Cholbam

Bile Acid Agents

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.

cholelithiasis / Delayed / Incidence not known

hyperbilirubinemia / Delayed / 6.0-9.0
cholestasis / Delayed / 6.0-9.0
elevated hepatic enzymes / Delayed / 6.0-9.0
jaundice / Delayed / 1.0-1.0
peripheral neuropathy / Delayed / 1.0-1.0

diarrhea / Early / 2.0-2.0
abdominal pain / Early / 1.0-1.0
nausea / Early / 1.0-1.0
gastroesophageal reflux / Delayed / 1.0-1.0
infection / Delayed / 1.0-1.0
malaise / Early / 1.0-1.0

Cholbam

Rx

Oral therapy to provide functional cholic acid
Used for bile acid synthesis disorders due to single enzyme defects and peroxisomal disorders (e.g., Zellweger spectrum disorders)
Specific laboratory monitoring required

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.

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.

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.

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.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Aluminum Hydroxide: (Moderate) Do not administer cholic acid simultaneously with aluminum-based antacids (i.e., aluminum hydroxide) because a reduction in cholic acid absorption will occur. Administer cholic acid at least 1 hour before or 4 to 6 hours (or the maximal interval possible) after an aluminum-based antacids.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Do not administer cholic acid simultaneously with aluminum-based antacids (i.e., aluminum hydroxide) because a reduction in cholic acid absorption will occur. Administer cholic acid at least 1 hour before or 4 to 6 hours (or the maximal interval possible) after an aluminum-based antacids.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Do not administer cholic acid simultaneously with aluminum-based antacids (i.e., aluminum hydroxide) because a reduction in cholic acid absorption will occur. Administer cholic acid at least 1 hour before or 4 to 6 hours (or the maximal interval possible) after an aluminum-based antacids.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Do not administer cholic acid simultaneously with aluminum-based antacids (i.e., aluminum hydroxide) because a reduction in cholic acid absorption will occur. Administer cholic acid at least 1 hour before or 4 to 6 hours (or the maximal interval possible) after an aluminum-based antacids.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Do not administer cholic acid simultaneously with aluminum-based antacids (i.e., aluminum hydroxide) because a reduction in cholic acid absorption will occur. Administer cholic acid at least 1 hour before or 4 to 6 hours (or the maximal interval possible) after an aluminum-based antacids.
Bile acid sequestrants: (Moderate) Do not administer cholic acid simultaneously with bile acid binding resins such as cholestyramine, colestipol, or colesevelam because a reduction in cholic acid absorption will occur. Administer cholic acid at least 1 hour before or 4 to 6 hours (or the maximal interval possible) after a bile acid binding resin.
Cholestyramine: (Moderate) Do not administer cholic acid simultaneously with bile acid binding resins such as cholestyramine, colestipol, or colesevelam because a reduction in cholic acid absorption will occur. Administer cholic acid at least 1 hour before or 4 to 6 hours (or the maximal interval possible) after a bile acid binding resin.
Colesevelam: (Moderate) Do not administer cholic acid simultaneously with bile acid binding resins such as cholestyramine, colestipol, or colesevelam because a reduction in cholic acid absorption will occur. Administer cholic acid at least 1 hour before or 4 to 6 hours (or the maximal interval possible) after a bile acid binding resin.
Colestipol: (Moderate) Do not administer cholic acid simultaneously with bile acid binding resins such as cholestyramine, colestipol, or colesevelam because a reduction in cholic acid absorption will occur. Administer cholic acid at least 1 hour before or 4 to 6 hours (or the maximal interval possible) after a bile acid binding resin.
Cyclosporine: (Major) Avoid concomitant use of cholic acid and inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine because there is a risk of increased accumulation of conjugated bile salts in the liver resulting in clinical symptoms. If concomitant use is unavoidable, then monitor serum transaminases and bilirubin closely.

Cholbam Oral Cap: 50mg, 250mg

15 mg/kg/day PO for most patients; 17 mg/kg/day PO for those with concomitant familial hypertriglyceridemia.

15 mg/kg/day PO for most patients; 17 mg/kg/day PO for those with concomitant familial hypertriglyceridemia.

15 mg/kg/day PO for most patients; 17 mg/kg/day PO for those with concomitant familial hypertriglyceridemia.

15 mg/kg/day PO for most patients; 17 mg/kg/day PO for those with concomitant familial hypertriglyceridemia.

15 mg/kg/day PO for most patients; 17 mg/kg/day PO for those with concomitant familial hypertriglyceridemia.

>= 3 weeks: 15 mg/kg/day PO.
< 3 weeks: Safety and efficacy have not been established.

Cholic acid is a primary bile acid produced by the liver where it is synthesized from cholesterol. 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. 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 provides 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.

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.

Studies of cholic acid in pregnant women or animals have not been conducted; however, limited published case reports have described pregnancies that resulted in healthy infants. If a woman becomes pregnant while taking cholic acid, monitor laboratory parameters more frequently than the standard recommended schedule. A pregnancy surveillance program is available to monitor outcomes in women exposed to cholic acid during pregnancy. Patients who become pregnant while taking cholic acid or their health care provider should call 1—844—202—6262 to enroll.

Endogenous cholic acid is present in human milk; studies have not been conducted to assess the transfer of cholic acid into breast milk or the effect exogenous cholic acid has on the breast fed infant or on milk production. Consider the developmental and health benefits of breast-feeding and the mother's clinical need for cholic acid therapy and possible adverse effects.