Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 20 February 2017

Indication(s)

1 INDICATIONS AND USAGE CHOLBAM is a bile acid indicated for: Treatment of bile acid synthesis disorders due to single enzyme defects (SEDs).

(1.1) 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) Limitation 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.

(1.3).

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) [see Clinical Trials (14.1)].

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 [see Clinical Trials (14.2)].

1.3 Limitation 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.

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions

6 ADVERSE REACTIONS Most common adverse reactions (?1 %) are diarrhea, reflux esophagitis, malaise, jaundice, skin lesion, nausea, abdominal pain, intestinal polyp, urinary tract infection, and peripheral neuropathy.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Manchester Pharmaceuticals, Inc.

A wholly owned subsidiary of Retrophin, Inc. at 1 - 844-Cholbam or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not 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, single-arm 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 3?

-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 2Adverse reactions that occurred in new patients 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 %) 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 3?

-HSD deficiency.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION 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) 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) 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) 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 a lower dose when parameters return to baseline.

(2.2, 5.1, 8.6) Administration Instructions: Take with food.

(2.3) 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) 2.1 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 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 of patients ' clinical response including steatorrhea, and laboratory values including transaminases, bilirubin and PT/INR.

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 (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 [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 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 gamma glutamyltransferase (GGT) and serum alanine aminotransferase (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.

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, 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: 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

Use in special populations

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry 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- 844-20 C-OCOA or 1-844-202-6262 to enroll.

Risk Summary No studies in pregnant women or animal reproduction studies have been conducted with CHOLBAM. Limited published case reports discuss pregnancies in women taking cholic acid for 3?

-HSD deficiency resulting in healthy infants.

These reports may not adequately inform the presence or absence of drug-associated risk with the use of CHOLBAM during pregnancy.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

However, the background risk in the U.S. general population of major birth defects is 2-4 % and of miscarriage is 15-20 % of clinically recognized pregnancies.

8.2 Lactation Risk Summary 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.

8.4 Pediatric Use The safety and effectiveness of CHOLBAM has been established in pediatric patients 3 weeks of age and older for the treatment of bile acid synthesis disorders due to SEDs, and for adjunctive treatment of patients with PDs including Zellweger spectrum disorders who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption [see Clinical Studies (14)].

8.5 Geriatric Use Clinical studies of CHOLBAM did not include any patients aged 65 years and over.

It is not known if elderly patients respond differently from younger patients.

8.6 Hepatic Impairment Discontinue treatment with CHOLBAM if liver function does not improve within 3 months of the start of treatment.

Discontinue treatment with CHOLBAM at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis [see Warnings and Precautions (5.1), Overdosage (10) and Nonclinical Toxicology (13.2)].

Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline.

Interactions

7 DRUG INTERACTIONS Bile Salt Efflux Pump (BSEP) Inhibitors (e.g., cyclosporine): Avoid concomitant use; if concomitant use is necessary, monitor serum transaminases and bilirubin (7.1) 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.

(2.3, 7.1) 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.

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 [see Dosage and Administration (2.3)].

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 [see Dosage and Administration (2.3)].

More information

Category Value
Authorisation number NDA205750
Agency product number G1JO7801AE
Orphan designation No
Product NDC 45043-002,45043-001
Date Last Revised 23-03-2015
Type HUMAN PRESCRIPTION DRUG
RXCUI 1440868
Storage and handling Storage and Handling Store at 20–25°C (69-77°F), excursions permitted between 15-30°C (59-86°F). [see USP Controlled Room Temperature].
Marketing authorisation holder Manchester Pharmaceuticals