Acetaminophen And Codeine and Safinamide: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 1, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Safinamide
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.
These two medicines should not be taken together. Safinamide (Xadago) is a type of Parkinson's medicine called an MAO inhibitor. Codeine, the pain reliever combined with acetaminophen in your medicine, can raise serotonin levels in the body. When you combine them, serotonin can climb too high and cause a dangerous reaction called serotonin syndrome. This can bring on agitation, a fast heartbeat, sweating, shivering, muscle stiffness, and confusion.
The good news is that this is very manageable. Do not start or stop anything on your own, but please talk with your pharmacist or doctor. They can choose a safer pain option and time things safely for you.
Contraindicated combination. Safinamide is an MAO-B inhibitor; codeine has serotonergic activity. Concurrent use produces additive serotonergic effects, raising the risk of serotonin syndrome.
- Direction: additive PD effect (increased serotonergic tone), not a CYP prodrug-activation issue.
- Evidence: theoretical; onset unspecified.
- Management: avoid concomitant use. Discontinue the MAOI at least 14 days before initiating codeine. If urgent opioid analgesia is needed, select an alternative (oxycodone, hydrocodone, oxymorphone, buprenorphine), begin with test doses of an immediate-release form, titrate carefully, and monitor blood pressure and for CNS and respiratory depression.
Monitor for hyperthermia, autonomic instability, clonus, hyperreflexia, and altered mental status.
What happens
Increased risk of serotonin syndrome
Interaction Deep Dive
Combining codeine with an MAOI is contraindicated because of the risk of serotonin syndrome. An MAOI should be stopped 14 days prior to starting codeine. When opioid therapy cannot wait, select a different opioid instead (for example, oxyCODONE, HYDROcodone, oxyMORphone, or buprenorphine), begin with test doses of an immediate-release formulation, and titrate the dose cautiously while watching blood pressure along with signs and symptoms of CNS and respiratory depression123.
Why it happens (mechanism)
Additive serotonergic effects
How to manage this interaction
This combination is generally avoided. Your care team can manage this safely, so keep taking your medicines as prescribed until you speak with them.
- Tell your pharmacist or prescriber that you are on safinamide (Xadago) before starting any codeine product.
- Your team will typically keep at least a 14-day gap between stopping the MAOI and starting codeine.
- If you need pain relief urgently, your team may choose a different opioid and start low, adjusting the dose carefully for you.
- Seek help right away for agitation, fast heartbeat, sweating, shivering, muscle stiffness, or confusion.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Safinamide together?
Do not combine codeine (with acetaminophen) and safinamide because of the risk of serotonin syndrome; contact your pharmacist or doctor, who can select a safer pain option and time it appropriately. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Safinamide interaction?
It is rated contraindicated. These should generally not be used together.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Acetaminophen And Codeine and Safinamide interaction managed?
This combination is generally avoided. Your care team can manage this safely, so keep taking your medicines as prescribed until you speak with them. Tell your pharmacist or prescriber that you are on safinamide (Xadago) before starting any codeine product. Your team will typically keep at least a 14-day gap between stopping the MAOI and starting codeine. If you need pain relief urgently, your team… 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 Acetaminophen And Codeine or Safinamide 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 (3)
- Product Information: Codeine sulfate oral tablets, codeine sulfate oral tablets. West-Ward Pharmaceuticals Corp (per DailyMed), Eatontown, NJ, 2016. DailyMed
- Product Information: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
- Product Information: Codeine sulfate oral solution, codeine sulfate oral solution. Hikma Pharmaceuticals USA Inc(per FDA), Berkeley Heights, NJ, 2023. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Safinamide
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