Resmetirom (Monograph)

Brand name: Rezdiffra
Drug class: GI Drugs, Miscellaneous

Introduction

Resmetirom is a thyroid hormone receptor-beta (THR-beta) agonist.¹

Uses for Resmetirom

Resmetirom has the following uses:

Resmetirom is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis).¹

This indication is approved under accelerated approval based on improvement of NASH and fibrosis.¹ Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. ¹

Avoid use of resmetirom in patients with decompensated cirrhosis.¹

Resmetirom Dosage and Administration

General

Resmetirom is available in the following dosage form(s) and strength(s):

Tablets: 60 mg, 80 mg or 100 mg¹

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

The recommended dosage of resmetirom is based on actual body weight.¹ For patients weighing <100 kg, the recommended dosage is 80 mg orally once daily.¹ For patients weighing ≥100 kg, the recommended dosage is 100 mg orally once daily. ¹

See full prescribing information for resmetirom dosage modifications with concomitant use of moderate CYP2C8 inhibitors. ¹

Administer resmetirom with or without food.¹

Related/similar drugs

Rezdiffra

Cautions for Resmetirom

Contraindications

None.¹

Warnings/Precautions

Hepatotoxicity

Hepatotoxicity has been observed with use of resmetirom.¹ One patient had normal alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) levels at baseline, who received resmetirom 80 mg daily, developed substantial elevations of liver biochemistries that resolved when treatment was interrupted.¹ After reinitiating resmetirom, the patient had elevations of ALT, AST, and TB.¹ 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).¹ Elevations in liver enzymes were accompanied by elevations in immunoglobulin G levels, suggesting drug-induced autoimmune-like hepatitis (DI-ALH).¹ The liver tests returned to baseline following hospitalization and discontinuation of resmetirom without any therapeutic intervention.¹

Monitor patients during treatment with resmetirom for elevations in liver tests and for the development of liver-related adverse reactions.¹ 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%]).¹ If hepatotoxicity is suspected, discontinue resmetirom and continue to monitor the patient.¹ If laboratory values return to baseline, weigh the potential risks against the benefits of restarting resmetirom.¹ If laboratory values do not return to baseline, consider DI-ALH or autoimmune liver disease in the evaluation of elevations in liver tests.¹

Gallbladder-related Adverse Reactions

In clinical trials, cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) were observed more often in resmetirom-treated patients than in placebo-treated patients.¹ If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.¹ If an acute gallbladder event is suspected, interrupt resmetirom treatment until the event is resolved.¹

Drug Interaction with Certain Statins

An increase in exposure of atorvastatin, pravastatin, rosuvastatin and simvastatin was observed when concomitantly administered with resmetirom, which may increase the risk of adverse reactions related to these drugs.¹ Dosage adjustment for certain statins is recommended.¹ Monitor for statin-related adverse reactions including, but not limited to, elevation of liver tests, myopathy, and rhabdomyolysis.¹

Specific Populations

Pregnancy

There are no available data on resmetirom use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.¹ There are risks to the mother and fetus related to underlying NASH with liver fibrosis.¹ In animal reproduction studies, adverse effects on embryo-fetal development occurred in pregnant rabbits treated with resmetirom at 3.5 times the maximum recommended dose during organogenesis.¹ These effects were associated with maternal toxicity, whereas no embryo-fetal effects were observed at lower dose levels with better tolerance in pregnant rabbits.¹ No embryo-fetal developmental effects occurred in pregnant rats treated with resmetirom or the metabolite MGL-3623.¹ A pre- and postnatal development study in rats with maternal dosing of resmetirom during organogenesis through lactation showed a decrease in birthweight and increased incidence of stillbirths and mortality (postnatal days 1-4) at 37 times the maximum recommended dose.¹ These effects were associated with marked suppression of maternal T4, T3, and TSH levels.¹

The background risk of major birth defects and miscarriage for the indicated population is unknown.¹ All pregnancies have a background risk of birth defect, loss, and other adverse outcomes.¹ In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.¹

Report pregnancies to Madrigal Pharmaceuticals, Inc. Adverse Event reporting line at 1-800-905-0324 and https://www.madrigalpharma.com/contact/. ¹

There are risks to the mother and fetus related to underlying maternal NASH with liver fibrosis, such as increased risks of gestational diabetes, hypertensive complications, preterm birth, and postpartum hemorrhage.¹

Lactation

There is no information regarding the presence of resmetirom in human or animal milk, the effects on the breast-fed infant, or the effects on milk production.¹ The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for resmetirom and any potential adverse effects on the breastfed infant from resmetirom or from the underlying maternal condition.^{1 1}

Pediatric Use

The safety and effectiveness of resmetirom have not been established in pediatric patients.¹

Geriatric Use

In the principal efficacy study, of the 594 patients with NASH who received at least one dose of resmetirom, 149 (25%) were 65 years of age and older and 13 (2%) were 75 years of age and older.¹ No overall differences in effectiveness, but numerically higher incidence of adverse reactions have been observed in patients 65 years of age and older compared to younger adult patients.¹

Renal Impairment

The recommended dosage in patients with mild or moderate renal impairment is the same as in patients with normal kidney function.¹ Resmetirom has not been studied in patients with severe renal impairment.¹

Hepatic Impairment

Avoid use of resmetirom in patients with decompensated cirrhosis (consistent with moderate to severe hepatic impairment).¹ Moderate or severe hepatic impairment (Child-Pugh Class B or C) increases resmetirom C_maxand AUC, which may increase the risk of adverse reactions.¹

No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A).¹

The safety and effectiveness of resmetirom have not been established in patients with NASH cirrhosis.¹

Common Adverse Effects

The most common adverse reactions with resmetirom (reported in at least 5% of patients and higher compared to placebo) are diarrhea, nausea, pruritus, vomiting, constipation, abdominal pain, and dizziness.¹

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong or Moderate CYP2C8 Inhibitors: Concomitant use not recommended (strong inhibitor [e.g., gemfibrozil]); or reduce resmetirom dosage (moderate inhibitor [e.g., clopidogrel]). ¹

• OATP1B1 and OATP1B3 Inhibitors: Concomitant use with OATP inhibitors (e.g., cyclosporine) is not recommended. ¹

• Atorvastatin, Pravastatin, Rosuvastatin and Simvastatin: Limit the daily dosage of the statin as recommended. ¹

• CYP2C8 Substrates: Monitor patients more frequently for substrate- related adverse reactions. ¹

Actions

Mechanism of Action

Resmetirom is a partial agonist of the thyroid hormone receptor-beta (THR-β).¹ Resmetirom produced 83.8% of the maximum response compared to triiodothyronine (T3), with an EC₅₀ of 0.21 µM in an in vitro functional assay for THR-β activation.¹ The same functional assay for thyroid hormone receptor-alpha (THR-α) agonism showed 48.6% efficacy for resmetirom relative to T3, with an EC₅₀ of 3.74 µM.¹ THR-β is the major form of THR in the liver, and stimulation of THR-β in the liver reduces intrahepatic triglycerides, whereas actions of thyroid hormone outside the liver, including in heart and bone, are largely mediated through THR-α.¹

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).¹

• Inform patients of the risk of hepatotoxicity.¹ Instruct patients to immediately report any signs or symptoms of severe liver injury (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash) to their healthcare provider.¹

• Inform patients of the potential risk for cholelithiasis, cholecystitis, and obstructive pancreatitis (gallstones) during treatment with resmetirom.¹ Instruct patients to contact their healthcare provider if they develop signs or symptoms of these conditions.¹

• Inform patients that concomitant use of resmetirom with some statins may increase the risk of statin- related adverse reactions (e.g., elevation of liver tests, myopathy, rhabdomyolysis).¹

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Medical Disclaimer