 76% consumer	no trial data cached
Application site pain	31	14.6 10.3–20.7ROR 14.8 · χ² 380 / p 6e-85	14.3 EB05 10.3 · IC025 +3.0 3/3 methods agree	Labeled (related wording) related wording	77% consumer	no trial data cached
Breast pain	15	14.6 8.8–24.2ROR 14.7 · χ² 177 / p 1e-40	13.7 EB05 8.1 · IC025 +2.5 3/3 methods agree	Labeled (related wording) related wording	serious n=4	no trial data cached
Night sweats	43	13.9 10.3–18.6ROR 14.2 · χ² 501 / p 3e-111	13.6 EB05 10.4 · IC025 +3.1 3/3 methods agree	Not in label — unassessed	serious PRR 10.3 · 77% consumer	no trial data cached
Wrong technique in product usage process	259	13.3 11.9–14.9ROR 15.1 · χ² 2,964 / p <1e-300	13.3 EB05 12.0 · IC025 +3.5 3/3 methods agree	Reporting / coding artifact	serious PRR 25.9	no trial data cached
Product packaging issue	11	12.3 6.8–22.2ROR 12.4 · χ² 103 / p 1e-24	10.5 EB05 5.5 · IC025 +2.0 3/3 methods agree	Reporting / coding artifact	serious n=1	no trial data cached
Product prescribing issue	21	10.7 7.0–16.4ROR 10.8 · χ² 175 / p 2e-40	9.8 EB05 6.4 · IC025 +2.4 3/3 methods agree	Reporting / coding artifact	serious PRR 12.4	no trial data cached
Product quality issue	134	10.3 8.8–12.2ROR 11.0 · χ² 1,125 / p 6e-247	10.2 EB05 8.8 · IC025 +3.0 3/3 methods agree	Reporting / coding artifact	serious PRR 6.0	no trial data cached
Product availability issue	20	9.3 6.0–14.3ROR 9.3 · χ² 139 / p 2e-32	8.2 EB05 5.4 · IC025 +2.2 3/3 methods agree	Reporting / coding artifact	serious PRR 4.5 · 80% consumer	no trial data cached
Abdominal pain lower	17	7.0 4.3–11.2ROR 7.0 · χ² 81 / p 1e-19	6.0 EB05 3.9 · IC025 +1.8 3/3 methods agree	Labeled (related wording) related wording	serious PRR 37.1	no trial data cached
Mood swings	18	5.9 3.7–9.3ROR 5.9 · χ² 68 / p 9e-17	5.1 EB05 3.4 · IC025 +1.6 3/3 methods agree	Not in label — unassessed	serious PRR 7.9	no trial data cached
Middle insomnia	10	5.6 3.0–10.4ROR 5.6 · χ² 33 / p 4e-9	4.5 EB05 2.7 · IC025 +1.1 3/3 methods agree	Not in label — unassessed	serious PRR 11.3	no trial data cached
Incorrect drug administration duration	15	5.5 3.3–9.0ROR 5.5 · χ² 50 / p 7e-13	4.7 EB05 3.1 · IC025 +1.4 3/3 methods agree	Reporting / coding artifact	serious PRR 9.5	no trial data cached
Drug dose omission	87	5.4 4.4–6.6ROR 5.6 · χ² 309 / p 2e-69	5.2 EB05 4.4 · IC025 +2.0 3/3 methods agree	Reporting / coding artifact	serious PRR 3.7	no trial data cached
Mood altered	13	5.0 2.9–8.5ROR 5.0 · χ² 37 / p 5e-10	4.3 EB05 2.7 · IC025 +1.2 3/3 methods agree	Not in label — unassessed	serious PRR 9.4	no trial data cached
Incorrect dose administered by device	12	4.9 2.8–8.6ROR 4.9 · χ² 34 / p 4e-9	4.2 EB05 2.6 · IC025 +1.1 3/3 methods agree	Reporting / coding artifact	serious n=3	no trial data cached
Skin irritation	18	4.1 2.6–6.4ROR 4.1 · χ² 39 / p 2e-10	3.7 EB05 2.5 · IC025 +1.1 3/3 methods agree	Labeled (related wording) related wording	serious n=3	no trial data cached
Adverse event	29	3.3 2.3–4.7ROR 3.3 · χ² 44 / p 2e-11	3.1 EB05 2.3 · IC025 +1.0 3/3 methods agree	Reporting / coding artifact	serious PRR 2.4 · 79% consumer	no trial data cached
Crying	11	3.1 1.7–5.6ROR 3.1 · χ² 14 / p 1e-4	2.8 EB05 1.7 · IC025 +0.5	Not in label — unassessed	serious PRR 9.0	no trial data cached
Device use error	10	3.0 1.6–5.7ROR 3.1 · χ² 12 / p 3e-4	2.8 EB05 1.6 · IC025 +0.4	Reporting / coding artifact	–	no trial data cached
Inappropriate schedule of drug administration	19	2.7 1.7–4.3ROR 2.7 · χ² 19 / p 6e-6	2.6 EB05 1.8 · IC025 +0.6	Reporting / coding artifact	serious PRR 2.3	no trial data cached
No adverse event	36	2.1 1.5–2.9ROR 2.1 · χ² 20 / p 4e-6	2.1 EB05 1.6 · IC025 +0.5	Reporting / coding artifact	serious PRR 13.4 · 86% consumer	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
Product adhesion issue	668	199.3 187.1–212.2ROR 297.2 · χ² 129,287 / p <1e-300	194.4 EB05 182.3 · IC025 +7.3 3/3 methods agree	Reporting / coding artifact	serious n=66	no trial data cached
Product physical issue	329	174.2 157.6–192.4ROR 207.8 · χ² 55,575 / p <1e-300	169.6 EB05 154.7 · IC025 +6.9 3/3 methods agree	Reporting / coding artifact	serious n=26	no trial data cached
Wrong technique in product usage process	259	13.3 11.9–14.9ROR 15.1 · χ² 2,964 / p <1e-300	13.3 EB05 12.0 · IC025 +3.5 3/3 methods agree	Reporting / coding artifact	serious PRR 25.9	no trial data cached
Device adhesion issue	245	169.9 150.9–191.2ROR 193.2 · χ² 40,324 / p <1e-300	165.0 EB05 148.4 · IC025 +6.8 3/3 methods agree	Reporting / coding artifact	serious n=17 · 87% consumer	no trial data cached
Hot flush (hot flashes)	226	31.2 27.6–35.3ROR 35.0 · χ² 6,579 / p <1e-300	31.0 EB05 27.8 · IC025 +4.6 3/3 methods agree	Labeled adverse reaction exact term	serious PRR 27.6 · 70% consumer	no trial data cached
Application site rash	189	144.1 125.7–165.2ROR 158.8 · χ² 26,360 / p <1e-300	140.1 EB05 124.1 · IC025 +6.5 3/3 methods agree	Labeled (related wording) related wording	serious n=3 · 79% consumer	no trial data cached
Product quality issue	134	10.3 8.8–12.2ROR 11.0 · χ² 1,125 / p 6e-247	10.2 EB05 8.8 · IC025 +3.0 3/3 methods agree	Reporting / coding artifact	serious PRR 6.0	no trial data cached
Application site pruritus	107	49.1 40.8–59.1ROR 51.8 · χ² 4,980 / p <1e-300	48.5 EB05 41.3 · IC025 +5.0 3/3 methods agree	Labeled (related wording) related wording	serious n=4 · 78% consumer	no trial data cached
Application site erythema	98	38.8 32.0–47.1ROR 40.7 · χ² 3,560 / p <1e-300	38.4 EB05 32.4 · IC025 +4.7 3/3 methods agree	Labeled adverse reaction exact term	serious n=4 · 75% consumer	no trial data cached
Device breakage	92	24.4 19.9–29.7ROR 25.5 · χ² 2,036 / p <1e-300	24.2 EB05 20.3 · IC025 +4.1 3/3 methods agree	Reporting / coding artifact	serious PRR 12.9	no trial data cached
Application site irritation	89	74.7 60.9–91.6ROR 78.1 · χ² 6,358 / p <1e-300	73.1 EB05 61.2 · IC025 +5.4 3/3 methods agree	Labeled adverse reaction exact term	serious n=7 · 77% consumer	no trial data cached
Drug dose omission	87	5.4 4.4–6.6ROR 5.6 · χ² 309 / p 2e-69	5.2 EB05 4.4 · IC025 +2.0 3/3 methods agree	Reporting / coding artifact	serious PRR 3.7	no trial data cached
Vaginal haemorrhage	73	17.8 14.2–22.3ROR 18.4 · χ² 1,142 / p 1e-250	17.7 EB05 14.5 · IC025 +3.6 3/3 methods agree	Labeled adverse reaction exact term	serious PRR 50.1 · 79% consumer	no trial data cached
Wrong technique in device usage process	71	16.1 12.8–20.3ROR 16.7 · χ² 993 / p 2e-218	16.0 EB05 13.1 · IC025 +3.5 3/3 methods agree	Reporting / coding artifact	serious n=8 · 82% consumer	no trial data cached
Metrorrhagia	51	30.7 23.4–40.2ROR 31.4 · χ² 1,432 / p <1e-300	30.3 EB05 23.9 · IC025 +4.1 3/3 methods agree	Not in label — unassessed	serious n=2 · 84% consumer	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.

Metrorrhagia — n=51, PRR 30.7
Night sweats — n=43, PRR 13.9

✓ 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 Levonorgestrel?

In FDA FAERS, the most frequently co-reported reaction terms for Estradiol and Levonorgestrel are hot flush, application site rash, application site pruritus, application site erythema, application site irritation, vaginal haemorrhage. 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 Levonorgestrel 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 Levonorgestrel 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, 50 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.