Treatment-emergent elevated hepatic enzymes were observed during maralixibat clinical trials. Elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reported in 17% to 19% 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 26% of patients and increases to more than 5 times baseline occurred in 3% of patients. AST increases to more than 3 times baseline occurred in 16% of maralixibat-treated patients and an increase to more than 5 times baseline occurred in 1 patient. Increased ALT led to treatment discontinuation in 7 (8%) patients and dose reduction or treatment interruption in 3 (4%) 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. 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 (5%); maralixibat was discontinued in 2 of these patients, who had elevated bilirubin at baseline. In a clinical trial involving patients with progressive familial intrahepatic cholestasis, 2 patients experienced drug-induced liver injury (DILI) attributable to maralixibat. One patient received 570 mg/kg twice daily and the second patient required dose interruption and reduction. Two additional patients experienced DILI in the open-label extension of the trial. Of these 4 patients, 1 patient required liver transplant and another patient died. Two maralixibat-treated patients developed cholangitis or cholecystitis within 3 weeks of drug discontinuation (84 days and 130 days after maralixibat treatment initiation). Four maralixibat-treated patients developed cholecystitis or cholangitis in the open-label extension portion of Trial 2; the average time to onset was 281 days. Increased gamma-glutamyltransferase was reported during postmarketing experience. Monitor hepatic enzymes, bilirubin, and INR at baseline and frequently during treatment. Decrease dose or 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 the last tolerated dose 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 (i.e., variceal hemorrhage, ascites, hepatic encephalopathy) event.[67014]

Diarrhea, abdominal pain, and vomiting are the most commonly reported adverse reactions in maralixibat-treated patients. Diarrhea was reported in 56% to 57% 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 28% to 54% of maralixibat-treated patients during clinicals trials. Vomiting (41%), nausea (8%), and hematochezia (rectal GI bleeding; 9%) were also reported. Treatment interruptions or dose reductions occurred in 5 (6%) patients with Alagille syndrome due to diarrhea, abdominal pain, or vomiting. In patients with progressive familial intrahepatic cholestasis, diarrhea was the most frequent adverse reaction. Most episodes were mild and transient with a median duration of 5.5 days; however, 40% of patients had diarrhea for at least 7 days. Treatment interruptions or dose reductions occurred in 3 (6%) patients due to diarrhea or vomiting. A decrease in hemoglobin of at least 2 g/dL from baseline occurred in 17% of maralixibat-treated patients. During postmarketing experience, hematemesis, liver transplant, post-endoscopy bleeding, and post-liver biopsy bleeding have been reported. Consider reducing the dosage or interrupt treatment if patients experience persistent diarrhea or abdominal pain or have diarrhea with accompanying signs and symptoms such as bloody stool, vomiting, dehydration requiring treatment, or fever. Consider discontinuing treatment if symptoms persist and no alternate etiology is identified. Monitor for dehydration due to diarrhea and treat promptly. Once diarrhea and/or vomiting have resolved, restart maralixibat at the last tolerated dose 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, vitamin K deficiency, and bleeding. In clinical trials, fat-soluble vitamin deficiency, defined as A, D, E, or K deficiency, or INR increase, was reported in 10% to 28% of maralixibat-treated patients. Intracranial bleeding has been reported during postmarketing experience. 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, femur fracture, foot fracture, humerus fracture, radius fracture, ulna fracture, hand fracture, clavicle fracture, rib fracture, and pathological fracture, were reported in 6% to 9% of maralixibat-treated patients. In a clinical trial involving patients with progressive familial intrahepatic cholestasis, 3 patients developed bone fractures with a median time to bone fracture of 73 days. In the open-label portion of the trial, 2 patients developed bone fractures with an average time to onset of 204 days.[67014]

Maralixibat is contraindicated in patients with prior or active hepatic decompensation events (e.g., variceal hemorrhage, ascites, hepatic encephalopathy). Patients with Alagille syndrome and progressive familial intrahepatic cholestasis 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 at baseline and frequently for the first 6 to 8 months after starting maralixibat therapy and as clinically indicated thereafter during treatment. Monitor for elevations in liver tests, for the development of liver-related adverse reactions, and for physical signs of hepatic decompensation. Decrease dose or 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 the last tolerated dose 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. 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). Treatment-emergent bone fractures and bleeding have been observed more frequently with maralixibat-treated patients compared to placebo-treated patients. Obtain serum fat-soluble vitamin (FSV) concentrations and INR (to monitor for vitamin K) at baseline and periodically during treatment, along with any clinical manifestations of FSV deficiency. Supplement with fat-soluble vitamins if vitamin A deficiency, vitamin D deficiency, vitamin E deficiency, or vitamin K deficiency is diagnosed. Consider maralixibat discontinuation if FSV deficiency persists or worsens despite adequate FSV supplementation. If complications of FSV deficiency occur, such as fracture or bleeding, consider interrupting maralixibat treatment and supplement with FSV. Maralixibat may be restarted once FSV deficiency is corrected and maintained at corrected concentrations.[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]

Maralixibat contains propylene glycol (364.5 mg/mL). Infants and children younger than 5 years are at highest risk for propylene glycol toxicity, and a safe concentration for propylene glycol exposure with repeated administration in this population has not been established. The exposure to propylene glycol will be 14.6 mg/kg/day when maralixibat is administered at the dose (380 mcg/kg/dose once daily) for treatment of cholestatic pruritus in patients with ALGS. The exposure to propylene glycol will be 21.9 mg/kg/day when maralixibat is administered at the dose (570 mcg/kg/dose twice daily) for treatment of cholestatic pruritus in patients with PFIC. Use only the 19 mg/mL formulation of maralixibat in patients with PFIC in order to minimize exposure to propylene glycol. Consider the total daily intake of propylene glycol from all sources for managing the risk of propylene glycol toxicity. Monitor patients for signs of potential propylene glycol toxicity, including hemolysis, hyperosmolarity with anion gap metabolic acidosis, acute kidney injury, and CNS toxicity. Discontinue maralixibat if propylene glycol toxicity is suspected.[67014]