Important Drug Interactions for the Antidepressant Nortriptyline (PAMELOR)

Patients taking the frequently prescribed antidepressant nortriptyline (PAMELOR) should be aware that it has clinically important and potentially dangerous interactions with many other prescription and over-the-counter medications.

Nortriptyline, which belongs to the family of tricyclic antidepressants, was initially approved by the Food and Drug Administration in 1964. It is approved only for the relief of depression symptoms.[1] Public Citizen’s Health Research Group has designated nortriptyline as a Limited Use drug.[2] For patients who need drug treatment for major depression, selective serotonin reuptake inhibitors (SSRIs) like citalopram (CELEXA) and fluoxetine (PROZAC) are first-choice medications because these are the safest antidepressants.[3]

Increased risk of fatal heart-rhythm abnormalities

Nortriptyline, like other tricyclic antidepressants, can cause prolongation of the QT interval[4] — a change in the electrical activity of the heart that can lead to a fatal heart-rhythm disturbance called torsades de pointes, which can cause cardiac arrest and sudden death.

Numerous oral drugs, when used concomitantly (at the same time) with nortriptyline, further increase the risk of QT prolongation, because they also directly cause QT prolongation (see Table 1, below, for examples).[5] Such drugs include certain medications for treating abnormal heart rhythms, bacterial infections, cancer, depression, fungal infections and psychosis, among other conditions.

For some drugs, the risk of QT prolongation and potentially fatal abnormal heart rhythms is so high that they should not be taken concomitantly with nortriptyline.

Table 1: Examples of Oral Drugs That May Increase the Risk of Fatal Heart-Rhythm Abnormalities When Used Concomitantly With Nortriptyline

†Brand-name combination products that contain other active ingredients were excluded.
*Designated as Limited Use by Worst Pills, Best Pills News
**Designated as Do Not Use by Worst Pills, Best Pills News

Serotonin syndrome[6],[7]

Nortriptyline rarely can cause serotonin syndrome, a potentially fatal condition characterized by agitation, confusion, hallucinations, rapid heartbeat, high blood pressure, high fever, shivering, sweating, nausea, vomiting, diarrhea and muscle rigidity. In severe cases, the syndrome can lead to seizures and coma.

The risk of serotonin syndrome increases when nortriptyline is taken concomitantly with other drugs that cause elevated serotonin levels in the body (see Table 2, below, for a list of examples). Such drugs include monoamine oxidase (MAO) inhibitors, which are used to treat depression or Parkinson’s disease, depending on the medication; lithium (LITHOBID), which is used to treat bipolar disorder; certain opioids; and other tricyclic antidepressants, among others. For the MAO inhibitors, the antibiotic linezolid (ZYVOX) and the Parkinson’s disease drug safinamide (XADAGO), the risk of serotonin syndrome is so great that they should never be taken concomitantly with nortriptyline.

Concomitant use of nortriptyline with the dietary supplement St. John’s wort also raises the risk of serotonin syndrome.

Table 2: Examples of Oral Drugs That Increase the Risk of Serotonin Syndrome When Used Concomitantly With Nortriptyline

†Brand-name combination products were excluded.
*Designated as Limited Use by Worst Pills, Best Pills News
**Designated as Do Not Use by Worst Pills, Best Pills News

Drugs that increase bleeding risk

Concomitant use of nortriptyline with any of the nonsteroidal antiinflammatory drugs (NSAIDs) can increase the risk of bleeding.[8] Examples of commonly used NSAIDs include the following:

• aspirin (BAYER ASPIRIN, DURLAZA, ECOTRIN, VAZALORE)
• ibuprofen (ADVIL, JUNIOR STRENGTH MOTRIN, MIDOL LIQUID GELS, MOTRIN IB, TAB-PROFEN)
• naproxen (ALEVE, ANAPROX DS, EC-NAPROSYN, NAPRELAN, NAPROSYN)

What You Can Do

If you need treatment with nortriptyline, review all your other medications with your doctor to assess for potentially significant drug interactions. If you are taking a medication that interacts with nortriptyline, your doctor may recommend that you stop or adjust the dosage of the interacting drug or may advise you to take a different drug for your depression. Be aware that other drugs not listed in this article also may have dangerous interactions with nortriptyline.

Report all serious adverse events related to nortriptyline or other medications to the FDA’s MedWatch adverseevent reporting program by visiting http://www.fda.gov/MedWatch or by calling 800-FDA-1088.

References

[1] Mallinckrodt Inc. Label: nortriptyline (PAMELOR). April 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018013s064lbl.pdf. Accessed December 7, 2022.

[2] Drug Profile: desipramine and nortriptyline. https://www.worstpills.org/monographs/view/62. Accessed December 7, 2022.

[3] How effective are antidepressants for depression? Worst Pills, Best Pills News. February 2014. https://www.worstpills.org/newsletters/view/890. Accessed December 7, 2022.

[4] Rochester MP, Kane AM, Linnebur SA, Fixen DR. Evaluating the risk of QTc prolongation associated with antidepressant use in older adults: a review of the evidence. Ther Adv Drug Saf. 2018;9(6):297-308.

[5] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Search term: “nortriptyline.” Accessed December 7, 2022.

[6] Mallinckrodt Inc. Label: nortriptyline (PAMELOR). April 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018013s064lbl.pdf. Accessed December 7, 2022.

[7] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Search term: “nortriptyline.” Accessed December 7, 2022.

[8] Ibid.