RESMETIROM TAB

Clinical Criteria Summary

Treatment of adults with noncirrhotic NASH with moderate to advanced liver fibrosis (stages F2 to F3) in conjunction with diet and exercise.
Approved under accelerated approval based on improvement of NASH and fibrosis; continued approval contingent upon verification of clinical benefit in confirmatory trials.

Requires diagnosis of MASH/NASH with F2–F3 fibrosis and NAS ≥ 4 based on liver biopsy.
Patients must participate in a comprehensive lifestyle intervention (CLI).

< 100 kg: 80 mg orally once daily.
≥ 100 kg: 100 mg orally once daily.
With moderate CYP2C8 inhibitors (e.g., clopidogrel): < 100 kg → 60 mg orally once daily; ≥ 100 kg → 80 mg orally once daily.

Monitor for hepatotoxicity during treatment.
Monitor for gallbladder-related adverse reactions.
Common adverse events (≥5%): diarrhea, nausea, pruritus, vomiting, constipation, abdominal pain, dizziness.
Median time to onset of diarrhea: 6–17 days; median duration: 20 days.
Gallbladder-related adverse reactions occurred in < 1 per 100 patient-years across all treatment groups.

Avoid use in patients with decompensated cirrhosis.
Avoid use in moderate to severe (Child-Pugh Class B or C) hepatic impairment.
Not indicated for MASH with cirrhosis; no evidence supports off-label use for MASH cirrhosis.

Avoid strong CYP2C8 inhibitors (e.g., gemfibrozil).
Avoid OATP1B1 and OATP1B3 inhibitors (e.g., cyclosporine).
Reduce statin doses as recommended for atorvastatin, pravastatin, rosuvastatin, simvastatin.
Monitor for substrate adverse effects with CYP2C8 substrates.

Patients should participate for at least 6 months.
Discontinue resmetirom if liver function worsens.
Onset of significant treatment benefit: No data before Week 52 for NASH resolution or fibrosis improvement; 36 weeks for change from baseline in ALT.

Child-Pugh score ≥ 7
Decompensated liver cirrhosis (e.g., noncardiac ascites, variceal hemorrhage, hepatic encephalopathy, spontaneous bacterial peritonitis)
Recent assessment indicating cirrhosis: FibroScan > 18 kPa / VCTE consistent with cirrhosis, MRE > 5.0 kPa, FIB-4 > 2.67 (unless LSM < 18 kPa), or liver biopsy indicating METAVIR stage F4
Hepatocellular carcinoma not actively managed by hepatology or a multidisciplinary team
Uncontrolled liver disease from non-metabolic dysfunction causes (e.g., biliary obstruction, viral hepatitis, autoimmune hepatitis, hereditary or drug-induced liver disease)
Heavy alcohol ingestion for > 3 consecutive months within the past year (≥4 drinks/day for men, ≥3 drinks/day for women)
Untreated hyperthyroidism or hypothyroidism
Concomitant use of strong CYP2C8 inhibitors (e.g., gemfibrozil)
Concomitant use of systemic OATP inhibitors (e.g., cyclosporine)

Documented noncirrhotic MASH with METAVIR F2–F3 fibrosis and NAS ≥ 4 on liver biopsy within the past 36 months
Prescribed by a VA/VA Community Care gastroenterologist/hepatologist or locally designated expert in MASH management
Documented plan for lifestyle interventions (nutrition, exercise, weight loss)
Documented plan to modify or replace medications that cause or exacerbate steatohepatitis with clinically appropriate alternatives

Overweight/obese patients: Must demonstrate medical inadvisability, intolerance, or inadequate response to a GLP-1RA with evidence for noncirrhotic MASH with moderate to advanced liver fibrosis
Patients who can become pregnant: Counseling on potential risks vs benefits of treatment
Females breastfeeding/providing breastmilk: Counseling on potential risks vs benefits of treatment

Withhold therapy during acute gallbladder events or acute cholecystitis until resolved due to risk of cholelithiasis and cholecystitis
Monitor for increased plasma concentrations of certain statins; limit rosuvastatin and simvastatin to 20 mg/day, and pravastatin and atorvastatin to 40 mg/day