Odevixibat treatment is associated with a potential drug-induced liver injury. Treatment-emergent elevated hepatic enzymes were observed during odevixibat clinical trials. Monitor hepatic enzymes and INR at baseline and during treatment. Interrupt treatment if new onset abnormalities occur or symptoms consistent with clinical hepatitis develop. Once hepatic enzymes return to baseline or stabilize at a new baseline, consider restarting odevixibat at 40 mcg/kg/day and increase as tolerated. Consider permanent discontinuation of odevixibat if liver test abnormalities recur. Permanently discontinue odevixibat if a patient experiences persistent or recurrent liver test abnormalities or, upon rechallenge, signs and symptoms consistent with clinical hepatitis, or a hepatic decompensation event (e.g., variceal hemorrhage, ascites, hepatic encephalopathy). Monitor patients with compensated hepatic cirrhosis or portal hypertension more frequently and discontinue odevixibat if hepatic decompensation occurs. During clinical trials, elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 150 units/L or more over baseline were reported in 11% to 37% of patients receiving odevixibat 120 mcg/kg/day (n = 54) compared with 4% to 9% of patients receiving odevixibat 40 mcg/kg/day (n = 23). Hyperbilirubinemia, presenting as total bilirubin elevations (2 mg/dL or more over baseline) and direct bilirubin elevations (1 mg/dL or more over baseline), occurred in 5% to 17% and 11% to 22% of odevixibat-treated patients, respectively. During clinical trials, treatment interruption for elevated hepatic enzymes ranged from 3 to 124 days; no patients permanently discontinued treatment. Splenomegaly (11%), and cholelithiasis (5%) were also reported in patients receiving odevixibat 120 mcg/kg/day in clinical trials (n = 19); no patients receiving odevixibat 40 mcg/kg/day reported these adverse reactions. Adverse reactions reported during postmarketing use include liver transplant and gamma-glutamyltransferase increase.[66816]

Diarrhea was reported in 21% to 39% of odevixibat-treated patients during clinicals trials. Dehydration was reported in 1 patient. If diarrhea occurs, monitor for dehydration and treat promptly. Interrupt treatment for persistent diarrhea. Once diarrhea has resolved, restart odevixibat at 40 mcg/kg/day and increase the dose as tolerated. Discontinue odevixibat if diarrhea persists and no alternative etiology is identified. During clinical trials, treatment interruption days due to diarrhea ranged from 3 to 7 days. One patient withdrew due to persistent diarrhea. Other gastrointestinal-related adverse reactions reported in odevixibat-treated patients in clinical trials include abdominal pain (13% to 16%), vomiting (16% to 17%), and weight loss (6%). Adverse reactions reported during postmarketing use include gastrointestinal hemorrhage and gingival hemorrhage.[66816]

Odevixibat may adversely 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. Obtain serum fat-soluble vitamin (FSV) concentrations and INR (to monitor for vitamin K) at baseline and periodically during treatment. Supplement with fat-soluble vitamins if a deficiency is diagnosed. If FSV deficiency persists or worsens despite adequate FSV supplementation, consider permanent discontinuation of odevixibat depending on the benefit and risk balance. If complications of odevixibat occur, consider interrupting treatment and reassess to ensure adequate supplementation with FSV. Consider restarting odevixibat once the patient is clinically stable. Interrupt treatment if bleeding occurs. Optimize treatment of FSV deficiency and consider restarting odevixibat once the patient is clinically stable. In clinical trials, new onset or worsening fat-soluble vitamin deficiency was reported in 8.6% to 16% of patients receiving odevixibat 120 mcg/kg/day (n = 54); these deficiencies were not observed in those receiving odevixibat 40 mcg/kg/day (n = 23).[66816]

Fracture (bone fractures) was reported in 4% of odevixibat-treated patients in clinical trials (n = 23).[66816]

Hematoma was reported in 9% of odevixibat-treated patients in clinical trials (n = 35). Adverse reactions observed in clinical trials include increased INR (16%), epistaxis (9%), coagulopathy (3%), iron deficiency anemia (3%) and prolonged bleeding time (or prolonged prothrombin time) (2%). Adverse reactions reported during postmarketing use include hemoglobin decrease and subdural hemorrhage.[66816]

Ileal bile acid transporter (IBAT) inhibitors, such as odevixibat, are contraindicated in patients with prior or active hepatic decompensation events (e.g., variceal hemorrhage, ascites, hepatic encephalopathy). Odevixibat is associated with a potential for drug-induced liver injury (DILI). Patients with progressive familial intrahepatic cholestasis (PFIC) or Alagille Syndrome (ALGS) may have hepatic impairment at baseline. Establish a baseline pattern of hepatic function variability prior to odevixibat initiation so that potential signs of liver injury can be identified. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, direct bilirubin, and INR frequently for the first 6 to 8 months after starting therapy and as clinically indicated thereafter during treatment. Monitor for elevation in liver tests, for the development of liver-related adverse reactions, and for physical signs of hepatic decompensation. Consider dose reduction or treatment interruption if liver test abnormalities or signs of clinical hepatitis occur in the absence of other causes. Once hepatic function returns to baseline or stabilizes at a new baseline, consider restarting odevixibat at the recommended indication-specific dose and increase as tolerated. Consider permanent discontinuation of odevixibat if liver test abnormalities recur. Permanently discontinue odevixibat if a patient experiences persistent or recurrent liver test abnormalities or, upon rechallenge, signs and symptoms consistent with clinical hepatitis, or a hepatic decompensation event (e.g., variceal hemorrhage, ascites, hepatic encephalopathy). Safety and efficacy of odevixibat have not been established in patients with decompensated cirrhosis. Monitor patients with compensated hepatic cirrhosis or portal hypertension more frequently and discontinue odevixibat if hepatic decompensation occurs.[66816]

Odevixibat may adversely affect the absorption of fat-soluble vitamins (FSV). FSV includes vitamin A, D, E, and K. Patients with progressive familial intrahepatic cholestasis (PFIC) and alagille syndrome (ALGS) can have FSV deficiency at baseline and are frequently supplemented with FSV. Obtain FSV concentrations and INR (to monitor for vitamin K) at baseline and monitor during treatment, along with any clinical manifestations of FSV deficiency. Supplement with FSV if vitamin A deficiency, vitamin D deficiency, vitamin E deficiency, or vitamin K deficiency is diagnosed. If FSV deficiency persists or worsens despite adequate FSV supplementation, consider permanent discontinuation of odevixibat depending on the benefit and risk balance. If complications of odevixibat occur, consider interrupting treatment and reassess to ensure adequate supplementation with FSV. Consider restarting odevixibat once the patient is clinically stable. Interrupt treatment if bleeding occurs. Optimize treatment of FSV deficiency and consider restarting odevixibat once the patient is clinically stable.[66816]

There are no data on odevixibat use in human pregnancy to establish a drug-associated risk of major birth defects, miscarriage, or adverse developmental outcomes. Animal reproduction studies suggest odevixibat may cause cardiac malformations in the exposed fetus. In pregnant rabbits receiving odevixibat during organogenesis, an increase in cardiovascular malformations (e.g., 5-chambered heart, small ventricle, large atrium, ventricular septal defect, misshapen aortic valve, dilated aortic arch, right sided and retroesophageal aortic arch, fusion of aortic arch and pulmonary trunk, ductus arteriosus atresia, absence of subclavian artery) occurred at all doses. At the lowest dose, maternal systemic exposure was 2.1 times the maximum recommended human dose (MRHD). There is a pregnancy registry study that monitors pregnancy outcomes in women exposed to odevixibat during pregnancy. Pregnant women exposed to odevixibat, or their health care providers, should report odevixibat exposure by calling 1-855-463-5127.[66816]

Breast-feeding is not expected to result in exposure of the infant to odevixibat at recommended doses; odevixibat has low absorption after oral administration. However, there are no data on the presence of odevixibat in human milk, the effects on the breast-fed infant, or the effects on milk production. Odevixibat 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.[66816]