Rezdiffra (Resmetirom) Pre-Surgery Hold Window: What Clinicians Need to Know

Does the label set a hold time?

No. The prescribing information gives weight-based once-daily dosing (80 mg under 100 kg, 100 mg at 100 kg or more), dose reductions with CYP2C8 inhibitors, and statin limits. It does not describe stopping the drug before a procedure [1]. For a missed dose, the label says to skip it and resume with the next scheduled dose [1]. Resmetirom has a terminal half-life of 4.5 hours, a median time to peak of about 4 hours, and reaches steady state within 3 to 6 days of once-daily dosing [1].

What the label does address

Liver injury

One patient on 80 mg daily with normal baseline liver tests developed ALT 58 times, AST 66 times and total bilirubin 15 times the upper limit of normal with raised IgG, suggesting drug-induced autoimmune-like hepatitis. Values returned to baseline after hospitalization and stopping the drug, and rose again on rechallenge [1]. In Trial 1, ALT above 3 times the upper limit of normal occurred in 10% on placebo, 11% on 80 mg and 13% on 100 mg; ALT above 5 times in 2%, 2% and 2% [1]. The label directs monitoring for liver test elevations and for symptoms such as fatigue, nausea, vomiting, right upper quadrant pain, jaundice, fever, rash and eosinophilia, and stopping the drug if hepatotoxicity is suspected [1].

Gallbladder events

Cholelithiasis, acute cholecystitis and obstructive pancreatitis (gallstone) occurred more often than with placebo, at rates under 1 per 100 person-years in all arms. The label says to interrupt treatment if an acute gallbladder event is suspected [1].

Statins and CYP2C8 drugs

Resmetirom raised exposure to rosuvastatin, simvastatin, pravastatin and atorvastatin. The label limits daily statin doses (rosuvastatin and simvastatin 20 mg; pravastatin and atorvastatin 40 mg) and says to monitor for liver test elevation, myopathy and rhabdomyolysis [1]. At steady state with resmetirom 100 mg, rosuvastatin 20 mg rose 1.8-fold in Cmax and 1.4-fold in AUC [1]. Clopidogrel, a moderate CYP2C8 inhibitor, raised resmetirom Cmax 1.3-fold and AUC 1.7-fold, and the label calls for a reduced resmetirom dose of 60 mg under 100 kg or 80 mg at 100 kg or more. Gemfibrozil, a strong CYP2C8 inhibitor, is not recommended [1].

Thyroid tests and heart rhythm

Mean free T4 fell 2% on placebo, 13% on 80 mg and 17% on 100 mg at 12 months, with minimal change in T3 or TSH and no clinical findings associated with the decrease [1]. At twice the maximum recommended dose, resmetirom did not prolong the QT interval to any clinically relevant extent [1].

Cirrhosis

Resmetirom is approved only for noncirrhotic MASH with F2 to F3 fibrosis, and the label says to avoid it in decompensated cirrhosis. AUC is 2.7-fold higher in Child-Pugh B and 19-fold higher in Child-Pugh C [1].