Eplerenone and Acetaminophen And Codeine: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jun 30, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Eplerenone
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Your pain medicine contains codeine, an opioid. The other medicine, eplerenone (Inspra), is a water pill that also helps control blood pressure and fluid. Codeine can nudge your body to hold onto more water by triggering a hormone that reduces urine output. In theory, this could make eplerenone work a little less well, so you might notice a bit more fluid buildup or a change in your blood pressure.
This is based on theory, not strong studies, so try not to worry. Keep taking both as prescribed, and let your care team know if you notice swelling, weight gain, or unusual blood pressure readings. They can easily adjust and monitor things for you.
Effect: Theoretical reduction in eplerenone diuretic/antihypertensive efficacy when combined with codeine.
Mechanism: Opioid-mediated stimulation of antidiuretic hormone (ADH/vasopressin) release, promoting water retention and opposing diuresis. This is a PD interaction, not a CYP-based PK effect.
- Direction: Reduced diuretic effect (fluid retention, possible BP rise).
- Onset: Unspecified.
- Evidence: Theoretical; low substantiation.
- Severity on file: Major.
Management: Monitor diuresis, weight, edema, and blood pressure. Eplerenone dose may be individualized and titrated upward if diminished response is observed; also monitor potassium given eplerenone's antimineralocorticoid activity.
What happens
Reduced diuretic efficacy
Interaction Deep Dive
Concomitant use of codeine with diuretics may reduce the efficacy of diuretics by inducing the release of anti-diuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed1.
Why it happens (mechanism)
Increased opioid-mediated release of antidiuretic hormone
How to manage this interaction
Good news: this is manageable, and you should keep taking both medicines exactly as prescribed unless your prescriber tells you otherwise.
- Watch for signs the water pill is working less well: new or worse swelling in the legs, sudden weight gain, or higher blood pressure readings at home.
- Report these to your pharmacist or doctor.
- Dose and monitoring: Your eplerenone dose may need to be adjusted and individualized by your care team, and they may check on you more closely while you use both.
Because this concern is theoretical, many people take both without issue, but staying in touch with your team keeps it safe.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Eplerenone and Acetaminophen And Codeine together?
Codeine may slightly weaken how well eplerenone removes fluid and controls blood pressure, so watch for swelling, weight gain, or rising blood pressure and tell your care team, who can adjust and monitor as needed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Eplerenone and Acetaminophen And Codeine interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Eplerenone and Acetaminophen And Codeine interaction managed?
Good news: this is manageable, and you should keep taking both medicines exactly as prescribed unless your prescriber tells you otherwise. Watch for signs the water pill is working less well: new or worse swelling in the legs, sudden weight gain, or higher blood pressure readings at home. Report these to your pharmacist or doctor. Dose and monitoring: Your eplerenone dose may need to be adjusted a… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Eplerenone or Acetaminophen And Codeine need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (1)
- Product Information: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Eplerenone
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
Check another combination
Our instant two-drug interaction checker is almost here.
Still have questions about this combination?
Every question gets a real answer from a licensed pharmacist — free, and usually within a day.
Ask the pharmacist