REZDIFFRA

Dosage and Administration ( 2.1 ) 12/2025

1 INDICATIONS AND USAGE REZDIFFRA ® is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). This indication is approved under accelerated approval based on improvement of MASH and fibrosis [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Limitations of Use Avoid use of REZDIFFRA in patients with decompensated cirrhosis [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . REZDIFFRA ® is a thyroid hormone receptor-beta (THR-beta) agonist indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). This indication is approved under accelerated approval based on improvement of MASH and fibrosis. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1) Limitations of Use Avoid use of REZDIFFRA in patients with decompensated cirrhosis. (1)

2 DOSAGE AND ADMINISTRATION The recommended dosage of REZDIFFRA is based on actual body weight. For patients weighing: o <100 kg, the recommended dosage is 80 mg orally once daily. o ≥100 kg, the recommended dosage is 100 mg orally once daily. Administer REZDIFFRA with or without food. Swallow REZDIFFRA tablets whole; do not split, crush, or chew tablets ( 2.1 ) See full prescribing information for REZDIFFRA dosage modifications with concomitant use of moderate CYP2C8 inhibitors. ( 2.2 ) 2.1 Recommended Dosage and Administration The recommended dosage of REZDIFFRA is based on actual body weight. For patients weighing: <100 kg, the recommended dosage is 80 mg orally once daily. ≥100 kg, the recommended dosage is 100 mg orally once daily. Administer REZDIFFRA with or without food [see Clinical Pharmacology (12.3) ] . Swallow REZDIFFRA tablets whole; do not split, crush, or chew tablets. Advise patients that if a dose is missed, do not take the missed dose and resume with the next scheduled dose. 2.2 Dosage Modifications for CYP2C8 Inhibitors Concomitant use of REZDIFFRA with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended [see Drug Interactions (7.1) ] . If REZDIFFRA is used concomitantly with a moderate CYP2C8 inhibitor (e.g., clopidogrel) [see Drug Interactions (7.1) ] , reduce the dosage of REZDIFFRA: <100 kg, reduce the dosage of REZDIFFRA to 60 mg once daily. ≥100 kg, reduce the dosage of REZDIFFRA to 80 mg once daily.

3 DOSAGE FORMS AND STRENGTHS REZDIFFRA Tablets: 60 mg: white oval-shaped film-coated tablets debossed with “P60” on one side and plain on the other side. 80 mg: yellow, oval-shaped, film-coated tablets debossed with “P80” on one side and plain on the other side. 100 mg: beige to pink, oval-shaped, film-coated tablets debossed with “P100” on one side and plain on the other side. Tablets: 60 mg, 80 mg, and 100 mg (3)

4 CONTRAINDICATIONS None. None.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Hepatotoxicity [see Warnings and Precautions (5.1) ] Gallbladder-Related Adverse Reactions [see Warnings and Precautions (5.2) ] The most common adverse reactions with REZDIFFRA (reported in at least 5% of patients and higher compared to placebo) are: diarrhea, nausea, pruritus, vomiting, constipation, abdominal pain, and dizziness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Madrigal Pharmaceuticals, Inc. at 1-800-905-0324 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of REZDIFFRA was evaluated in two randomized, double-blind, placebo-controlled trials that enrolled a total of 2019 patients. Trial 1 Trial 1 included patients who had noncirrhotic MASH with stages F2 and F3 fibrosis at eligibility (n=888) [see Clinical Studies (14) ] . Adverse Reactions Leading to Discontinuations The exposure-adjusted incidence rates (EAIRs) per 100 person-years (PY) for treatment discontinuation due to any adverse reaction were higher in the REZDIFFRA dosage arms: 4 per 100 PY, 5 per 100 PY, and 8 per 100 PY in placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Diarrhea and nausea were the most common causes of treatment discontinuation. Common Adverse Reactions Table 1 displays EAIRs per 100 PY for the common adverse reactions that occurred in at least 5% of patients with F2 or F3 fibrosis treated in either drug arm with REZDIFFRA and were greater than that reported for placebo. Table 1: Exposure-Adjusted Incidence Rates (EAIR) of Common Adverse Reactions Reported with REZDIFFRA in Adult Patients with Noncirrhotic MASH (Trial 1) a, b, c a Population includes adult patients with noncirrhotic MASH with liver fibrosis (stages F2 and F3 at eligibility). b Median exposure duration was 68 weeks for placebo, 74 weeks for REZDIFFRA 80 mg once daily, and 66 weeks for REZDIFFRA 100 mg once daily. c EAIRs are per 100 person-years (PY) where total PYs were 435, 435, and 407 for placebo, 80 mg once daily, and 100 mg once daily arms, respectively. d The EAIR per 100 PY can be interpreted as an estimated number of first occurrences of the adverse reaction of interest if 100 patients are treated for one year. Abbreviations: EAIR, exposure-adjusted incidence rate; PY, person-years; MASH, metabolic dysfunction-associated steatohepatitis Adverse Reaction Placebo N=294 n (EAIR d ) REZDIFFRA 80 mg Once Daily N=298 n (EAIR d ) REZDIFFRA 100 mg Once Daily N=296 n (EAIR d ) Diarrhea 52 (14) 78 (23) 98 (33) Nausea 36 (9) 65 (18) 51 (15) Pruritus 18 (4) 24 (6) 36 (10) Vomiting 15 (4) 27 (7) 30 (8) Constipation 18 (4) 20 (5) 28 (8) Abdominal pain 18 (4) 22 (5) 27 (7) Dizziness 6 (1) 17 (4) 17 (4) Gastrointestinal Adverse Reactions The incidence of gastrointestinal adverse reactions was higher for the REZDIFFRA drug arms compared to placebo. The EAIRs for gastrointestinal adverse reactions were 57 per 100 PY, 73 per 100 PY, and 89 per 100 PY in the placebo, REZDIFFRA 80 mg once daily, REZDIFFRA 100 mg once daily arms, respectively. Diarrhea typically began early in treatment initiation and was mild to moderate in severity. The median time (Q1 to Q3) to a diarrheal event was 39 (2 to 195) days, 17 (3 to 70) days, and 6 (2 to 54) days in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Median duration of diarrhea was 9 days for placebo compared to 20 days for both REZDIFFRA 80 mg once daily and REZDIFFRA 100 mg once daily dosage arms. Nausea also began early in treatment and was mild to moderate in severity. Among patients with nausea, the median time (Q1 to Q …

7 DRUG 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.

8 USE IN SPECIFIC POPULATIONS Hepatic Impairment: Avoid use of REZDIFFRA in patients with moderate to severe hepatic impairment (Child-Pugh Class B or C). (8.7) 8.1 Pregnancy Risk Summary There are no available data on REZDIFFRA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus related to underlying MASH with liver fibrosis (see Clinical Considerations ). 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. These effects were associated with maternal toxicity, whereas no embryo-fetal effects were observed at lower dose levels with better tolerance in pregnant rabbits. No embryo-fetal developmental effects occurred in pregnant rats treated with resmetirom or the metabolite MGL-3623. 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 (see Data ) . These effects were associated with marked suppression of maternal T4, T3, and TSH levels. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, and other adverse outcomes. 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. Report pregnancies to Madrigal Pharmaceuticals, Inc. Adverse Event reporting line at 1-800-905-0324 or https://pregnancyregistry.madrigalpharma.com . Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk There are risks to the mother and fetus related to underlying maternal MASH with liver fibrosis, such as increased risks of gestational diabetes, hypertensive complications, preterm birth, and postpartum hemorrhage. Data Animal Data No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 100 mg/kg/day (21 times the maximum recommended dose based on AUC [area under the plasma concentration-time curve]) or in pregnant rabbits treated orally with up to 30 mg/kg/day (2.8 times the maximum recommended dose based on AUC) during the period of organogenesis. Oral administration of 75 mg/kg/day in pregnant rabbits (3.5 times the maximum recommended dose based on AUC) produced an increase in post-implantation loss and decreases in viable fetuses and fetal weight. These effects were likely due to maternal toxicity (i.e., marked reductions in weight gain and food consumption). A pre- and postnatal development study was performed using oral administration of 3, 30, or 100 mg/kg/day in female rats during organogenesis through lactation. Treatment with 100 mg/kg/day (37 times the maximum recommended dose based on AUC) produced increases in number of stillborn, pup deaths during postnatal days 1-4, and pups with absence of milk in stomach. Birthweight was decreased by 10% in this dose group, with recovery to normal body weight thereafter. The effects in offspring were associated with marked reductions in maternal plasma levels of T4 (88% decrease), T3 (79% decrease), and TSH (44% decrease). No effects on postnatal development were observed at doses up to 30 mg/kg/day (7.2 times the maximum recommended dose based on AUC). This study lacked a complete evaluation of physical and neurobehavioral development in offspring; however, no effects of resmetirom were noted in tests of learning and memory. The metabolite MGL-3623 was tested for its effects on embryo-fetal development. No effects were observed in pregnant rats treated orally with up to 100 mg/kg/day MGL-3623 (4.7 times the maximum recommended dose based on …

11 DESCRIPTION REZDIFFRA (resmetirom) tablets contain resmetirom, a thyroid hormone receptor-beta agonist. The chemical name for REZDIFFRA is 2-[3,5-Dichloro-4-((6-oxo-5-(propan-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. The molecular formula is C 17 H 12 Cl 2 N 6 O 4 and the molecular weight is 435.22. The chemical structure is: Resmetirom has low aqueous solubility below pH 6 and higher solubility above pH 7 (0.44 mg/mL at pH 7.04). REZDIFFRA tablets are supplied in 60 mg, 80 mg, and 100 mg strengths for oral administration. Each tablet contains the active ingredient, resmetirom, and the following USP/NF excipients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. REZDIFFRA tablets are film-coated with an Opadry coating comprised of polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, red iron oxide (100 mg tablets), yellow iron oxide (80 mg and 100 mg tablets). image description

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied REZDIFFRA (resmetirom) tablets are packaged in white high-density polyethylene bottles closed with a child-resistant closure containing an induction seal. 60 mg Tablets : white oval-shaped film-coated tablets, debossed “P60” on one side and plain on the other side. Bottle of 30 count (NDC 82576-060-30) 80 mg Tablets : yellow, oval-shaped, film-coated tablets, debossed with “P80” on one side and plain on the other side. Bottle of 30 count (NDC 82576-080-30) Bottle of 90 count (NDC 82576-080-90) 100 mg Tablets: beige to pink, oval-shaped, film-coated tablets, debossed with “P100” on one side and plain on the other side. Bottle of 30 count (NDC 82576-100-30) Bottle of 90 count (NDC 82576-100-90) Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [ see USP Controlled Room Temperature ].