Livmarli (maralixibat chloride)

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Maralixibat is administered orally as tablets and a solution. Selection of the tablet or oral solution is based on the patient's weight and ability to swallow tablets.

The tablets can be used for the treatment of both Alagille syndrome and progressive familial intrahepatic cholestasis in patients weighing >=25 kg who can swallow tablets.

The 9.5 mg of maralixibat per mL solution should be used for treatment of Alagille syndrome and the 19 mg of maralixibat per mL solution should be used for treatment of progressive familial intrahepatic cholestasis. The 2 strengths of maralixibat oral solution should not be substituted for one another when treating patients with progressive familial intrahepatic cholestasis.

Clinicians should carefully calculate the maralixibat dose volume. For patients <5 years of age this is especially important as maralixibat oral solution contains propylene glycol (364.5 mg/mL).

Administer tablets and oral solution 30 minutes before a meal. The oral solution should be administered using the provided calibrated measuring device (0.5 mL, 1 mL, or 3 mL oral dispenser).

If a once daily dose is missed, the missed dose should be taken as soon as possible within 12 hours of the time it is usually taken, and then resume the normal dosing schedule. If the dose is missed by more than 12 hours, skip the missed dose and take the next dose at the regularly scheduled time.

If a twice daily dose is missed, the missed dose should be taken as soon as possible within 6 hours of the time it is usually taken, and then resume the normal dosing schedule. If the dose is missed by more than 6 hours, skip the missed dose and take the next dose at the regularly scheduled time.

Store unopened maralixibat oral solution and tablets at 20-25degreesC (excursions permitted between 15-30degreesC). After opening the bottle of maralixibat oral solution, store at <30degreesC. Discard any remaining solution 100 days after the first opening of the bottle.

Maralixibat should be administered at least 4 hours before or after administration of bile acid sequestrants.

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In vitro studies indicate that maralixibat does not induce cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, or 3A4, or inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant concentrations. Maralixibat inhibits CYP3A4 in vitro; however, clinically important pharmacokinetic interactions with CYP3A4 substrates are unlikely.

In vitro studies indicate that maralixibat does not inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, peptide transporter (PEPT) 1, organic cation transporter (OCT) 1, OCT2, OCT3, OCTN1, OCTN2, multidrug resistance protein (MRP) 2, multidrug and toxin extrusion (MATE) 1, or MATE2-K at clinically relevant concentrations. In vitro, maralixibat is an inhibitor of OATP2B1, which can result in decreased absorption of drugs requiring OATP2B1-mediated uptake in the GI tract.

Maralixibat is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, or OATP2B2; therefore, concomitant therapy with drugs affecting these transporters is not expected to affect the pharmacokinetics of maralixibat.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Ileal Bile Acid Transporter Inhibitors/Bile Acid Sequestrant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants may bind to linerixibat, maralixibat and odevixibat in the gut, resulting in decreased absorption of the IBAT inhibitor.(1-3)

CLINICAL EFFECTS: Coadministration of bile acid sequestrants with IBAT inhibitors may cause reduced efficacy of IBAT inhibitors.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers state to administer bile acid sequestrants (cholestyramine, colesevelam, and colestipol) at least 4 hours before or 4 hours after administration of IBAT inhibitors.(1-3)

DISCUSSION: Bile acid sequestrants are known to bind to drugs when given concurrently. Administration with IBAT inhibitors may result in decreased systemic absorption.(1-3)

*Prior or active hepatic decompensation events.

There are no contraindication contraindications for this drug.

• Ascites
• Bleeding esophageal varices
• Hepatic encephalopathy
• Vitamin A deficiency
• Vitamin D deficiency
• Vitamin E deficiency
• Vitamin K deficiency

• Disease of liver

The most common adverse reactions (>=5%) reported with maralixibat in clinical studies for Alagille syndrome were diarrhea, abdominal pain, vomiting, fat-soluble vitamin deficiency, liver test abnormalities, and bone fractures.

The most common adverse reactions (>=5%) reported with maralixibat in clinical studies for progressive familial intrahepatic cholestasis were diarrhea, fat-soluble vitamin deficiency, abdominal pain, liver test abnormalities, hematochezia, and bone fractures.

More Frequent

• Abnormal hepatic function tests
• Fracture
• Gastrointestinal hemorrhage

Less Frequent

• Hyperbilirubinemia

Rare or Very Rare

• Intracranial bleeding

More Frequent

• Acute abdominal pain
• Diarrhea
• Vitamin A deficiency
• Vitamin D deficiency
• Vitamin E deficiency
• Vitamin K deficiency
• Vomiting

Less Frequent

• Nausea

Rare or Very Rare

• Bloody vomit
• Gamma-glutamyl transferase raised

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Safety and efficacy of maralixibat for the treatment of cholestatic pruritus in pediatric patients with Alagille syndrome have been established in the ICONIC study, which included 31 patients 1-15 years of age. Use of maralixibat in patients 3 to <12 months of age is supported by an open label, multicenter study which demonstrated similar safety, tolerability, and pharmacokinetic parameters compared with patients with Alagille syndrome >=12 months of age. Additional safety information was obtained from 4 studies in 55 patients up to 21 years of age. Safety and efficacy of maralixibat have not been established in patients with Alagille syndrome <3 months of age.

Safety and efficacy of maralixibat for the treatment of cholestatic pruritus in pediatric patients >=12 months of age with progressive familial intrahepatic cholestasis have been established. Clinicians should use the 19 mg/mL formulation of maralixibat in patients with this condition in order to minimize exposure to propylene glycol. Safety and efficacy of maralixibat have not been established in patients with progressive familial intrahepatic cholestasis <12 months of age.

Administration of maralixibat during pregnancy is not expected to result in measurable fetal exposure because the drug is minimally absorbed following oral administration. In animal reproduction studies, no developmental effects were observed.

Maralixibat may inhibit the absorption of fat-soluble vitamins. Increased supplementation of fat-soluble vitamins may be necessary during pregnancy.

Maralixibat is minimally absorbed following oral administration; therefore, breast-feeding is not expected to result in exposure of the infant to the drug at the recommended dosage. It is not known whether maralixibat is distributed into human milk. The effects of the drug on breast-fed infants or on the production of milk also are unknown. Consider the developmental and health benefits of breast-feeding along with the mother's need for maralixibat and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Patients with Alagille syndrome or progressive familial intrahepatic cholestasis may have concomitant fat-soluble vitamin deficiency. Because maralixibat may further reduce absorption of fat-soluble vitamins, levels of these vitamins should be monitored and supplementation should be provided if a deficiency is diagnosed during lactation.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Safety and efficacy of maralixibat for the treatment of pruritus in patients with Alagille syndrome or progressive familial intrahepatic cholestasis have not been established in patients >=65 years of age.