Rezdiffra (Resmetirom) Hair and Skin Changes: What Patients and Clinicians Need to Know

Does resmetirom cause hair loss?

The Rezdiffra label does not list it. Its common adverse reactions, those occurring in at least 5% of patients and more often than on placebo, are diarrhea, nausea, pruritus, vomiting, constipation, abdominal pain and dizziness. Its less common reactions include decreased appetite, flatulence, abnormal feces, dysgeusia, vertigo, arrhythmia, palpitations, depression, erythema, hypoglycemia, tendinopathy and abnormal uterine bleeding. Alopecia appears on neither list [1].

The phase 3 MAESTRO-NASH trial (966 patients in the week-52 analysis, randomized to 80 mg, 100 mg or placebo) had NASH resolution and fibrosis improvement as its primary end points [2]. The 52-week safety trial, MAESTRO-NAFLD-1, reported treatment-emergent adverse events in 86.1% of patients on 100 mg, 88.4% on 80 mg and 81.8% on placebo, with excess diarrhea and nausea early in treatment [3].

What the label does list: itching, rash, hives, erythema

Pruritus is one of the seven most common adverse reactions on the label [1]. In the label's trial of 888 patients with F2 to F3 fibrosis (294 on placebo, 298 on 80 mg, 296 on 100 mg; median exposure 66 to 74 weeks), pruritus was recorded in 18 patients on placebo, 24 on 80 mg and 36 on 100 mg. The exposure-adjusted rates were 4, 6 and 10 per 100 person-years [1]. For scale, diarrhea carried an exposure-adjusted rate of 33 per 100 person-years at 100 mg [1].

Rash was reported at 3 per 100 person-years on placebo, 3 on 80 mg and 5 on 100 mg. Urticaria was reported at 0.2, 0.7 and 1.5 per 100 person-years respectively. The label notes that urticaria and rash may reflect drug hypersensitivity [1]. Erythema is among the less common reactions, meaning fewer than 5% of patients and more often than placebo, and the label gives no rate for it [1].

Does the dose change the itching?

Pruritus was more frequent at the higher dose: 6 per 100 person-years on 80 mg versus 10 on 100 mg [1]. Dosing itself is weight-based, 80 mg once daily for patients under 100 kg and 100 mg once daily at 100 kg or more. The label's dose modifications address moderate and strong CYP2C8 inhibitors rather than skin reactions [1].

Overall discontinuation for any adverse reaction ran at 4, 5 and 8 per 100 person-years on placebo, 80 mg and 100 mg, with diarrhea and nausea the most common causes [1].

Rash is named in the liver warning

Rash appears in the label's list of symptoms and signs of hepatotoxicity to monitor, alongside fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever and eosinophilia above 5%. The label says to discontinue resmetirom and continue monitoring if hepatotoxicity is suspected [1].

The hepatotoxicity warning describes one patient on 80 mg daily, with normal liver tests at baseline, who developed ALT 58 times, AST 66 times and total bilirubin 15 times the upper limit of normal together with raised IgG, suggesting drug-induced autoimmune-like hepatitis. Liver tests returned to baseline after hospitalization and stopping the drug, and rose again on rechallenge [1]. ALT above 3 times the upper limit of normal occurred in 10% of placebo patients, 11% on 80 mg and 13% on 100 mg [1].

Thyroid hormone changes the label did measure

Free T4 fell by a mean of 2% on placebo, 13% on 80 mg and 17% on 100 mg at 12 months, with minimal change in T3 or TSH and no clinical findings associated with the decrease [1]. About 14% of trial patients were taking thyroxine, and the label lists no levothyroxine interaction [1]. The mechanism section describes THR-beta as the main thyroid hormone receptor in the liver, with heart and bone effects largely mediated through THR-alpha. It does not describe hair follicle effects [1].

What the label says to monitor

The label's monitoring instructions centre on liver tests and gallbladder events. It lists the hepatotoxicity symptoms above. It says to interrupt treatment for a suspected acute gallbladder event such as acute cholecystitis. Cholelithiasis, acute cholecystitis and obstructive pancreatitis (gallstone) occurred more often than on placebo, at rates under 1 per 100 person-years in all arms [1]. It lists no hair-related adverse reaction and no skin monitoring instruction beyond the symptoms in the liver warning [1].

Putting it together for hair and skin

Skin: itching, rash and hives are recognized reactions, and itching is more frequent at 100 mg than at 80 mg [1]. Hair: alopecia is not among the reactions the label records [1]. For the liver endpoints, the label's Month 12 biopsy results for resolution of steatohepatitis with no worsening of fibrosis were 13% on placebo, 27% on 80 mg and 36% on 100 mg by Pathologist A, and 9%, 26% and 24% by Pathologist B [1].