Obeticholic Acid tablets are indicated for the treatment of adult patients

• with primary biliary cholangitis (PBC),
• including those without cirrhosis or those with compensated cirrhosis who show no evidence of portal hypertension.

It may be used in combination with ursodeoxycholic acid (UDCA) in patients with an inadequate response to UDCA, or as monotherapy in patients who are unable to tolerate UDCA.

Mechanism of Action: Obeticholic acid is an agonist of the Farnesoid X Receptor (FXR), a nuclear receptor found in the liver and intestine. FXR plays a central role in regulating bile acid, inflammatory, fibrotic, and metabolic pathways. Activation of FXR reduces intracellular bile acid levels in hepatocytes by inhibiting bile acid synthesis from cholesterol and increasing bile acid transport out of liver cells. These effects reduce the total circulating bile acid pool and enhance bile flow, thereby decreasing liver exposure to bile acids.

Pharmacodynamics: In clinical trials, Obeticholic acid 10 mg once daily increased FGF-19 levels by 173% from baseline to 12 months. It also reduced cholic acid and chenodeoxycholic acid levels by 2.7 micromolar and 1.4 micromolar respectively over the same period. The clinical significance of these changes is not fully established.

Cardiac Electrophysiology: At doses up to 10 times the maximum recommended dose, Obeticholic acid does not cause clinically significant QT interval prolongation.

Important Dosage and Administration Instructions: Prior to the initiation of Obeticholic acid, healthcare providers should determine whether the patient has decompensated cirrhosis (e.g., Child-Pugh Class B or C) has had a prior decompensation event or has compensated cirrhosis with evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) because Obeticholic acid is contraindicated in these patients.

Recommended Dosage Regimen: The recommended dosage of Obeticholic acid for PBC patients without cirrhosis or with compensated cirrhosis who do not have evidence of portal hypertension, who have not achieved an adequate biochemical response to an appropriate dosage of UDCA for at least 1 year or are intolerant to UDCA follows below:

• Start with a dosage of 5 mg once daily for the first 3 months.
• After the first 3 months, for patients who have not achieved an adequate reduction in ALP and/or total bilirubin and who are tolerating Obeticholic acid increase to a maximum dosage of 10 mg once daily.

Monitoring to Assess Safety, Need for Obeticholic acid Discontinuation: Routinely monitor patients during Obeticholic acid treatment for biochemical response, tolerability and progression of PBC. Closely monitor patients with compensated cirrhosis, concomitant hepatic disease (e.g., autoimmune hepatitis, alcoholic liver disease) and/or severe intercurrent illness for new evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) or increases above the upper limit of normal in total bilirubin, direct bilirubin or prothrombin time. Permanently discontinue Obeticholic acid in patients who develop laboratory or clinical evidence of hepatic decompensation, have compensated cirrhosis and develop evidence of portal hypertension, experience clinically significant hepatic adverse reactions, or develop complete biliary obstruction.

Management of Patients with Intolerable Pruritus on Obeticholic acid: For patients with intolerable pruritus on Obeticholic acid consider one or more of the following management strategies. Add an antihistamine or bile acidbinding resin.

Reduce the dosage of Obeticholic acid to:

• 5 mg every other day, for patients intolerant to 5 mg once daily.
• 5 mg once daily, for patients intolerant to 10 mg once daily.
• Temporarily interrupt Obeticholic acid dosing for up to 2 weeks. Restart at a reduced dosage. For patients whose dosage is reduced or interrupted, titrate the dosage based on biochemical response and tolerability. Consider discontinuing Obeticholic acid treatment in patients who continue to experience persistent, intolerable pruritus despite management strategies.

Bile Acid Binding Resins: Medicines such as cholestyramine, colestipol, and colesevelam bind bile acids in the intestine and reduce their absorption. This may reduce the absorption and effectiveness of Obeticholic acid. If coadministration is necessary, Obeticholic acid should be taken at least 4 hours before or 4 hours after the bile acid binding resin, or with the longest possible time gap between doses.

Warfarin: Concomitant use of Obeticholic acid with warfarin may decrease INR levels. INR should be closely monitored and the warfarin dose adjusted as needed to maintain the target therapeutic range.

CYP1A2 Substrates (narrow therapeutic index): Obeticholic acid may increase plasma concentrations of drugs metabolized by CYP1A2. Careful monitoring is recommended when using drugs such as theophylline and tizanidine.

BSEP Inhibitors: Concomitant use with bile salt efflux pump (BSEP) inhibitors such as cyclosporine should be avoided, as they may increase bile salt accumulation in the liver. If unavoidable, liver function tests including transaminases and bilirubin should be monitored.

Obeticholic acid is contraindicated in:

• Decompensated cirrhosis (Child-Pugh Class B or C) or history of decompensation
• Compensated cirrhosis with portal hypertension (ascites, varices, persistent thrombocytopenia)
• Complete biliary obstruction

Common side effects include pruritus (itching), fatigue, and abdominal pain or discomfort. Other possible effects include rash, joint pain (arthralgia), throat pain, dizziness, constipation, thyroid abnormalities, and eczema.

Pregnancy: Limited human data on the use of obeticholic acid during pregnancy are insufficient to determine drug-related risks. In animal studies, no fetal harm or developmental abnormalities were observed in rats or rabbits when exposed during organ development at doses approximately 13 times (rats) and 6 times (rabbits) higher than the human maximum recommended dose (10 mg).

Lactation: There is no information available on the presence of obeticholic acid in human breast milk or its effects on the breastfed infant or milk production. The decision to use Obeticholic acid during breastfeeding should consider the benefits of breastfeeding, the mother’s clinical need, and any potential risk to the infant.

Hepatic Decompensation and Failure in PBC Patients with Cirrhosis: Hepatic decompensation and liver failure, including fatal cases or need for liver transplant, have been reported in patients with cirrhosis (both compensated and decompensated) treated with Obeticholic acid. In postmarketing reports, median time to decompensation (e.g., ascites) was about 4 months in compensated cirrhosis, and 2.5 months to new events (e.g., encephalopathy) in decompensated cirrhosis.Dose-dependent liver toxicity has been observed in clinical trials, including jaundice, worsening ascites, and disease flare. These events may occur as early as 1 month after starting treatment. Higher doses showed significantly increased liver-related adverse events compared to placebo.

Severe Pruritus: Severe itching occurred in 23% of patients receiving 10 mg, 19% in the titration group, and 7% in the placebo group. It may interfere with daily activities or sleep. In patients increasing dose from 5 mg to 10 mg, severe pruritus occurred in 0% during the first 6 months and 15% during months 6–12. Onset ranged from 11 to 158 days. Management may include antihistamines, bile acid binding resins, dose reduction, or temporary interruption.

Reduction in HDL-C: Patients with PBC often have elevated cholesterol, mainly HDL-C. Obeticholic acid causes dose-dependent reductions in HDL-C. At 2 weeks, reductions were 20% (10 mg), 9% (titration), and 2% (placebo). At 12 months, reductions were 19%, 12%, and 2% respectively. Some patients experienced HDL-C levels below 40 mg/dL. Lipid levels should be monitored, and continuation of therapy should be reassessed if response is inadequate after 1 year at the maximum tolerated dose.

Pediatric Use: The safety and effectiveness of Obeticholic acid in children and adolescents have not been established.

Geriatric Use: In clinical trials, 201 patients received the recommended dose (5 mg or 10 mg once daily), of whom 41 (20%) were aged 65 years or older and 9 (4%) were 75 years or older. No major differences in safety or effectiveness were observed compared to younger adults, although increased sensitivity in some elderly patients cannot be excluded.

Hepatic Impairment: Hepatic decompensation and liver failure, sometimes fatal or requiring liver transplant, have been reported in PBC patients with cirrhosis treated with Obeticholic acid. It is contraindicated in patients with decompensated cirrhosis (Child-Pugh B or C), prior decompensation events, or compensated cirrhosis with portal hypertension (ascites, varices, or persistent thrombocytopenia). A dose-dependent increase in liver-related adverse reactions has been observed in clinical trials.

In clinical trials, patients receiving higher-than-recommended doses (25 mg or 50 mg once daily) experienced a dose-dependent increase in liver-related adverse effects, including abnormal liver tests, ascites, jaundice, portal hypertension, and disease flare. Serious hepatic events have also been reported postmarketing, including in some patients at recommended doses. In case of overdose, patients should be closely monitored and given supportive treatment.

Farnesoid X Receptor (FXR) Agonists

Store below 30°C in a dry place. Protect from light and keep out of reach of children.