Chenodiol

1 INDICATIONS AND USAGE CTEXLI is indicated for the treatment of cerebrotendinous xanthomatosis (CTX) in adults. CTEXLI is a bile acid indicated for treatment of cerebrotendinous xanthomatosis (CTX) in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION • Before initiating CTEXLI, obtain baseline liver transaminase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and total bilirubin levels in all patients. ( 2.1 ) • The recommended dosage is 250 mg orally three times daily. ( 2.2 ) 2.1 Important Recommendation Prior to CTEXLI Treatment Initiation Before initiating CTEXLI, obtain baseline liver transaminase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and total bilirubin levels in all patients [see Warnings and Precautions ( 5.1 )] . 2.2 Recommended Dosage The recommended dosage of CTEXLI is 250 mg administered orally three times daily. Administer CTEXLI with or without food. Swallow tablets whole. Missed Dose If a dose of CTEXLI is missed, advise the patient to skip the missed dose and to resume taking the prescribed dose at the next scheduled time. Patients should not take a double dose. 2.3 Administration Modification and Monitoring If liver transaminase (ALT, AST) levels are elevated > 3 times the upper limit of normal (ULN) or total bilirubin level is >2 times ULN, interrupt treatment with CTEXLI until the levels have returned to baseline values. Monitor liver transaminase and total bilirubin levels yearly and as clinically indicated [see Warnings and Precautions ( 5.1 )].

6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in the labeling: • Hepatotoxicity [see Warnings and Precautions ( 5.1 )] The most common adverse reactions (incidence > 14%) are diarrhea, headache, abdominal pain, constipation, hypertension, muscular weakness, and upper respiratory tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mirum Pharmaceuticals at 1-855-MRM-4YOU or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of CTEXLI was evaluated in a randomized, double blind, placebo-controlled, 2-period, 2-treatment crossover trial in 14 patients (16 to 55 years of age) with CTX (Trial 1). CTEXLI is not approved for use in pediatric patients. The dosage of CTEXLI was 250 mg orally three times a day [see Clinical Studies ( 14 )]. The mean (SD) chenodiol exposure during Trial 1 was 139.1 (26.7) days. The most common adverse reactions which occurred in two or more patients ( > 14%) during CTEXLI treatment (including the two 8-week open-label treatment periods) were diarrhea (36%), headache (21%), and abdominal pain (including abdominal pain upper) (14%), constipation (14%), hypertension (14%), muscular weakness (14%), and upper respiratory tract infection (14%). In Trial 1, one CTEXLI-treated patient (7%) had increased ALT levels > 3x ULN, which led to treatment interruption. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of chenodiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Hepatobiliary Disorders: Hepatotoxicity [see Warnings and Precautions ( 5.1 )] • Immune System Disorders: Hypersensitivity reactions such as facial swelling, pruritus, rash, urticaria.

12.3 Pharmacokinetics In CTX patients, the geometric mean (%CV) maximum plasma concentration (C max ), trough plasma concentration (C trough ), and area under the plasma concentration-time curve (AUC 0-8h ) of chenodiol at steady state following the recommended dosage (250 mg administered orally three times daily) were 3.7 mcg/mL (60%), 0.7 mcg/mL (90%), and 12.5 mcg*h/mL (60%), respectively. Absorption The median (range) T max of chenodiol following an oral administration in CTX patients was 3 (0.5‑8) hours. Distribution Due to first-pass hepatic clearance, the body pool of chenodiol resides mainly in the enterohepatic circulation. The apparent volume of distribution of chenodiol at steady-state was 0.36 L/kg. The plasma protein binding of chenodiol was approximately 98%. Elimination The geometric mean total apparent clearance of chenodiol in CTX patients was 20 L/h. Metabolism Chenodiol is well absorbed from the small intestine and taken up by the liver where it is converted to its taurine and glycine conjugates and secreted into the bile along with other endogenous bile acids in the enterohepatic circulation. Chenodiol that escapes to the colon is converted by bacterial action to lithocholic acid. Humans have the capacity to form sulfate conjugates of lithocholic acid. About 80% of the lithocholate is excreted in the feces and the remainder is absorbed and converted in the liver to its poorly absorbed sulfolithocholyl conjugates. Excretion Conjugated chenodiol is either reabsorbed in the terminal ileum, deconjugated before excretion, or decomposed by bacteria to lithocholic acid. Drug Interaction Studies Based on in vitro studies, chenodiol and its glyco- and tauro- conjugates are not expected to inhibit CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, or induce CYPs 1A2 or 2B6 at the recommended dose of chenodiol of 250 mg TID. Chenodiol and its tauro- conjugate may upregulate CYP3A4 mRNA in vitro. The clinical significance of this upregulation is unknown. The glyco- and tauro- conjugates of chenodiol are high affinity substrates for BSEP, and in vitro studies suggest that chenodiol may inhibit OATP1B1 and OATP1B3 at the recommended dose of 250 mg TID (clinical significance unknown), but chenodiol and its glyco- and tauro- conjugates are not predicted to inhibit P-gp, BCRP, OATP2B1, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K.