Lorlatinib and Acetaminophen And Codeine: 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
Lorlatinib
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 turn it into morphine before it can relieve pain. Lorlatinib (Lorbrena) can speed up the liver enzyme that handles codeine. When that enzyme works faster, more of your codeine gets pushed down a path that makes less morphine, so you may get less pain relief.
If your body is used to the opioid, this drop can also bring on withdrawal feelings like aches, chills, sweating, or a runny nose. The good news is your care team can manage this by watching how you feel and adjusting your dose if needed. Please don't change anything on your own. Talk with your pharmacist or doctor.
Mechanism: Lorlatinib is a CYP3A4 inducer. Codeine is a prodrug requiring O-demethylation (CYP2D6) to morphine, its active metabolite. Induction of CYP3A4 shunts codeine toward norcodeine, lowering the substrate available for CYP2D6 conversion and reducing morphine exposure.
Effect / direction: Reduced codeine and morphine exposure, decreased analgesic efficacy, and possible precipitation of withdrawal in opioid-dependent patients.
- Evidence: theoretical; magnitude not quantified.
- Onset: unspecified.
- Management: Monitor for reduced efficacy or withdrawal; consider increasing codeine dose as needed. If lorlatinib is discontinued, consider codeine dose reduction and monitor for sedation/respiratory depression.
What happens
Reduced codeine and morphine exposure, reduced opioid efficacy and precipitation of opioid withdrawal
Interaction Deep Dive
When codeine is taken together with CYP3A4 inducers, codeine concentrations may fall while norcodeine concentrations rise, and CYP2D6-mediated metabolism may decrease, producing lower morphine levels. This can diminish efficacy or trigger a withdrawal syndrome in patients who have become physically dependent. Should combined use be necessary, monitor patients carefully for reduced efficacy or indications of opioid withdrawal syndrome, and consider raising the codeine dose as required. When a CYP3A4 inducer is being stopped, consider lowering the codeine dose and watch patients closely for signs of sedation or respiratory depression12.
Why it happens (mechanism)
Induction of CYP3A4-mediated codeine metabolism
How to manage this interaction
Keep taking both medicines as prescribed unless your care team tells you otherwise. This interaction is manageable.
- Your team may monitor you more closely for reduced pain control or withdrawal signs (aches, chills, sweating, runny nose, anxiety).
- Your codeine dose may need to be adjusted and individualized if it isn't controlling your pain.
- If lorlatinib is ever stopped, your codeine may need to be lowered, since its effect could increase again. Watch for excess drowsiness or slow breathing.
Tell your pharmacist or prescriber if your pain relief drops off or you feel withdrawal symptoms.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Lorlatinib and Acetaminophen And Codeine together?
Lorlatinib can speed up codeine's breakdown, making it produce less morphine and work less well, and possibly triggering withdrawal in people who are opioid-dependent. Watch for reduced pain relief or withdrawal signs and let your care team adjust and monitor as needed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Lorlatinib 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 Lorlatinib and Acetaminophen And Codeine interaction managed?
Keep taking both medicines as prescribed unless your care team tells you otherwise. This interaction is manageable. Your team may monitor you more closely for reduced pain control or withdrawal signs (aches, chills, sweating, runny nose, anxiety). Your codeine dose may need to be adjusted and individualized if it isn't controlling your pain. If lorlatinib is ever stopped, your codeine may need to… 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 Lorlatinib 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 (2)
- Product Information: Codeine sulfate oral solution, codeine sulfate oral solution. Hikma Pharmaceuticals USA Inc(per FDA), Berkeley Heights, NJ, 2023. DailyMed
- Product Information: Codeine sulfate oral tablets, codeine sulfate oral tablets. Hikma Pharmaceuticals USA Inc. (per FDA), Berkeley Heights, NJ, 2023. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Lorlatinib
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