Version October 2024
Alagille syndrome; cholestatic pruritus:
Infants ≥3 months, Children, and Adolescents:
Weight-directed dosing: Oral solution (9.5 mg/mL): Oral: Initial: 0.19 mg/kg/dose once daily for 7 days (maximum initial daily dose: 14.25 mg/day) then increase to target dose of 0.38 mg/kg/dose once daily. Maximum maintenance daily dose: 28.5 mg/day.
Fixed dose (weight-band): Oral solution (9.5 mg/mL): Oral:
|
Body weight |
Days 1 to 7 (first week) 0.19 mg/kg once daily |
Starting Day 8 0.38 mg/kg once daily |
|---|---|---|
|
a Dosing adapted from dose volumes presented in manufacturer labeling. | ||
|
5 to <7 kg |
0.95 mg |
1.9 mg |
|
7 to <10 kg |
1.43 mg |
2.85 mg |
|
10 to <13 kg |
1.9 mg |
4.28 mg |
|
13 to <16 kg |
2.85 mg |
5.7 mg |
|
16 to <20 kg |
3.33 mg |
6.65 mg |
|
20 to <25 kg |
4.28 mg |
8.55 mg |
|
25 to <30 kg |
4.75 mg |
9.5 mg |
|
30 to <35 kg |
5.7 mg |
11.88 mg |
|
35 to <40 kg |
6.65 mg |
14.25 mg |
|
40 to <50 kg |
8.55 mg |
16.63 mg |
|
50 to <60 kg |
9.5 mg |
21.38 mg |
|
60 to <70 kg |
11.88 mg |
23.75 mg |
|
≥70 kg |
14.25 mg |
28.5 mg |
Progressive familial intrahepatic cholestasis; pruritus:
Children ≥5 years and Adolescents:
Weight-directed dosing: Oral solution (9.5 mg/mL): Oral: Initial: 0.285 mg/kg/dose once daily in the morning; as tolerated titrate as follows: 0.285 mg/kg/dose twice daily, 0.428 mg/kg/dose twice daily, and then 0.57 mg/kg/dose twice daily; maximum daily dose: 38 mg/day.
Fixed dose (weight-band): Oral solution (9.5 mg/mL): Oral:
|
Body weight |
First and second dose levels 0.285 mg/kg/dose once daily (first dose level) and twice daily (second dose level) |
Third dose level 0.428 mg/kg/dose twice daily |
Maximum dose level 0.57 mg/kg/dose twice daily |
|---|---|---|---|
|
a Dosing adapted from dose volumes presented in manufacturer labeling. | |||
|
10 to <13 kg |
3.33 mg |
4.75 mg |
5.7 mg |
|
13 to <16 kg |
3.8 mg |
5.7 mg |
7.6 mg |
|
16 to <20 kg |
4.75 mg |
7.6 mg |
9.5 mg |
|
20 to <25 kg |
5.7 mg |
9.5 mg |
11.88 mg |
|
25 to <30 kg |
7.6 mg |
11.88 mg |
14.25 mg |
|
30 to <35 kg |
8.55 mg |
14.25 mg |
19 mg |
|
35 to <40 kg |
11.88 mg |
14.25 mg |
19 mg |
|
40 to <50 kg |
11.88 mg |
19 mg |
19 mg |
|
50 to <60 kg |
14.25 mg |
19 mg |
19 mg |
|
≥60 kg |
19 mg |
19 mg |
19 mg |
Dosage adjustment for toxicity:
GI toxicity:
Persistent abdominal pain or diarrhea or diarrhea accompanied by bloody stools, vomiting, dehydration requiring treatment, or fever: Initially consider interrupting therapy or reducing the dose. Monitor for dehydration and treat promptly. Discontinue therapy if symptoms (diarrhea, abdominal pain) persist with no alternative etiology. Once diarrhea or abdominal pain resolves, restart at the last dose tolerated and increase as tolerated. If diarrhea or abdominal pain recur during a rechallenge, consider discontinuing maralixibat therapy.
Other toxicity:
Fat-soluble vitamin deficiency: If occurs, supplement with deficient vitamin as appropriate. If bone fracture, consider interruption in therapy; if bleeding occurs, interrupt maralixibat therapy; supplement until deficiency corrected. If deficiency worsens or persists despite adequate supplementation, consider discontinuation of maralixibat therapy.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosing adjustments provided in the manufacturer's labeling (has not been studied).
Infants ≥3 months, Children, and Adolescents: Oral:
Baseline liver impairment: There are no dosing adjustments provided in the manufacturer's labeling; patients with Alagille syndrome and progressive familial intrahepatic cholestasis may have elevated liver enzymes as part of disease state; clinical trials included patients with baseline LFT elevations. Establish the patient's baseline pattern of liver test variability. Maralixibat has not been studied in patients with decompensated cirrhosis or significant portal hypertension and use is contraindicated in patients with prior or active hepatic decompensation events.
Liver impairment (new-onset liver test abnormalities) during therapy: Initially consider interrupting therapy or reducing the dose if signs of clinical hepatitis or new-onset liver test abnormalities in the absence of other etiologies. Once liver test abnormalities return to baseline or stabilize, consider restarting maralixibat at the last tolerated dose and titrate as tolerated. Permanently discontinue maralixibat if any of the following occur: persistent or recurrent liver test abnormalities, signs of clinical hepatitis with maralixibat rechallenge, or a hepatic decompensation event (eg, variceal hemorrhage, ascites, hepatic encephalopathy).
(For additional information see "Maralixibat: Drug information")
Cholestatic pruritus due to Alagille syndrome: Oral solution (9.5 mg/mL): Oral: Initial: 0.19 mg/kg/dose (maximum: 14.25 mg/dose) once daily for 7 days, then increase to target dose of 0.38 mg/kg/dose (maximum: 28.5 mg/dose) once daily. Maximum daily dose: 28.5 mg/day.
Cholestatic pruritus due to progressive familial intrahepatic cholestasis: Oral solution (9.5 mg/mL): Oral: Initial: 0.285 mg/kg/dose once daily, then increase to 0.285 mg/kg/dose twice daily, 0.428 mg/kg/dose twice daily, and then to 0.57 mg/kg/dose twice daily as tolerated. Maximum single dose: 19 mg/dose; maximum daily dose: 38 mg/day.
Missed dose:
Once-daily dosing: If <12 hours from usual time, administer missed dose as soon as possible and return to original dosing schedule; if >12 hours have elapsed, omit dose and resume dosing at original dosing schedule.
Twice-daily dosing: If <6 hours from usual time, administer missed dose as soon as possible and return to original dosing schedule; if >6 hours have elapsed, omit dose and resume dosing at original dosing schedule.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Baseline hepatic impairment: There are no dosage adjustments provided in the manufacturer's labeling; patients with Alagille syndrome and progressive familial intrahepatic cholestasis may have elevated liver enzymes as part of disease state; clinical trials included patients with baseline LFT elevations. Contraindicated in patients with prior or active hepatic decompensation. Has not been studied in patients with significant portal hypertension or decompensated cirrhosis.
Hepatic impairment during therapy:
New-onset liver test abnormalities (eg, ALT, AST, bilirubin [direct/total], INR): Reduce the dose or hold maralixibat therapy. If liver test abnormalities return to baseline or stabilize at a new baseline value (and no signs/symptoms of hepatitis or decompensation are present), may consider restarting at the last tolerated dose and increase the dose as tolerated. If liver test abnormalities recur, consider permanent discontinuation.
Hepatic decompensation (eg, variceal hemorrhage, ascites, hepatic encephalopathy, symptoms consistent with clinical hepatitis): Discontinue permanently.
Portal hypertension: Discontinue permanently.
Signs and symptoms consistent with clinical hepatitis (upon rechallenge): Discontinue permanently.
Diarrhea, abdominal pain, nausea, and vomiting have been reported and may lead to dehydration. GI effects may require dosage reduction, interruption of therapy, or permanent discontinuation.
Mechanism: Related to sequelae of bile acid malabsorption (Ref).
Onset: Delayed; in one clinical trial, most events occurred within the first 4 weeks of treatment (Ref).
Elevations of liver functions tests (LFTs) and decompensated liver disease have been reported with maralixibat, including a life-threatening case and a case requiring liver transplant. Reported LFT abnormalities include increased gamma-glutamyl transferase, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, and increased serum bilirubin; dosage reduction, interruption of therapy, or permanent discontinuation may be required.
Onset: Delayed; in a clinical trial, serum alanine aminotransferase increased above baseline after >1 year of treatment (Ref).
Risk factors:
• History of persistent or recurrent LFT abnormalities
Fat-soluble vitamin (FSV) deficiency, including vitamin A deficiency, vitamin D deficiency, vitamin E deficiency, and vitamin K deficiency, has been reported. Complications of FSV deficiency, including bone fracture, hemorrhage, and increased INR, have also been reported and may require interruption of therapy.
Mechanism: Dose-related; related to the pharmacologic action (ie, decreased absorption of FSVs).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in children, adolescents, and young adults.
>10%:
Endocrine & metabolic: Vitamin deficiency (including vitamin A deficiency, vitamin D deficiency, vitamin E deficiency, vitamin K deficiency)
Gastrointestinal: Abdominal pain, diarrhea, vomiting
Hematologic & oncologic: Decreased hemoglobin, increased INR
Hepatic:Increased serum alanine aminotransferase, increased serum aspartate aminotransferase
1% to 10%:
Gastrointestinal: Cholangitis, cholecystitis, hematochezia, nausea, rectal hemorrhage
Hepatic: Increased serum bilirubin
Neuromuscular & skeletal: Bone fracture
Frequency not defined: Hepatic: Decompensated liver disease
Postmarketing:
Gastrointestinal: Hematemesis
Hematologic & oncologic: Hemorrhage (post-endoscopy, post-liver biopsy)
Hepatic: Increased gamma-glutamyl transferase
Nervous system: Intracranial hemorrhage
Patients with prior or active hepatic decompensation events (eg, ascites, hepatic encephalopathy, variceal hemorrhage).
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to maralixibat or any component of the formulation.
Dosage form specific issues:
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.
Some dosage forms may contain propylene glycol; in neonates, large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral, as chloride:
Livmarli: 9.5 mg/mL (30 mL) [contains edetate (edta) disodium, propylene glycol]
No
Solution (Livmarli Oral)
9.5 mg/mL (per mL): $2,136.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral, as chloride:
Livmarli: 9.5 mg/mL (30 mL) [contains edetate (edta) disodium, propylene glycol]
Oral: Administer 30 minutes before a meal in the morning; patient should be seated upright or standing and should remain upright for a few minutes after administration. Administer using calibrated oral dosing syringe; do not use a household teaspoon or other dosing device; for dose volumes ≤0.5 mL, use a 0.5 mL syringe; for dose volumes 0.6 to ≤1 mL, use a 1 mL syringe; for dose volumes >1 mL, use 3 mL dosing syringe.
Missed dose:
Once-daily dosing: If <12 hours from usual time, administer missed dose as soon as possible and return to original dosing schedule; if >12 hours have elapsed, omit dose and resume dosing at original dosing schedule.
Twice-daily dosing: If <6 hours from usual time, administer missed dose as soon as possible and return to original dosing schedule; if >6 hours have elapsed, omit dose and resume dosing at original dosing schedule.
Oral: Administer 30 minutes before a meal; patient should be seated upright or standing; patient should remain upright for a few minutes after administration. Administer using calibrated oral dosing syringe; do not use a household teaspoon or other dosing device; for dose volumes ≤0.5 mL, use a 0.5 mL syringe; for dose volumes 0.6 to ≤1 mL, use a 1 mL syringe; for dose volumes >1 mL, use 3 mL dosing syringe.
Store intact bottle at 20°C and 25°C (68°F and 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Store open bottle at <30°C (86°F); discard any unused portion 100 days after opening.
Treatment of cholestatic pruritus in patients with Alagille syndrome (FDA approved in ages ≥3 months and adults); treatment of cholestatic pruritus in patients with progressive familial intrahepatic cholestasis (PFIC) (FDA approved in ages ≥5 years and adults). Note: In patients with PFIC, use is not recommended in PFIC type 2 subgroup with specific ABCB11 variants in nonfunctional or complete absence of bile salt export pump protein.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
Bile Acid Sequestrants: May decrease the serum concentration of Maralixibat. Management: Bile acid sequestrants should be administered either at least 4 hours before, or 4 hours after, maralixibat. Risk D: Consider therapy modification
Adverse events were not observed in animal reproduction studies.
Due to low systemic absorption following oral administration, potential fetal exposure is expected to be limited. Maternal use of maralixibat may decrease the absorption of fat-soluble vitamins; supplementation may be needed.
Monitor LFTs (ALT, AST, bilirubin [total/direct], INR) (baseline, periodically), fat-soluble vitamin serum concentrations; GI symptoms (diarrhea, vomiting).
Reversibly inhibits the ileal bile acid transporter, decreasing the reabsorption of bile acids from the terminal ileum.
Absorption: Minimal systemic absorption.
Protein binding: 91%.
Half-life elimination: 1.6 hours.
Excretion: Feces (primary route; 94% as unchanged drug).
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