Cobicistat 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
Cobicistat
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. Your pain medicine contains codeine. Codeine itself doesn't do much until your body converts it into morphine, which is the part that relieves pain. Cobicistat (Tybost), part of your HIV treatment, slows down the liver enzymes that handle codeine.
Because of this, the amount of codeine in your body can rise, and the morphine it turns into may go either up or down. If morphine goes up, you could feel more sleepy or breathe more slowly. If it goes down, your pain relief may not work as well. This is based on theory, not strong proof, so please don't stop anything. Your care team can watch you closely and adjust your dose so both medicines work safely together.
Mechanism: Cobicistat inhibits both CYP3A4 and CYP2D6. Codeine is a prodrug requiring CYP2D6-mediated O-demethylation to morphine (its active metabolite), while CYP3A4 clears codeine via N-demethylation.
- Direction: CYP3A4 inhibition increases parent codeine exposure; CYP2D6 inhibition may reduce morphine formation (loss of analgesia, withdrawal) or, via shunting/accumulation, raise it (sedation, respiratory depression). Net effect is unpredictable.
- Evidence: theoretical; onset unspecified.
- Management: If used together, monitor for withdrawal, inadequate analgesia, oversedation and respiratory depression. Codeine dose may be adjusted and individualized. Consider an alternative analgesic not dependent on CYP2D6.
What happens
Increased codeine exposure and increased or reduced active metabolite (morphine) exposure
Interaction Deep Dive
Concomitant use of codeine with a CYP3A4 inhibitor that is also a CYP2D6 inhibitor may either increase the codeine exposure and may either increase or reduce plasma concentrations of morphine, the active metabolite of codeine, thus potentially leading to reduced efficacy and withdrawal symptoms or an increased risk of adverse effects such as respiratory depression and sedation. If concomitant use is necessary, monitor patients for withdrawal symptoms, respiratory depression and sedation, and consider adjusting the codeine dose as needed123.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated codeine metabolism; inhibition of CYP2D6-mediated codeine metabolism
How to manage this interaction
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. Because the effect can go either way, your care team's main tool is close monitoring.
- Your codeine dose may need to be adjusted and individualized by your care team.
- Watch for too much sedation, unusually slow or shallow breathing, or confusion, and get help promptly if these occur.
- Also watch for the opposite: poor pain control or withdrawal-type symptoms.
- Ask your pharmacist or prescriber whether a different pain reliever that doesn't rely on the same enzymes might suit you better.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Cobicistat and Acetaminophen And Codeine together?
Cobicistat can unpredictably raise or lower the morphine your body makes from codeine, so pain relief or side effects like heavy sedation could change. Keep taking both as prescribed and let your care team monitor you and adjust the dose. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Cobicistat 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 Cobicistat and Acetaminophen And Codeine interaction managed?
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. Because the effect can go either way, your care team's main tool is close monitoring. Your codeine dose may need to be adjusted and individualized by your care team. Watch for too much sedation, unusually slow or shallow breathing, or confusion, and get help promptly if these occur. Also watch for the opposite: po… 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 Cobicistat 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 (3)
- 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
- 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 Cobicistat
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