REZDIFFRA Tablet Ref.[108866] Active ingredients: Resmetirom

5.1 Hepatotoxicity

Hepatotoxicity has been observed with use of REZDIFFRA. One patient had normal alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) levels at baseline, who received REZDIFFRA 80 mg daily, developed substantial elevations of liver biochemistries that resolved when treatment was interrupted. After reinitiating REZDIFFRA, the patient had elevations of ALT, AST, and TB. Peak values observed were 58 x upper limit of normal (ULN) for ALT, 66 x ULN for AST, 15 x ULN for TB, with no elevation of alkaline phosphatase (ALP). Elevations in liver enzymes were accompanied by elevations in immunoglobulin G levels, suggesting drug-induced autoimmune-like hepatitis (DI-ALH). The liver tests returned to baseline following hospitalization and discontinuation of REZDIFFRA without any therapeutic intervention.

Monitor patients during treatment with REZDIFFRA 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.

5.2 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 [see Adverse Reactions (6.1)].

5.3 Drug Interaction with Certain Statins

An increase in exposure of atorvastatin, pravastatin, rosuvastatin and simvastatin was observed when concomitantly administered with REZDIFFRA [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these drugs. Dosage adjustment for certain statins is recommended [see Drug Interactions (7.2)]. Monitor for statin-related adverse reactions including but not limited to elevation of liver tests, myopathy, and rhabdomyolysis.

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)]

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 NASH 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 NASH (Trial 1)^a,b,c:

^a Population includes adult patients with noncirrhotic NASH 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; NASH, nonalcoholic steatohepatitis

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 Q3) to a nausea event was 85 (24 to 347) days, 28 (2 to 162) days, and 5 (2 to 40) days in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Median duration of nausea was 17 days, 26 days, and 28 days for patients in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. 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. The EAIRs for urticaria were 0.2 per 100 PY, 0.7 per 100 PY, and 1.5 per 100 PY in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. The EAIRs for rash were 3 per 100 PY in the placebo and REZDIFFRA 80 mg once daily arms compared to 5 per 100 PY in the REZDIFFRA 100 mg once daily arm.

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 5% of patients, included decreased appetite, flatulence, abnormal feces, dysgeusia, vertigo, arrythmia, 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 1:

^a TB elevations include patients with Gilbert syndrome.

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 placebocontrolled safety trial which included 969 patients from a relevant patient population (placebo [n=318], REZDIFFRA 80 mg once daily [n=327], and REZDIFFRA 100 mg once daily [n=324]).

Data from the safety trial was combined with data from NASH 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. In the combined safety population (n=2019), the median (Q1 to Q3) age of patients at baseline was 58 (50 to 65) years; 55% were female, 28% were Hispanic, 89% were White, 2% were Asian, and 4% were Black or African American.

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 [see Warnings and Precautions (5.1)].

7.1 Effects of Other Drugs on REZDIFFRA

Table 3 includes clinically significant drug interactions affecting REZDIFFRA.

Table 3. Clinically Significant Interactions Affecting REZDIFFRA:

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:

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 NASH 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 post-natal 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, Adverse Event reporting line at 1-800-905-0324 and https://www.madrigalpharma.com/contact/.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

There are risks to the mother and fetus related to underlying maternal NASH 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 AUC for MGL-3623) during the period of organogenesis.

Risk Summary

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.

The safety and effectiveness of REZDIFFRA have not been established in pediatric patients.

In Trial 1, of the 594 patients with NASH who received at least one dose of REZDIFFRA, 149 (25%) were 65 years of age and older and 13 (2%) were 75 years of age and older [see Clinical Studies (14)]. No overall differences in effectiveness but numerically higher incidence of adverse reactions have been observed in patients 65 years of age and older compared to younger adult patients.

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 [see Clinical Pharmacology (12.3)].

Avoid use of REZDIFFRA 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 C_max and AUC [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions.

No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3)].

The safety and effectiveness of REZDIFFRA have not been established in patients with NASH cirrhosis.