DRUG INTERACTIONS-(details)

 1.Effects of Other Drugs on LIVMARLI Bile acid binding resins -                                    Bile acid binding resins may bind to maralixibat in the gut. Administer bile acid binding resins (e.g., cholestyramine, colesevelam, or colestipol) at least 4 hours before or 4 hours after administration of LIVMARLI.

2 Effects of LIVMARLI on Other Drugs OATP2B1 substrates- Maralixibat is an OATP2B1 inhibitor based on in vitro studies. A decrease in the oral absorption of OATP2B1 substrates (e.g., statins) due to OATP2B1 inhibition in the GI tract cannot be ruled out. Consider monitoring the drug effects of OATP2B1 substrates (e.g. statins) as needed

BRIEF SUMMARY

MARALIXBAT- (Sep 2021

Indn- To treat Cholestatic Puritus associated with Allergic   Syndrome

Comp-  Oral solution: 9.5 mg of maralixibat per mL.    The recommended dosage is 380 mcg/kg once daily, taken 30 minutes before the first meal of the day.

 • Starting dose is 190 mcg/kg orally once daily, and should be increased to 380 mcg/kg once daily after one week, as tolerated.

ADR-     Most common adverse reactions  are diarrhea, abdominal pain, vomiting, fat-soluble vitamin deficiency, liver test abnormalities, gastrointestinal bleeding, and bone fractures

CI-   None. 

WARNINGS -

 • Liver Test Abnormalities: Obtain baseline liver tests and monitor during treatment. Dose reduction or treatment interruption may be considered if abnormalities occur. For persistent or recurrent liver test abnormalities, consider I discontinuation.

Pat Inform-

Risks                                                                                                                                    • Abdominal pain, vomiting, diarrhea, and dehydration have been reported with the use . Advise patients to contact their healthcare provider if they experience new onset or worsening of these gastrointestinal adverse events.                                                           • Elevations in liver tests (for example, AST, ALT, TB) have been observed with use f

. Advise patients that their healthcare provider will obtain liver tests before starting LIVMARLI and periodically during treatment.

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 41

Name of the Drug-    LIVMARLI

Active Ingredient -   Maralixbat

Pharmacological Classification- To treat Cholestatic Puritus associated with Allergic   Syndrome                                                                                                                                                                                                                                                                                                                                                                       Date of Approval-          9/29/21    

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                                    LIVMARLI safely and effectively.                                                                                     See full prescribing information for LIVMARLI. LIVMARLI™ (maralixibat) oral solution

Initial U.S. Approval: 2021

INDICATIONS AND USAGE-

 LIVMARLI is an ileal bile acid transporter (IBAT) inhibitor indicated for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) 1 year of age and older. 

ADVERSE REACTIONS-

 Most common adverse reactions (=5%) are diarrhea, abdominal pain, vomiting, fat-soluble vitamin deficiency, liver test abnormalities, gastrointestinal bleeding, and bone fractures.

CONTRAINDICATIONS-

 None. 

WARNINGS AND PRECAUTIONS-

 • Liver Test Abnormalities: Obtain baseline liver tests and monitor during treatment. Dose reduction or treatment interruption may be considered if abnormalities occur. For persistent or recurrent liver test abnormalities, consider LIVMARLI discontinuation.

 • Gastrointestinal Adverse Reactions:                                                                  Consider interrupting LIVMARLI treatment if a patient experiences persistent diarrhea, abdominal pain, vomiting, or has diarrhea with bloody stool, vomiting, dehydration requiring treatment, or fever. If diarrhea, abdominal pain, or vomiting persists and no alternate etiology is identified, consider stopping LIVMARLI treatment.

 • Fat-Soluble Vitamin (FSV) Deficiency: Obtain baseline levels and monitor during treatment. Supplement if deficiency is observed. If FSV deficiency persists or worsens despite FSV supplementation, consider discontinuing LIVMARLI treatment.

DOSAGE AND ADMINISTRATION-

 • The recommended dosage is 380 mcg/kg once daily, taken 30 minutes before the first meal of the day.

 • Starting dose is 190 mcg/kg orally once daily, and should be increased to 380 mcg/kg once daily after one week, as tolerated. 

DOSAGE FORMS AND STRENGTHS-

 Oral solution: 9.5 mg of maralixibat per mL.

PATIENT COUNSELING INFORMATION -

Advise the caregiver and patient of the following LIVMARLI risks and oral administration procedures:

Risks                                                                                                                                    • Abdominal pain, vomiting, diarrhea, and dehydration have been reported with the use of LIVMARLI. Advise patients to contact their healthcare provider if they experience new onset or worsening of these gastrointestinal adverse events.                                             • Elevations in liver tests (for example, AST, ALT, TB) have been observed with use of LIVMARLI. Advise patients that their healthcare provider will obtain liver tests before starting LIVMARLI and periodically during treatment with LIVMARLI.

Advise patients to report any symptoms of liver problems (for example, nausea, vomiting, skin or the whites of eyes turn yellow, dark or brown urine, pain on the right side of the abdomen, loss of appetite).

• LIVMARLI may impair absorption of fat-soluble vitamins (FSV). FSV deficiencies, which include vitamins A, D, E and K have been reported in some patients during treatment with LIVMARLI. Advise patients that their healthcare provider will obtain serum levels of vitamins A, D, E, and INR (for vitamin K) before starting and periodically during treatment to assess for worsening of FSV deficiency.

Administration                                                                                                                    • Take LIVMARLI approximately 30 minutes before the first meal of the day, using a calibrated measuring device (0.5 mL, 1 mL or 3 mL oral dispenser) provided by the pharmacist to measure and deliver the prescribed dose accurately [see Dosage and Administration (2.1 and 2.3) and Instructions for Use].

• Discard any remaining LIVMARLI 45 days after first opening of bottle [see How Supplied/Storage and Handling (16) and Instructions for Use]. Patients taking bile acid binding resins should take LIVMARLI at least 4 hours before or 4 hours after taking a bile acid binding resin [see Drug Interactions (7.1)]. Rx only

Manufactured for: Mirum Pharmaceuticals, Inc. 950 Tower Lane, Suite 1050 Foster City, CA 94404 © 2021 Mirum Pharmaceuticals, Inc. LIVMARLI™ is a trademark of Mirum Pharmaceuticals, Inc. LB00003v

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                       Maralixibat is a reversible inhibitor of the ileal bile acid transporter (IBAT). It decreases the reabsorption of bile acids (primarily the salt forms) from the terminal ileum. Pruritus is a common symptom in patients with ALGS and the pathophysiology of pruritus in patients with ALGS is not completely understood. Although the complete mechanism by which maralixibat improves pruritus in ALGS pa

tients is unknown, it may involve inhibition of the IBAT, which results in decreased reuptake of bile salts, as observed by a decrease in serum bile acids

2. Pharmacodynamics-                                                                                                       In Trial 1, pediatric patients with ALGS were administered open-label treatment with LIVMARLI 380 mcg/kg once daily for 13 weeks after an initial 5-week dose-escalation period..

At baseline, serum bile acids were highly variable among patients ranging from 20 to 749 µmol/L and mean (SD) serum bile acid level was 283 (210.6) µmol/L. Serum bile acid levels decreased from baseline in the majority of patients as early as at Week 12 and the reduction in serum bile acids was generally maintained for the treatment period.

3. Pharmacokinetics-                                                                                                      Due to the low systemic absorption of maralixibat, pharmacokinetic parameters cannot be reliably calculated at the recommended dose. Concentrations of maralixibat in the pediatric ALGS patients were below the limit of quantification (0.25 ng/mL) in the majority of plasma samples.

Absorption-                                                                                                              Maralixibat is minimally absorbed and plasma concentrations are often below the limit of quantification (0.25 ng/mL) after single or multiple doses at recommended doses.

Following a single oral administration of maralixibat 30, 45, and 100 mg liquid formulation under fasted condition, AUClast and Cmax increased in a dose-dependent manner with increase of 4.6-and 2.4-fold, respectively, following a 3.3-fold dose increase from 30 to 100 mg.

No accumulation of maralixibat was observed following repeated oral administration of maralixibat in healthy adults at doses up to 100 mg once daily.

Effect of Food-                                                                                                        Concomitant administration of a high-fat meal with a single oral dose of maralixibat decreased both the rate and extent of absorption. AUC and Cmax of maralixibat values in the fed state were 64.8% to 85.8% lower relative to oral administration of 30 mg in fasted conditions.

The effect of food on the changes of systemic exposures to maralixibat is not clinically significant

 Distribution-                                                                                                               Maralixibat shows high binding (91%) to human plasma proteins in vitro.

Elimination-                                                                                                                   Following a single oral dose of 30 mg maralixibat in healthy adults, the mean half-life (t1/2) was 1.6 hours.

Metabolism-                                                                                                                     No maralixibat metabolites have been detected in plasma. Three minor metabolites, accounting for <3% of maralixibat-associated fecal radioactivity in total, were identified following oral administration of [14C]maralixibat.

Excretion-                                                                                                                        Fecal excretion was found to be the major route of elimination. Following a single oral dose of 5 mg 14C-maralixibat, 73% of the dose was excreted in the feces with 0.066% excreted in the urine. 94% of the fecal excretion was as unchanged maralixibat.

Specific Populations-                                                                                              Patients with Renal Impairment-                                                                                      The pharmacokinetics of maralixibat were not studied in patients with impaired renal

Drug Interaction Studies-                                                                                             Effect of Other Drugs on Maralixibat -Maralixibat is not a substrate of the drug transporters MDR1 (P-gp), BCRP, OATP1B1, OATP1B3, or OATP2B2; therefore, concomitant drug products are not predicted to affect the disposition of maralixibat.

Effect of Maralixibat on Other Drugs -In vitro, maralixibat did not induce CYP isoforms 1A2, 2B6, or 3A4, nor inhibit CYP isoforms 1A2, 2B6, 2C8, 2C9, 2C19 or 2D6 at clinically relevant concentrations.

Maralixibat inhibits CYP3A4 in vitro, however clinically relevant effects on the pharmacokinetics of CYP3A4 substrates are unlikely. In vitro, maralixibat did not inhibit the transporters MDR1 (P-gp), BCRP, OAT1, OAT3, OATP1B1, Reference ID: 4864725 OATP1B3, PEPT1, OCT1, OCT2, OCT3, OCTN1, OCTN2, MRP2, MATE1, or MATE2-K at clinically relevant concentrations.

Maralixibat inhibits the drug transporter OATP2B1 in vitro, which can potentially result in reduced absorption of drugs that rely on OATP2B1-mediated uptake in the GI tract.

In clinical studies coadministration of 4.75 mg maralixibat (once daily in the morning) with daily doses of either simvastatin, or lovastatin in the evening, did not have a clinically relevant effect on the pharmacokinetics of these statins and their metabolites.

Coadministration of 4.75 mg maralixibat did not affect pharmacokinetics of atorvastatin. However, the effect of maralixibat on the pharmacokinetics of OATP2B1 substrates at higher doses has not been evaluated in a clinical study.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                  Maternal use at the recommended clinical dose of LIVMARLI is not expected to result in measurable fetal exposure because systemic absorption following oral administration is low

 Maralixibat may inhibit the absorption of fat-soluble vitamins.

The estimated background risk of major birth defects for the indicated population is higher than the general population because Alagille syndrome is an autosomal dominant condition.

The estimated background risk of miscarriage for the indicated population is unknown.

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.

2. Lactation Risk Summary-                                                                                      LIVMARLI has low absorption following oral administration, and breastfeeding is not expected to result in exposure of the infant to LIVMARLI at the recommended dose

 There are no data on the presence of LIVMARLI in human milk, the effects on the breastfed infant, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s need for LIVMARLI and any potential adverse effects on the breastfed child from LIVMARLI or from the underlying maternal condition.

3.Pediatric Use-                                                                                                              The safety and effectiveness of LIVMARLI for the treatment of cholestatic pruritus in pediatric patients with Alagille syndrome have been established in one study of patients 1 to 15 years of age (N=31) that included 18 weeks of open-label treatment followed by a 4 week placebo-controlled randomized withdrawal period and a subsequent 26-week open-label treatment period.

Additional safety information was obtained from four studies in patients up to 21 years of age (N=55)

 The safety and effectiveness of LIVMARLI have not been established in patients less than 1 year of age.

4.Geriatric Use-                                                                                                              The safety and effectiveness of LIVMARLI for the treatment of pruritus in ALGS in adult patients, 65 years of age and older, have not been established.

5. Hepatic Impairment-                                                                                                     Clinical studies of LIVMARLI included ALGS patients with impaired hepatic function at baseline. The efficacy and safety in ALGS patients with clinically significant portal hypertension and in patients with decompensated cirrhosis have not been established

 OVERDOSAGE-                                                                                                               Single doses of maralixibat up to 500 mg, approximately 18-fold higher than the recommended dose, have been administered in healthy adults and were tolerated without a meaningful increase in adverse effects when compared to lower doses.

If an overdose occurs, discontinue LIVMARLI, monitor the patient for any signs and symptoms and institute general supportive measures if needed. LIVMARLI contains propylene glycol (364.5 mg/mL) as an excipient. Oral doses of propylene glycol up to 50 mg/kg/day (1 month to <5 years of age) and 500 mg/kg/day (=5 years of age) are generally considered safe.

Overdoses of propylene glycol may manifest with hyperosmolality, CNS, cardiovascular, and/or respiratory effects and may subside with the elimination of propylene glycol.