Cholic acid

CHOLBAM is a bile acid indicated for: • Treatment of bile acid synthesis disorders due to single enzyme defects (SEDs). • 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. Limitations of use: The safety and effectiveness of CHOLBAM on extrahepatic manifestations of bile acid synthesis disorders due to SEDs or PDs including Zellweger spectrum disorders have not been established.

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).

• The recommended dosage is 10 to 15 mg/kg once daily or in two divided doses, in pediatric patients and adults. See prescribing information for weight-based dosing tables. • The recommended dosage in patients with concomitant familial hypertriglyceridemia is 11 to 17 mg/kg once daily or in two divided doses and is adjusted based on clinical response. • Monitor AST, ALT, GGT, alkaline phosphatase, bilirubin and INR every month for the first 3 months, every 3 months for the next 9 months, every 6 months during the next three years and annually thereafter. Administer the lowest dose that effectively maintains liver function.

None. None

Exacerbation of Liver Impairment: Monitor liver function. Discontinue CHOLBAM if liver function worsens while on treatment. Exacerbation of Liver Impairment In clinical trials, evidence of liver impairment was present before treatment with CHOLBAM 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. Five additional patients (2 SED and 3 PD) who did not have baseline cholestasis experienced exacerbation of their liver disease while on treatment.

The following clinically significant adverse reaction is described elsewhere in the labeling: • Exacerbation of Liver Impairment Most common adverse reactions (≥1%) are diarrhea, reflux esophagitis, malaise, jaundice, skin lesion, nausea, abdominal pain, intestinal polyp, urinary tract infection, and peripheral neuropathy.

• Bile Salt Efflux Pump (BSEP) Inhibitors (e.g., cyclosporine): Avoid concomitant use, if concomitant use is necessary, monitor serum transaminases and bilirubin. • Bile Acid Resins and Aluminum-Based Antacids: Take CHOLBAM 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 antacids. 7.1. Effects of Other Drugs on CHOLBAM Drug interactions with CHOLBAM 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.

Store at 20°C–25 ○ C (68°F–77 ○ F), excursions permitted between 15°C–30 ○ C (59°F–86 ○ F).