WARNINGS AND PRECAUTIONS
Hepatotoxicity
Hepatotoxicity has been observed in one patient. Please see full Prescribing Information for more details on
this specific case of Hepatotoxicity [see Warnings and Precautions (5.1)].
Monitor patients during treatment for elevations in liver tests and for the development of liver-related
adverse reactions. 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%]). If hepatotoxicity is
suspected, discontinue Rezdiffra and continue to monitor the patient. If laboratory values return to baseline, weigh the potential risks against the benefits of restarting Rezdiffra. If laboratory values do not return to
baseline, consider DI-ALH or autoimmune liver disease in the
evaluation of elevations in liver tests.
Gallbladder-Related Adverse Reactions
In clinical trials, cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) were
observed more often in Rezdiffra-treated patients than in placebo-treated patients. If cholelithiasis is
suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute
gallbladder event is suspected, interrupt Rezdiffra treatment until the event is resolved.
Drug Interaction with Certain Statins
Dosage adjustment for certain statins is recommended. Monitor for statin-related adverse reactions including
but not limited to elevation of liver tests, myopathy, and rhabdomyolysis. Please see the upcoming Drug
Interaction section of the Important Safety Information for more details.
ADVERSE REACTIONS
The most common adverse reactions with Rezdiffra (reported in ≥ 5% of patients and higher compared to
placebo) are: diarrhea, nausea, pruritus, vomiting, constipation, abdominal pain, and
dizziness. Diarrhea and nausea were the most common causes of treatment discontinuation.
Hypersensitivity Reactions
Reactions such as urticaria and rash, which may reflect drug hypersensitivity, were observed in patients receiving
Rezdiffra.
Laboratory Abnormalities
Increases in mean ALT and AST levels were observed in the first 4 weeks after initiating treatment with
Rezdiffra. 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.
DRUG INTERACTIONS
Clinically Significant Interactions Affecting Rezdiffra
-
Strong or Moderate CYP2C8 Inhibitors: Resmetirom is a CYP2C8 substrate. Concomitant use
with strong
CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended. Reduce dosage if used concomitantly with a
moderate CYP2C8 inhibitor (e.g., clopidogrel).
-
Organic Anion-Transporting Polypeptides (OATP) 1B1 and OATP1B3 Inhibitors: Resmetirom
is an OATP1B1 and
OATP1B3 substrate. Concomitant use with OATP1B1 or OATP1B3 inhibitors (e.g., cyclosporine) is not
recommended.
Clinically Significant Interactions Affecting Other Drugs
-
Statins
-
Limit daily rosuvastatin and simvastatin dosage to 20 mg
-
Limit daily pravastatin and atorvastatin dosage to 40 mg
-
CYP2C8 Substrates: Resmetirom is a weak CYP2C8 inhibitor. 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.
USE IN SPECIFIC POPULATIONS
Pregnancy
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 NASH with liver fibrosis, such as increased risks of gestational
diabetes, hypertensive complications, preterm birth, and postpartum hemorrhage. Report pregnancies to
Madrigal Pharmaceuticals, Inc.’s Adverse Event reporting line at 1-800-905-0324 and https://www.madrigalpharma.com/contact/.
Lactation
There is no information regarding the presence of Rezdiffra in human or animal milk, the effects on the
breast-fed infant, or the effects on milk production. The developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for Rezdiffra and any potential
adverse effects on the breastfed infant from Rezdiffra or from the underlying maternal condition.
Pediatric Use
The safety and effectiveness have not been established in pediatric patients.
Geriatric Use
No overall differences in effectiveness but numerically higher incidence of adverse reactions have been
observed in patients ≥65 years of age compared to younger adult patients.
Renal Impairment
The recommended dosage in patients with mild or moderate renal impairment is the same as in patients
with normal kidney function. Rezdiffra has not been studied in patients with severe renal impairment.
Hepatic Impairment
Avoid use in patients with decompensated cirrhosis (consistent with moderate to severe hepatic
impairment). Moderate or severe hepatic impairment (Child-Pugh Class B or C) increases resmetirom Cmax
and AUC, which may increase the risk of adverse reactions.
No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A).
The safety and effectiveness have not been established in patients with NASH cirrhosis.
INDICATION
Rezdiffra 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).
This indication is approved under accelerated approval based on improvement of NASH and fibrosis. Continued
approval for this indication may be contingent upon verification and description of clinical benefit in
confirmatory trials.
Limitation of Use: Avoid use in patients with decompensated cirrhosis.
Please see the full Prescribing Information for Rezdiffra.
