Fedratinib 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
Fedratinib
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.
Here's what's going on. Codeine is a prodrug, meaning your body has to switch it on to give pain relief. It uses an enzyme called CYP2D6 to turn codeine into morphine. Fedratinib (Inrebic) slows down that enzyme, plus another one called CYP3A4.
Because of this, less codeine may get changed into the active form, so you might get less pain relief. At the same time, more of the un-activated codeine can build up, which could raise the chance of side effects like drowsiness, nausea, or constipation. The acetaminophen part is generally not the main concern here. The good news: your care team can manage this by watching how you respond and adjusting your dose if needed.
Effect: Fedratinib inhibits CYP3A4 and CYP2D6, altering exposure to dual substrates. In PK studies it raised midazolam (CYP3A4) AUC ~4-fold and metoprolol (CYP2D6) AUC ~2-fold.
Direction (drug-specific): Codeine is a prodrug requiring CYP2D6 for conversion to morphine. CYP2D6 inhibition by fedratinib is expected to reduce analgesic efficacy while parent codeine accumulates (opioid-type adverse effects still possible). Acetaminophen is minimally affected.
Evidence: Probable. Severity: Major. Onset: Unspecified.
- If coadministration is necessary, monitor for reduced analgesia and for opioid adverse effects.
- Individualize and adjust the codeine dose per response.
What happens
Increased CYP3A4/CYP2D6 substrate exposure
Interaction Deep Dive
Concomitant use of fedratinib (a CYP3A4 inhibitor and a CYP2D6 inhibitor) with dual CYP3A4 and CYP2D6 substrates may increase the substrate concentrations and the risk of adverse reactions of these substrates. In single-dose pharmacokinetic studies, fedratinib increased midazolam (CYP3A4 substrate) and metoprolol (CYP2D6 substrate) AUC by 4-fold and 2-fold respectively. If coadministration is necessary, monitor for adverse reactions and adjust the dose of drugs that are dual CYP3A4 and CYP2D6 substrates1.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated substrate metabolism by fedratinib; inhibition of CYP2D6-mediated substrate metabolism by fedratinib
How to manage this interaction
Keep taking both medications exactly as prescribed unless your care team tells you otherwise. This interaction can usually be managed.
- Watch how you respond: tell your team if your pain is not controlled, or if you feel unusually sleepy, dizzy, nauseated, or constipated.
- Dose: your codeine dose may need to be adjusted and individualized by your care team.
- Monitoring: your team may check on you more closely while you use both drugs together.
Ask your pharmacist or prescriber before making any changes, and whether an alternative pain option might suit you better.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
2 reports — tap to read
Common questions
Can I take Fedratinib and Acetaminophen And Codeine together?
Fedratinib blocks the enzyme that activates codeine, so you may get less pain relief while codeine can still build up; keep taking both as prescribed and let your care team adjust the dose and monitor you. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Fedratinib 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 Fedratinib and Acetaminophen And Codeine interaction managed?
Keep taking both medications exactly as prescribed unless your care team tells you otherwise. This interaction can usually be managed. Watch how you respond: tell your team if your pain is not controlled, or if you feel unusually sleepy, dizzy, nauseated, or constipated. Dose: your codeine dose may need to be adjusted and individualized by your care team. Monitoring: your team may check on you mor… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
Questions for your pharmacist
- Does my dose of Fedratinib 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: INREBIC(R) oral capsules, fedratinib oral capsules. Bristol-Myers Squibb Company (per FDA), Princeton, NJ, 2023. DailyMed
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