Precautions of Odevixibat

1. Hepatotoxicity

Odevixibat treatment carries a potential risk of drug-induced liver injury (DILI).

Elevations or worsening of liver function tests during treatment were observed in PFIC and ALGS trials. Among the six patients who experienced DILI, two underwent liver transplantation.

Obtain baseline liver function test results, as some ALGS and PFIC patients may already have abnormal liver function tests at baseline. Monitor patients frequently during the first 6 to 8 months after initiating odevixibat treatment, and thereafter as clinically indicated throughout the treatment period. Monitor for elevated liver function tests, the occurrence of liver-related adverse reactions, and physical signs of hepatic decompensation. If abnormal liver function tests or signs of clinical hepatitis occur without other identifiable causes, consider dose reduction or treatment interruption.

Permanently discontinue odevixibat if a patient experiences any of the following:

Persistent or recurrent abnormal liver function tests; or

Development of signs and symptoms consistent with clinical hepatitis upon re-administration; or

Occurrence of a hepatic decompensation event.

The safety and efficacy of odevixibat in patients with decompensated cirrhosis have not been established. Monitor patients with compensated cirrhosis or portal hypertension more frequently, and discontinue odevixibat if hepatic decompensation occurs.

2. Diarrhea

In Trial 1, the reporting of diarrhea in PFIC patients was as follows: 2 patients (10%) in the placebo group, 9 patients (39%) in the odevixibat 40 mcg/kg/day group, and 4 patients (21%) in the odevixibat 120 mcg/kg/day group. During treatment with odevixibat 120 mcg/kg/day, 2 patients interrupted treatment due to diarrhea, with a total of 3 events. The duration of treatment interruption due to diarrhea ranged from 3 to 7 days. One patient receiving odevixibat 120 mcg/kg/day withdrew from Trial 1 due to persistent diarrhea.

In Trial 3, the reporting of diarrhea in ALGS patients was as follows: 1 patient (6%) in the placebo group and 10 patients (29%) in the odevixibat treatment group. No patients interrupted or permanently discontinued odevixibat due to diarrhea.

If diarrhea occurs, monitor for dehydration and provide prompt treatment. If a patient experiences persistent diarrhea, interrupt odevixibat administration. When diarrhea resolves, reinitiate odevixibat at a dose of 40 mcg/kg/day and increase the dose as appropriate if tolerated. If diarrhea persists and no other etiology is identified, discontinue odevixibat treatment.

3. Fat-soluble Vitamin Deficiency

Odevixibat may adversely affect the absorption of fat-soluble vitamins (FSVs). FSVs include vitamins A, D, E, and K (measured using INR levels). PFIC and ALGS patients may already have FSV deficiency at baseline and often receive FSV supplementation.

In PFIC patients in Trial 1, the reporting of new-onset or worsening of existing FSV deficiency was as follows: 1 patient (5%) in the placebo group and 3 patients (16%) in the odevixibat 120 mcg/kg/day group; no cases of new-onset or worsening existing FSV deficiency were reported in patients receiving odevixibat 40 mcg/kg/day.

In ALGS patients in Trial 3, the reporting of new-onset or worsening of existing FSV deficiency was as follows: 3 patients (17.6%) in the placebo group and 3 patients (8.6%) in the odevixibat treatment group.

Obtain baseline serum FSV levels and monitor them during treatment, along with monitoring for any clinical manifestations of FSV deficiency. If FSV deficiency is diagnosed, initiate FSV supplementation. Despite adequate FSV supplementation, if FSV deficiency persists or worsens, consider permanent discontinuation of odevixibat based on a benefit-risk assessment.

If complications of FSV deficiency occur, consider interrupting odevixibat treatment and re-evaluating to ensure adequate FSV supplementation. Consider reinitiating odevixibat after the patient has achieved clinical stability.

Hemorrhage

If hemorrhage occurs, interrupt odevixibat treatment. Optimize the management of FSV deficiency and consider reinitiating odevixibat after the patient has achieved clinical stability.

FDA，2025.03