Usage
- Obeticholic acid is prescribed for the treatment of primary biliary cholangitis (PBC), a chronic liver disease, in adults. It is used in combination with ursodeoxycholic acid (UDCA) in patients with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. It is specifically indicated for patients without cirrhosis or with compensated cirrhosis who do not have evidence of portal hypertension.
- Pharmacological Classification: Farnesoid X receptor (FXR) agonist.
- Mechanism of Action: Obeticholic acid activates FXR, a nuclear receptor that regulates bile acid, inflammatory, fibrotic, and metabolic pathways in the liver and intestine. FXR activation decreases bile acid levels within liver cells (hepatocytes) by suppressing bile acid production and increasing bile acid transport out of hepatocytes. This reduces the overall circulating bile acid pool, promotes bile flow (choleresis), and minimizes liver exposure to potentially damaging bile acids.
Alternate Names
- International Nonproprietary Name (INN): Obeticholic acid
- Brand Name: Ocaliva
How It Works
- Pharmacodynamics: Obeticholic acid is a potent and selective FXR agonist. Activation of FXR in the liver and intestine leads to a reduction in hepatic bile acid synthesis, increased bile acid transport, and suppression of inflammation and fibrosis.
- Pharmacokinetics:
- Absorption: Obeticholic acid is readily absorbed after oral administration, with or without food.
- Metabolism: It is extensively metabolized in the liver, primarily through conjugation with glycine and taurine to form active metabolites, glyco-obeticholic acid and tauro-obeticholic acid.
- Elimination: Primarily eliminated through the feces via biliary excretion, with minimal renal excretion. The metabolites undergo enterohepatic recirculation.
- Mode of Action: Binds to and activates FXR, a nuclear receptor that regulates gene expression. This alters the transcription of genes involved in bile acid synthesis, transport, and inflammation.
- Receptor Binding: Obeticholic acid selectively binds to and activates FXR.
- Elimination Pathways: Primarily biliary excretion via feces, with minimal renal excretion.
Dosage
Standard Dosage
Adults:
- Initial Dose: 5 mg orally once daily for the first 3 months or 6 months depending on regional guidelines.
- Maintenance Dose: After 3 or 6 months, the dose may be increased to 10 mg orally once daily in patients who have not achieved an adequate reduction in alkaline phosphatase (ALP) and/or total bilirubin and who are tolerating the medication.
- Maximum Dose: 10 mg orally once daily.
Children:
- The safety and efficacy of obeticholic acid have not been established in pediatric patients.
Special Cases:
- Elderly Patients: No dose adjustment is necessary.
- Patients with Renal Impairment: No dose adjustment is necessary.
- Patients with Hepatic Dysfunction:
- Mild Hepatic Impairment (Child-Pugh A): No dose adjustment is generally required but should be closely monitored.
- Moderate to Severe Hepatic Impairment (Child-Pugh B or C): Contraindicated.
- Patients with Comorbid Conditions: Dose adjustments may be necessary.
Clinical Use Cases
Obeticholic acid is not indicated for use in clinical situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its use is limited to the treatment of PBC.
Dosage Adjustments
- Intolerable Pruritus: Consider dose reduction (5 mg every other day or 5 mg once daily), temporary interruption (up to 2 weeks), addition of antihistamines or bile acid-binding resins, or discontinuation.
- Concomitant Use of Bile Acid-Binding Resins: Administer obeticholic acid at least 4-6 hours before or after bile acid-binding resins.
Side Effects
Common Side Effects:
- Pruritus (itching)
- Fatigue
- Abdominal pain and discomfort
- Rash
- Joint pain
- Mouth and throat pain
- Dizziness
- Constipation
Rare but Serious Side Effects:
- Liver decompensation and liver failure (especially in patients with advanced cirrhosis)
- Worsening of portal hypertension.
Long-Term Effects:
- Reduced levels of high-density lipoprotein cholesterol (HDL-C, “good cholesterol”)
- Potential for chronic liver damage.
Adverse Drug Reactions (ADR):
- Severe pruritus
- Hepatotoxicity
Contraindications
- Decompensated cirrhosis (Child-Pugh B or C)
- Prior history of hepatic decompensation
- Compensated cirrhosis with evidence of portal hypertension (e.g., ascites, varices, thrombocytopenia)
- Complete biliary obstruction
- Hypersensitivity to obeticholic acid.
Drug Interactions
- CYP3A4 Inhibitors/Inducers: Obeticholic acid can inhibit CYP1A2 and CYP3A4 enzymes. May require therapeutic monitoring for drugs metabolized by these enzymes, especially those with narrow therapeutic indexes (e.g., theophylline, tizanidine).
- Bile Acid-Binding Resins: These can reduce the absorption of obeticholic acid. Administer at least 4-6 hours apart.
- Warfarin: Obeticholic acid can affect the international normalized ratio (INR). Close monitoring and dose adjustment of warfarin are needed.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Not assigned by the FDA. Limited human data are insufficient to determine drug-associated risk. As a precautionary measure, use of obeticholic acid is generally avoided during pregnancy.
- Breastfeeding: Unknown if obeticholic acid is excreted in human milk. A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.
Drug Profile Summary
- Mechanism of Action: FXR agonist, reducing hepatic bile acid exposure.
- Side Effects: Pruritus, fatigue, abdominal pain, rash. Serious: liver injury.
- Contraindications: Decompensated cirrhosis, portal hypertension.
- Drug Interactions: Bile acid-binding resins, warfarin, CYP1A2 substrates.
- Pregnancy & Breastfeeding: Avoid if possible.
- Dosage: Adults: 5 mg once daily initially, titrate to 10 mg if needed and tolerated.
- Monitoring Parameters: Liver function tests (ALP, total bilirubin, AST, ALT), lipid profile (HDL-C), INR (if on warfarin).
Popular Combinations
- Ursodeoxycholic acid (UDCA): Used in combination with obeticholic acid in PBC patients who have an inadequate response to UDCA alone.
Precautions
- General Precautions: Monitor liver function, lipid profile.
- Specific Populations: Avoid in pregnancy if possible. Use with caution in breastfeeding mothers. Not for pediatric use.
- Lifestyle Considerations: No specific restrictions are typically needed.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Obeticholic acid?
A: Initial dose: 5 mg orally once daily. May increase to 10 mg once daily after 3 to 6 months in patients who have not achieved an adequate biochemical response and are tolerating the medication.
Q2: What is the mechanism of action of Obeticholic acid?
A: Obeticholic acid is an FXR agonist that reduces hepatic exposure to bile acids.
Q3: What are the common side effects of Obeticholic acid?
A: Common side effects include pruritus, fatigue, abdominal pain/discomfort, rash, joint pain, mouth and throat pain, dizziness, and constipation.
Q4: Is Obeticholic acid safe to use during pregnancy?
A: Obeticholic acid is generally avoided during pregnancy due to limited human data. Consult with a specialist.
Q5: Can Obeticholic acid be used in patients with decompensated cirrhosis?
A: No, Obeticholic acid is contraindicated in patients with decompensated cirrhosis.
Q6: How should Obeticholic acid be administered if a patient is also taking a bile acid-binding resin?
A: Administer Obeticholic acid at least 4-6 hours before or after the bile acid-binding resin.
Q7: What is the role of FXR in the body?
A: FXR is a nuclear receptor that plays a key role in regulating bile acid metabolism, inflammation, fibrosis, and other metabolic processes.
Q8: What monitoring parameters are important when prescribing Obeticholic acid?
A: Monitor liver function tests (ALP, bilirubin, AST, ALT), lipid profile (HDL-C), and INR if the patient is also taking warfarin.
Q9: Are there any dietary restrictions associated with Obeticholic acid use?
A: Generally, no special dietary restrictions are needed. However, follow your physician’s recommendation.
