Esketamine 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
Esketamine
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, which is an opioid, and it's teamed with acetaminophen (Tylenol). Esketamine (Spravato) is a nasal spray for depression that can make you very drowsy for a while after each dose. Both of these medicines calm down the brain and nervous system, so taking them together can add up and make you more sleepy or more sedated than either one alone.
This is a caution based on how these drugs work, not on a proven problem in people taking both. The good news is your care team can manage it. Please talk with your pharmacist or doctor so they can keep an eye on how sleepy you feel and adjust things if needed.
Effect: Additive CNS depression, increasing risk of sedation.
Mechanism/direction: Esketamine is a CNS depressant with delayed and prolonged sedation; codeine (opioid) plus its acetaminophen combination also depresses the CNS. Combined use potentiates sedation, respiratory depression, and psychomotor impairment. No CYP prodrug-activation issue drives this PD interaction.
Evidence: Theoretical; onset unspecified. Severity rated major.
Management:
- Esketamine is given under REMS-required observation, monitor sedation and respiratory status closely.
- Anticipate deeper/longer sedation; adjust and individualize opioid dosing as the care team judges appropriate.
- Counsel against driving until effects clear.
What happens
Increased risk of sedation
Interaction Deep Dive
Esketamine is associated with delayed and prolonged sedation, requiring restricted access and specific patient observation. Concomitant use with another CNS depressant may potentiate each other's effects. Ensure close monitoring for sedation with any concomitant use1.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. This combination is managed mainly by watching you more closely.
- Your esketamine (Spravato) is already given in a clinic where staff watch you after each dose, expect them to keep a close eye on how sedated you are.
- Your opioid dose may be adjusted and individualized by your care team if you seem overly sleepy.
- Do not drive or do anything that needs alertness until the drowsiness fully wears off.
Tell your pharmacist or prescriber if you feel unusually drowsy, confused, or have slowed breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Esketamine and Acetaminophen And Codeine together?
Taking codeine/acetaminophen with esketamine can add up to make you more sedated, so your care team will watch you closely and may individualize your dosing. Keep both as prescribed and avoid driving until you know how it affects you. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Esketamine 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 Esketamine and Acetaminophen And Codeine interaction managed?
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. This combination is managed mainly by watching you more closely. Your esketamine (Spravato) is already given in a clinic where staff watch you after each dose, expect them to keep a close eye on how sedated you are. Your opioid dose may be adjusted and individualized by your care team if you seem overly sle… 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.
Questions for your pharmacist
- Does my dose of Esketamine 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: SPRAVATO(TM) nasal spray, esketamine nasal spray. Janssen Pharmaceuticals Inc (per FDA), Titusville, NJ, 2019. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Esketamine
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