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Cholic Acid

Class: GI Drugs, Miscellaneous
Chemical Name: (3α,5β,7α,12α)-3,7,12-Trihydroxy-cholan-24-oic acid
Molecular Formula: C24H40O5
CAS Number: 81-25-4
Brands: Cholbam

Introduction

A primary bile acid; used as replacement therapy.1 5

Uses for Cholic Acid

Bile Acid Synthesis Disorders

Management of bile acid synthesis disorders due to single enzyme defects (designated an orphan drug by FDA for this use).1 2 5

Safety and efficacy for management of extrahepatic manifestations of bile acid synthesis disorders due to single enzyme defects not established.1

Peroxisomal Disorders

Adjunctive management of peroxisomal disorders (e.g., Zellweger spectrum disorders) in patients experiencing symptoms of liver disease, steatorrhea, or complications resulting from decreased absorption of fat-soluble vitamins (designated an orphan drug by FDA for this use).1 2 5 10

Safety and efficacy for management of extrahepatic manifestations of peroxisomal disorders not established.1

Cholic Acid Dosage and Administration

General

  • Monitor liver function tests (i.e., AST, ALT, γ-glutamyltransferase [GGT, γ-glutamyl transpeptidase, GGTP], alkaline phosphatase, bilirubin concentrations, INR) every month for first 3 months, every 3 months for next 9 months, every 6 months for next 3 years, and annually thereafter.1 Monitor more frequently during periods of rapid growth, concomitant disease, and pregnancy.1 (See Pregnancy under Cautions.)

  • Discontinue treatment if complete biliary obstruction develops or in presence of persistent clinical or laboratory indicators of worsening liver function or cholestasis.1 Continue to monitor liver function tests after drug discontinuance.1 Consider resuming drug at lower dosage when results of liver function tests return to baseline.1

Restricted Distribution Program

  • Obtain through a specialty pharmacy (Dohmen Life Sciences Services) at 844-246-5226 or may consult the Cholbam Total Care Hub website for specific ordering and availability information ().8 9

Administration

Oral Administration

Administer orally in 1 or 2 divided doses daily with food.1

Swallow whole; do not chew or crush capsules.1

Take cholic acid at least 1 hour before or 4–6 hours (or as long an interval as possible) after administration of bile acid sequestrant or aluminum-containing antacid.1 (See Specific Drugs under Interactions.)

For patients unable to swallow capsules whole, twist cholic acid capsules open gently and mix entire contents with 15–30 mL of either infant formula or breast milk for younger children or soft foods (e.g., mashed potatoes, applesauce) for older children to mask unpleasant taste.1 Stir mixture for 30 seconds and administer immediately thereafter.1 Capsule contents will remain as fine granules and will not dissolve.1

Dosage

Round calculated dosage to the nearest whole capsule strength available (i.e., 50 or 250 mg) either alone or in combination.1 For more detailed information on selection of capsule strengths to provide a specific dosage of cholic acid, consult the dosage tables in the manufacturer's labeling.1

Administer lowest dosage required to effectively maintain liver function.1 Discontinue drug if liver function does not improve within 3 months of therapy initiation.1

Familial hypertriglyceridemia (newly diagnosed or family history) associated with poor intestinal absorption of cholic acid.1 Patients with bile acid synthesis disorders due to single enzyme defects or peroxisomal disorders and concomitant familial hypertriglyceridemia may require 10% increase in usual recommended dosage to account for losses due to malabsorption.1 Monitor clinical response (e.g., steatorrhea) and laboratory values (e.g., AST, ALT, and bilirubin concentrations; PT/INR) to assess adequacy of dosage in such patients.1

Pediatric Patients

Bile Acid Synthesis Disorders due to Single Enzyme Defects
Oral

10–15 mg/kg daily in 1 or 2 divided doses.1

Bile Acid Synthesis Disorders due to Single Enzyme Defects and Concomitant Familial Hypertriglyceridemia
Oral

11–17 mg/kg daily in 1 or 2 divided doses.1

Peroxisomal Disorders
Oral

10–15 mg/kg daily in 1 or 2 divided doses.1

Peroxisomal Disorders and Concomitant Familial Hypertriglyceridemia
Oral

11–17 mg/kg daily in 1 or 2 divided doses.1

Adults

Bile Acid Synthesis Disorders due to Single Enzyme Defects
Oral

10–15 mg/kg daily in 1 or 2 divided doses.1

Bile Acid Synthesis Disorders due to Single Enzyme Defects and Concomitant Familial Hypertriglyceridemia
Oral

11–17 mg/kg daily in 1 or 2 divided doses.1

Peroxisomal Disorders
Oral

10–15 mg/kg daily in 1 or 2 divided doses.1

Peroxisomal Disorders and Concomitant Familial Hypertriglyceridemia
Oral

11–17 mg/kg daily in 1 or 2 divided doses.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.1

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Cholic Acid

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Exacerbation of Hepatic Impairment

Exacerbation of hepatic impairment (e.g., elevations in AST, ALT, and bilirubin concentrations, worsening cholestasis on liver biopsy), sometimes necessitating liver transplant, reported in patients with and without baseline evidence of hepatic impairment (e.g., cholestasis) during treatment with cholic acid.1 Exacerbation of hepatic impairment due to cholic acid cannot be ruled out.1

Monitor liver function; discontinue treatment in patients who develop worsening of liver function.1 Discontinue treatment for clinical or laboratory indicators of worsening liver function or cholestasis.1

Specific Populations

Pregnancy

No studies assessing risks of cholic acid in pregnant women or animals.1 In 2 out of 15 patients receiving cholic acid for a median of 12 years, 4 normal pregnancies resulted in the birth of 4 healthy infants.4 Limited data may not adequately predict presence or absence of risk during pregnancy.1

Encourage patients to enroll in COCOA Pregnancy registry (Cholbam: Child and Mother's Health) at 844-202-6262 to monitor pregnancy outcomes in women exposed to cholic acid.1

Lactation

Endogenous cholic acid distributed into human milk; no data available in nursing women or lactating animals to determine distribution of exogenously administered cholic acid in milk.1 Effects of drug on nursing infants or human milk production unknown.1

Consider benefits of breast-feeding and importance of drug to the woman; also consider potential adverse effects on the breast-fed child from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in infants <3 weeks of age.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Hepatic Impairment

If liver function does not improve within 3 months of therapy initiation or if persistent worsening of clinical or laboratory parameters of liver function or cholestasis occurs at any time, discontinue therapy.1

Monitor laboratory parameters of liver function; consider restarting the drug at lower dosage when parameters return to baseline.1

Common Adverse Effects

Diarrhea,1 reflux esophagitis,1 malaise,1 jaundice,1 skin lesion,1 nausea,1 abdominal pain,1 intestinal polyp,1 urinary tract infection,1 peripheral neuropathy.1

Interactions for Cholic Acid

Drugs Affecting or Affected by Bile Acid Transport

Possible symptomatic exacerbation of accumulation of conjugated bile salts in the liver with inhibitors of canalicular membrane bile acid transporters (e.g., the bile salt export pump [BSEP]).1 Avoid concomitant use.1 If concomitant use cannot be avoided, monitor AST, ALT, and bilirubin concentrations.1

Specific Drugs

Drug

Interaction

Comments

Antacids, aluminum-containing

Possible decreased bioavailability of cholic acid1

Administer cholic acid at least 1 hour before or 4–6 hours (or as long an interval as possible) after aluminum-containing antacid1

Bile acid sequestrants (cholestyramine, colesevelam, colestipol)

Possible reduced efficacy of cholic acid1

Administer cholic acid at least 1 hour before or 4–6 hours (or as long an interval as possible) after bile acid sequestrant1

Cyclosporine

Possible exacerbation of accumulation of conjugated bile salts in the liver1

Avoid concomitant use.1 If concomitant use cannot be avoided, monitor AST, ALT, and bilirubin concentrations1

Cholic Acid Pharmacokinetics

Absorption

Bioavailability

Absorbed by passive diffusion in GI tract.1

Distribution

Extent

Endogenous cholic acid distributed into human milk; no data available in nursing women or lactating animals to determine distribution of exogenously administered cholic acid in milk.1 (See Lactation under Cautions.)

Elimination

Metabolism

Same metabolic pathway as endogenous cholic acid; undergoes conjugation with glycine or taurine in liver to form bile salts.1 5

Elimination Route

Undergoes enterohepatic circulation.1 Conjugated cholic acid not absorbed in colon is deconjugated and dehydroxylated to form cholic acid and deoxycholic acid, which may be reabsorbed in colon or excreted in feces.1

Half-life

Approximately 3 hours in healthy adults.5

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).1

Actions

  • Cholic acid is a primary bile acid synthesized from cholesterol in the liver.1 3 4 Endogenous primary bile acids (i.e., cholic acid, chenodeoxycholic acid) improve bile flow and provide physiologic feedback inhibition of bile acid synthesis.1 5

  • Cholic acid and its conjugates are endogenous ligands of the nuclear farnesoid X receptor (FXR), which regulates enzymes and transporters involved in bile acid synthesis and enterohepatic circulation to maintain bile acid homeostasis under normal physiologic conditions.1 4 Activation of the FXR through binding of cholic acid results in upregulation of transcription of genes coding for hepatic conjugation enzymes, resulting in increased metabolic conjugation of bile acids and bile acid-dependent bile flow.5

  • Activated FXR also results in downregulation of cholesterol 7α-hydroxylase encoded by the CYP7A1 gene, potentially resulting in reduction in de novo synthesis of primary bile acids; clinical importance of such downregulation is not fully known.5

Advice to Patients

  • Risk of worsening liver impairment.1 Importance of periodic laboratory monitoring to assess liver function during treatment.1 Importance of advising patients to immediately inform clinician of any symptoms associated with liver impairment (e.g., jaundice, dark or brown tea-colored urine, right-sided abdominal pain, unusual bleeding or bruising, increased lethargy).1

  • Advise patients to take cholic acid with food.1 Do not crush or chew capsules.1 Importance of advising patients to take cholic acid at least 1 hour before or 4–6 hours (or as long an interval as possible) after administration of an aluminum-containing antacid or bile acid sequestrant.1

  • Importance of advising caregivers that for patients unable to swallow the capsule whole, capsules may be opened and entire contents mixed with 15–30 mL of either infant formula or breast milk for younger children or soft foods for older children to mask any unpleasant taste.1 (See Administration under Dosage and Administration.)

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of informing women who become pregnant while taking cholic acid about the existence of the COCOA Registry (Cholbam: Child and Mother's Health) pregnancy registry.1 (See Pregnancy under Cautions.)

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of cholic acid is restricted.8 9 (See Restricted Distribution Program under Dosage and Administration.)

Cholic acid

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

50 mg

Cholbam

Retrophin

250 mg

Cholbam

Retrophin

AHFS DI Essentials. © Copyright 2017, Selected Revisions July 3, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Retrophin, Inc. Cholbam (cholic acid) capsules prescribing information. San Diego, CA; 2015 Mar.

2. Food and Drug Administration. Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2016 Mar 22.

3. National Organization for Rare Disorders. Bile acid synthesis disorders. From NORD website. Accessed 2016 Jun 3.

4. Gonzales E, Gerhardt MF, Fabre M et al. Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy. Gastroenterology. 2009; 137:1310-1320.e1-3. [PubMed 19622360]

5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 205750Orig1s000: Medical review(s). From FDA website.

6. Aubourg P, Wanders R. Peroxisomal disorders. Handb Clin Neurol. 2013; 113:1593-609. [PubMed 23622381]

7. Ferdinandusse S, Denis S, Faust PL et al. Bile acids: the role of peroxisomes. J Lipid Res. 2009; 50:2139-47. [PubMed 19357427]

8. Retrophin, Inc. Cholbam Financial Assistance Program. San Diego, CA. Accessed 2016 Nov 3.

9. Retrophin, Inc. Cholbam Total Care Hub. San Diego, CA. Accessed 2016 Oct 18.

10. Retrophin, Inc San Diego, CA: Personal communication.

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