CHOLBAM

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
-Administer with food.
-Do not crush or chew capsules.
-For patients unable to swallow whole capsules:-Capsules may be opened and the entire contents administered with soft foods (e.g., mashed potatoes or apple puree). For neonates and infants, the capsules may be mixed with 15 to 30 mL of breast milk/formula.
-Stir the soft food or milk mixture for 30 seconds; the capsule contents will not dissolve and will remain as fine granules in the milk or food. Administer immediately.

-Separate doses by at least 1 hour before or 4 to 6 hours (or the maximum possible interval) after a bile acid binding resin or aluminum-based antacid.

Safety data associated with cholic acid therapy are based on 2 clinical trials: Trial 1 included 79 patients and Trial 2 included 43 patients, 31 of whom also participated in Trial 1. Safety data were available over 18 years for Trial 1 and over nearly 4 years for Trial 2. Adverse events were not systematically collected in either of these trials; therefore, the true incidence of adverse events is not known.

The most common adverse events associated with cholic acid use in clinical trials were gastrointestinal effects, with diarrhea (2%) being the most frequent. Gastroesophageal reflux with esophagitis, nausea, abdominal pain, and intestinal polyp were each reported in 1% of patients during pre-marketing clinical trials.

Exacerbation of liver impairment, elevated hepatic enzymes, and jaundice can occur during cholic acid therapy. During the 18-year study period, 10 (5 with single enzyme defects [SED] and 5 with peroxisomal disorders [PD]) out of 122 patients experienced worsening serum transaminases, hyperbilirubinemia, or worsening cholestasis on liver biopsy during treatment. Jaundice was reported in 1% of patients during clinical trials. Follow the recommended schedule for monitoring liver function tests, and discontinue cholic acid in any patient who develops clinical or laboratory findings suggestive of new onset or worsening hepatotoxicity or cholestasis. During the study period, a total of 25 deaths occurred. Five patients with SED (aged <= 1 year), 12 patients with PD (aged 7 months to 2.5 years), and 4 patients with PD (aged 4 to 8 years) died from progression of underlying liver disease or worsening of their primary illness. Two additional patients with SED, who had not received study medication for over a year, also died from progression of 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 underling cholestasis. Two additional patients with SED died; however, the cause of death was unrelated to their primary treatment or progression of their underlying liver disease.

Malaise, skin lesion, urinary tract infection, and peripheral neuropathy occurred in 1% of patients receiving cholic acid during clinical trials. Only peripheral neuropathy resulted in discontinuation of medication.

Systematic cholelithiasis requiring cholecystectomy was reported in one patient with 3-beta-HSD deficiency who received cholic acid therapy.

Use caution when initiating cholic acid therapy in patients with pre-existing hepatic disease. Evidence of liver impairment is not uncommon in patients with bile acid synthesis disorders or peroxisomal disorders, and worsening of liver function can develop while on treatment. Discontinue cholic acid if liver function does not improve within 3 months of the start of treatment or if complete biliary obstruction develops. Exacerbation of liver disease may also occur in patients without baseline cholestasis. Follow the recommended schedule for monitoring liver function tests, and discontinue treatment in any patient who develops clinical or laboratory findings suggestive of new onset or worsening hepatotoxicity or cholestasis. Concurrent elevations of serum gamma glutamyltransferase (GGT) and alanine aminotransferase (ALT) may indicate cholic acid overdose.

Cholic acid therapy requires an experienced clinician; only experienced hepatologists or pediatric gastroenterologists should prescribe cholic acid.

Description: Cholic acid is an oral therapy for patients with bile acid synthesis disorders due to single enzyme defects (SED) and for patients with peroxisomal disorders (PD), including Zellweger spectrum disorders. Although the incidence of bile acid synthesis disorders is unknown, it is believed to represent 1-2% of childhood cholestatic disorders. Most of the known defects cause progressive liver injury, usually accompanied by inflammation. Synthesis of bile acids from cholesterol requires modifications to the cholesterol nucleus and oxidation of the cholesterol side chain. In bile acid synthesis disorders, the side chain or the cholesterol nucleus may be affected. Inborn errors have been demonstrated for 4 single enzymes involved in modification of the sterol nucleus and in 5 steps in modification of the side-chain to form cholic and chenodeoxycholic acids, the primary bile acids. When diagnosed early, bile acid synthesis defects can be successfully treated with the addition of substitute bile acids. Numerous different disorders with both clinical and biochemical heterogeneity linked to peroxisomal dysfunction have been identified. Peroxisomes are cell organelles found in all human cells except erythrocytes. They are mainly involved in lipid metabolism, are involved in the oxidation of phytanic acid, and in the formation of bile acids from mevalonate via cholesterol. Cholic acid is a primary bile acid produced by the liver where it is synthesized from cholesterol. In bile acid synthesis disorders, due to both bile synthesis disorders in the biosynthetic pathway and in peroxisomal disorders, deficiency of primary bile acids leads to unregulated accumulation of intermediate bile acids and cholestasis. Cholic acid enhances bile flow and provides the physiologic feedback inhibition of bile acid synthesis. In a long-term trial followed by an extension trial, improvements were noted in both baseline liver function tests (LFTs) and growth. An uncontrolled trial involving 50 patients with bile acid synthesis disorders treated over an 18-year period (plus a 21-month extension trial that included 21 of the original patients plus 12 new patients) showed a positive response in 64% of patients with evaluable data. Twenty-nine patients with Zellweger spectrum disorders were also included (the extension trial included 10 of the original patients plus 2 new patients). A response was noted in 46% of patients. Cholic acid was approved by the FDA for patients 3 weeks of age and older in March 2015.

General dosing information:
-Treatment with cholic acid should be initiated and monitored by an experienced hepatologist or pediatric gastroenterologist.
-Adequacy of the dosage regimen can be determined by monitoring the patient's clinical response including steatorrhea, and laboratory values including transaminases, bilirubin, and PT/INR.

Limitations of Use
-The safety and efficacy of cholic acid on extrahepatic manifestations of disorders of bile acid synthesis or peroxisomes have not been established.

For the treatment of bile acid synthesis disorders due to single enzyme defects and the adjunctive treatment of peroxisomal disorders, including Zellweger spectrum disorders:
Oral dosage:
Infants, Children, and Adolescents: 10 to 15 mg/kg/day PO once daily or in 2 divided doses; round dose to the nearest capsule size. In patients with concomitant familial hypertriglyceridemia, doses of 11 to 17 mg/kg/day PO are necessary to account for losses due to malabsorption. Discontinue if liver function does not improve within 3 months of initiation or if complete biliary obstruction develops. If there are persistent indicators of worsening liver function or cholestasis, discontinue therapy; cholic acid may be restarted at a lower dose when the parameters return to baseline. Administer the lowest dosage that effectively maintains liver function.
Neonates 3 weeks and older: 10 to 15 mg/kg/day PO once daily or in 2 divided doses; round dose to the nearest capsule size. In patients with concomitant familial hypertriglyceridemia, doses of 11 to 17 mg/kg/day PO are necessary to account for losses due to malabsorption. Discontinue if liver function does not improve within 3 months of initiation or if complete biliary obstruction develops. If there are persistent indicators of worsening liver function or cholestasis, discontinue therapy; cholic acid may be restarted at a lower dose when the parameters return to baseline. Administer the lowest dosage that effectively maintains liver function.

Therapeutic Drug Monitoring:
-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 3 years, and then annually thereafter. Monitor more frequently during periods of rapid growth, concomitant disease, and pregnancy.
-Discontinue cholic acid therapy at any time if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis.
-Concurrent elevations of GGT and ALT may indicate cholic acid toxicity. Discontinue therapy, and continue to monitor laboratory parameters. Consider restarting at a lower dosage when the parameters return to baseline.

Maximum Dosage Limits:
-Neonates
< 3 weeks: Safety and efficacy have not been established.
>= 3 weeks: 15 mg/kg/day PO.
-Infants
15 mg/kg/day PO for most patients; 17 mg/kg/day PO for those with concomitant familial hypertriglyceridemia.
-Children
15 mg/kg/day PO for most patients; 17 mg/kg/day PO for those with concomitant familial hypertriglyceridemia.
-Adolescents
15 mg/kg/day PO for most patients; 17 mg/kg/day PO for those with concomitant familial hypertriglyceridemia.

Patients with Hepatic Impairment Dosing
Discontinue treatment with cholic acid if there are clinical or laboratory indicators of worsening liver function or cholestasis. Follow the recommended schedule for monitoring liver function tests.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Cholic acid is a primary bile acid produced by the liver where it is synthesized from cholesterol. In bile acid synthesis disorders in the biosynthetic pathway and in peroxisomal disorders, deficiency of primary bile acids leads to unregulated accumulation of intermediate bile acids and cholestasis. Bile acids facilitate fat digestion and absorption and 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. Although the mechanism of action of cholic acid has not been fully established, it is known that cholic acid and its conjugates bind to the farnesoid X receptor (FXR). FXR inhibits liver receptor homologue (LRH), which normally activates cholesterol 7 alpha-hydroxylase and sterol 12 alpha-hydroxylase. This helps to maintain bile acid homeostasis under normal physiologic conditions. A second mechanism for negative feedback involves the detection of elevated bile acid levels by the enterocyte. When bile acids bind to FXR in the enterocyte, fibroblast growth factor is produced (FGF 15). The FGF15 travels to the liver where it binds to a heterodimeric receptor and suppresses synthesis of cholesterol 7 alpha-hydroxylase and sterol 12 alpha-hydroxylase.

Pharmacokinetics: Cholic acid is administered orally and is subject to the same metabolic pathway as endogenous cholic acid. Absorption occurs via passive diffusion along the length of the gastrointestinal tract. After absorption, cholic acid enters into the body's bile acid pool and undergoes enterohepatic circulation, mainly in conjugated forms. Cholic acid is conjugated with glycine or taurine by bile acid-CoA synthetase and bile acid-CoA: amino acid N-acetyltranserferase in the liver. After conjugation, it is actively secreted into the bile mainly by the Bile Salt Efflux Pump (BSEP), before being released into the small intestine. Conjugated cholic acid is mostly re-absorbed in the ileum 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. 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.