Cholbam

CHOLBAM is a bile acid indicated
for:

• Treatment of bile acid synthesis disorders due to single
  enzyme defects (SEDs). (
  1.1 Bile Acid Synthesis
  Disorders due to Single Enzyme Defects

  CHOLBAM is indicated for the 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. (
  1.2 Peroxisomal Disorders
  Including Zellweger Spectrum Disorders

  CHOLBAM 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.
  )

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. (

• 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. (
  2.1 Dosage Regimen for Bile Acid Synthesis Disorders Due to SEDs
  and PDs Including Zellweger Spectrum Disorders

  The recommended dosage of CHOLBAM 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 dosage of 10 mg/kg/day and 15 mg/kg/day, respectively, using the available 50 mg and 250 mg capsules alone or in combination.

  Table 1: Number of CHOLBAM Capsules Needed to Achieve a Recommended Dosage of 10 mg/kg/day

  	10 mg/kg/day Dosage
  Body Weight (kg)	Number of 50 mg capsules	Number of 250 mg capsules
  4 to 6	1	0
  7 to 10	2	0
  11 to 15	3	0
  16 to 20	4	0
  21 to 25	0	1
  26 to 30	1	1
  31 to 35	2	1
  36 to 40	3	1
  41 to 45	4	1
  46 to 50	0	2
  51 to 55	1	2
  56 to 60	2	2
  61 to 65	3	2
  66 to 70	4	2
  71 to 75	0	3
  76 to 80	1	3

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

  	15 mg/kg/day Dosage
  Body Weight (kg)	Number of 50 mg capsules	Number of 250 mg capsules
  4 to 5	1	0
  6 to 9	2	0
  10 to 13	3	0
  14 to 16	4	0
  17 to 19	0	1
  20 to 23	1	1
  24 to 26	2	1
  27 to 29	3	1
  30 to 33	4	1
  34 to 36	0	2
  37 to 39	1	2
  40 to 43	2	2
  44 to 46	3	2
  47 to 49	4	2
  50 to 53	0	3
  54 to 56	1	3
  57 to 59	2	3
  60 to 63	3	3
  64 to 66	4	3
  67 to 69	0	4
  70 to 73	1	4
  74 to 76	2	4
  77 to 79	3	4
  80	4	4

  Patients with newly diagnosed, or a family history of, familial hypertriglyceridemia may have poor absorption of CHOLBAM from the intestine and require a 10% increase in the recommended dosage to account for losses due to malabsorption. The recommended dosage of CHOLBAM 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 the patient’s clinical response including steatorrhea and laboratory values of serum transaminases, bilirubin, and prothrombin time/international normalized ratio (PT/INR).
  )
• 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 (
  2.1 Dosage Regimen for Bile Acid Synthesis Disorders Due to SEDs
  and PDs Including Zellweger Spectrum Disorders

  The recommended dosage of CHOLBAM 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 dosage of 10 mg/kg/day and 15 mg/kg/day, respectively, using the available 50 mg and 250 mg capsules alone or in combination.

  Table 1: Number of CHOLBAM Capsules Needed to Achieve a Recommended Dosage of 10 mg/kg/day

  	10 mg/kg/day Dosage
  Body Weight (kg)	Number of 50 mg capsules	Number of 250 mg capsules
  4 to 6	1	0
  7 to 10	2	0
  11 to 15	3	0
  16 to 20	4	0
  21 to 25	0	1
  26 to 30	1	1
  31 to 35	2	1
  36 to 40	3	1
  41 to 45	4	1
  46 to 50	0	2
  51 to 55	1	2
  56 to 60	2	2
  61 to 65	3	2
  66 to 70	4	2
  71 to 75	0	3
  76 to 80	1	3

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

  	15 mg/kg/day Dosage
  Body Weight (kg)	Number of 50 mg capsules	Number of 250 mg capsules
  4 to 5	1	0
  6 to 9	2	0
  10 to 13	3	0
  14 to 16	4	0
  17 to 19	0	1
  20 to 23	1	1
  24 to 26	2	1
  27 to 29	3	1
  30 to 33	4	1
  34 to 36	0	2
  37 to 39	1	2
  40 to 43	2	2
  44 to 46	3	2
  47 to 49	4	2
  50 to 53	0	3
  54 to 56	1	3
  57 to 59	2	3
  60 to 63	3	3
  64 to 66	4	3
  67 to 69	0	4
  70 to 73	1	4
  74 to 76	2	4
  77 to 79	3	4
  80	4	4

  Patients with newly diagnosed, or a family history of, familial hypertriglyceridemia may have poor absorption of CHOLBAM from the intestine and require a 10% increase in the recommended dosage to account for losses due to malabsorption. The recommended dosage of CHOLBAM 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 the patient’s clinical response including steatorrhea and laboratory values of serum transaminases, bilirubin, and prothrombin time/international normalized ratio (PT/INR).
  )
• 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. (
  2.2 Treatment Monitoring

  Treatment with CHOLBAM 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, 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 CHOLBAM that effectively maintains liver function

  [see Warnings and Precautions (5.1)]

  .

  Discontinue treatment with CHOLBAM if liver function does not improve within 3 months of the start of treatment or if complete biliary obstruction develops.

  Discontinue treatment with CHOLBAM 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 GGT and serum ALT may indicate CHOLBAM overdose [

  see Overdosage (10)].

  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.
  )
• Discontinue CHOLBAM if liver function does not improve within
  3 months of starting treatment, if complete biliary obstruction develops,
  or if there are persistent clinical or laboratory indicators of worsening
  liver function or cholestasis; continue to monitor liver function
  and consider restarting at a lower dose when parameters return to
  baseline. (
  2.2 Treatment Monitoring

  Treatment with CHOLBAM 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, 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 CHOLBAM that effectively maintains liver function

  [see Warnings and Precautions (5.1)]

  .

  Discontinue treatment with CHOLBAM if liver function does not improve within 3 months of the start of treatment or if complete biliary obstruction develops.

  Discontinue treatment with CHOLBAM 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 GGT and serum ALT may indicate CHOLBAM overdose [

  see Overdosage (10)].

  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.
  ,
  5.1 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 (3SED 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. In patients with cirrhosis, cases of severe hepatotoxicity have also been observed following postmarket use of Cholbam Exacerbation of liver impairment by CHOLBAM in these patients cannot be ruled out.

  Six patients with SEDs underwent liver transplant, including four patients diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency, and one with CYP7A1 deficiency.

  Concurrent elevations of serum GGT and ALT may indicate CHOLBAM overdose

  [see Dosage and Administration (2.2)and Overdosage (10)]

  .

  Monitor liver function and discontinue CHOLBAM in patients who develop worsening of liver function while on treatment. Discontinue treatment with CHOLBAM at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis

  [see Dosage and Administration (2.2)]

  .
  )

• Take with food. (
  2.3 Administration Instructions

  • Take CHOLBAM with food.
  • 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 antacid.
  • Do not crush or chew the capsules.
  • For patients unable to swallow the capsules, open the capsules and mix the contents with 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:
    • Hold the capsule over the prepared liquid/food, gently twist open, and allow the contents to fall into the liquid/food.
    • 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.
    • Stir for 30 seconds.
    • The capsule contents will remain as fine granules in the milk or food and will not dissolve.
    • Administer the mixture immediately
  )
• Do not crush or chew the capsules. For patients unable to
  swallow the capsules, the capsules can be opened and the contents
  mixed with drink/food (
  2.3 Administration Instructions

  • Take CHOLBAM with food.
  • 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 antacid.
  • Do not crush or chew the capsules.
  • For patients unable to swallow the capsules, open the capsules and mix the contents with 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:
    • Hold the capsule over the prepared liquid/food, gently twist open, and allow the contents to fall into the liquid/food.
    • 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.
    • Stir for 30 seconds.
    • The capsule contents will remain as fine granules in the milk or food and will not dissolve.
    • Administer the mixture immediately
  )

CHOLBAM is available in two
capsule strengths:

• 50 mg capsule: Size number 2 Swedish orange capsule with
  cap imprinted with "50mg" and body imprinted with "ASK001". The capsules
  contain a white to off-white powder.
• 250 mg capsule: Size number 0 white capsule with a cap
  imprinted with "250mg" and body imprinted with "ASK002". The capsules
  contain a white to off-white powder.

There is a pregnancy surveillance program that monitors pregnancy outcomes in women exposed to CHOLBAM during pregnancy [COCOA Registry (ChOlbam: Child and mOther's heAlth)]. Women who become pregnant during CHOLBAM treatment are encouraged to enroll. Patients or their health care provider should call 1-844-20C-OCOA or 1-844-202-6262 to enroll.