Norethindrone and Ethinyl Estradiol side effects: what 1,147 FDA adverse event reports show
Drug class
Progestin
Label matched
Norethindrone (Norethindrone)
Who reports
1,147 reports · 43% serious · 22 with death outcome · 99% female
Used for
1. Indications Progestin-only oral contraceptives are indicated for the prevention of pregnancy. 2. Efficacy If used perfectly, the first-year failure rate for progestin-only oral contraceptives is 0.3%. However, the typical failure rate is estimated to be closer to 9%, due to late or omitted pills. Table 1 lists the pregnancy rates for users of all major methods of contraception.
Boxed warning
None in the current label
Causality screen of the 21 strongest signals
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.
- Likely indication confounding The term appears in the label's indications: reports probably describe the disease being treated (or its progression), not a drug effect. Classic confounding by indication.
- 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.
| Reaction | Reports | PRR 95% CI · ROR · χ²/p | EBGM EB05 · IC025 | Label screen | Serious-only & strata | Trial cross-check |
|---|---|---|---|---|---|---|
| Metrorrhagia | 22 | 23.3 15.4–35.2ROR 23.7 · χ² 446 / p 2e-99 | 22.8 EB05 15.8 · IC025 +3.2 3/3 methods agree | Not in label — unassessed | serious n=5 · 76% consumer | no trial data cached |
| Coeliac disease | 12 | 22.4 12.7–39.3ROR 22.6 · χ² 224 / p 7e-51 | 21.4 EB05 12.7 · IC025 +2.6 3/3 methods agree | Not in label — unassessed | serious PRR 36.9 | no trial data cached |
| Dysmenorrhoea | 13 | 18.2 10.6–31.2ROR 18.4 · χ² 194 / p 2e-44 | 17.3 EB05 10.1 · IC025 +2.5 3/3 methods agree | Not in label — unassessed | – | no trial data cached |
| Menorrhagia (heavy periods) | 11 | 10.1 5.6–18.2ROR 10.2 · χ² 81 / p 1e-19 | 8.2 EB05 4.5 · IC025 +1.8 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 19.2 | no trial data cached |
| Inflammatory bowel disease | 5 | 9.3 3.9–22.3ROR 9.3 · χ² 29 / p 3e-8 | 5.9 EB05 2.6 · IC025 +0.8 3/3 methods agree | Not in label — unassessed | serious PRR 12.6 | no trial data cached |
| Vaginal haemorrhage | 21 | 9.0 5.9–13.8ROR 9.2 · χ² 142 / p 5e-33 | 8.0 EB05 5.4 · IC025 +2.2 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 6.0 | no trial data cached |
| Back injury | 5 | 8.4 3.5–20.2ROR 8.5 · χ² 26 / p 2e-7 | 5.4 EB05 2.4 · IC025 +0.8 3/3 methods agree | Not in label — unassessed | serious PRR 14.8 | no trial data cached |
| Menstruation irregular | 11 | 7.6 4.2–13.6ROR 7.6 · χ² 56 / p 3e-14 | 6.0 EB05 3.5 · IC025 +1.5 3/3 methods agree | Labeled (related wording) related wording | serious n=1 | no trial data cached |
| Product substitution issue | 20 | 6.3 4.1–9.8ROR 6.4 · χ² 85 / p 1e-20 | 5.6 EB05 3.8 · IC025 +1.7 3/3 methods agree | Reporting / coding artifact | serious PRR 9.0 | no trial data cached |
| Amenorrhoea (missed periods) | 5 | 5.5 2.3–13.1ROR 5.5 · χ² 14 / p 9e-5 | 3.9 EB05 1.8 · IC025 +0.4 | Likely indication confounding shares a disease stem with the indications wording | serious PRR 6.6 | no trial data cached |
| Pregnancy | 6 | 5.4 2.4–12.0ROR 5.4 · χ² 17 / p 1e-5 | 4.0 EB05 2.0 · IC025 +0.6 3/3 methods agree | Likely indication confounding term in indications; also in warnings | serious PRR 10.5 | no trial data cached |
| Exposure during pregnancy | 16 | 4.7 2.9–7.6ROR 4.8 · χ² 43 / p 3e-11 | 4.2 EB05 2.7 · IC025 +1.2 3/3 methods agree | Reporting / coding artifact | serious PRR 4.1 | no trial data cached |
| Activities of daily living impaired | 5 | 4.5 1.9–10.9ROR 4.6 · χ² 11 / p 6e-4 | 3.4 EB05 1.6 · IC025 +0.2 | Not in label — unassessed | serious PRR 4.9 | no trial data cached |
| Product dispensing error | 5 | 4.2 1.8–10.1ROR 4.2 · χ² 9 / p 0.001 | 3.2 EB05 1.6 · IC025 +0.1 | Reporting / coding artifact | serious n=1 | no trial data cached |
| Product dose omission | 14 | 3.9 2.3–6.5ROR 3.9 · χ² 27 / p 1e-7 | 3.5 EB05 2.2 · IC025 +0.9 3/3 methods agree | Reporting / coding artifact | serious PRR 1.5 | no trial data cached |
| Abortion spontaneous | 7 | 3.2 1.5–6.7ROR 3.2 · χ² 8 / p 0.002 | 2.8 EB05 1.5 · IC025 +0.2 | Labeled (related wording) related wording | serious PRR 4.2 | no trial data cached |
| Injection site bruising | 12 | 2.8 1.6–4.9ROR 2.8 · χ² 12 / p 3e-4 | 2.6 EB05 1.6 · IC025 +0.4 | Not in label — unassessed | serious PRR 3.7 | no trial data cached |
| Extra dose administered | 6 | 2.7 1.2–6.1ROR 2.8 · χ² 5 / p 0.012 | 2.4 EB05 1.2 · IC025 -0.1 PRR-only: not supported by EBGM or IC | Not in label — unassessed | serious n=1 | no trial data cached |
| Injection site pruritus | 10 | 2.7 1.5–5.1ROR 2.8 · χ² 9 / p 0.001 | 2.5 EB05 1.5 · IC025 +0.3 | Not in label — unassessed | – | no trial data cached |
| Injection site erythema (redness where injected) | 18 | 2.7 1.7–4.2ROR 2.7 · χ² 17 / p 2e-5 | 2.5 EB05 1.7 · IC025 +0.6 | Not in label — unassessed | serious PRR 2.4 | no trial data cached |
| Multiple sclerosis relapse | 10 | 2.6 1.4–4.9ROR 2.7 · χ² 9 / p 0.002 | 2.4 EB05 1.5 · IC025 +0.2 | Not in label — unassessed | serious PRR 2.0 | no trial data cached |
Trial evidence (ClinicalTrials.gov)
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 |
|---|---|---|---|---|---|---|
| Metrorrhagia | 22 | 23.3 15.4–35.2ROR 23.7 · χ² 446 / p 2e-99 | 22.8 EB05 15.8 · IC025 +3.2 3/3 methods agree | Not in label — unassessed | serious n=5 · 76% consumer | no trial data cached |
| Vaginal haemorrhage | 21 | 9.0 5.9–13.8ROR 9.2 · χ² 142 / p 5e-33 | 8.0 EB05 5.4 · IC025 +2.2 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 6.0 | no trial data cached |
| Product substitution issue | 20 | 6.3 4.1–9.8ROR 6.4 · χ² 85 / p 1e-20 | 5.6 EB05 3.8 · IC025 +1.7 3/3 methods agree | Reporting / coding artifact | serious PRR 9.0 | no trial data cached |
| Injection site erythema (redness where injected) | 18 | 2.7 1.7–4.2ROR 2.7 · χ² 17 / p 2e-5 | 2.5 EB05 1.7 · IC025 +0.6 | Not in label — unassessed | serious PRR 2.4 | no trial data cached |
| Exposure during pregnancy | 16 | 4.7 2.9–7.6ROR 4.8 · χ² 43 / p 3e-11 | 4.2 EB05 2.7 · IC025 +1.2 3/3 methods agree | Reporting / coding artifact | serious PRR 4.1 | no trial data cached |
| Product dose omission | 14 | 3.9 2.3–6.5ROR 3.9 · χ² 27 / p 1e-7 | 3.5 EB05 2.2 · IC025 +0.9 3/3 methods agree | Reporting / coding artifact | serious PRR 1.5 | no trial data cached |
| Dysmenorrhoea | 13 | 18.2 10.6–31.2ROR 18.4 · χ² 194 / p 2e-44 | 17.3 EB05 10.1 · IC025 +2.5 3/3 methods agree | Not in label — unassessed | – | no trial data cached |
| Injection site bruising | 12 | 2.8 1.6–4.9ROR 2.8 · χ² 12 / p 3e-4 | 2.6 EB05 1.6 · IC025 +0.4 | Not in label — unassessed | serious PRR 3.7 | no trial data cached |
| Coeliac disease | 12 | 22.4 12.7–39.3ROR 22.6 · χ² 224 / p 7e-51 | 21.4 EB05 12.7 · IC025 +2.6 3/3 methods agree | Not in label — unassessed | serious PRR 36.9 | no trial data cached |
| Menstruation irregular | 11 | 7.6 4.2–13.6ROR 7.6 · χ² 56 / p 3e-14 | 6.0 EB05 3.5 · IC025 +1.5 3/3 methods agree | Labeled (related wording) related wording | serious n=1 | no trial data cached |
| Menorrhagia (heavy periods) | 11 | 10.1 5.6–18.2ROR 10.2 · χ² 81 / p 1e-19 | 8.2 EB05 4.5 · IC025 +1.8 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 19.2 | no trial data cached |
| Multiple sclerosis relapse | 10 | 2.6 1.4–4.9ROR 2.7 · χ² 9 / p 0.002 | 2.4 EB05 1.5 · IC025 +0.2 | Not in label — unassessed | serious PRR 2.0 | no trial data cached |
| Injection site pruritus | 10 | 2.7 1.5–5.1ROR 2.8 · χ² 9 / p 0.001 | 2.5 EB05 1.5 · IC025 +0.3 | Not in label — unassessed | – | no trial data cached |
| Abortion spontaneous | 7 | 3.2 1.5–6.7ROR 3.2 · χ² 8 / p 0.002 | 2.8 EB05 1.5 · IC025 +0.2 | Labeled (related wording) related wording | serious PRR 4.2 | no trial data cached |
| Dermatitis atopic | 6 | 2.2 1.0–4.9ROR 2.2 · χ² 3 / p 0.047 | 2.0 EB05 1.0 · IC025 -0.4 PRR-only: not supported by EBGM or IC | Not in label — unassessed | – | 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=22, PRR 23.3
✓ 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 Norethindrone and Ethinyl Estradiol?
In FDA FAERS, the most frequently co-reported reaction terms for Norethindrone and Ethinyl Estradiol are metrorrhagia, vaginal haemorrhage, injection site erythema, dysmenorrhoea, injection site bruising, coeliac disease. 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 Norethindrone and Ethinyl Estradiol have an FDA boxed warning?
No. The FDA label retrieved for Norethindrone and Ethinyl Estradiol has no boxed warning; see the label's Warnings and Precautions for the recognised risks.
Do FAERS signals prove that Norethindrone and Ethinyl Estradiol 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 0d2f8fea-3675-40d2-afd9-9fcb148dbd4b, effective 20260131; matched on
openfda.generic_name.exact:"NORETHINDRONE") - 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, fieldpatient.drug.openfda.generic_name.exact, 35 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.