Desvenlafaxine XR Drug Interactions: What You Need to Know

If you take Desvenlafaxine XR (also sold as Pristiq or Khedezla), knowing what medications, supplements, and substances can interact with it is essential. Some interactions are life-threatening, while others can make your medication less effective or increase side effects.

This guide covers the most important Desvenlafaxine XR drug interactions based on FDA labeling and clinical data.

How Drug Interactions Work

Drug interactions happen when one substance changes how another works in your body. With Desvenlafaxine XR, interactions generally fall into three categories:

1. Serotonin buildup — Combining Desvenlafaxine XR with other drugs that raise serotonin levels can cause a dangerous condition called serotonin syndrome.
2. Metabolism changes — Some drugs affect how quickly your body processes Desvenlafaxine XR, or Desvenlafaxine XR can affect how your body processes other drugs.
3. Additive effects — Combining drugs with similar side effects (like bleeding risk or drowsiness) can make those effects worse.

Major Drug Interactions — Avoid These Combinations

MAO Inhibitors (MAOIs)

This is the most dangerous interaction. Never take Desvenlafaxine XR with an MAO inhibitor or within 14 days of stopping one. The combination can cause fatal serotonin syndrome.

MAOIs include:

• Phenelzine (Nardil)
• Tranylcypromine (Parnate)
• Isocarboxazid (Marplan)
• Selegiline (Emsam, Eldepryl) — especially at higher doses

You must wait at least 14 days after stopping an MAOI before starting Desvenlafaxine XR, and at least 7 days after stopping Desvenlafaxine XR before starting an MAOI.

Linezolid (Zyvox) and IV Methylene Blue

Linezolid is an antibiotic that also has MAOI-like properties. IV methylene blue (used in some medical procedures) works similarly. Both can trigger serotonin syndrome when combined with Desvenlafaxine XR. If you need these medications, your doctor should stop Desvenlafaxine XR first.

Other Serotonergic Drugs

Taking Desvenlafaxine XR with other medications that increase serotonin raises the risk of serotonin syndrome. These include:

• SSRIs — Sertraline (Zoloft), Fluoxetine (Prozac), Escitalopram (Lexapro), Paroxetine (Paxil), Citalopram (Celexa)
• Other SNRIs — Venlafaxine (Effexor XR), Duloxetine (Cymbalta), Levomilnacipran (Fetzima)
• Triptans — Sumatriptan (Imitrex), Rizatriptan (Maxalt), and other migraine medications
• Tramadol (Ultram) — A pain medication with serotonergic activity
• Fentanyl — Both prescription patches and illicit fentanyl
• Lithium — Used for bipolar disorder
• Buspirone (Buspar) — An anti-anxiety medication

Symptoms of serotonin syndrome include agitation, rapid heartbeat, high body temperature, muscle twitching, loss of coordination, and in severe cases, seizures or death. Seek emergency medical care immediately if you experience these symptoms.

Moderate Drug Interactions

Blood Thinners and Anti-Inflammatory Drugs

Desvenlafaxine XR affects serotonin in platelets, which can increase your risk of abnormal bleeding. Be cautious with:

• Warfarin (Coumadin) — Your doctor may need to monitor your INR more closely
• Aspirin — Including low-dose daily aspirin
• NSAIDs — Ibuprofen (Advil, Motrin), Naproxen (Aleve), Celecoxib (Celebrex)
• Other anticoagulants — Apixaban (Eliquis), Rivaroxaban (Xarelto)

Tell your doctor if you notice unusual bruising or bleeding.

CYP3A4 Inhibitors

Medications that block the CYP3A4 liver enzyme can increase Desvenlafaxine XR levels in your blood:

• Ketoconazole (antifungal)
• Clarithromycin (antibiotic)
• Grapefruit juice (in large amounts)

Your doctor may not need to adjust your dose, but it's worth mentioning if you take these regularly.

CYP2D6 Substrates

Desvenlafaxine XR can increase the levels of drugs processed by the CYP2D6 enzyme:

• Desipramine — A tricyclic antidepressant; levels can increase significantly
• Metoprolol — A beta-blocker for blood pressure and heart conditions

If you take these medications, your doctor may need to adjust the dose.

Dextromethorphan

Dextromethorphan (found in many over-the-counter cough medicines like Robitussin DM and NyQuil) has serotonergic properties. Taking it with Desvenlafaxine XR could increase the risk of serotonin-related side effects. Check cold and cough medicine labels before taking them.

Supplements and OTC Products to Watch

• St. John's Wort — This herbal supplement is one of the most dangerous interactions. It significantly increases serotonin levels and can cause serotonin syndrome when combined with Desvenlafaxine XR. Do not take them together.
• Tryptophan supplements — Including L-tryptophan and 5-HTP. These are serotonin precursors and can increase the risk of serotonin syndrome.
• SAMe (S-adenosylmethionine) — Another supplement with serotonergic activity that should be used cautiously.
• Omega-3 fish oil — Generally safe but may slightly increase bleeding risk when combined with Desvenlafaxine XR's platelet effects.

Food and Drink Interactions

Alcohol

Alcohol increases central nervous system (CNS) depression when combined with Desvenlafaxine XR. This means increased drowsiness, dizziness, impaired judgment, and slowed reaction times. While the FDA label doesn't say you must completely avoid alcohol, it recommends caution. Most doctors advise limiting or avoiding alcohol while taking Desvenlafaxine XR — especially when you're first starting the medication.

Grapefruit

Large amounts of grapefruit or grapefruit juice can inhibit CYP3A4 and slightly increase Desvenlafaxine XR levels. A small glass occasionally is unlikely to cause problems, but regular consumption is worth mentioning to your doctor.

What to Tell Your Doctor

Before starting Desvenlafaxine XR, give your doctor a complete list of:

• All prescription medications you take — including those prescribed by other doctors
• Over-the-counter medications — especially pain relievers, cold medicines, and cough syrups
• Supplements and herbal products — including St. John's Wort, 5-HTP, and tryptophan
• Alcohol and substance use
• Any planned surgeries — Desvenlafaxine XR's bleeding risk may affect surgical planning

Don't assume your doctor knows about everything you take. Many interactions involve OTC products that patients forget to mention.

Final Thoughts

Most people take Desvenlafaxine XR without any dangerous drug interactions — as long as their doctor knows the full picture. The critical interactions to remember are MAOIs (never combine), other serotonergic drugs (risk of serotonin syndrome), and St. John's Wort (avoid completely).

When in doubt, always check with your pharmacist or doctor before starting a new medication or supplement. To learn more about Desvenlafaxine XR, see our guide on what it is and how it works, or use Medfinder to find it at a pharmacy near you.