LIVMARLI™ (maralixibat) oral solution
LIVMARLI (maralixibat) oral solution
LIVMARLI (maralixibat) oral solution is an ileal bile acid transporter (IBAT) inhibitor. Maralixibat is present as a chloride salt with the chemical name 1-[[4-[[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicyclo[2.2.2]octane chloride. The molecular formula of maralixibat chloride is C40H56ClN3O4S with a molecular weight of 710.42.
LIVMARLI is supplied in a multiple-dose bottle containing 9.5 mg of maralixibat per mL (equivalent to 10 mg of maralixibat chloride per mL). The oral solution contains the following inactive ingredients: edetate disodium, grape flavor, propylene glycol, purified water, and sucralose. The pH of the oral solution is 3.8 – 4.8.
INDICATIONS AND USAGE
LIVMARLI is indicated for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) 1 year of age and older.
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 patients 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.
DOSAGE AND ADMINISTRATION
The recommended dosage is 380 mcg/kg once daily, taken 30 minutes before the first meal of the day. Start dosing at 190 mcg/kg administered orally once daily; after one week, increase to 380 mcg/kg once daily, as tolerated. The maximum daily dose volume for patients above 70kg is 3 mL or 28.5 mg per day.
If a dose is missed, it should be taken as soon as possible within 12 hours of the time it is usually taken, and the original dosing schedule should be resumed. If a dose is missed by more than 12 hours, the dose can be omitted and the original dosing schedule resumed.
For patients taking bile acid binding resins, take LIVMARLI at least 4 hours before or 4 hours after taking a bile acid binding resin.
A calibrated measuring device (0.5 mL, 1 mL or 3 mL oral dosing dispenser) will be provided by the pharmacy to measure and deliver the prescribed dose accurately.
Store LIVMARLI between 20°C and 25°C (68°F and 77°F). Discard any remaining LIVMARLI 45 days after first opening of bottle.
WARNINGS AND PRECAUTIONS
Liver Test Abnormalities: Patients enrolled in Trial 1 had abnormal liver tests at baseline. Obtain baseline liver tests and monitor during treatment. Dose reduction or treatment interruption may be considered if abnormalities occur in the absence of other causes. For persistent or recurrent liver test abnormalities, consider treatment discontinuation.
LIVMARLI was not evaluated in ALGS patients with cirrhosis. Monitor patients during treatment with LIVMARLI for elevations in liver tests and for the development of liver-related adverse reactions. Weigh the potential risks against the benefits of continuing treatment with LIVMARLI in patients who have experienced persistent or recurrent liver tests abnormalities. Discontinue LIVMARLI permanently if a patient progresses to portal hypertension or experiences a hepatic decompensation event.
Gastrointestinal Adverse Reactions
Diarrhea, abdominal pain, and vomiting were reported as the most common adverse reactions in patients treated with LIVMARLI. Three patients (3%) experienced vomiting as a serious adverse event requiring hospitalization or intravenous fluid administration.
If diarrhea, abdominal pain, and/or vomiting occur and no other etiologies are found, consider reducing the dose of LIVMARLI or interrupting LIVMARLI dosing. For diarrhea or vomiting, monitor for dehydration and treat promptly.
Consider interrupting LIVMARLI dosing if a patient experiences persistent diarrhea or has diarrhea with accompanying signs and symptoms such as bloody stool, vomiting, dehydration requiring treatment, or fever.
When diarrhea, abdominal pain, and/or vomiting resolve, restart LIVMARLI at 190 mcg/kg/day and increase the dose as tolerated. If they recur upon re-challenge with LIVMARLI, then consider stopping LIVMARLI treatment.
Fat-Soluble Vitamin (FSV) Deficiency
Fat-soluble vitamins (FSV) include vitamin A, D, E, and K (measured using INR levels). ALGS patients can have FSV deficiency at baseline. LIVMARLI may affect absorption of fat-soluble vitamins. In Trial 1, treatment emergent FSV deficiency was reported in 3 (10%) patients during 48 weeks of treatment.
Obtain serum FSV levels at baseline and monitor during treatment, along with any clinical manifestations. If FSV deficiency is diagnosed, supplement with FSV. Consider discontinuing LIVMARLI if FSV deficiency persists or worsens despite adequate FSV supplementation.
USE IN SPECIFIC POPULATIONS
Pregnancy: 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. In animal reproduction studies, no developmental effects were observed.
Lactation: 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. Patients with ALGS can have FSV deficiency as part of their disease. Maralixibat may reduce absorption of fat-soluble vitamins. Monitor FSV levels and supplement FSV intake, if FSV deficiency is observed during lactation.
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.
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.
Geriatric Use: The safety and effectiveness of LIVMARLI for the treatment of pruritus in ALGS in adult patients, 65years of age and older, have not been established.
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.
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.
- livmarli uses
- alagille syndrome treatment
- livmarli side effects
- livmarli mechanism of action
- livmarli adverse reactions
- livmarli dosage
Post a Comment