Peginterferon Alfa-2B and Amitriptyline: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Amitriptyline
Peginterferon Alfa-2B
No brand names on record
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. Amitriptyline (Elavil) is broken down by a liver enzyme called CYP2D6. Peginterferon alfa-2b can slow that enzyme down. When the enzyme works slower, amitriptyline can build up in your blood, which can lead to more side effects like drowsiness, dry mouth, constipation, dizziness, a fast or irregular heartbeat, or confusion.
This can come on fairly quickly if the peginterferon is started while you're already on a steady amitriptyline dose. The good news is this is very manageable. Please don't stop or change either medicine on your own. Talk with your pharmacist or doctor so they can adjust your dose and keep a closer eye on you.
Mechanism: Peginterferon alfa-2b inhibits CYP2D6, reducing metabolism of amitriptyline (a CYP2D6 substrate). Neither agent is activated by this pathway, so the net effect is increased TCA plasma exposure and greater toxicity risk.
- Direction/magnitude: Increased amitriptyline levels; a desipramine probe study showed ~30% rise in AUC after 2 doses of peginterferon.
- Evidence: Probable; major severity. Onset can be abrupt when peginterferon is initiated on a stable TCA.
- Monitoring: Watch for anticholinergic/CNS effects, QT/conduction changes; consider TCA plasma level monitoring.
- Management: Lower TCA dose may be needed; on peginterferon discontinuation, an increased TCA dose may be required.
What happens
Increased plasma concentrations of tricyclic antidepressants metabolized by CYP2D6 and increased risk for toxicities; abrupt toxicity may occur when peginterferon alfa-2b is initiated in patient on a stable dose of a tricyclic antidepressant
Interaction Deep Dive
When a tricyclic antidepressant that undergoes CYP2D6 metabolism is given together with an inhibitor of CYP2D6 (namely peginterferon alfa-2b), the plasma concentrations of the tricyclic antidepressant may rise, heightening the potential for toxic effects. Sudden toxicity can develop if peginterferon alfa-2b is started in a patient already maintained on stable tricyclic antidepressant doses1. In a study where healthy volunteers received 50 mg of desipramine (a CYP2D6 substrate) both before and after 2 doses of peginterferon alfa-2b 3 mcg/kg, the geometric mean desipramine AUC (last) rose by 30% relative to desipramine given by itself 2. It may be necessary to reduce the dose of the tricyclic antidepressant or of the CYP2D6 inhibitor (namely peginterferon alfa-2b). Furthermore, once peginterferon alfa-2b is stopped, a higher tricyclic antidepressant dose could become necessary. Tricyclic antidepressant levels should be monitored whenever these agents are used alongside a CYP2D6 inhibitor 1.
Why it happens (mechanism)
Inhibition of CYP2D6-mediated metabolism of tricyclic antidepressants by peginterferon alfa-2b
How to manage this interaction
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. This interaction is manageable with the right adjustments and monitoring.
- Your amitriptyline dose may need to be adjusted and individualized by your care team, often lowered while you're on peginterferon.
- Your team may check amitriptyline blood levels and monitor you more closely for side effects.
- When peginterferon is stopped, your amitriptyline dose may need to be raised again.
- Tell your pharmacist or prescriber right away if you notice new drowsiness, confusion, a racing or irregular heartbeat, or dizziness.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) In a drug interaction study, peginterferon alfa-2b suppressed CYP2D6 activity. When healthy participants received 50 mg of desipramine both before and after 2 doses of peginterferon alfa-2b 3 mcg/kg, the geometric mean desipramine AUC (last) rose by 30% relative to giving desipramine on its own 2.
Common questions
Can I take Peginterferon Alfa-2B and Amitriptyline together?
Peginterferon alfa-2b can slow the breakdown of amitriptyline, raising its levels and side-effect risk, sometimes soon after peginterferon is started. Keep taking both as prescribed and ask your care team about dose adjustments and monitoring. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Peginterferon Alfa-2B and Amitriptyline 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 Peginterferon Alfa-2B and Amitriptyline interaction managed?
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. This interaction is manageable with the right adjustments and monitoring. Your amitriptyline dose may need to be adjusted and individualized by your care team, often lowered while you're on peginterferon. Your team may check amitriptyline blood levels and monitor you more closely for side effects. When pegi… 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.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Peginterferon Alfa-2B or Amitriptyline 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: Tofranil(TM) oral tablets, imipramine HCl oral tablets. Mallinckrodt Inc. (per manufacturer), Hazelwood, MO, 2014. DailyMed
- Product Information: SYLATRON(TM) subcutaneous injection, peginterferon alfa-2b subcutaneous injection. Schering Corporation (per FDA), Whitehouse Station, NJ, 2014.
Keep reading about Amitriptyline
Keep reading about Peginterferon Alfa-2B
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