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

Entrectinib (Rozlytrek) interacts with a significant number of other medications, including common drugs for infections, heart conditions, seizures, and HIV. Understanding these interactions is critical for your safety. Here is a comprehensive guide to the key drug interactions you need to know about — and what to tell your oncologist and pharmacist.

How Entrectinib Is Metabolized (The CYP3A4 Connection)

Entrectinib is primarily metabolized (broken down) in the liver by an enzyme called CYP3A4 (cytochrome P450 3A4). This means that any drug that strongly affects CYP3A4 activity will also affect entrectinib blood levels — potentially causing serious side effects (if levels go too high) or reducing the drug's effectiveness (if levels go too low).

Category 1: Strong and Moderate CYP3A Inhibitors — AVOID

These drugs block CYP3A4, causing entrectinib blood levels to rise dramatically. For example, the antifungal drug itraconazole (a strong CYP3A inhibitor) increased entrectinib levels by 6-fold in clinical studies — a dangerous increase that can worsen side effects significantly. Moderate CYP3A inhibitors are predicted to increase entrectinib levels by approximately 3-fold.

Examples of strong CYP3A inhibitors to avoid with entrectinib:

Azole antifungals: itraconazole, ketoconazole, voriconazole, posaconazole

HIV protease inhibitors: ritonavir, atazanavir, lopinavir/ritonavir, nelfinavir

Macrolide antibiotics: clarithromycin (Biaxin)

Grapefruit and grapefruit juice (contains CYP3A inhibitors)

Examples of moderate CYP3A inhibitors to avoid or use with caution:

Fluconazole (common antifungal)

Erythromycin (antibiotic)

Aprepitant (anti-nausea medication used in chemotherapy)

Diltiazem and verapamil (heart medications)

Category 2: Strong and Moderate CYP3A Inducers — AVOID

These drugs speed up CYP3A4 activity, causing entrectinib to be broken down too quickly and blood levels to fall. For example, rifampin reduced entrectinib levels by 77% in clinical studies — meaning the drug may no longer be effective if taken with strong inducers.

Strong and moderate CYP3A inducers to avoid:

Rifampin, rifabutin (antibiotics/anti-tuberculosis drugs)

Phenytoin, carbamazepine, phenobarbital (anti-seizure medications)

St. John's Wort (herbal supplement — often overlooked but clinically significant)

Apalutamide (prostate cancer drug)

Armodafinil, modafinil (wakefulness agents)

Category 3: QT-Prolonging Drugs — AVOID or USE WITH CAUTION

Entrectinib itself can prolong the QT interval on an EKG — a measure of the heart's electrical cycle. When combined with other QT-prolonging drugs, the risk of a dangerous heart rhythm abnormality called Torsade de Pointes increases. Drugs in this category that commonly interact with entrectinib include:

Amiodarone (heart rhythm drug)

Ondansetron (Zofran) — commonly prescribed for nausea in cancer patients

Levofloxacin, azithromycin (antibiotics)

Adagrasib (another targeted cancer therapy)

Haloperidol and many other antipsychotics

Category 4: Drugs That Entrectinib Affects

Entrectinib can also affect the blood levels of other drugs by mildly inhibiting CYP3A4 and the P-glycoprotein (P-gp) transporter. This increases levels of:

Midazolam (sedative): entrectinib increases midazolam levels by approximately 50%

Digoxin (heart medication): entrectinib increases digoxin peak levels by ~28%

Lomitapide (cholesterol medication): dose adjustment may be needed

What to Tell Your Oncologist and Pharmacist

Before starting entrectinib, give your oncologist and specialty pharmacist a complete, up-to-date list of ALL medications, supplements, vitamins, and herbal products you take. Don't forget:

Over-the-counter medications (antacids, antihistamines, pain relievers)

Herbal supplements (especially St. John's Wort)

Any vitamins or nutritional supplements

Prescription drugs from other doctors (cardiologist, psychiatrist, neurologist, etc.)

The Bottom Line

Entrectinib has serious interactions with many common medications. The safest approach is to be completely transparent with your entire care team about everything you take. For more on managing side effects during treatment, see our guide to entrectinib side effects. And if you need help finding a pharmacy that can fill your prescription, medfinder is here to help.