Rezdiffra

Drug overview for REZDIFFRA (resmetirom):

Generic name: resmetirom (RES-me-TIR-om)
Drug class:
Therapeutic class: Hepatobiliary System Treatment Agents

Resmetirom is a thyroid hormone receptor-beta (THR-beta) agonist.

No enhanced Uses information available for this drug.

DRUG IMAGES

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The following indications for REZDIFFRA (resmetirom) have been approved by the FDA:

Indications:
Steatosis of liver

Professional Synonyms:
Hepatic steatosis
Hepatomegaly with steatosis
Non-alcoholic fatty liver disease

Dosing information for REZDIFFRA
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
REZDIFFRA 60 MG TABLET	Maintenance	Adults take 1 tablet (60 mg) by oral route once daily
REZDIFFRA 80 MG TABLET	Maintenance	Adults take 1 tablet (80 mg) by oral route once daily
REZDIFFRA 100 MG TABLET	Maintenance	Adults take 1 tablet (100 mg) by oral route once daily

The following drug interaction information is available for REZDIFFRA (resmetirom):

Contraindicated
Severe
Moderate

There are 6 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Elbasvir-Grazoprevir/OATP1B1-3 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of OATP1B1/3 may decrease the hepatocyte uptake and increase the plasma concentrations of elbasvir and grazoprevir.(1-3) CLINICAL EFFECTS: Concurrent use of an inhibitor of OATP1B1/3 may result in elevated levels of grazoprevir and an increased risk of ALT elevations.(1-3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of elbasvir-grazoprevir and OATP1B1/3 inhibitors is contraindicated.(1-2,4) If concurrent use is deemed medically necessary, monitor the patient for toxicity and elevated AST levels. DISCUSSION: In a study in 10 subjects, atazanavir/ritonavir (300/100 mg daily) increased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of elbasvir (50 mg daily) by 4.15-fold, 4.76-fold, and 6.45-fold, respectively. There were no clinically significant effects on atazanavir levels.(1,2) In a study in 12 subjects, atazanavir/ritonavir (300/100 mg daily) increased the Cmax, AUC, and Cmin of grazoprevir (200 mg daily) by 6.24-fold, 10.58-fold, and 11.64-fold, respectively. There were no clinically significant effects on atazanavir levels.(1,2) In a study in 14 subjects, cyclosporine (400 mg single dose) increased the Cmax, AUC, and Cmin of elbasvir (50 mg daily) by 1.95-fold, 1.98-fold, and 2.21-fold, respectively. The Cmax, AUC, and Cmin of grazoprevir (200 mg daily) increased by 17-fold, 15.21-fold, and 3.39-fold, respectively. There were no clinically significant effects on cyclosporine levels.(1,2) In a study in 10 subjects, darunavir/ritonavir (600/100 mg twice daily) increased the Cmax, AUC, and Cmin of elbasvir (50 mg daily) by 1.67-fold, 1.66-fold, and 1.82-fold, respectively. There were no clinically significant effects on darunavir levels.(1,2) In a study in 13 subjects, darunavir/ritonavir (600/100 mg twice daily) increased the Cmax, AUC, and Cmin of grazoprevir (200 mg daily) by 5.27-fold, 7.50-fold, and 8.05-fold, respectively. There were no clinically significant effects on darunavir levels.(1,2) In a study in 10 subjects, lopinavir/ritonavir (400/100 mg twice daily) increased the Cmax, AUC, and Cmin of elbasvir (50 mg daily) by 2.87-fold, 3.71-fold, and 4.58-fold, respectively. There were no clinically significant effects on lopinavir levels.(1,2) In a study in 13 subjects, lopinavir/ritonavir (400/100 mg twice daily) increased the Cmax, AUC, and Cmin of grazoprevir (200 mg daily) by 7.31-fold, 12.86-fold, and 21.70-fold, respectively. There were no clinically significant effects on lopinavir levels.(1,2) In single dose studies, rifampin increased levels of both elbasvir and grazoprevir. In a study in 14 subjects, rifampin (600 mg single IV dose) increased the Cmax, AUC, and Cmin of a single dose of elbasvir (50 mg) by 41%, 22%, and 31%, respectively. In a study in 14 subjects, rifampin (600 mg single oral dose) increased the Cmax, AUC, and Cmin of a single dose of elbasvir (50 mg) by 29%, 17%, and 21%, respectively. In a study in 12 subjects, rifampin (600 mg single IV dose) increased the Cmax, AUC, and Cmin of a single dose of grazoprevir (200 mg) by 10.94-fold, 10.21-fold, and 1.77-fold, respectively. In a study in 12 subjects, rifampin (600 mg single oral dose) increased the Cmax, AUC, and Cmin of a single dose of grazoprevir (200 mg) by 6.52-fold, 8.35-fold, and 1.61-fold, respectively.(1) OATP1B1/3 inhibitors include asciminib, atazanavir, belumosudil, cyclosporine, darunavir, fostemsavir, letermovir, lopinavir, nirmatrelvir/ritonavir, paritaprevir, resmetirom, roxadustat, saquinavir, tipranavir, vadadustat, and voclosporin.(1-3)	ZEPATIER
Elagolix/Strong OATP1B1 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of OATP1B1 may decrease the hepatic uptake of elagolix.(1,2) CLINICAL EFFECTS: Concurrent use of an inhibitor of OATP1B1 may result in elevated levels of and side effects from elagolix, including an increased risk of ALT elevations.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of elagolix and strong OATP1B1 inhibitors is contraindicated.(1) DISCUSSION: Strong OATP1B1 inhibitors linked to this monograph include asciminib, belumosudil, cyclosporine, encorafenib, gemfibrozil, letermovir, paritaprevir, resmetirom, roxadustat, and vadadustat.(1,2)	ORIAHNN, ORILISSA
Rosuvastatin (Greater Than 20 mg)/Resmetirom SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Resmetirom is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of rosuvastatin.(1-3) CLINICAL EFFECTS: Concurrent use of resmetirom may result in increased levels and side effects from rosuvastatin, including rhabdomyolysis.(1-3) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US manufacturer of resmetirom states that the dose of rosuvastatin should not exceed 20 mg daily when used concurrently with resmetirom.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2) DISCUSSION: In a study, resmetirom (as steady state) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose rosuvastatin 10 mg by 1.8-fold and 2.9-fold, respectively.(1)	CRESTOR, EZALLOR SPRINKLE, ROSUVASTATIN CALCIUM, ROSUVASTATIN-EZETIMIBE, ROSZET
Simvastatin (Greater Than 20 mg)/Resmetirom SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Resmetirom inhibits the BCRP, OATP1B1, and OATP1B3 transporters, which may result in increased absorption and decreased hepatic uptake of simvastatin.(1,2) CLINICAL EFFECTS: Concurrent resmetirom may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The US manufacturer of resmetirom states that the dose of simvastatin should not exceed 20 mg daily when used concurrently with resmetirom.(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: Concurrent use of resmetirom increased the concentration maximum (Cmax) and area-under-curve (AUC) of a 20 mg single dose of simvastatin by 1.4-fold and 1.7-fold, respectively.(1)	EZETIMIBE-SIMVASTATIN, FLOLIPID, SIMVASTATIN, VYTORIN, ZOCOR
Pravastatin (Greater Than 40 mg)/Resmetirom SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Resmetirom is an inhibitor of OATP1B1 and OATP1B3.(1) Pravastatin is a substrate for OATP1B1 and OATP1B3 transport.(2) CLINICAL EFFECTS: Concurrent use of resmetirom may lead to higher systemic concentrations of pravastatin, increasing the risk for statin-induced myopathy or rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The US manufacturer of resmetirom states that the dose of pravastatin should not exceed 40 mg daily when used concurrently with resmetirom.(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: In an interaction study, resmetirom increased pravastatin (40 mg single dose) maximum concentration (Cmax) 1.3-fold and area-under-curve (AUC) 1.4-fold. respectively.(1)	PRAVASTATIN SODIUM
Atorvastatin (Greater Than 40 mg)/Resmetirom SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Resmetirom is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of atorvastatin.(1,2) CLINICAL EFFECTS: Concurrent use of resmetirom may result in elevated levels of atorvastatin, which could result in rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The US manufacturer of resmetirom states that the dose of atorvastatin should not exceed 40 mg daily when used concurrently with resmetirom.(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: In a study, resmetirom (100 mg daily) increased the area-under-curve (AUC) of atorvastatin 20 mg by 1.4-fold, with no change in the maximum concentration (Cmax). Atorvastatin lactone Cmax and AUC increased 2.0-fold and 1.8-fold, respectively.(1)	AMLODIPINE-ATORVASTATIN, ATORVALIQ, ATORVASTATIN CALCIUM, CADUET, LIPITOR

There are 6 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Eluxadoline/OATP1B1 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: OATP1B1 inhibitors may decrease the hepatic uptake of eluxadoline.(1) CLINICAL EFFECTS: Concurrent use of OATP1B1 inhibitors may result in elevated levels of and side effects from eluxadoline, including constipation, nausea, abdominal pain, and impaired mental and physical abilities.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent OATP1B1 inhibitors should receive a dose of eluxadoline of 75 mg twice daily. Monitor patients for impaired mental or physical abilities, abdominal pain, nausea, and constipation.(1) DISCUSSION: Concurrent administration of a single dose (600 mg) of cyclosporine, an OATP1B1 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of eluxadoline (100 mg) by 4.4-fold and 6.2-fold, respectively.(1) OATP1B1 inhibitors include asciminib, atazanavir, belumosudil, boceprevir, cyclosporine, darunavir, encorafenib, eltrombopag, erythromycin, gemfibrozil, leflunomide, letermovir, lopinavir, paritaprevir, resmetirom, rifampin, ritonavir, roxadustat, saquinavir, simeprevir, telaprevir, teriflunomide, tipranavir, vadadustat, and voclosporin.(1,2)	VIBERZI
Voxilaprevir/Selected OATP1B1-3 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: OATP1B1 and OATP1B3 inhibitors may increase exposure to voxilaprevir.(1) CLINICAL EFFECTS: Concurrent use of OATP1B1 and OATP1B3 inhibitors may result in increased levels of and toxicity from voxilaprevir.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent administration of voxilaprevir with OATP1B1 and OATP1B3 inhibitors is not recommended.(1,4) If concurrent therapy is warranted, monitor patients for adverse effects. The American Society of Transplantation guidelines state that the combination of voxilaprevir and cyclosporine is contraindicated.(3) DISCUSSION: In a study in 25 subjects, cyclosporine (600 mg single dose) increased the maximum concentration (Cmax) and area-under-curve (AUC) of voxilaprevir (100 mg single dose) by 19.02-fold and 9.39-fold, respectively. There were no significant effects on cyclosporine levels.(1) OATP inhibitors include asciminib, atazanavir, belumosudil, cyclosporine, encorafenib, fostemsavir, letermovir, lopinavir, paritaprevir, resmetirom, roxadustat, vadadustat, and voclosporin.(1,2,4)	VOSEVI
Brincidofovir/OATP1B1-3 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: OATP1B1 and 1B3 inhibitors may increase the absorption and/or decrease the hepatic uptake of brincidofovir.(1) CLINICAL EFFECTS: Concurrent use of OATP1B1 or 1B3 inhibitors may result in elevated levels of and side effects from brincidofovir.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of brincidofovir states that alternative medications that are not OATP1B1 or 1B3 inhibitors should be considered. If concurrent use is necessary, instruct the patient to take the OATP1B1 or 1B3 inhibitor at least 3 hours after brincidofovir and increase monitoring for side effects, including transaminase and bilirubin elevations and GI side effects like diarrhea.(1) DISCUSSION: In a clinical trial, single-dose oral cyclosporine (600 mg, an OATP1B1 and 1B3 inhibitor) increased the mean brincidofovir area-under-curve (AUC) and maximum concentration (Cmax) by 374% and 269%, respectively.(1) OATP1B1 and 1B3 inhibitors include asciminib, atazanavir, belumosudil, boceprevir, clarithromycin, cyclosporine, darunavir, eltrombopag, encorafenib, erythromycin, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, leflunomide, letermovir, lopinavir, ombitasvir-paritaprevir, paritaprevir, resmetirom, rifampin, ritonavir, roxadustat, saquinavir, simeprevir, sofosbuvir, telaprevir, teriflunomide, tipranavir, vadadustat, velpatasvir, and voclosporin.(1,2)	TEMBEXA
Zavegepant/OATP1B3 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Zavegepant is a substrate of the organic anion transporting polypeptide 1B3 (OATP1B3) transporter. Inhibitors of OATP1B3 may increase zavegepant exposure.(1) CLINICAL EFFECTS: Concurrent use of OATP1B3 inhibitors may result in increased levels of and toxicity from zavegepant.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent administration of zavegepant with OATP1B3 inhibitors should be avoided.(1) DISCUSSION: In a study, rifampin (an OATP1B3 and NTCP inhibitor) at steady state increased the area-under-curve (AUC) and maximum concentration (Cmax) of zavegepant by 2.3-fold and 2.2-fold. Since rifampin is also a CYP3A4 inducer and zavegepant is metabolized by CYP3A4, concurrent use of zavegepant with other OATP1B3 inhibitors that are not CYP3A4 inducers may have an even more significant effect on zavegepant exposure.(1) OATP1B3 inhibitors include asciminib, atazanavir, belumosudil, cobicistat, cyclosporine, darolutamide, enasidenib, encorafenib, fostemsavir, glecaprevir/pibrentasvir, leflunomide, letermovir, lopinavir/ritonavir, paritaprevir, resmetirom, rifampin, ritonavir, teriflunomide, velpatasvir, voclosporin, and voxilaprevir.(2-9)	ZAVZPRET
Resmetirom/Strong CYP2C8 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inhibitors of CYP2C8 may inhibit the metabolism of resmetirom.(1) CLINICAL EFFECTS: Concomitant use of a strong CYP2C8 inhibitor may increase resmetirom plasma concentrations, which may increase the risk of resmetirom toxicity, including hepatotoxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concomitant use of resmetirom with strong CYP2C8 inhibitors is not recommended.(1) DISCUSSION: Multiple doses of resmetirom 100 mg daily were given with clopidogrel, a moderate CYP2C8 inhibitor, and the resmetirom area-under-curve (AUC) and maximum concentration (Cmax) increased 1.7-fold and 1.3-fold, respectively.(1) Strong CYP2C8 inhibitors linked to this monograph include gemfibrozil.(2)	GEMFIBROZIL, LOPID
Atrasentan/OATP1B1-3 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: OATP1B1 and 1B3 inhibitors may increase the absorption and/or decrease the hepatic uptake of atrasentan.(1) CLINICAL EFFECTS: Concurrent use of OATP1B1 or 1B3 inhibitors may result in elevated levels of and side effects from atrasentan, including fluid retention and hepatotoxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of atrasentan states that concurrent use of OATP1B1 or 1B3 inhibitors should be avoided.(1) DISCUSSION: In a clinical study, atrasentan maximum concentration (Cmax) was 4.3 times higher and area-under-curve (AUC) was 3.8 times higher following coadministration of a single dose of 0.75 mg atrasentan with cyclosporine (OATP1B1 and 1B3 inhibitor) compared to atrasentan alone. OATP1B1 and 1B3 inhibitors include asciminib, atazanavir, belumosudil, boceprevir, clarithromycin, cobicistat, cyclosporine, eltrombopag, erythromycin, fostemsavir, gemfibrozil, glecaprevir-pibrentasvir, leflunomide, letermovir, lopinavir, nirmatrelvir, ombitasvir-paritaprevir, resmetirom, ritonavir, roxadustat, saquinavir, simeprevir, telaprevir, teriflunomide, tipranavir, vadadustat, velpatasvir, voclosporin, and voxilaprevir.(1,2)	VANRAFIA

There are 8 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Atogepant/OATP1B1-3 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Atogepant is a substrate of OATP1B1 and 1B3. Inhibitors of these transporters may increase the GI absorption and/or decrease the hepatic uptake of atogepant.(1) CLINICAL EFFECTS: Concurrent use of OATP1B1 or 1B3 inhibitors may result in elevated levels of and side effects from atogepant, including nausea, constipation and fatigue.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of atogepant states that, when used concurrently with an OATP inhibitor for prevention of episodic migraine, the atogepant dose should be limited to 10 mg or 30 mg once daily. When used concurrently with an OATP inhibitor for prevention of chronic migraines, the atogepant dose should be limited to 30 mg once daily.(1) DISCUSSION: In a clinical trial of healthy subjects, single-dose rifampin, an OATP inhibitor, increased the atogepant area-under-curve (AUC) and maximum concentration (Cmax) by 2.85-fold and 2.23-fold, respectively.(1) OATP1B1 and 1B3 inhibitors include asciminib, atazanavir, belumosudil, cyclosporine, darunavir, eltrombopag, erythromycin, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, leflunomide, letermovir, paritaprevir, resmetirom, ritonavir, roxadustat, simeprevir, sofosbuvir, teriflunomide, vadadustat, velpatasvir, and voclosporin.(1,2)	QULIPTA
Momelotinib/OATP1B1-3 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: OATP1B1 and 1B3 inhibitors may decrease the hepatic uptake of momelotinib.(1) CLINICAL EFFECTS: Concurrent use of OATP1B1 and 1B3 inhibitors may result in elevated levels of and side effects from momelotinib, including myelosuppression and hepatotoxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of momelotinib with OATP1B1 and 1B3 inhibitors should be approached with caution. Monitor patients closely for adverse reactions and consider dose modifications per momelotinib prescribing recommendations.(1) DISCUSSION: Concurrent administration of a single dose rifampin, an OATP1B1/1B3 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of momelotinib by 40% and 57%, respectively. The M21 metabolite Cmax increased 6% and AUC increased 12%.(1) OATP1B1 inhibitors include asciminib, atazanavir, belumosudil, boceprevir, cobicistat, cyclosporine, darolutamide, darunavir, eltrombopag, enasidenib, encorafenib, erythromycin, fostemsavir, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, letermovir, lopinavir, nirmatrelvir, paritaprevir, resmetirom, rifampin, roxadustat, saquinavir, simeprevir, telaprevir, tipranavir, vadadustat, velpatasvir, and voclosporin.(1,2)	OJJAARA
Resmetirom/Moderate CYP2C8 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Moderate inhibitors of CYP2C8 may inhibit the metabolism of resmetirom.(1) CLINICAL EFFECTS: Concomitant use of a moderate CYP2C8 inhibitor may increase resmetirom plasma concentrations, which may increase the risk of resmetirom toxicity, including hepatotoxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concomitant use of resmetirom with moderate CYP2C8 inhibitors is not recommended. If concurrent use is warranted, reduce the dose of resmetirom based on the patient's weight. -If <100 kg, reduce the dose of resmetirom to 60 mg once daily; -If >=100 kg, reduce the dose of resmetirom to 80 mg once daily.(1) DISCUSSION: Multiple doses of resmetirom 100 mg daily were given with clopidogrel, a moderate CYP2C8 inhibitor, and the resmetirom area-under-curve (AUC) and maximum concentration (Cmax) increased 1.7-fold and 1.3-fold, respectively.(1) Moderate CYP2C8 inhibitors linked to this monograph include: clopidogrel, deferasirox, leflunomide, mifepristone (chronic therapy), pirtobrutinib, selpercatinib, and teriflunomide.(2)	ARAVA, AUBAGIO, CLOPIDOGREL, CLOPIDOGREL BISULFATE, DEFERASIROX, EXJADE, JADENU, JADENU SPRINKLE, JAYPIRCA, KORLYM, LEFLUNICLO, LEFLUNOMIDE, MIFEPREX, MIFEPRISTONE, PLAVIX, RETEVMO, TERIFLUNOMIDE
Rosuvastatin (Less Than or Equal to 20 mg)/Resmetirom SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Resmetirom is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of rosuvastatin.(1-3) CLINICAL EFFECTS: Concurrent use of resmetirom may result in increased levels and side effects from rosuvastatin, including rhabdomyolysis.(1-3) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US manufacturer of resmetirom states that the dose of rosuvastatin should not exceed 20 mg daily when used concurrently with resmetirom.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2) DISCUSSION: In a study, resmetirom (as steady state) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose rosuvastatin 10 mg by 1.8-fold and 2.9-fold, respectively.(1)	CRESTOR, EZALLOR SPRINKLE, ROSUVASTATIN CALCIUM, ROSUVASTATIN-EZETIMIBE, ROSZET
Simvastatin (Less Than or Equal to 20 mg)/Resmetirom SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Resmetirom inhibits the BCRP, OATP1B1, and OATP1B3 transporters, which may result in increased absorption and decreased hepatic uptake of simvastatin.(1,2) CLINICAL EFFECTS: Concurrent resmetirom may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The US manufacturer of resmetirom states that the dose of simvastatin should not exceed 20 mg daily when used concurrently with resmetirom.(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: Concurrent use of resmetirom increased the concentration maximum (Cmax) and area-under-curve (AUC) of a 20 mg single dose of simvastatin by 1.4-fold and 1.7-fold, respectively.(1)	EZETIMIBE-SIMVASTATIN, SIMVASTATIN, VYTORIN, ZOCOR
Pravastatin (Less Than or Equal to 40 mg)/Resmetirom SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Resmetirom is an inhibitor of OATP1B1 and OATP1B3.(1) Pravastatin is a substrate for OATP1B1 and OATP1B3 transport.(2) CLINICAL EFFECTS: Concurrent use of resmetirom may lead to higher systemic concentrations of pravastatin, increasing the risk for statin-induced myopathy or rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The US manufacturer of resmetirom states that the dose of pravastatin should not exceed 40 mg daily when used concurrently with resmetirom.(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: In an interaction study, resmetirom increased pravastatin (40 mg single dose) maximum concentration (Cmax) 1.3-fold and area-under-curve (AUC) 1.4-fold. respectively.(1)	PRAVASTATIN SODIUM
Atorvastatin (Less Than or Equal to 40 mg)/Resmetirom SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Resmetirom is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of atorvastatin.(1,2) CLINICAL EFFECTS: Concurrent use of resmetirom may result in elevated levels of atorvastatin, which could result in rhabdomyolysis. PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: The US manufacturer of resmetirom states that the dose of atorvastatin should not exceed 40 mg daily when used concurrently with resmetirom.(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine. DISCUSSION: In a study, resmetirom (100 mg daily) increased the area-under-curve (AUC) of atorvastatin 20 mg by 1.4-fold, with no change in the maximum concentration (Cmax). Atorvastatin lactone Cmax and AUC increased 2.0-fold and 1.8-fold, respectively.(1)	AMLODIPINE-ATORVASTATIN, ATORVASTATIN CALCIUM, CADUET, LIPITOR
Resmetirom/Letermovir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Letermovir is a moderate CYP2C8 inhibitor and substrate of OATP1B1 and 1B3. Resmetirom is an inhibitor of OATP1B1 and a substrate of CYP2C8.(1,2) Moderate inhibitors of CYP2C8 may inhibit the metabolism of resmetirom.(1) OATP1B1 and 1B3 inhibitors may inhibit the metabolism of letermovir.(2) CLINICAL EFFECTS: Concomitant use of a moderate CYP2C8 inhibitor may increase resmetirom plasma concentrations, which may increase the risk of resmetirom toxicity, including hepatotoxicity.(1) Concurrent use of OATP1B1 and 1B3 inhibitors may result in elevated levels of and side effects from letermovir, including diarrhea, nausea, abdominal pain, and peripheral edema.(2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of letermovir with OATP1B1 and 1B3 inhibitors should be approached with caution. Monitor patients closely for adverse reactions and consider dose modifications per prescribing recommendations.(2) Concomitant use of resmetirom with moderate CYP2C8 inhibitors is not recommended. If concurrent use is warranted, reduce the dose of resmetirom based on the patient's weight. -If <100 kg, reduce the dose of resmetirom to 60 mg once daily; -If >=100 kg, reduce the dose of resmetirom to 80 mg once daily.(1) DISCUSSION: Multiple doses of resmetirom 100 mg daily were given with clopidogrel, a moderate CYP2C8 inhibitor, and the resmetirom area-under-curve (AUC) and maximum concentration (Cmax) increased 1.7-fold and 1.3-fold, respectively.(1) Letermovir is a substrate of OATP1B1 and 1B3. Co-administration of letermovir with drugs that are inhibitors of OATP1B1 and 1B3 transporters may result in increases in letermovir plasma concentrations.(2)	PREVYMIS

Severe List
Hepatic cirrhosis

The following adverse reaction information is available for REZDIFFRA (resmetirom):

Overview
Severe
Less Severe

Adverse reaction overview.

The most common adverse reactions with resmetirom (reported in >=5% of patients and more frequently than placebo) are diarrhea, nausea, pruritus, vomiting, constipation, abdominal pain, and dizziness.

There are 4 severe adverse reactions.

More Frequent	Less Frequent
None.	Cardiac arrhythmia

Rare/Very Rare
Biliary calculus Cholecystitis Pancreatitis

There are 19 less severe adverse reactions.

More Frequent	Less Frequent
Acute abdominal pain Constipation Diarrhea Dizziness Nausea Pruritus of skin Vomiting	Abnormal hepatic function tests Abnormal uterine bleeding Anorexia Depression Dysgeusia Erythema Flatulence Hyperbilirubinemia Hypoglycemic disorder Low serum concentration of free t4 with normal thyroid-stimulating hormone (TSh) and t3 Palpitations Vertigo

Rare/Very Rare
None.

The following precautions are available for REZDIFFRA (resmetirom):

Pediatric
Pregnant
Lactation
Geriatric

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

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

There are no available data on resmetirom use in pregnant females to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, adverse effects on embryofetal development occurred in pregnant rabbits treated with resmetirom at 3.5 times the maximum recommended dosage during organogenesis.

These effects were associated with maternal toxicity; no embryofetal effects were observed at lower dosage levels with better maternal tolerance. No embryofetal developmental effects occurred in pregnant rats treated with resmetirom or its principal metabolite MGL-3623. A pre- and postnatal development study in rats showed a decrease in birthweight and an increased incidence of stillbirths and mortality at 37 times the maximum recommended dosage.

These effects were associated with marked suppression of maternal thyroxine (T4), triiodothyronine (T3), and thyroid stimulating hormone (TSH) levels. There are risks to the mother and fetus related to underlying maternal noncirrhotic nonalcoholic steatohepatitis (NASH) with liver fibrosis, such as increased risks of gestational diabetes, hypertensive complications, preterm birth, and postpartum hemorrhage. Report pregnancies to the Madrigal Pharmaceuticals Adverse Event Reporting Line at 1-800-905-0324 or https://www.madrigalpharma.com/contact/.

There are no data regarding the presence of resmetirom 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 resmetirom and any potential adverse effects on the breast-fed infant from resmetirom or from the underlying maternal condition.

In the principal efficacy study of resmetirom, 25% of the 594 patients who received at least 1 dose of resmetirom were >=65 years of age and 2% were >=75 years of age. No overall differences in effectiveness were observed in patients >=65 years of age compared to younger adult patients; however, numerically higher rates of adverse events were observed among older patients.

Steatosis of liver
K76.0	Fatty (change of) liver, not elsewhere classified