Liverty 5mg Tablet

✔️ Words of Advice:

• Closely monitor liver function, lipid profiles, and clinical symptoms in all patients.
• Avoid exceeding the recommended dosage.
• Manage adverse effects like pruritus with dose adjustments or temporary treatment interruption.
• Carefully evaluate treatment continuation in patients with HDL-C reduction or non-response after 1 year.

✔️ Mechanism of Action:

• Obeticholic acid activates the Farnesoid X Receptor (FXR), a nuclear receptor in the liver and intestine that regulates bile acid, inflammatory, fibrotic, and metabolic pathways.
• FXR activation reduces bile acid production and promotes bile acid excretion, lowering hepatic bile acid levels and minimizing liver damage.

✔️ Pharmacodynamics:

• Increases FGF-19 (a marker for bile acid regulation).
• Reduces bile acid concentrations (cholic and chenodeoxycholic acid).

Cardiac Safety: Does not prolong the QT interval at 10x the maximum recommended dose.

✔️ Side Effects

• Common: Pruritus, fatigue, stomach discomfort, rash, joint pain, throat pain, constipation, abnormal thyroid function, dizziness, and eczema.
• Severe: Hepatic decompensation or portal hypertension in at-risk patients.

✔️ Dosage & Administration

• Baseline Assessments: Before starting therapy, assess for decompensated cirrhosis, history of decompensation, or portal hypertension, as the drug is contraindicated in these conditions.

✔️ Dosage for PBC:

1. Starting dose: 5 mg once daily for the first 3 months.
2. Titration: If a biochemical response (e.g., ALP, bilirubin) is inadequate and the patient tolerates the drug, increase to 10 mg once daily.

✔️ Monitoring & Dose Adjustments:

• Routinely monitor:
  • Liver function (ALP, bilirubin, prothrombin time).
  • Signs of portal hypertension (ascites, varices, thrombocytopenia).
• Discontinue if:
  • Evidence of hepatic decompensation or portal hypertension arises.
  • Complete biliary obstruction develops.
  • Severe hepatic adverse effects occur.

✔️ Managing Pruritus:

• Pruritus is a common side effect. Management options include:
  • Adding antihistamines or bile acid-binding resins.
  • Reducing the dose to:
    • 5 mg every other day for those intolerant to 5 mg once daily.
    • 5 mg once daily for those intolerant to 10 mg once daily.
  • Temporarily discontinuing therapy for up to 2 weeks, followed by gradual reintroduction.
  • Discontinuing treatment if intolerable pruritus persists.

✔️ Drug Interactions

Bile Acid Binding Resins:

• Resins (e.g., cholestyramine) reduce the absorption of Obeticholic acid.
• Take Liverty 4 hours before or after resins.

Warfarin:

• May decrease INR. Monitor INR and adjust the warfarin dose accordingly.

CYP1A2 Substrates:

• Increases exposure to drugs like theophylline and tizanidine. Monitor therapeutic levels.

Inhibitors of BSEP (Bile Salt Efflux Pump):

• Drugs like cyclosporine may worsen bile salt accumulation. Monitor liver enzymes if used concurrently.

✔️ Do not use in patients with:

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

✔️ Pregnancy & Lactation

• Pregnancy:
  • Limited human data; animal studies show no developmental abnormalities.
  • Use only if clinically necessary.
• Lactation:
  • No data on human milk excretion or its effects on the infant.
  • Weigh the benefits of breastfeeding against the mother’s need for treatment.

✔️ Overdose Effects

Overdose Observations:

• Patients receiving 25 mg/day (2.5x recommended dosage) or 50 mg/day (5x recommended dosage) experienced dose-dependent increases in hepatic adverse reactions, including:
  • Elevated liver biochemical markers.
  • Ascites.
  • Jaundice.
  • Portal hypertension.
  • PBC flares.
• Postmarketing reports confirm serious hepatic adverse events even with recommended doses.

Management: Observe patients closely for signs of overdose and provide supportive care as necessary.

✔️ Hepatic Decompensation and Failure in PBC Patients with Cirrhosis

Hepatic decompensation and failure (fatal in some cases or requiring liver transplantation) have been reported in patients treated with Liverty for PBC.

• Median time to hepatic decompensation for compensated cirrhosis: 4 months.
• Median time to a new decompensation event for decompensated cirrhosis: 2.5 months.
• Hepatic decompensation occurred more frequently when higher than recommended dosages were used but has also been reported with the correct dosage.
• Clinical trials demonstrated a dose-dependent increase in hepatic adverse reactions, including jaundice, worsening ascites, and PBC flares, starting as early as one month.

Regular assessment of liver function is critical. Discontinue Liverty if signs of hepatic decompensation (e.g., ascites, varices, elevated bilirubin) appear.

✔️ Severe Pruritus

• Severe pruritus was reported in 23% of patients in the 10 mg arm, 19% in the titration arm, and 7% in the placebo group.
• Median time to onset:
  • 11 days (10 mg arm).
  • 158 days (titration arm).
  • 75 days (placebo).

Severe pruritus refers to intense, widespread itching that interferes with daily activities, disrupts sleep, and requires medical intervention.

• Evaluate patients for new or worsening pruritus.
• Consider bile acid-binding resins, antihistamines, dose reduction, or temporary treatment interruption.

✔️ Pediatric Use

• Safety and effectiveness in pediatric patients are not established.

✔️ Geriatric Use

• Of 201 patients in clinical trials:
  • 20% were aged 65 years or older.
  • 4% were aged 75 years or older.
• No significant differences in safety or efficacy were observed, but older patients may exhibit increased sensitivity.

✔️ Reduction in HDL-C

Liverty causes dose-dependent reductions in HDL-C (high-density lipoprotein cholesterol):

• At 2 weeks:
  • 20% reduction (10 mg arm).
  • 9% reduction (titration arm).
  • 2% reduction (placebo).
• At 12 months:
  • 19% reduction (10 mg arm).
  • 12% reduction (titration arm).
  • 2% reduction (placebo).

Assess lipid levels during treatment.

If patients experience a significant reduction in HDL-C (<40 mg/dL) or fail to respond after 1 year, weigh the risks and benefits of continued treatment.

✔️ Hepatic Impairment

• Contraindicated in:
  • Decompensated cirrhosis (Child-Pugh Class B or C).
  • Patients with a prior decompensation event.
  • Patients with compensated cirrhosis and evidence of portal hypertension (e.g., ascites, varices, persistent thrombocytopenia).
• Clinical trials confirm a dose-response relationship for hepatic adverse reactions.

✔️ Storage:

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