Fxr

Fxr Uses, Dosage, Side Effects, Food Interaction and all others data.

Fxr is an agonist for FXR, a nuclear receptor expressed in the liver and intestine. FXR is a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways. FXR activation decreases the intracellular hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol as well as by increased transport of bile acids out of the hepatocytes. These mechanisms limit the overall size of the circulating bile acid pool while promoting choleresis, thus reducing hepatic exposure to bile acids.

The activation of the FXR by obeticholic acid acts to reduce the synthesis of bile acids, inflammation, and the resulting hepatic fibrosis. This may increase the survival of patients with PBC, but to date, an association between obeticholic acid and survival in PBC has not been established.

Trade Name Fxr
Generic Obeticholic Acid
Obeticholic Acid Other Names 6-ECDCA, 6-Ethyl-CDCA, Obeticholic acid
Weight 10mg, 5mg
Type Tablet
Formula C26H44O4
Weight Average: 420.6252
Monoisotopic: 420.323959896
Protein binding

Obeticholic acid and its metabolic conjugates are >99% plasma protein-bound.

Groups Approved
Therapeutic Class Farnesoid X Receptor Agonists
Manufacturer Dr Reddys Laboratories Ltd, Beacon Pharmaceuticals Ltd,
Available Country India, Bangladesh
Last Updated: September 19, 2023 at 7:00 am
Fxr
Fxr

Uses

Fxr is used for the treatment of primary biliary cholangitis (PBC) in combination with Ursodeoxycholic Acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA, cholestatic liver disease & non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH).
Geriatric Use: No dosage adjustment is recommended in elderly patientless than 65 years of age.

Pediatric Use: Safety and efficacy have not been established in patients younger than 18 years.

Use in Patients with Impaired Renal Function: Fxr has not been studied in patients with moderate and severe renal impairment (estimated glomerular filtration rate [eGFR] less than 60 ml/min/1.73 m2). In the population pharmacokinetic analysis, an eGFR greater than 50 ml/min/1.73 m2 did not have a meaningful effect on the pharmacokinetics of Fxr and its conjugated metabolites.

Use in Patients with Impaired Hepatic Function: Fxr is metabolized in the liver. Plasma exposure to Fxr and its active conjugates, increases significantly in patients with moderate to severe hepatic impairment (Child-Pugh Classes B and C).The recommended starting dosage of Fxr for moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment is 5 mg once weekly. If an adequate reduction in ALP and/or total bilirubin has not been achieved after 3 months of Fxr 5 mg once weekly, and the patient is tolerating the drug, increase the dosage of Fxr to 5 mg twice weekly (at least three days apart) and subsequently to 10 mg twice weekly (at least three days apart) depending on response and tolerability.

Fxr is also used to associated treatment for these conditions: Primary Biliary Cholangitis

How Fxr works

Primary biliary cirrhosis is an autoimmune process by which the bile ducts and liver are damaged progressively, leading to fibrosis and cirrhosis. Bile acids increase the risk of damage and fibrosis to the damaged bile ducts.

Obeticholic acid is a potent agonist of the farnesoid X receptor, which serves to regulate the hepatic metabolism of bile and cholesterol. This drug acts by binding to the farnesoid X receptor (FXR), found in the nucleus of liver and intestinal cells, which in turn increases liver bile flow, suppressing its production and decreasing hepatocyte exposure to excess levels of bile with cholestasis. Cholestasis is a process that normally causes inflammation and cirrhosis of the liver.

Dosage

Fxr dosage

Starting Dosage: The recommended starting dosage of Fxr is 5 mg orally once daily in adult patients who have not achieved an adequate biochemical response to an appropriate dosage of Ursodeoxycholic Acid (UDCA) for at least 1 year or are intolerant to UDCA.

Dosage Titration: If an adequate reduction in alkaline phosphatase (ALP) and/or total bilirubin has not been achieved after 3 months of Fxr 5 mg once daily, and the patient is tolerating Fxr, increase the dosage of Fxr to 10 mg once daily.

Maximum Dosage: The maximum recommended dosage of Fxr is 10 mg once daily.

Management of Patients with Intolerable Pruritus on Fxr: For patients with intolerable pruritus on Fxr, consider one or more of the following:

Add an antihistamine or bile acid binding resin. Reduce the dosage of Fxr 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 Fxr dosing for up to 2 weeks followed by restarting at a reduced dosage

Increase the dosage of Fxr to 10 mg once daily, as tolerated, to achieve optimal response. Consider discontinuing Fxr treatment in patients who continue to experience persistent, intolerable pruritus.

Side Effects

The most common side effects of Fxr include: Pruritus, Fatigue & Stomach pain and discomfort. Other common side effects include rash, arthralgia (joint pain), oropharyngeal pain (pain in the middle part of the throat), dizziness, constipation, abnormal thyroid function, and eczema (inflammation of the skin).

Toxicity

LD50 information for obeticholic acid is not readily available in the literature.

The maximum documented exposure to obeticholic acid was 500 mg in healthy research volunteers. Doses of 250 mg have been administered to healthy volunteers for 12 consecutive days. Pruritus and reversible transaminase liver elevations were observed. In PBC patients who received 25mg daily to 50mg daily (2.5 to 5 times the maximum recommended dose), dose-dependent transaminase and bilirubin elevations, ascites, primary biliary cholangitis aggravation, and new-onset jaundice were reported.

In the case of an overdose with obeticholic acid, clinical monitoring and supportive care should be offered as they are required.

Precaution

The following clinically significant reactions are described:

  • Liver-Related Adverse Reactions
  • Severe Pruritus
  • Reduction in high density lipoprotein-cholesterol (HDL-C)
Special monitoring is essential for the patient with such type of problems

Interaction

Bile Acid Binding Resins: Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of Fxr. If taking a bile acid binding resin, take Fxr at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as great an interval as possible.

Warfarin: The International Normalized Ratio (INR) decreased following co-administration of warfarin and Fxr. Monitor INR and adjust the dosage of warfarin, as needed, to maintain the target INR range when co-administering Fxr and warfarin.

CYP1A2 Substrates with Narrow Therapeutic Index: Fxr may increase the exposure to concomitant drugs that are CYP1A2 substrates. Therapeutic monitoring of CYP1A2 substrates with a narrow therapeutic index.

Food Interaction

  • Take with or without food.

Volume of Distribution

The volume of distribution of obeticholic acid is 618 L.

Elimination Route

Obeticholic acid is absorbed in the gastrointestinal tract. The Cmax of obeticholic acid occurs at approximately 1.5 hours after an oral dose and ranges from 28.8-53.7 ng/mL at doses of 5-10mg. The median Tmax for both the conjugates of obeticholic acid is about 10 hours. One product monograph reports a Tmax of 4.5h for both 5 and 10mg doses. The AUC ranged from 236.6-568.1 ng/h/mL with 5mg to 10 mg doses.

Half Life

The biological half-life of obeticholic acid is reported to be 24 hours.

Clearance

Clearance information for obeticholic acid is not readily available in the literature.

Elimination Route

About 87% of an orally administered dose is accounted for in the feces. Less than 3% of the dose can be recovered in the urine.

Pregnancy & Breastfeeding use

The limited available human data on the use of Fxr during pregnancy are not sufficient to inform a drug-associated risk.There is no information on the presence of Fxr in human milk, the effects on the breast-fed infant or the effects on milk production.

Contraindication

Contraindicated in patients known to have hypersensitivity to the drug or any of its components & in patients with complete biliary obstruction.

Acute Overdose

In PBC patients who received Fxr 25 mg once daily (2.5 times the highestrecommended dosage) or 50 mg once daily (5 times the highest recommended dosage), a dose-dependent increase in the incidence of liver-related adverse reactions, including elevations in liver biochemical tests, ascites, jaundice, portal hypertension, and primary biliary cholangitis flare, was reported. In the case of over dosage, patients should be carefully observed and supportive care administered, as appropriate.

Storage Condition

Store at 15°C to 30°C in a dry place protected from light. Keep out of reach of children

Innovators Monograph

You find simplified version here Fxr

http://classyfire.wishartlab.com/tax_nodes/C0000000
http://classyfire.wishartlab.com/tax_nodes/C0000012
http://classyfire.wishartlab.com/tax_nodes/C0000258
http://classyfire.wishartlab.com/tax_nodes/C0001445
http://classyfire.wishartlab.com/tax_nodes/C0000516
http://classyfire.wishartlab.com/tax_nodes/C0003238
http://classyfire.wishartlab.com/tax_nodes/C0003232
http://classyfire.wishartlab.com/tax_nodes/C0001661
http://classyfire.wishartlab.com/tax_nodes/C0001292
http://classyfire.wishartlab.com/tax_nodes/C0001137
http://classyfire.wishartlab.com/tax_nodes/C0001205
http://classyfire.wishartlab.com/tax_nodes/C0003940
http://classyfire.wishartlab.com/tax_nodes/C0004150
http://classyfire.wishartlab.com/tax_nodes/C0001831
https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:43602
http://www.genome.jp/dbget-bin/www_bget?drug:D09360
http://www.genome.jp/dbget-bin/www_bget?cpd:C15636
https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=447715
https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=347827752
https://www.chemspider.com/Chemical-Structure.394730.html
http://www.bindingdb.org/bind/chemsearch/marvin/MolStructure.jsp?monomerid=21675
https://mor.nlm.nih.gov/RxNav/search?searchBy=RXCUI&searchTerm=1798288
https://www.ebi.ac.uk/chebi/searchId.do?chebiId=43602
https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL566315
https://zinc.docking.org/substances/ZINC000014164617
https://www.ebi.ac.uk/pdbe-srv/pdbechem/chemicalCompound/show/CHC
https://en.wikipedia.org/wiki/Obeticholic_acid
*** Taking medicines without doctor's advice can cause long-term problems.
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