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Reports of hepatic decompensation and failure have been documented in cirrhotic PBC patients (including those with compensated and decompensated cirrhosis) receiving Obeticholic Acid Tablets (OCALIVA®), with some cases being fatal or requiring liver transplantation.
Among such post-marketing reports:
The median time to onset of hepatic decompensation (e.g., new-onset ascites) in patients with compensated cirrhosis was 4 months;
The median time to new decompensation events (e.g., hepatic encephalopathy) in patients with decompensated cirrhosis was 2.5 months.
Some cases of decompensation in patients with decompensated cirrhosis occurred when the patients were treated with doses higher than the recommended dosage for this population; however, cases of hepatic decompensation and failure have continued to be reported even in patients with decompensated cirrhosis who received the recommended dose.
Hepatotoxicity was observed in clinical trials of Obeticholic Acid Tablets (OCALIVA®). In two 3-month placebo-controlled clinical trials involving predominantly patients with early-stage PBC, a dose-response relationship was observed for the occurrence of hepatic adverse reactions (including jaundice, worsening ascites, and acute exacerbation of primary biliary cholangitis) when obeticholic acid was administered at doses ranging from 10 mg once daily to 50 mg once daily (up to 5 times the maximum recommended dose). Some of these reactions occurred as early as 1 month after the initiation of treatment.
A pooled analysis of three placebo-controlled clinical trials in predominantly patients with early-stage PBC showed that the exposure-adjusted incidence rates (per 100 patient-exposure years, PEY) of all serious and other clinically significant hepatic adverse reactions, as well as isolated elevations in liver biochemical parameters, were as follows:
Obeticholic acid 10 mg group (maximum recommended dose): 5.2/100 PEY;
Obeticholic acid 25 mg group (2.5 times the maximum recommended dose): 19.8/100 PEY;
Obeticholic acid 50 mg group (5 times the maximum recommended dose): 54.5/100 PEY;
Placebo group: 2.4/100 PEY.
Patient Management
Patients should be monitored regularly through laboratory tests and clinical assessments for disease progression of PBC (including hepatic adverse reactions) to determine if treatment discontinuation is necessary.
For patients with compensated cirrhosis, concomitant liver diseases (e.g., autoimmune hepatitis, alcoholic liver disease) and/or severe comorbidities, close monitoring is required for the emergence of new evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), or elevations of total bilirubin, direct bilirubin, and prothrombin time beyond the upper limit of normal, to decide whether treatment discontinuation is needed.
Permanent discontinuation of Obeticholic Acid Tablets (OCALIVA®) is required for patients who develop any of the following conditions:
Presence of laboratory or clinical evidence of hepatic decompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy);
New onset of portal hypertension evidence in patients with compensated cirrhosis (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia);
Occurrence of clinically significant hepatic adverse reactions;
Development of complete biliary obstruction.
If a patient develops a severe comorbidity, treatment with Obeticholic Acid Tablets (OCALIVA®) should be suspended and liver function monitored. After resolution of the comorbidity, the potential risks and benefits of reinitiating Obeticholic Acid Tablets (OCALIVA®) treatment must be carefully weighed.
In Trial 1 (a 12-month double-blind randomized controlled clinical trial involving 216 patients), the reported incidence rates of severe pruritus were as follows:
Obeticholic acid 10 mg group: 23%;
Obeticholic acid dose-escalation group: 19%;
Placebo group: 7%.
Severe pruritus is defined as intense or generalized itching that interferes with daily activities, causes severe sleep disturbance, or results in intolerable discomfort, usually requiring medical intervention. In the obeticholic acid dose-escalation group, 33 patients had their dose increased from 5 mg once daily to 10 mg once daily after 6 months of treatment. The incidence of severe pruritus in this subgroup was 0% during months 0–6 of treatment and 15% during months 6–12 of treatment.
The median time to onset of severe pruritus was 11 days in the obeticholic acid 10 mg group, 158 days in the obeticholic acid dose-escalation group, and 75 days in the placebo group.
Clinical evaluation should be considered for patients with new-onset or worsening severe pruritus. Management strategies include addition of bile acid sequestrants or antihistamines, reduction of obeticholic acid dose, and/or temporary interruption of obeticholic acid administration.
Patients with PBC typically present with hyperlipidemia, characterized by a significant elevation in total cholesterol, which is mainly attributable to increased levels of high-density lipoprotein cholesterol (HDL-C).
In the trials:
At 2 weeks of treatment, the mean HDL-C levels in obeticholic acid-treated groups decreased in a dose-dependent manner compared with baseline: a 20% reduction in the 10 mg group, a 9% reduction in the dose-escalation group, versus a 2% reduction in the placebo group;
At 12 months of treatment, the magnitude of reduction in mean HDL-C levels from baseline was: a 19% reduction in the obeticholic acid 10 mg group, a 12% reduction in the dose-escalation group, versus a 2% reduction in the placebo group;
Number of patients with HDL-C levels dropping below 40 mg/dL: 9 cases in the obeticholic acid 10 mg group, 6 cases in the dose-escalation group, and 3 cases in the placebo group.
Serum lipid levels should be monitored during treatment. For patients who have received treatment with the maximum tolerated recommended dose (up to 10 mg once daily) for 1 year without achieving a response to obeticholic acid and who have developed a decrease in HDL-C, the potential risks and benefits of continued treatment must be carefully weighed.
FDA，2022.02
