Empirical formula: C24H40O5 - Molecular weight: 408.57
Cholic acid is a white to off-white powder. It is practically insoluble in water and in 0.1 M HCl at 20°C and is sparingly soluble in 0.1 M NaOH at 20°C. It is soluble in glacial acetic acid, alcohols and acetone. A saturated solution in water at 20°C has a pH of 4.4.
Cholic acid capsules contain 50 mg or 250 mg of cholic acid as the active ingredient in size 2 Swedish orange or size 0 white opaque gelatin capsules, respectively. Inactive ingredients in cholic acid include silicified microcrystalline cellulose, magnesium stearate and hard gelatin capsules. The size 2 shells contain gelatin, red iron oxide and titanium dioxide and the size 0 shells contain gelatin and titanium dioxide. Cholic acid capsule is administered orally.
2. INDICATIONS AND USAGE 
2.1 Bile Acid Synthesis Disorders due to Single Enzyme Defects
Cholic acid is indicated for the treatment of bile acid synthesis disorders due to single enzyme defects (SEDs) [see Clinical Trials].
2.2 Peroxisomal Disorders Including Zellweger Spectrum Disorders
Cholic acid is indicated for adjunctive treatment of peroxisomal disorders (PDs) including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption [see Clinical Trials].
2.3 Limitation of Use
The safety and effectiveness of cholic acid on extrahepatic manifestations of bile acid synthesis disorders due to SEDs or PDs including Zellweger spectrum disorders have not been established.
3. DOSAGE AND ADMINISTRATION 
3.1 Dosage Regimen for Bile Acid Synthesis Disorders due to Single Enzyme Defects and Peroxisomal Disorders including Zellweger Spectrum Disorders
The recommended dosage of cholic acid is 10 to 15 mg/kg administered orally once daily, or in two divided doses, in pediatric patients and in adults.
Tables 1 and 2 show the number of capsules that should be administered daily to approximate a 10 mg/kg/day and 15 mg/kg/day dosage, respectively, using the available 50 mg and 250 mg capsules alone or in combination.
Table 1: Number of Cholic Acid Capsules Needed to Achieve a Recommended Dosage of 10 mg/kg/day

Table 2: Number of Cholic Acid Capsules Needed to Achieve a Recommended Dosage of 15 mg/kg/day

Patients with newly diagnosed, or a family history of, familial hypertriglyceridemia may have poor absorption of cholic acid from the intestine and require a 10% increase in the recommended dosage to account for losses due to malabsorption. The recommended dosage of cholic acid in patients with concomitant familial hypertriglyceridemia is 11 to 17 mg/kg orally once daily, or in two divided doses. Adequacy of the dosage regimen can be determined by monitoring of patients’ clinical response including steatorrhea, and laboratory values including transaminases, bilirubin and PT/INR.
3.2 Treatment Monitoring
Treatment with cholic acid should be initiated and monitored by an experienced hepatologist or pediatric gastroenterologist.
Monitor serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum gamma glutamyltransferase (GGT), alkaline phosphatase (ALP), bilirubin and INR every month for the first 3 months, every 3 months for the next 9 months, every 6 months during the subsequent three years and annually thereafter. Monitor more frequently during periods of rapid growth, concomitant disease, and pregnancy. Administer the lowest dose of cholic acid that effectively maintains liver function [see Warnings and Precautions (5.1)].
Discontinue treatment with cholic acid if liver function does not improve within 3 months of the start of treatment or complete biliary obstruction develops.
Discontinue treatment with cholic acid at any time if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis [see Warnings and Precautions (5.1)]. Concurrent elevations of serum gamma glutamyltransferase (GGT) and serum alanine aminotransferase (ALT) may indicate cholic acid overdose [see Overdosage (9)]. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline.
Assessment of serum or urinary bile acid levels using mass spectrometry is used in the diagnosis of bile acid synthesis disorders due to SEDs and PDs including Zellweger spectrum disorders. The utility of bile acid measurements in monitoring the clinical course of patients and in decisions regarding dose adjustment has not been demonstrated.
3.3 Administration Instructions
• Take cholic acid with food.
• Take cholic acid at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin or aluminum-based antacid.
• Do not crush or chew the capsules.
• For patients unable to swallow the capsules, the capsules can be opened and the contents mixed with either infant formula or expressed breast milk (for younger children), or soft food such as mashed potatoes or apple puree (for older children and adults) in order to mask any unpleasant taste:
1. Hold the capsule over the prepared liquid/food, gently twist open, and allow the contents to fall into the liquid/food.
2. Mix the entire capsule contents with one or two tablespoons (15 mL to 30 mL) of infant formula, expressed breast milk, or soft food such as mashed potatoes or apple puree.
3. Stir for 30 seconds.
4. The capsule contents will remain as fine granules in the milk or food, and will not dissolve.
5. Administer the mixture immediately
4. CONTRAINDICATIONS 
None.
5. WARNINGS AND PRECAUTIONS 
5.1 Exacerbation of Liver Impairment
Monitor liver function and discontinue cholic acid in patients who develop worsening of liver function while on treatment. Concurrent elevations of serum gamma glutamyltransferase (GGT), alanine aminotransferase (ALT) may indicate cholic acid overdose. [see Overdosage (9)]. Discontinue treatment with cholic acid at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis.
Evidence of liver impairment was present before treatment with cholic acid in approximately 86% (44/51) of patients with bile acid synthesis disorders due to SEDs and in approximately 50% (14/28) of patients with PDs including Zellweger spectrum disorders. Five of the patients (3 SED and 2 PD) with liver impairment at baseline experienced worsening serum transaminases, elevated bilirubin values, or worsening cholestasis on liver biopsy following treatment. An additional 5 patients (2 SED and 3 PD) who did not have baseline cholestasis experienced an exacerbation of their liver disease while on treatment. Exacerbation of liver impairment by cholic acid in these patients cannot be ruled out.
Six patients with single enzyme defects underwent liver transplant, including four patients diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency, and one with CYP7A1 deficiency.
6. ADVERSE REACTIONS 
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical safety experience with cholic acid consists of:
• Trial 1: a non-randomized, open-label, uncontrolled trial of 50 patients with bile acid synthesis disorders due to SEDs and 29 patients with PDs including Zellweger spectrum disorders. Safety data are available over the 18 years of the trial.
• Trial 2: an extension trial of 12 new patients (10 SED and 2 PD) along with 31 (21 SED and 10 PD) patients who rolled-over from Trial 1. Safety data are available for 3 years and 11 months of treatment.
Adverse events were not collected systematically in either of these trials. Most patients received an oral dose of 10 to 15 mg/kg/day of cholic acid.
Deaths
In Trial 1, among the 50 patients with SEDs, 5 patients aged 1 year or less died, which included three patients originally diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency and one with CYP7A1 deficiency. The cause of death was attributed to progression of underlying liver disease in every patient.
Of the 29 patients in Trial 1 with PDs including Zellweger spectrum disorders, 12 patients between the ages of 7 months and 2.5 years died. In the majority of these patients (8/12), the cause of death was attributed to progression of underlying liver disease or to a worsening of their primary illness.
Two additional patients in Trial 1 (1 SED and 1 PD) died who had been off study medication for more than one year with the cause of death most likely being a progression of their underlying liver disease. Of the patients who died with disease progression, laboratory testing showed abnormal serum transaminases, bilirubin, or cholestasis on liver biopsy suggesting worsening of their underlying cholestasis.
In Trial 2, among the 31 patients with SED, two patients (1 new patient and 1 who rolled over from Trial 1) died. The cause of death in both cases was unrelated to their primary treatment or progression of their underlying liver disease.
Of the 12 patients with PD in Trial 2, four patients died between the ages of 4 and 8 years (1 new patient and 3 who rolled over from Trial 1). The cause of death in three of these patients was attributed to progression of underlying liver disease or to a worsening of their primary illness.
Worsening Liver Impairment
Seven patients in Trial 1(4 SED and 3 PD) and 3 patients in Trial 2 (1 SED and 2 PD) experienced worsening serum transaminases, elevated bilirubin values, or worsening cholestasis on liver biopsy during treatment.
Common Adverse Reactions
There were 12 adverse reactions reported across 9 patients in the trials, with diarrhea being the most common reaction in approximately 2% of the patient population. All other adverse reactions represented 1% of the patient population. The breakdown by trial follows:
Table 3: Most Common Adverse Reactions in Trials 1 and 2

* Adverse reactions that occurred in new patients
Only one of the reactions (peripheral neuropathy) resulted in discontinuation of medication for a patient in Trial 2. An additional five SED patients (3 from Trial 1 and 2 from Trial 2) and 1 PD patient (Trial 1) discontinued medication and withdrew from the study due to a worsening of their primary disease.
The development of symptomatic cholelithiasis requiring cholecystectomy has been reported in a single patient with 3β-HSD deficiency.
7. DRUG INTERACTIONS 
7.1. Effects of other drugs on Cholic Acid
Drug interactions with cholic acid mainly relate to agents capable of interrupting the enterohepatic circulation of bile acids.
Inhibitors of Bile Acid Transporters
Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitoring of serum transaminases and bilirubin is recommended.
Bile Acid Binding Resins
Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the efficacy of cholic acid. Take cholic acid at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin [see Dosage and Administration (3.3)].
Aluminum-Based Antacids
Aluminum-based antacids have been shown to adsorb bile acids in vitro and can reduce the bioavailability of cholic acid. Take cholic acid at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after an aluminum-based antacid [see Dosage and Administration (3.3)].
8. USE IN SPECIFIC POPULATIONS 
8.1 Usage in Pregnancy
Pregnancy Exposure Registry
There is a pregnancy surveillance program that monitors pregnancy outcomes in women exposed to cholic acid during pregnancy [COCOA Registry (ChOlbam: Child and mOther's heAlth)]. Women who become pregnant during cholic acid treatment are encouraged to enroll. Patients or their health care provider should call 1-844-20C-OCOA or 1-844-202-6262 to enroll.
Risk Summary
No studies in pregnant women or animal reproduction studies have been conducted with cholic acid.
Limited published case reports discuss pregnancies in women taking cholic acid for 3β-HSD deficiency resulting in healthy infants. These reports may not adequately inform the presence or absence of drug-associated risk with the use of cholic acid during pregnancy. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
8.2 Lactation
Risk Summary
Endogenous cholic acid is present in human milk. Clinical lactation studies have not been conducted to assess the presence of cholic acid in human milk, the effects of cholic acid on the breastfed infant, or the effects of cholic acid on milk production. There are no animal lactation data and no data from case reports available in the published literature. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for cholic acid and any potential adverse effects on the breastfed infant from cholic acid or from the underlying maternal condition.
8.4 Pediatric Use
The safety and effectiveness of cholic acid has been established in pediatric patients 3 weeks of age and older for the treatment of bile acid synthesis disorders due to SEDs, and for adjunctive treatment of patients with PDs including Zellweger spectrum disorders who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption [see Clinical Studies].
8.5 Geriatric Use
Clinical studies of cholic acid did not include any patients aged 65 years and over. It is not known if elderly patients respond differently from younger patients.
8.6 Hepatic Impairment
Discontinue treatment with cholic acid if liver function does not improve within 3 months of the start of treatment.
Discontinue treatment with cholic acid at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis [see Warnings and Precautions (5.1), Overdosage (9) and Nonclinical Toxicology\]. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline.
9. OVERDOSAGE 
Concurrent elevations of serum gamma glutamyltransferase (GGT) and serum alanine aminotransferase (ALT) may indicate cholic acid overdose. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline [see Dosage and Administration (3.2)].
In the event of overdose the patient should be monitored and treated symptomatically.
10. MECHANISM OF ACTION 
Cholic acid is a primary bile acid synthesized from cholesterol in the liver. In bile acid synthesis disorders due to SEDs in the biosynthetic pathway, and in PDs including Zellweger spectrum disorders, deficiency of primary bile acids leads to unregulated accumulation of intermediate bile acids and cholestasis. Bile acids facilitate fat digestion and absorption by forming mixed micelles, and facilitate absorption of fat-soluble vitamins in the intestine.
Endogenous bile acids including cholic acid enhance bile flow and provide the physiologic feedback inhibition of bile acid synthesis. The mechanism of action of cholic acid has not been fully established; however, it is known that cholic acid and its conjugates are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR). FXR regulates enzymes and transporters that are involved in bile acid synthesis and in the enterohepatic circulation to maintain bile acid homeostasis under normal physiologic conditions.
11. PHARMACOKINETICS  
Orally administered cholic acid is subject to the same metabolic pathway as endogenous cholic acid.
Cholic acid is absorbed by passive diffusion along the length of the gastrointestinal tract. Once absorbed, cholic acid enters into the body’s bile acid pool and undergoes enterohepatic circulation mainly in conjugated forms.
In the liver, cholic acid is conjugated with glycine or taurine by bile acid-CoA synthetase and bile acid-CoA: amino acid Nacetyltransferase. Conjugated cholic acid is actively secreted into bile mainly by the Bile Salt Efflux Pump (BSEP), and then released into the small intestine, along with other components of bile.
Conjugated cholic acid is mostly re-absorbed in the ileum mainly by the apical-sodium-dependent-bile acid transporter, passed back to the liver by transporters including sodium-taurocholate cotransporting polypeptide and organic anion transport protein and enters another cycle of enterohepatic circulation. Any conjugated cholic acid not absorbed in the ileum passes into the colon where deconjugation and 7-dehydroxylation are mediated by bacteria to form cholic acid and deoxycholic acid which may be re-absorbed in the colon or excreted in the feces. The loss of cholic acid is compensated by de-novo synthesis of cholic acids from cholesterol to maintain the bile acid pool in healthy subjects.
12. HOW SUPPLIED/STORAGE AND HANDLING 
1) How Available:
a) Brand name: CHOLBAM, by Asklepion Pharmaceuticals LLC.
b) Generic drugs: None.
2) How Supplied:
50 mg Capsules
CHOLBAM capsules are available as two-piece gelatin capsules with a Swedish orange cap imprinted with “50mg” and Swedish orange body with imprinted with “ASK001”. The capsules contain a white or off-white powder and are supplied in bottles of:
• 90 capsules (NDC 43472-001-02)
250 mg Capsules
CHOLBAM capsules are available as two-piece gelatin capsules with a white cap imprinted with “250mg” and white body with imprinted with “ASK002”. The capsules contain a white or off-white powder and are supplied in bottles of:
• 90 capsules (NDC 43472-002-02)
3) Storage and Handling:
Store at 20–25°C (69-77°F), excursions permitted between 15-30°C (59-86°F). [see USP Controlled Room Temperature].