Rezdiffra (Resmetirom) Drug Interactions: What to Avoid and What to Tell Your Doctor

Rezdiffra (resmetirom) is metabolized in a way that creates meaningful interactions with several commonly prescribed medications — particularly statins and certain drugs used to treat high cholesterol, infections, and immune conditions. Understanding these interactions is essential before you start Rezdiffra and at every medication review with your doctor.

This guide covers the most clinically important Rezdiffra drug interactions, organized by severity, so you know exactly what to avoid and what to monitor.

How Rezdiffra Interacts With Other Drugs: The Short Explanation

Rezdiffra is a substrate (processed by) of two enzyme and transport systems in the body:

CYP2C8 enzyme: Resmetirom is metabolized by the liver enzyme CYP2C8. Drugs that inhibit CYP2C8 can increase Rezdiffra blood levels, raising the risk of adverse effects.

OATP1B1 and OATP1B3 transporters: Rezdiffra is also transported into liver cells via these proteins. Drugs that block these transporters raise Rezdiffra levels.

On the other side, Rezdiffra itself is a weak inhibitor of these same transporters — meaning it can raise the blood levels of other drugs that rely on them, most importantly statins.

Drugs to AVOID With Rezdiffra (Contraindicated or Strong Caution)

Gemfibrozil (Strong CYP2C8 Inhibitor)

Gemfibrozil is a fibrate medication used to lower triglycerides. The prescribing information states that concomitant use with Rezdiffra is not recommended because gemfibrozil is a strong CYP2C8 inhibitor and significantly increases resmetirom blood levels, raising the risk of adverse effects. If you are taking gemfibrozil, discuss alternatives with your doctor before starting Rezdiffra.

Cyclosporine (OATP1B1/1B3 Inhibitor)

Cyclosporine is an immunosuppressant used in organ transplant patients and some autoimmune conditions. It is a potent OATP1B1 and OATP1B3 inhibitor and significantly increases Rezdiffra exposure. Avoid concomitant use if possible. If coadministration cannot be avoided, discuss the risk-benefit with your transplant or immunology specialist.

Atazanavir and Certain Antiretrovirals (OATP1B1/1B3 Inhibitors)

Atazanavir (an HIV medication) and other antiretroviral drugs that inhibit OATP1B1/1B3 transporters can significantly raise Rezdiffra blood levels. If you are on HIV therapy, review your full medication list with your hepatologist before starting Rezdiffra.

Erythromycin (Macrolide Antibiotic — OATP1B1/1B3 Inhibitor)

Erythromycin base, ethylsuccinate, lactobionate, and stearate forms all inhibit OATP transporters and are listed as drugs to avoid with Rezdiffra in the prescribing information. If you need an antibiotic, ask your provider whether an alternative such as azithromycin or amoxicillin could be used instead.

Drugs That Need Dose ADJUSTMENT When Used With Rezdiffra

Statins — The Most Important Class to Manage

MASH patients often take statins to manage the dyslipidemia that frequently accompanies the disease. Rezdiffra inhibits the same drug transporters (BCRP, OATP1B1/1B3) that remove statins from the bloodstream, raising statin exposure and the risk of statin-related adverse effects:

Rosuvastatin: Cmax increases 4.6-fold with resmetirom. Limit to 20 mg/day.

Simvastatin: Significant exposure increase. Limit to 20 mg/day.

Pravastatin: Cmax increases 1.3-fold, AUC increases 1.4-fold. Limit to 40 mg/day.

Atorvastatin: AUC increases 1.4-fold. Limit to 40 mg/day.

Monitor all patients on statins for signs of myopathy (muscle pain, weakness) and rhabdomyolysis (muscle breakdown — signaled by darkened, cola-colored urine). Report these symptoms to your doctor immediately.

Clopidogrel (Moderate CYP2C8 Inhibitor)

Clopidogrel (Plavix) is a blood thinner commonly used in patients with cardiovascular disease — a population that overlaps significantly with MASH patients. As a moderate CYP2C8 inhibitor, clopidogrel increases Rezdiffra blood levels. When clopidogrel must be used with Rezdiffra, reduce the Rezdiffra dose: to 60 mg/day for patients under 100 kg, and to 80 mg/day for patients 100 kg or over.

Repaglinide and Sensitive CYP2C8 Substrates

Rezdiffra is a weak CYP2C8 inhibitor itself, meaning it can modestly raise the levels of drugs that are primarily metabolized by CYP2C8 — including repaglinide (a diabetes medication) and certain other drugs. If you take any CYP2C8-sensitive medications, your doctor should be aware before you start Rezdiffra, so they can monitor for increased effects.

What to Tell Your Doctor Before Starting Rezdiffra

Before starting Rezdiffra, give your hepatologist or prescriber a complete list of all medications, including:

All prescription medications, including dosages

Over-the-counter medications (including antacids like omeprazole/rabeprazole, which interact with Rezdiffra)

Vitamins and dietary supplements (including herbal supplements, which can affect drug metabolism)

Any HIV, immunosuppressant, or transplant medications

Your statin name and current dose (this will almost certainly need adjustment)

Pregnancy and Breastfeeding

There are no adequate studies on Rezdiffra use during pregnancy. Animal studies suggested potential risk at very high doses. If you become pregnant while taking Rezdiffra, report it immediately to Madrigal Pharmaceuticals' Adverse Event reporting line (1-800-905-0324) and discuss stopping the medication with your doctor. Rezdiffra is not recommended during breastfeeding due to unknown effects on breast milk and the infant.

For the full list of Rezdiffra side effects and when to seek medical attention, see: Rezdiffra Side Effects: What to Expect and When to Call Your Doctor.