Rezdiffra Drug Information

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. 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.

Recommended Dosage and Administration

The recommended dosage of REZDIFFRA is based on actual body weight. Administer REZDIFFRA with or without food. 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.

Dosage Modifications for CYP2C8 Inhibitors

Concomitant use of REZDIFFRA with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended. If REZDIFFRA is used concomitantly with a moderate CYP2C8 inhibitor (e.g., clopidogrel), 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.

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).

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: 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 s The incidence of gastrointestinal adverse reactions was higher for the REZDIFFRA drug arms compared to placebo. Diarrhea typically began early in treatment initiation and was mild to moderate in severity. Nausea also began early in treatment and was mild to moderate in severity.

Vomiting and abdominal pain adverse reactions were mild to moderate in severity. Hypersensitivity Reactions Reactions such as urticaria and rash, which may reflect drug hypersensitivity, were observed in patients receiving REZDIFFRA. Gallbladder-Related Adverse Reactions A higher incidence of cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) was observed in the treatment arms compared to placebo.

However, the EAIRs for these events were less than 1 per 100 PY for all treatment arms. Less Common Adverse Reactions Additional adverse reactions that occurred more frequently in the REZDIFFRA arms compared to placebo, in less than 5% of patients, included decreased appetite, flatulence, abnormal feces, dysgeusia, vertigo, arrhythmia, palpitations, depression, erythema, hypoglycemia, tendinopathy, abnormal uterine bleeding. Laboratory Abnormalities Liver Tests Increases in mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were observed in the first 4 weeks after initiating treatment with REZDIFFRA.

In both REZDIFFRA dosage arms, the mean elevation in ALT and AST values was less than 1.5 times baseline at 4 weeks after treatment initiation. These values returned to baseline around 8 weeks after initiating treatment. Table 2 presents the frequency of liver test elevations during Trial 1.

Table 2: Frequency of Liver Test Elevations in Trial Thyroid Function Tests A decrease in levels of prohormone free T4 (FT4) of mean 2%, 13%, and 17% was seen at 12 months in patients treated with placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily, respectively, with minimal changes in active hormone T3 or in TSH. There were no clinical findings associated with FT4 decreases. Additional Safety Data The safety evaluation of REZDIFFRA also included an analysis of an additional randomized placebo-controlled safety trial which included 969 patients from a relevant patient population (placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily ).

Data from the safety trial was combined with data from MASH patients with F2 and F3 fibrosis at eligibility (n=888) and data from an additional 162 patients from a relevant patient population enrolled in Trial 1. The safety profile from this combined analysis was similar to that in Trial 1, other than the one case of hepatotoxicity in the safety trial.

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, 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).

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), which may increase the risk of adverse reactions related to these drugs. Intervention Rosuvastatin and simvastatin: Limit daily statin dosage to 20 mg.

CYP2C8 Substrates Clinical Impact Resmetirom is a weak CYP2C8 inhibitor. Resmetirom increases exposure of CYP2C8 substrates, 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.