Resmetirom (Monograph)

Brand name: Rezdiffra
Drug class: GI Drugs, Miscellaneous

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

[Web]

Introduction

Thyroid hormone receptor-beta (THR-β) agonist.

Uses for Resmetirom

Noncirrhotic Nonalcoholic Steatohepatitis (NASH)

Treatment of adults with NASH and moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis); use in conjunction with diet and exercise.

Approved under accelerated approval based on improvement of NASH and fibrosis; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

Do not use in decompensated cirrhosis.

Current guidelines from the American Association for the Study of Liver Diseases (AASLD), American Association of Clinical Endocrinology (AACE), and American Gastroenterological Association (AGA) do not address place in therapy. Other experts recommend considering resmetirom in adults with noncirrhotic NASH and significant liver fibrosis (stage 2 or 3), in accordance with labeling.

Resmetirom Dosage and Administration

General

Patient Monitoring

Monitor liver function tests and signs/symptoms of hepatotoxicity.

Administration

Administer tablets orally with or without food.

Dosage

Adults

Noncirrhotic nonalcoholic steatohepatitis (NASH)

Oral

Actual body weight (ABW) <100 kg: 80 mg once daily.

ABW ≥100 kg: 100 mg once daily.

Dosage Modification for Drug Interactions

Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil) not recommended.

If used concomitantly with a moderate CYP2C8 inhibitor (e.g., clopidogrel), recommended dosage is 60 mg once daily for patients with ABW <100 kg and 80 mg once daily for patients with ABW ≥100 kg.

Special Populations

Hepatic Impairment

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

Avoid use in patients with decompensated cirrhosis (consistent with moderate to severe hepatic impairment [Child-Pugh Class B or C]).

Renal Impairment

No dosage adjustment recommended for patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–89 mL/minute per 1.73m²).

Use in severe renal impairment (eGFR <30 mL/minute per 1.73m²) not studied.

Geriatric Patients

No dosage recommendations at this time.

Cautions for Resmetirom

Contraindications

None.

Warnings/Precautions

Hepatotoxicity

Hepatotoxicity observed.

Monitor for elevations in liver function tests and for development of liver-related adverse reactions. Monitor for signs and symptoms of hepatotoxicity (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash, and/or eosinophilia). If hepatotoxicity suspected, discontinue resmetirom and monitor patient. If laboratory values return to baseline, weigh potential risks against benefits of restarting resmetirom. If laboratory values do not return to baseline, consider drug-induced autoimmune-like hepatitis or autoimmune liver disease.

Gallbladder-related Adverse Reactions

Cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstones) observed.

If cholelithiasis is suspected, conduct gallbladder diagnostic studies and appropriate clinical follow-up.

If an acute gallbladder event is suspected, interrupt resmetirom treatment until the event is resolved.

Drug Interaction with Certain Statins

Possible increased risk of adverse reactions related to atorvastatin, pravastatin, rosuvastatin, and simvastatin when used concomitantly with resmetirom.

Dosage adjustment for certain statins recommended. Monitor for statin-related adverse reactions including, but not limited to, elevation of liver enzymes, myopathy, and rhabdomyolysis.

Specific Populations

Pregnancy

No available data on resmetirom use in pregnant females to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Risks to the mother and fetus related to underlying maternal NASH with liver fibrosis include increased risks of gestational diabetes, hypertensive complications, preterm birth, and postpartum hemorrhage.

Report pregnancies to Madrigal Pharmaceuticals Adverse Event Reporting Line at 1-800-905-0324 and [Web].

Lactation

No data regarding the presence of resmetirom in human or animal milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for resmetirom and any potential adverse effects on the breast-fed infant from resmetirom or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness not established.

Geriatric Use

No overall differences in effectiveness observed in patients ≥65 years of age compared to younger adult patients; numerically higher rates of adverse events observed among older patients.

Hepatic Impairment

Following repeat dosing of resmetirom 80 mg once daily for 6 days, resmetirom AUC increased by 1.3-fold, 2.7-fold, and 19-fold in patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment, respectively. Maximum concentrations of resmetirom increased by 1.2-fold, 1.7-fold, and 8.1-fold in patients with mild, moderate, or severe hepatic impairment, respectively. In patients with NASH cirrhosis and mild hepatic impairment, AUC and maximum concentrations of resmetirom were 6% higher and 10% lower, respectively, than those observed in noncirrhotic NASH patients following repeated dosing of resmetirom 100 mg daily for 6 days.

Avoid use of resmetirom in decompensated cirrhosis (consistent with moderate to severe hepatic impairment) due to increased risk of adverse reactions.

No dosage adjustment required for patients with mild hepatic impairment.

Safety and effectiveness of resmetirom not established in patients with NASH cirrhosis.

Renal Impairment

No clinically significant differences in pharmacokinetics of resmetirom observed based on mild to moderate renal impairment (eGFR 30–89 mL/minute per 1.73m²); no dosage adjustment required.

Use in severe renal impairment (eGFR <30 mL/minute per 1.73m²) not studied.

Common Adverse Effects

Most common adverse reactions with resmetirom (reported in ≥5% of patients and more frequently than placebo) are diarrhea, nausea, pruritus, vomiting, constipation, abdominal pain, and dizziness.

Drug Interactions

Inhibitor of CYP2C8, UGT1A4, UGT1A9, organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, breast cancer resistance protein (BCRP), organic anion transporter (OAT) 3, and bile salt export pump (BSEP).

Substrate of CYP2C8, OATP1B1, OATP1B3, and BCRP.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP2C8 Inhibitors

Concomitant use with strong or moderate CYP2C8 inhibitors may increase resmetirom maximum concentrations and AUC, which may increase the risk of adverse reactions.

Concomitant use of resmetirom and strong CYP2C8 inhibitors (e.g., gemfibrozil) not recommended.

Adjust dosage of resmetirom if used concomitantly with a moderate CYP2C8 inhibitor (e.g., clopidogrel).

CYP2C8 Substrates

Resmetirom may increase exposure to CYP2C8 substrates and increase risk of adverse events related to the CYP2C8 substrate.

If administering resmetirom with a CYP2C8 substrate where minimal concentration changes may lead to serious adverse reactions, monitor more frequently for substrate-related adverse reactions.

Drugs Affecting Efflux Transport Systems

Concomitant use with OATP1B1 and OATP1B3 inhibitors (e.g., cyclosporine) may increase maximum concentrations and AUC of resmetirom, which may increase the risk of adverse reactions.

Concomitant use with OATP1B1 or OATP1B3 inhibitors not recommended.

Specific Drugs

Drug	Interaction	Comments
Atorvastatin	Atorvastatin: maximum concentration unchanged, AUC increased 1.4-fold Atorvastatin lactone: maximum concentrations increased 2-fold, AUC increased 1.8-fold	Limit daily atorvastatin dosage to 40 mg
Clopidogrel	Resmetirom maximum concentrations increased 1.3-fold and resmetirom AUC increased 1.7-fold	Adjust dosage of resmetirom
Pioglitazone	Maximum concentration of pioglitazone unchanged, but AUC increased 1.5-fold	Monitor for pioglitazone-related adverse reactions
Pravastatin	Maximum concentration of pravastatin increased 1.3-fold and AUC increased 1.4-fold	Limit daily pravastatin dosage to 40 mg
Rosuvastatin	Maximum concentration of rosuvastatin increased 2.9-fold and AUC increased 1.8-fold	Limit daily rosuvastatin dosage to 20 mg
Simvastatin	Maximum concentration of simvastatin increased 1.4-fold and AUC increased 1.7-fold	Limit daily simvastatin dosage to 20 mg
Warfarin	No clinically significant interaction observed

Resmetirom Pharmacokinetics

Absorption

Bioavailability

Steady state exposure increases in a dose proportional manner at doses of 40–100 mg.

Steady state reached within 3–6 days of dosing.

Resmetirom exposure increases 1.5- to 3-fold with once daily dosing, but major metabolite (MGL-3623) does not accumulate.

Time to maximum concentration: 4 hours following multiple daily doses of 80 or 100 mg.

Food

Administering with food leads to 33% decrease in maximum concentrations, 11% decrease in AUC, and delay in median time to maximum concentrations of approximately 2 hours.

Distribution

Extent

Unknown if present in human milk.

Plasma Protein Binding

>99%

Elimination

Metabolism

Metabolism occurs via CYP2C8.

Major metabolite MGL-3623 has a 28-times lower potency for THR-β than resmetirom. MGL-3623 represents 33–51% of resmetirom AUC at steady state.

Elimination Route

Fecal: 67% (mostly as metabolites); MGL-3623 metabolite accounted for 3.3% of drug recovered in feces.

Urine: 24% (1% as unchanged drug); MGL-3623 metabolite accounted for 16% of drug recovered in urine.

Half-life

4.5 hours.

Special Populations

No clinically significant differences in pharmacokinetics observed based on age (18–83 years), sex, race, or ABCG2 genotype.

Stability

Storage

Oral

Tablets

20–25ºC (excursions permitted between 15–30ºC).

Actions

Partial agonist of THR-β.
THR-β is the major form of THR in the liver; stimulation of THR-β reduces intrahepatic triglycerides.
In an in vitro functional assay, resmetirom produced 83.8% of the maximum response compared to triiodothyronine (T3) at the THR-β receptor.
Reductions in liver fat content (as measured by magnetic resonance imaging-protein density fat fraction [MRI-PDFF]) observed after 16 and 52 weeks of resmetirom treatment.
Resmetirom also demonstrates some thyroid hormone receptor-alpha (THR-α) agonism, with functional assays demonstrating 48.6% efficacy for resmetirom relative to T3 at this receptor.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling.
Inform patients of the risk of hepatotoxicity. 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.
Inform patients of the potential risk for cholelithiasis, cholecystitis, and obstructive pancreatitis (gallstones) during treatment with resmetirom. Instruct patients to contact their healthcare provider if they develop signs or symptoms of these conditions.
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).
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.
Advise females to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Report pregnancies to the Madrigal Pharmaceuticals Adverse Event reporting line at 1-800-905-0324 or [Web].
Advise patients of other important precautionary information.

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.