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Cholbam (cholic acid)

What is Cholbam, and how does it work?

Cholbam (cholic acid) is a bile acid used to treat bile acid synthesis disorders due to single enzyme defects (SEDs). It is also used 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. 

What are the side effects of Cholbam?

Common side effects of Cholbam include

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 Cholbam 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 Cholbam.

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
Trial 1
Trial 2*
Overall (%)

Diarrhea
1
2*
3 (2%)

Reflux Esophagitis
1
0
1 (1%)

Malaise
1
0
1 (1%)

Jaundice
1
0
1 (1%)

Skin lesion
1
0
1 (1%)

Nausea
0
1*
1 (1%)

Abdominal Pain
0
1*
1 (1%)

Intestinal Polyp
0
1*
1 (1%)

Urinary Tract Infection
0
1*
1 (1%)

Peripheral Neuropathy
0
1
1 (1%)

*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.

What is the dosage for Cholbam?

Dosage Regimen For Bile Acid Synthesis Disorders Due To Single
Enzyme Defects And Peroxisomal Disorders 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 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 Cholbam Capsules Needed to Achieve
a Recommended Dosage of 10 mg/kg/day

Body Weight (kg)
10 mg/kg/day Dosage

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

Body Weight (kg)
15 mg/kg/day Dosage

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 of patients’ clinical response
    including steatorrhea, and laboratory values including transaminases, bilirubin
    and PT/INR.

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 (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 Cholbam that effectively
    maintains liver function.
  • Discontinue treatment with
    Cholbam if liver function does not improve within 3 months of the start of
    treatment or 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.
    Concurrent elevations of serum gamma glutamyltransferase (GGT) and serum
    alanine
    aminotransferase (ALT) may indicate Cholbam overdose.
    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.

Administration Instructions

  • Take Cholbam with food./li>
  • 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, 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

 

What drugs interact with Cholbam?

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.
  • 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 Cholbam.
  • 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.
Aluminum-Based Antacids
  • Aluminum-based antacids have
    been shown to adsorb bile acids in vitro and can reduce the
    bioavailability of Cholbam.
  • Take Cholbam at least 1 hour before or 4 to 6 hours
    (or at as great an interval as possible) after an aluminum-based antacid.

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Is Cholbam safe to use while pregnant or breastfeeding?

  • No studies in pregnant women or animal reproduction studies have been conducted with
    Cholbam.

  • 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.
  • Endogenous cholic acid is present in human milk.
  • Clinical lactation studies have not been conducted to assess the presence of
    Cholbam in human milk, the effects of Cholbam on the breastfed infant, or the effects of
    Cholbam 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
    Cholbam and any potential adverse effects on the breastfed infant from
    Cholbam or from the underlying maternal condition.
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