Treatment-emergent elevated hepatic enzymes were observed during maralixibat clinical trials. Elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reported in 18.6% of maralixibat-treated patients. In a pooled analysis of patients with Alagille syndrome receiving maralixibat treatment (n = 86), ALT increases to more than 3 times baseline occurred in 24% of patients and increases to more than 5 times baseline occurred in 2% of patients. Increased ALT led to treatment discontinuation in 7 (8.1%) patients and dose reduction or treatment interruption in 3 (3.5%) patients. In most patients, the elevations resolved or improved after treatment discontinuation or dose modification. In some patients, the elevations resolved or improved without dosing modification. AST increases to more than 3 times baseline occurred in 14% of maralixibat-treated patients and an increase to more than 5 times baseline occurred in 1 patient. Elevations in transaminases were asymptomatic and not associated with bilirubin elevations or other laboratory abnormalities. Increases in bilirubin above baseline were reported in 4 patients (4.6%); maralixibat was discontinued in 2 of these patients, who had elevated bilirubin at baseline. Monitor hepatic enzymes and INR at baseline and during treatment. Interrupt treatment if new onset abnormalities occur. Once hepatic enzymes return to baseline or stabilize at a new baseline, consider restarting maralixibat at 190 mcg/kg/day and increase as tolerated. Consider treatment discontinuation for persistent or recurrent hepatic enzyme abnormalities or development of symptoms consistent with clinical hepatitis. Permanently discontinue treatment if a patient progresses to portal hypertension or experiences a hepatic decompensation event (e.g., variceal hemorrhage, ascites, hepatic encephalopathy).[67014]

Diarrhea, abdominal pain, and vomiting are the most commonly reported adverse reactions in maralixibat-treated patients. Diarrhea was reported in 55.8% of maralixibat-treated patients during clinicals trials. Abdominal pain, defined as abdominal discomfort, abdominal distension, abdominal pain, lower abdominal pain, and upper abdominal pain, occurred in 53.5% of maralixibat-treated patients during clinicals trials. Vomiting (40.7%), nausea (8.1%), and GI bleeding (10.4%), defined as hematochezia, hematemesis, gastrointestinal hemorrhage, and melena, were also reported. Three patients (3%) experienced vomiting as a serious adverse reaction requiring hospitalization or intravenous fluid. Treatment interruptions or dose reductions occurred in 5 (6%) patients due to diarrhea, abdominal pain, or vomiting. If diarrhea or vomiting occurs, monitor for dehydration and treat promptly. If diarrhea, abdominal pain, and/or vomiting occurs, and no other etiologies are identified, consider reducing the maralixibat dose or interrupting treatment. Consider treatment interruption if patients experience persistent diarrhea or have diarrhea with accompanying signs and symptoms such as bloody stool, vomiting, dehydration requiring treatment, or fever. Once diarrhea, abdominal pain, and/or vomiting have resolved, restart maralixibat at 190 mcg/kg/day and increase the dose as tolerated. Consider discontinuing treatment if symptoms occur upon rechallenge.[67014]

Maralixibat may affect the absorption of fat-soluble vitamins (A, D, E, and K) resulting in vitamin A deficiency, vitamin D deficiency, vitamin E deficiency, and vitamin K deficiency. In clinical trials, fat-soluble vitamin deficiency, defined as A, D, E, or K deficiency, or INR increase, was reported in 25.6% of maralixibat-treated patients. Obtain serum fat-soluble vitamin concentrations and INR (to monitor for vitamin K) at baseline and periodically during treatment. Supplement with fat-soluble vitamins if a deficiency is diagnosed. Discontinue maralixibat if the deficiency persists or worsens despite supplementation.[67014]

Bone fractures, defined as tibia fracture, rib fracture, hand fracture, humerus fracture, pathological fracture, forearm fracture, and clavicle fracture, were reported in 9.3% of maralixibat-treated patients.[67014]

Patients with Alagille syndrome may have hepatic impairment at baseline. Establish a baseline pattern of hepatic function variability prior to maralixibat initiation so that potential signs of liver injury can be identified. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, direct bilirubin, and INR during treatment. Interrupt treatment if new onset hepatic function abnormalities occur. Once hepatic function returns to baseline or stabilizes at a new baseline, consider restarting maralixibat at 190 mcg/kg/day and increase as tolerated. Consider treatment discontinuation for persistent or recurrent hepatic function abnormalities or development of symptoms consistent with clinical hepatitis. Permanently discontinue treatment if a patient progresses to portal hypertension or experiences a hepatic decompensation event (e.g., variceal hemorrhage, ascites, hepatic encephalopathy). Safety and efficacy of maralixibat have not been established in patients with clinically significant portal hypertension or decompensated cirrhosis.[67014]

Maralixibat may affect the absorption of fat-soluble vitamins (A, D, E, and K). Obtain serum fat-soluble vitamin concentrations and INR (to monitor for vitamin K) at baseline and periodically during treatment. Supplement with fat-soluble vitamins if vitamin A deficiency, vitamin D deficiency, vitamin E deficiency, or vitamin K deficiency is diagnosed. Discontinue maralixibat if the deficiency persists or worsens despite supplementation.[67014]

Maralixibat use during pregnancy is not expected to result in measurable fetal exposure due to low systemic absorption after oral administration. Maralixibat may inhibit the absorption of fat-soluble vitamins; increased fat-soluble vitamin supplementation may be needed during pregnancy. Monitor for fat-soluble vitamin deficiency and supplement as needed. In animal reproduction studies, no developmental effects were observed.[67014]

Breast-feeding is not expected to result in exposure of the infant to maralixibat at recommended doses; maralixibat has low absorption after oral administration. However, there are no data on the presence of maralixibat in human milk, the effects on the breast-fed infant, or the effects on milk production. Maralixibat may reduce the absorption of fat-soluble vitamins. Monitor fat-soluble vitamin concentrations and increase intake if deficiency is observed during lactation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.[67014]