RESMETIROM Drug Interactions: What You Need to Know

INTERACTIONS Strong or Moderate CYP2C8 Inhibitors: Concomitant use not recommended (strong inhibitor [e.g., gemfibrozil]); or reduce REZDIFFRA dosage (moderate inhibitor [e.g., clopidogrel]). (2.2 , 7.1) Atorvastatin, Pravastatin, Rosuvastatin and Simvastatin : Limit the daily dosage of the statin as recommended. (5.3 , 7.2) CYP2C8 Substrates: Monitor patients more frequently for substrate- related adverse reactions. (7.2)

7.1 Effects of Strong or Moderate CYP2C8 Inhibitors on REZDIFFRA Table 3 includes clinically significant drug interaction effects of strong or moderate CYP2C8 inhibitors on REZDIFFRA.

Table

3: Clinically Significant Interaction Effects of Strong or Moderate CYP2C8 Inhibitors on REZDIFFRA Clinical Impact Resmetirom is a CYP2C8 substrate. Concomitant use with a strong or moderate CYP2C8 inhibitor can increase resmetirom Cmax and AUC [ see Clinical Pharmacology (12.3) ], which may increase the risk of REZDIFFRA adverse reactions.

Intervention

Concomitant use of REZDIFFRA with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended. Reduce REZDIFFRA dosage if used concomitantly with a moderate CYP2C8 inhibitor (e.g., clopidogrel) [ see Dosage and Administration (2.2) ].

7.2 Effects of REZDIFFRA on Other Drugs Table 4 includes clinically significant drug interactions affecting other drugs.

Table

4: Clinically Significant Interactions Affecting Other Drugs Statins (Atorvastatin, Pravastatin, Rosuvastatin, or Simvastatin)

Clinical

Impact REZDIFFRA increased plasma concentrations of some statins (atorvastatin, pravastatin, rosuvastatin and simvastatin) [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these drugs.

Intervention

Rosuvastatin and simvastatin: Limit daily statin dosage to 20 mg. Pravastatin and atorvastatin: Limit daily statin dosage to 40 mg. CYP2C8 Substrates Clinical Impact Resmetirom is a weak CYP2C8 inhibitor. Resmetirom increases exposure of CYP2C8 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.

Intervention

Monitor patients more frequently for substrate-related adverse reactions if REZDIFFRA is co-administered with CYP2C8 substrates where minimal concentration changes may lead to serious adverse reactions.

None. None.

AND PRECAUTIONS Hepatotoxicity : Monitor patients during treatment with REZDIFFRA for elevations in liver tests and for the development of liver-related adverse reactions. Discontinue REZDIFFRA and continue to monitor the patient if hepatotoxicity is suspected. (5.1) Gallbladder-Related Adverse Reactions : Cholelithiasis and cholecystitis were observed more often in REZDIFFRA-treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute gallbladder event such as acute cholecystitis is suspected, interrupt REZDIFFRA treatment until the event is resolved. (5.2)

5.1 Hepatotoxicity Hepatotoxicity has been observed with use of REZDIFFRA. One patient had normal alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) levels at baseline, who received REZDIFFRA 80 mg daily, developed substantial elevations of liver biochemistries that resolved when treatment was interrupted. After reinitiating REZDIFFRA, the patient had elevations of ALT, AST, and TB. Peak values observed were 58 x upper limit of normal (ULN) for ALT, 66 x ULN for AST, 15 x ULN for TB, with no elevation of alkaline phosphatase (ALP). Elevations in liver enzymes were accompanied by elevations in immunoglobulin G levels, suggesting drug-induced autoimmune-like hepatitis (DI-ALH). The liver tests returned to baseline following hospitalization and discontinuation of REZDIFFRA without any therapeutic intervention. Monitor patients during treatment with REZDIFFRA for elevations in liver tests and for the development of liver-related adverse reactions. Monitor for symptoms and signs of hepatotoxicity (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash, and/or eosinophilia [>5%]). If hepatotoxicity is suspected, discontinue REZDIFFRA and continue to monitor the patient. If laboratory values return to baseline, weigh the potential risks against the benefits of restarting REZDIFFRA. If laboratory values do not return to baseline, consider DI-ALH or autoimmune liver disease in the evaluation of elevations in liver tests.

5.2 Gallbladder-Related Adverse Reactions In clinical trials, cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) were observed more often in REZDIFFRA-treated patients than in placebo-treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute gallbladder event is suspected, interrupt REZDIFFRA treatment until the event is resolved <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

5.3 Drug Interaction with Certain Statins An increase in exposure of atorvastatin, pravastatin, rosuvastatin and simvastatin was observed when concomitantly administered with REZDIFFRA <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>, which may increase the risk of adverse reactions related to these drugs. Dosage adjustment for certain statins is recommended <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> . Monitor for statin-related adverse reactions including but not limited to elevation of liver tests, myopathy, and rhabdomyolysis .