Levonorgestrel and Ethinyl Estradiol side effects: what 2,842 FDA adverse event reports show
Drug class
Progestin, Progestin-containing Intrauterine System
Label matched
Levonorgestrel (Liletta)
Who reports
2,842 reports · 45% serious · 39 with death outcome · 99% female
Used for
LILETTA is a progestin-containing intrauterine system indicated for: Prevention of pregnancy for up to 8 years ( 1.1 ) Treatment of heavy menstrual bleeding for up to 5 years in patients who choose intrauterine contraception as their method of contraception ( 1.2 ) 1.1 Contraception LILETTA is indicated for prevention of pregnancy for up to 8 years.
What it is
the following structural formula: Levonorgestrel USP, (-)-13-ethyl-17-hydroxy-18,19-dinor-17-pregn-4-en-20-yn-3-one, the active ingredient in LILETTA, is the levorotatory form of norgestrel, which consists of a racemic mixture of D-(–)-norgestrel (levonorgestrel) and L-(+)-norgestrel (dextronorgestrel).
Boxed warning
None in the current label
Causality screen of the 40 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. 96 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 | 47 | 20.1 15.1–26.7ROR 20.4 · χ² 832 / p 2e-183 | 19.9 EB05 15.5 · IC025 +3.6 3/3 methods agree | Not in label — unassessed | serious n=10 | no trial data cached |
| Menorrhagia (heavy periods) | 38 | 14.1 10.3–19.3ROR 14.3 · χ² 449 / p 6e-100 | 13.8 EB05 10.3 · IC025 +3.0 3/3 methods agree | Not in label — unassessed | serious PRR 14.8 | no trial data cached |
| Dysmenorrhoea | 22 | 12.4 8.2–18.9ROR 12.5 · χ² 220 / p 5e-50 | 11.7 EB05 7.7 · IC025 +2.6 3/3 methods agree | Not in label — unassessed | serious n=12 | no trial data cached |
| Coeliac disease | 16 | 12.0 7.4–19.6ROR 12.1 · χ² 151 / p 5e-35 | 10.9 EB05 6.5 · IC025 +2.3 3/3 methods agree | Not in label — unassessed | serious PRR 19.0 | no trial data cached |
| Menstruation irregular | 43 | 12.0 8.9–16.1ROR 12.1 · χ² 421 / p 6e-94 | 11.6 EB05 8.8 · IC025 +2.9 3/3 methods agree | Labeled (related wording) related wording | serious n=8 · 88% consumer | no trial data cached |
| Unintended pregnancy | 16 | 11.3 6.9–18.4ROR 11.4 · χ² 140 / p 1e-32 | 10.1 EB05 6.1 · IC025 +2.3 3/3 methods agree | Likely indication confounding shares a disease stem with the indications wording | serious PRR 15.3 | no trial data cached |
| Vaginal haemorrhage | 63 | 10.9 8.6–14.0ROR 11.2 · χ² 559 / p 7e-124 | 10.7 EB05 8.5 · IC025 +2.9 3/3 methods agree | Not in label — unassessed | serious PRR 9.3 · 75% consumer | no trial data cached |
| Menstruation delayed | 15 | 10.7 6.4–17.7ROR 10.7 · χ² 122 / p 1e-28 | 9.3 EB05 5.6 · IC025 +2.2 3/3 methods agree | Labeled (related wording) related wording | serious n=3 | no trial data cached |
| Pelvic pain | 25 | 10.2 6.9–15.0ROR 10.2 · χ² 197 / p 4e-45 | 9.3 EB05 6.4 · IC025 +2.4 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 11.3 · 74% consumer | no trial data cached |
| Amenorrhoea (missed periods) | 19 | 8.4 5.4–13.2ROR 8.5 · χ² 117 / p 2e-27 | 7.3 EB05 4.8 · IC025 +2.0 3/3 methods agree | Not in label — unassessed | serious PRR 14.1 | no trial data cached |
| Abortion induced | 10 | 7.8 4.2–14.5ROR 7.9 · χ² 53 / p 2e-13 | 6.1 EB05 3.5 · IC025 +1.5 3/3 methods agree | Labeled (related wording) related wording | serious PRR 9.3 | no trial data cached |
| Sleep apnoea syndrome | 18 | 6.9 4.4–11.0ROR 7.0 · χ² 86 / p 1e-20 | 6.0 EB05 4.0 · IC025 +1.8 3/3 methods agree | Not in label — unassessed | serious PRR 9.9 | no trial data cached |
| Pharyngitis streptococcal | 10 | 6.8 3.7–12.7ROR 6.8 · χ² 44 / p 2e-11 | 5.4 EB05 3.1 · IC025 +1.3 3/3 methods agree | Not in label — unassessed | serious n=7 | no trial data cached |
| Genital haemorrhage | 10 | 5.7 3.1–10.6ROR 5.7 · χ² 34 / p 2e-9 | 4.6 EB05 2.7 · IC025 +1.1 3/3 methods agree | Not in label — unassessed | serious PRR 8.1 | no trial data cached |
| Product substitution issue | 43 | 5.5 4.1–7.4ROR 5.6 · χ² 155 / p 8e-36 | 5.2 EB05 4.0 · IC025 +1.9 3/3 methods agree | Reporting / coding artifact | serious PRR 5.5 · 78% consumer | no trial data cached |
| Seasonal allergy | 10 | 5.2 2.8–9.7ROR 5.2 · χ² 30 / p 2e-8 | 4.3 EB05 2.5 · IC025 +1.0 3/3 methods agree | Not in label — unassessed | serious n=8 | no trial data cached |
| Pneumothorax | 11 | 5.1 2.8–9.2ROR 5.1 · χ² 32 / p 6e-9 | 4.3 EB05 2.6 · IC025 +1.1 3/3 methods agree | Not in label — unassessed | serious PRR 6.5 | no trial data cached |
| Pulmonary embolism (lung blood clot) | 65 | 5.0 4.0–6.4ROR 5.1 · χ² 206 / p 4e-47 | 4.9 EB05 3.9 · IC025 +1.9 3/3 methods agree | Labeled (related wording) related wording | serious PRR 6.4 | no trial data cached |
| Dermatitis atopic | 32 | 4.7 3.3–6.7ROR 4.8 · χ² 91 / p 9e-22 | 4.4 EB05 3.3 · IC025 +1.6 3/3 methods agree | Not in label — unassessed | – | no trial data cached |
| Abdominal pain lower | 16 | 4.7 2.9–7.6ROR 4.7 · χ² 42 / p 4e-11 | 4.1 EB05 2.7 · IC025 +1.2 3/3 methods agree | Labeled (related wording) related wording | serious PRR 6.1 | no trial data cached |
| Mood swings | 19 | 4.4 2.8–6.9ROR 4.4 · χ² 47 / p 4e-12 | 4.0 EB05 2.7 · IC025 +1.2 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 5.1 | no trial data cached |
| Drug exposure during pregnancy | 20 | 4.3 2.8–6.6ROR 4.3 · χ² 47 / p 3e-12 | 3.9 EB05 2.7 · IC025 +1.2 3/3 methods agree | Reporting / coding artifact | serious PRR 5.4 | no trial data cached |
| Migraine | 54 | 4.2 3.2–5.5ROR 4.3 · χ² 129 / p 3e-30 | 4.1 EB05 3.2 · IC025 +1.6 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 5.8 · 76% consumer | no trial data cached |
| Acute respiratory distress syndrome | 10 | 4.2 2.2–7.7ROR 4.2 · χ² 21 / p 2e-6 | 3.6 EB05 2.1 · IC025 +0.8 3/3 methods agree | Not in label — unassessed | serious PRR 5.3 | no trial data cached |
| Poor quality sleep | 12 | 4.1 2.4–7.3ROR 4.2 · χ² 26 / p 2e-7 | 3.6 EB05 2.2 · IC025 +0.9 3/3 methods agree | Reporting / coding artifact | serious PRR 5.6 | no trial data cached |
| Intentional dose omission | 15 | 4.0 2.4–6.7ROR 4.1 · χ² 31 / p 1e-8 | 3.6 EB05 2.4 · IC025 +1.0 3/3 methods agree | Reporting / coding artifact | serious PRR 6.3 | no trial data cached |
| Panic attack | 20 | 4.0 2.6–6.3ROR 4.1 · χ² 43 / p 3e-11 | 3.7 EB05 2.6 · IC025 +1.2 3/3 methods agree | Not in label — unassessed | serious PRR 3.4 | no trial data cached |
| Eczema | 26 | 3.8 2.6–5.6ROR 3.8 · χ² 51 / p 4e-13 | 3.6 EB05 2.6 · IC025 +1.2 3/3 methods agree | Not in label — unassessed | serious PRR 2.2 | no trial data cached |
| Mood altered | 14 | 3.8 2.3–6.4ROR 3.8 · χ² 26 / p 2e-7 | 3.4 EB05 2.2 · IC025 +0.9 3/3 methods agree | Labeled (related wording) related wording | serious PRR 4.9 | no trial data cached |
| Night sweats | 16 | 3.7 2.2–6.0ROR 3.7 · χ² 28 / p 5e-8 | 3.4 EB05 2.2 · IC025 +0.9 3/3 methods agree | Not in label — unassessed | serious PRR 5.5 | no trial data cached |
| Injury | 34 | 3.6 2.5–5.0ROR 3.6 · χ² 60 / p 5e-15 | 3.4 EB05 2.6 · IC025 +1.2 3/3 methods agree | Not in label — unassessed | serious PRR 5.4 | no trial data cached |
| Suicidal ideation (thoughts of suicide) | 44 | 3.5 2.6–4.8ROR 3.6 · χ² 78 / p 5e-19 | 3.4 EB05 2.7 · IC025 +1.3 3/3 methods agree | Not in label — unassessed | serious PRR 4.5 | no trial data cached |
| Deep vein thrombosis (leg blood clot) | 30 | 3.4 2.4–4.8ROR 3.4 · χ² 48 / p 2e-12 | 3.2 EB05 2.4 · IC025 +1.1 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 4.4 | no trial data cached |
| Depression | 102 | 3.3 2.7–4.0ROR 3.4 · χ² 162 / p 2e-37 | 3.3 EB05 2.8 · IC025 +1.4 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 3.7 | no trial data cached |
| Anhedonia | 11 | 3.1 1.7–5.5ROR 3.1 · χ² 13 / p 1e-4 | 2.8 EB05 1.7 · IC025 +0.5 | Not in label — unassessed | serious PRR 3.9 | no trial data cached |
| Injection site urticaria | 10 | 3.0 1.6–5.6ROR 3.0 · χ² 12 / p 3e-4 | 2.8 EB05 1.6 · IC025 +0.4 | Labeled (related wording) related wording | – | no trial data cached |
| Abortion spontaneous | 16 | 2.9 1.8–4.8ROR 2.9 · χ² 19 / p 8e-6 | 2.8 EB05 1.8 · IC025 +0.6 | Labeled (related wording) related wording | serious PRR 3.8 | no trial data cached |
| Acne | 30 | 2.9 2.0–4.1ROR 2.9 · χ² 36 / p 1e-9 | 2.8 EB05 2.1 · IC025 +0.9 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 4.2 | no trial data cached |
| Depressed mood | 20 | 2.8 1.8–4.3ROR 2.8 · χ² 21 / p 2e-6 | 2.7 EB05 1.8 · IC025 +0.7 | Not in label — unassessed | serious PRR 4.4 | no trial data cached |
| Procedural pain | 10 | 2.7 1.4–5.0ROR 2.7 · χ² 9 / p 0.001 | 2.5 EB05 1.5 · IC025 +0.2 | Not in label — unassessed | serious PRR 2.9 | 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 |
|---|---|---|---|---|---|---|
| Depression | 102 | 3.3 2.7–4.0ROR 3.4 · χ² 162 / p 2e-37 | 3.3 EB05 2.8 · IC025 +1.4 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 3.7 | no trial data cached |
| Pulmonary embolism (lung blood clot) | 65 | 5.0 4.0–6.4ROR 5.1 · χ² 206 / p 4e-47 | 4.9 EB05 3.9 · IC025 +1.9 3/3 methods agree | Labeled (related wording) related wording | serious PRR 6.4 | no trial data cached |
| Vaginal haemorrhage | 63 | 10.9 8.6–14.0ROR 11.2 · χ² 559 / p 7e-124 | 10.7 EB05 8.5 · IC025 +2.9 3/3 methods agree | Not in label — unassessed | serious PRR 9.3 · 75% consumer | no trial data cached |
| Migraine | 54 | 4.2 3.2–5.5ROR 4.3 · χ² 129 / p 3e-30 | 4.1 EB05 3.2 · IC025 +1.6 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 5.8 · 76% consumer | no trial data cached |
| Injection site pain (pain where injected) | 51 | 1.2 0.9–1.6ROR 1.2 · χ² 2 / p 0.071 | 1.2 EB05 1.0 · IC025 -0.2 PRR-only: not supported by EBGM or IC | Labeled (related wording) related wording | serious PRR 1.6 | no trial data cached |
| Metrorrhagia | 47 | 20.1 15.1–26.7ROR 20.4 · χ² 832 / p 2e-183 | 19.9 EB05 15.5 · IC025 +3.6 3/3 methods agree | Not in label — unassessed | serious n=10 | no trial data cached |
| Suicidal ideation (thoughts of suicide) | 44 | 3.5 2.6–4.8ROR 3.6 · χ² 78 / p 5e-19 | 3.4 EB05 2.7 · IC025 +1.3 3/3 methods agree | Not in label — unassessed | serious PRR 4.5 | no trial data cached |
| Product substitution issue | 43 | 5.5 4.1–7.4ROR 5.6 · χ² 155 / p 8e-36 | 5.2 EB05 4.0 · IC025 +1.9 3/3 methods agree | Reporting / coding artifact | serious PRR 5.5 · 78% consumer | no trial data cached |
| Menstruation irregular | 43 | 12.0 8.9–16.1ROR 12.1 · χ² 421 / p 6e-94 | 11.6 EB05 8.8 · IC025 +2.9 3/3 methods agree | Labeled (related wording) related wording | serious n=8 · 88% consumer | no trial data cached |
| Drug dose omission | 41 | 1.8 1.3–2.4ROR 1.8 · χ² 14 / p 9e-5 | 1.8 EB05 1.4 · IC025 +0.3 | Reporting / coding artifact | serious PRR 2.4 · 82% consumer | no trial data cached |
| Menorrhagia (heavy periods) | 38 | 14.1 10.3–19.3ROR 14.3 · χ² 449 / p 6e-100 | 13.8 EB05 10.3 · IC025 +3.0 3/3 methods agree | Not in label — unassessed | serious PRR 14.8 | no trial data cached |
| Dry skin | 35 | 2.0 1.4–2.7ROR 2.0 · χ² 16 / p 4e-5 | 1.9 EB05 1.5 · IC025 +0.4 | Not in label — unassessed | serious PRR 3.1 | no trial data cached |
| Injection site erythema (redness where injected) | 35 | 2.1 1.5–2.9ROR 2.1 · χ² 19 / p 7e-6 | 2.1 EB05 1.6 · IC025 +0.5 | Not in label — unassessed | serious PRR 1.9 · 71% consumer | no trial data cached |
| Injury | 34 | 3.6 2.5–5.0ROR 3.6 · χ² 60 / p 5e-15 | 3.4 EB05 2.6 · IC025 +1.2 3/3 methods agree | Not in label — unassessed | serious PRR 5.4 | no trial data cached |
| Dermatitis atopic | 32 | 4.7 3.3–6.7ROR 4.8 · χ² 91 / p 9e-22 | 4.4 EB05 3.3 · IC025 +1.6 3/3 methods agree | 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=47, PRR 20.1
- Menorrhagia — n=38, PRR 14.1
- Dysmenorrhoea — n=22, PRR 12.4
- Vaginal haemorrhage — n=63, PRR 10.9
- Dermatitis atopic — n=32, PRR 4.7
- Panic attack — n=20, PRR 4.0
- Eczema — n=26, PRR 3.8
- Injury — n=34, PRR 3.6
- Suicidal ideation — n=44, PRR 3.5
- Depressed mood — n=20, PRR 2.8
✓ 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 Levonorgestrel and Ethinyl Estradiol?
In FDA FAERS, the most frequently co-reported reaction terms for Levonorgestrel and Ethinyl Estradiol are depression, pulmonary embolism, vaginal haemorrhage, migraine, injection site pain, metrorrhagia. 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 Levonorgestrel and Ethinyl Estradiol have an FDA boxed warning?
No. The FDA label retrieved for Levonorgestrel and Ethinyl Estradiol has no boxed warning; see the label's Warnings and Precautions for the recognised risks.
Do FAERS signals prove that Levonorgestrel 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 aaf0eb2a-f88a-4f26-a445-0fd30176c326, effective 20230629; matched on
openfda.generic_name.exact:"LEVONORGESTREL" AND openfda.product_type:"HUMAN PRESCRIPTION DRUG") - 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, 136 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.