Rexulti Drug Interactions: What to Avoid and What to Tell Your Doctor

Rexulti Drug Interactions You Need to Know About

When you take Rexulti (Brexpiprazole), it's processed in your liver by specific enzymes. Other medications, supplements, and even certain foods can speed up or slow down these enzymes, changing how much Rexulti is active in your body. This can make the medication less effective or increase the risk of side effects.

This guide covers the most important drug interactions to be aware of, so you can have an informed conversation with your doctor or pharmacist.

How Drug Interactions Work with Rexulti

Rexulti is metabolized (broken down) in the liver primarily by two enzyme systems:

• CYP2D6 — One of the main enzymes that processes Rexulti
• CYP3A4 — The other major enzyme involved

Medications that inhibit (slow down) these enzymes cause Rexulti to build up in your blood, increasing the risk of side effects. Medications that induce (speed up) these enzymes cause your body to clear Rexulti faster, potentially making it less effective.

According to FDA labeling, combining a strong CYP2D6 inhibitor with a strong CYP3A4 inhibitor can cause Rexulti blood levels to increase by approximately 5-fold — a dramatic change that requires significant dose adjustments.

Medications That Interact with Rexulti

Strong CYP2D6 Inhibitors (Increase Rexulti Levels)

These medications slow down the CYP2D6 enzyme, causing higher Rexulti concentrations in your blood. Your doctor will typically reduce your Rexulti dose by half if you take one of these:

• Fluoxetine (Prozac) — A widely used SSRI antidepressant
• Paroxetine (Paxil) — Another common SSRI
• Quinidine — A heart rhythm medication
• Bupropion (Wellbutrin) — An antidepressant and smoking cessation aid

This is especially relevant because Rexulti is often prescribed alongside antidepressants for depression. If your antidepressant is Fluoxetine or Paroxetine, your doctor needs to account for this interaction.

Strong CYP3A4 Inhibitors (Increase Rexulti Levels)

These medications slow down CYP3A4, also raising Rexulti levels. A dose reduction to half the usual dose is recommended:

• Ketoconazole (Nizoral) — An antifungal medication
• Itraconazole (Sporanox) — Another antifungal
• Clarithromycin (Biaxin) — A macrolide antibiotic
• Ritonavir (Norvir) — An HIV protease inhibitor
• Nefazodone — An older antidepressant

Combined CYP2D6 + CYP3A4 Inhibitors (Most Dangerous)

If you take a strong inhibitor of both CYP2D6 and CYP3A4 at the same time, Rexulti levels can increase approximately 5.1 times. In this case, your doctor should reduce your Rexulti dose to one-quarter of the usual amount.

For example, taking Fluoxetine (strong CYP2D6 inhibitor) plus Ketoconazole (strong CYP3A4 inhibitor) alongside Rexulti would require a significant dose reduction.

Strong CYP3A4 Inducers (Decrease Rexulti Levels)

These medications speed up CYP3A4, causing your body to clear Rexulti faster. This can make Rexulti less effective. Your doctor may need to increase your Rexulti dose:

• Rifampin (Rifadin) — An antibiotic used for tuberculosis and other infections
• Carbamazepine (Tegretol) — An anticonvulsant and mood stabilizer
• Phenytoin (Dilantin) — An anti-seizure medication
• Phenobarbital — A barbiturate used for seizures

Other Medications to Watch

• Other antipsychotics — Taking Rexulti with other antipsychotic medications increases the risk of side effects including sedation, metabolic problems, and movement disorders.
• Benzodiazepines (Lorazepam, Alprazolam, Clonazepam) — Combining with Rexulti can increase sedation and dizziness.
• Opioid pain medications (Oxycodone, Hydrocodone, Morphine) — Increased risk of sedation, respiratory depression, and falls.
• Blood pressure medications — Rexulti can lower blood pressure on its own, so combining it with antihypertensives may cause excessive drops in blood pressure (orthostatic hypotension).
• Levodopa and other dopamine agonists — Rexulti may reduce the effectiveness of Parkinson's disease medications because of its effects on dopamine receptors.

Supplements and OTC Medications to Watch

Some over-the-counter products can also interact with Rexulti:

• St. John's Wort — This herbal supplement is a strong CYP3A4 inducer. Taking it with Rexulti can significantly reduce Rexulti's effectiveness. Avoid this combination.
• Grapefruit juice — Grapefruit inhibits CYP3A4 and can increase Rexulti levels. While occasional small amounts may not cause a problem, regular consumption should be discussed with your doctor.
• Diphenhydramine (Benadryl) — Can increase drowsiness when taken with Rexulti.
• Melatonin — Generally considered safe to take with Rexulti, but the combination may increase drowsiness. Talk to your doctor.
• NSAIDs (Ibuprofen, Naproxen) — No direct interaction, but both Rexulti and NSAIDs can affect blood pressure and should be monitored.

Food and Drink Interactions

• Alcohol — Avoid alcohol while taking Rexulti. Alcohol increases sedation, dizziness, and impaired judgment. It can also worsen depression and schizophrenia symptoms.
• Grapefruit and grapefruit juice — As mentioned above, grapefruit can raise Rexulti levels by inhibiting CYP3A4. Discuss with your doctor if you consume grapefruit regularly.
• Caffeine — No direct pharmacological interaction, but caffeine can worsen akathisia (restlessness), which is a common Rexulti side effect. Consider reducing caffeine if you experience restlessness.

Rexulti can be taken with or without food — meals do not significantly affect its absorption.

What to Tell Your Doctor

Before starting Rexulti, give your doctor a complete list of:

• All prescription medications you take, including dosages
• Over-the-counter medications, including pain relievers, allergy medications, and sleep aids
• Herbal supplements, especially St. John's Wort, Kava, and Valerian
• Vitamins and other supplements
• Recreational substances, including alcohol, cannabis, and others

Also tell your doctor if:

• You've been told you are a CYP2D6 poor metabolizer (your body processes certain drugs slowly due to genetics)
• You're starting or stopping any medication while taking Rexulti
• You're planning surgery (anesthesia medications may interact with Rexulti)

Your pharmacist is also an excellent resource. They can run an interaction check every time you fill a new prescription.

Final Thoughts

Drug interactions with Rexulti are manageable, but only if your healthcare team knows everything you're taking. The most important interactions involve medications that affect the CYP2D6 and CYP3A4 enzymes — particularly strong inhibitors like Fluoxetine, Paroxetine, and Ketoconazole, and strong inducers like Rifampin and Carbamazepine.

Never start or stop a medication without telling your doctor, and always bring your full medication list to every appointment. For more about Rexulti side effects or how Rexulti works, check out our other guides.

Ready to fill your prescription? Use Medfinder to find a pharmacy with Rexulti in stock near you.