ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significantadverse reaction is described elsewhere in the labeling:Exacerbation of Liver Impairment [see Warnings and Precautions (5.1)] Exacerbation of Liver Impairment [see Warnings and Precautions (5.1)] 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 Retrophin, Inc. at 1-877-659-5518 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical TrialsExperience. Because clinical trials are conducted under widely varying conditions,adverse reaction rates observed in the clinical trials of drug cannotbe directly compared to rates in the clinical trials of another drugand may not reflect the rates observed in practice.Clinical safety experience with CHOLBAMconsists of:Trial 1: non-randomized, open-label, single-arm trialof 50 patients with bile acid synthesis disorders due to SEDs and29 patients with PDs including Zellweger spectrum disorders. Safetydata are available over the 18 years of the trial.Trial 2: an extension trial of 12 new patients (10 SEDand PD) along with 31 (21 SED and 10 PD) patients who rolled overfrom Trial 1. Safety data are available for years and 11 monthsof treatment.Adverse events were notcollected systematically in either of these trials. Most patientsreceived an oral dose of 10 to 15 mg/kg/day of CHOLBAM.. Trial 1: non-randomized, open-label, single-arm trialof 50 patients with bile acid synthesis disorders due to SEDs and29 patients with PDs including Zellweger spectrum disorders. Safetydata are available over the 18 years of the trial.. Trial 2: an extension trial of 12 new patients (10 SEDand PD) along with 31 (21 SED and 10 PD) patients who rolled overfrom Trial 1. Safety data are available for years and 11 monthsof treatment.. DeathsIn Trial 1, among the 50 patients with SEDs, patients aged yearor less died, which included three patients originally diagnosed withAKR1D1 deficiency, one with 3-HSD deficiency and one with CYP7A1deficiency. The cause of death was attributed to progression of underlyingliver disease in every patient.Of the 29 patients in Trial with PDs includingZellweger spectrum disorders, 12 patients between the ages of monthsand 2.5 years died. In the majority of these patients (8/12), thecause of death was attributed to progression of underlying liver diseaseor to worsening of their primary illness.Two additional patients in Trial (1 SEDand PD) died who had been off study medication for more than oneyear with the cause of death most likely being progression of theirunderlying 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 underlyingcholestasis.In Trial2, among the 31 patients with SED, two patients (1 new patient and1 who rolled over from Trial 1) died. The cause of death in both caseswas unrelated to their primary treatment or progression of their underlyingliver disease.Ofthe 12 patients with PD in Trial 2, four patients died between theages of and years (1 new patient and who rolled over from Trial1). The cause of death in three of these patients was attributedto progression of underlying liver disease or to worsening of theirprimary illness.. Worsening Liver ImpairmentSeven patients in Trial 1(4 SED and PD)and patients in Trial (1 SED and PD) experienced worsening serumtransaminases, elevated bilirubin values, or worsening cholestasison liver biopsy during treatment [see Warnings and Precautions (5.1)] . Common Adverse ReactionsThere were 12 adverse reactions reportedacross patients in the trials, with diarrhea being the most commonreaction in approximately 2% of the patient population. All otheradverse reactions represented 1% of the patient population. The breakdownby trial follows:Table 3: Most Common Adverse Reactions in Trials and 2Adverse ReactionsTrial 1Trial Adversereactions that occurred in new patients Overall (%) Diarrhea12 (2)Reflux Esophagitis101 (1)Malaise101 (1)Jaundice101 (1)Skin lesion101 (1)Nausea01 (1)Abdominal Pain01 (1)Intestinal Polyp01 (1)Urinary Tract Infection01 (1)Peripheral Neuropathy011 (1)Only one of the reactions(peripheral neuropathy) resulted in discontinuation of medicationfor patient in Trial 2. An additional five SED patients (3 fromTrial and from Trial 2) and PD patient (Trial 1) discontinuedmedication and withdrew from the study due to worsening of theirprimary disease.Thedevelopment of symptomatic cholelithiasis requiring cholecystectomyhas been reported in single patient with 3-HSD deficiency.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. In the PEX2 -/- mouse model of peroxisomal disorders, feeding with combinationof cholic acid and ursodeoxycholic acid normalized 24 bile acid concentrations in bile to that of untreated control animals. Although growth was only mildly improved, there was near completenormalization of stool fat content, resolution of steatorrhea, andimproved survival. Bile acid feeding reduced the number of cholestaticdeposits in bile ducts and alleviated cholangitis but exacerbatedthe degree of hepatic steatosis and mitochondrial and cellular damagein the peroxisome-deficient livers of these animals.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis,Mutagenesis, Impairment of Fertility. Carcinogenicity, genetic toxicology, andnonclinical fertility studies have not been performed with cholicacid.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Cholic acid is primary bileacid synthesized from cholesterol in the liver. In bile acid synthesisdisorders due to SEDs in the biosynthetic pathway, and in PDs includingZellweger spectrum disorders, deficiency of primary bile acids leadsto unregulated accumulation of intermediate bile acids and cholestasis. Bile acids facilitate fat digestion and absorption by forming mixedmicelles and facilitate absorption of fat-soluble vitamins in theintestine.Endogenousbile acids including cholic acid enhance bile flow and provide thephysiologic feedback inhibition of bile acid synthesis. The mechanismof action of cholic acid has not been fully established; however,it is known that cholic acid and its conjugates are endogenous ligandsof the nuclear receptor, farnesoid receptor (FXR). FXR regulatesenzymes and transporters that are involved in bile acid synthesisand in the enterohepatic circulation to maintain bile acid homeostasisunder normal physiologic conditions.. 12.2 Pharmacokinetics. Orally administered cholic acid is subjectto the same metabolic pathway as endogenous cholic acid.Cholic acid is absorbed by passivediffusion along the length of the gastrointestinal tract. Once absorbed,cholic acid enters into the bodys bile acid pool and undergoes enterohepaticcirculation mainly in conjugated forms.In the liver, cholic acid is conjugatedwith glycine or taurine by bile acid-CoA synthetase and bile acid-CoA:aminoacid N-acetyltransferase. Conjugated cholic acid is actively secretedinto bile by the BSEP, and then released into the small intestines,along with other components of bile.Conjugated cholic acid is mostly re-absorbedin the ileum mainly by the apical-sodium-dependent-bile acid transporter,passed back to the liver by transporters including sodium-taurocholatecotransporting polypeptide and organic anion transport protein andenters another cycle of enterohepatic circulation. Any conjugatedcholic acid not absorbed in the ileum passes into the colon wheredeconjugation and 7-dehydroxylation are mediated by bacteria to formcholic acid and deoxycholic acid, which may be re-absorbed in thecolon or excreted in the feces. The loss of cholic acid is compensatedby de-novo synthesis of cholic acids from cholesterol to maintainthe bile acid pool in healthy subjects.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. CHOLBAM is available in twocapsule strengths: 50 mg capsule: Size number Swedish orange capsule withcap imprinted with 50mg and body imprinted with ASK001. The capsulescontain white to off-white powder. 250 mg capsule: Size number white capsule with capimprinted with 250mg and body imprinted with ASK002. The capsulescontain white to off-white powder.. 50 mg capsule: Size number Swedish orange capsule withcap imprinted with 50mg and body imprinted with ASK001. The capsulescontain white to off-white powder.. 250 mg capsule: Size number white capsule with capimprinted with 250mg and body imprinted with ASK002. The capsulescontain white to off-white powder.. Capsules: 50 mg, 250 mg 3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Bile Salt Efflux Pump (BSEP) Inhibitors (e.g.,cyclosporine): Avoid concomitant use; if concomitant useis necessary, monitor serum transaminases and bilirubin 7.1) Bile Acid Resins and Aluminum-Based Antacids: Take CHOLBAM at least hour before or to hours (or at as greatan interval as possible) after bile acid binding resin or aluminum-basedantacids. 2.3, 7.1) Bile Salt Efflux Pump (BSEP) Inhibitors (e.g.,cyclosporine): Avoid concomitant use; if concomitant useis necessary, monitor serum transaminases and bilirubin 7.1) Bile Acid Resins and Aluminum-Based Antacids: Take CHOLBAM at least hour before or to hours (or at as greatan interval as possible) after bile acid binding resin or aluminum-basedantacids. 2.3, 7.1) 7.1 Effects of otherdrugs on CHOLBAM Drug interactions with CHOLBAM mainly relateto agents capable of interrupting the enterohepatic circulation ofbile acids. Inhibitors of Bile Acid TransportersAvoid concomitant use of inhibitors of thebile salt efflux pump (BSEP) such as cyclosporine. Concomitant medicationsthat inhibit canalicular membrane bile acid transporters such as theBSEP may exacerbate accumulation of conjugated bile salts in the liverand result in clinical symptoms. If concomitant use is deemed necessary,monitoring of serum transaminases and bilirubin is recommended.. Bile Acid Binding ResinsBile acid binding resins such as cholestyramine,colestipol, or colesevelam adsorb and reduce bile acid absorptionand may reduce the efficacy of CHOLBAM. Take CHOLBAM at least hourbefore or to hours (or at as great an interval as possible) aftera bile acid binding resin [see Dosage andAdministration (2.3)] . Aluminum-Based AntacidsAluminum-based antacids have been shownto adsorb bile acids in vitro and can reduce thebioavailability of CHOLBAM. Take CHOLBAM at least hour before or4 to hours (or at as great an interval as possible) after an aluminum-basedantacid [see Dosage and Administration (2.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of CHOLBAMdid not include any patients aged 65 years and over. It is not knownif elderly patients respond differently from younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 50 mg CapsulesCHOLBAM capsules are available as two-piecegelatin capsules with Swedish orange cap imprinted with 50mg andSwedish orange body imprinted with ASK001. The capsules containa white or off-white powder and are supplied in bottles of:90 capsules (NDC 45043-001-02). 90 capsules (NDC 45043-001-02). 250 mg CapsulesCHOLBAM capsules are available as two-piecegelatin capsules with white cap imprinted with 250mg and whitebody imprinted with ASK002. The capsules contain white or off-whitepowder and are supplied in bottles of:90 capsules (NDC 45043-002-02). 90 capsules (NDC 45043-002-02). Storage and HandlingStore at 20C-25C(69F-77F), excursions permitted between 15C-30C (59F-86F). [seeUSP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. CHOLBAM is bile acid indicatedfor:Treatment of bile acid synthesis disorders due to singleenzyme defects (SEDs). 1.1) Adjunctive treatment of peroxisomal disorders (PDs) includingZellweger spectrum disorders in patients who exhibit manifestationsof liver disease, steatorrhea or complications from decreased fat-solublevitamin absorption. 1.2) Limitations of use:The safety and effectiveness ofCHOLBAM on extrahepatic manifestations of bile acid synthesis disordersdue to SEDs or PDs including Zellweger spectrum disorders have notbeen established. 1.3). Treatment of bile acid synthesis disorders due to singleenzyme defects (SEDs). 1.1) Adjunctive treatment of peroxisomal disorders (PDs) includingZellweger spectrum disorders in patients who exhibit manifestationsof liver disease, steatorrhea or complications from decreased fat-solublevitamin absorption. 1.2) 1.1 Bile Acid SynthesisDisorders due to Single Enzyme Defects. CHOLBAM is indicated for the treatment ofbile acid synthesis disorders due to single enzyme defects (SEDs). 1.2 Peroxisomal DisordersIncluding Zellweger Spectrum Disorders. CHOLBAM is indicated for adjunctive treatmentof peroxisomal disorders (PDs) including Zellweger spectrum disordersin patients who exhibit manifestations of liver disease, steatorrheaor complications from decreased fat-soluble vitamin absorption.. 1.3 Limitation of Use. The safety and effectivenessof CHOLBAM on extrahepatic manifestations of bile acid synthesis disordersdue to SEDs or PDs including Zellweger spectrum disorders have notbeen established.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Bile Acid SynthesisDisorders due to Single Enzyme Defects. The effectiveness of CHOLBAM at dosagesof 10 to 15 mg/kg per day in patients with SEDs was assessed in:Trial 1: non-randomized, open-label, single-arm trialin 50 patients over an 18-year period.Trial 2: an extension trial of 12 new patients along with21 patients who rolled-over from Trial (n=33 total). Efficacy dataare available for 21 months of treatment.A published case series of 15 patients patients with SEDsand patients with PDs.Enrollment criteria inTrials and were based on abnormal urinary bile acid by Fast AtomBombardment ionization Mass Spectrometry (FAB-MS).Pre- and post-treatment liver biopsies wereperformed in limited number of patients. Documentation of adherenceto treatment, concomitant medications, and response to treatment wereincomplete during Trial 1. Additional interventions in some patientsincluded supplementation with fat-soluble vitamins, as dictated bythe patients clinical signs and symptoms. Trial 1: non-randomized, open-label, single-arm trialin 50 patients over an 18-year period.. Trial 2: an extension trial of 12 new patients along with21 patients who rolled-over from Trial (n=33 total). Efficacy dataare available for 21 months of treatment.. published case series of 15 patients patients with SEDsand patients with PDs.. Trials and 2On average, patients were years of ageat the start of cholic acid treatment (range three weeks to 36 years). The majority of patients were treated for an average of 310 weeks(6 years). Patient ages at the end of treatment ranged from 19 to36 years.These trialswere carried out over many years, and data are not available on allpatients. Thirty-nine patients in Trial and new patients in Trial2 received at least one dose of CHOLBAM and had sufficient data availableto assess baseline liver function and effects of CHOLBAM treatment. responder analysis was performed to determine the response to treatmentwith CHOLBAM.Responseto CHOLBAM treatment was assessed by the following laboratory criteria:ALT or AST values reduced to less than 50 U/L, or baselinelevels reduced by 80%;total bilirubin values reduced to less than or equal to1 mg/dL; andno evidence of cholestasis on liver biopsy;and the following clinicalcriteria:body weight increased by 10% or stable at greater than the50th percentile; andsurvival for greater than years on treatment or aliveat the end of Trial 2CHOLBAM responders weredefined as patients who either:met at least two laboratory criteria and were alive atthe last follow-up; ormet at least one laboratory criterion, had increased bodyweight and were alive at the last follow-up.Overall, 28 of 44 patients(64%) were responders. The breakdown by defect type is as follows:Table 4: Response to CHOLBAM Treatment by Type of SingleEnzyme DefectSingleEnzyme DefectResponders/NumberTreated (%)3-HSD22/37 (59%)AKR1D13/4 (75%)CTX2/2 (100%)AMACR1/1 (100%)CYP7A1N/A N/A indicatesno evaluable patients in the defect subgroup are represented. Smith-Lemli-OpitzN/A Among SED responsivepatients, 45% of the responders met the two clinical criteria plus1 to laboratory criteria and 55% met the weight criteria.Only six patients had pre- andpost-treatment liver biopsies in Trial 1. Where biopsies were available,pre-treatment biopsies showed varying degrees of inflammation, bridgingfibrosis, and giant cell formation. Post-treatment biopsies generallyshowed reduced or absent inflammation and reduced or absent giantcell formation. Fibrosis remained but did not progress.It is difficult to evaluatelong term survival in patients with SEDs since there is little naturalhistory survival data for comparison. Overall, 41 of 62 (67%) patientswith SEDs survived greater than years from trial entry. Thirteenof these 41 patients (32%) survived for 10 to 24 years on treatment.Four patients in Trial underwentliver transplant, including two patients diagnosed with AKR1D1 deficiency,one with 3-HSD deficiency, and one with CYP7A1 deficiency and twopatients in Trial 2, both with AKR1D1.CHOLBAMs effects on extrahepatic manifestationsof SEDs, such as neurologic symptoms have not been established.. ALT or AST values reduced to less than 50 U/L, or baselinelevels reduced by 80%;. total bilirubin values reduced to less than or equal to1 mg/dL; and. no evidence of cholestasis on liver biopsy;. body weight increased by 10% or stable at greater than the50th percentile; and. survival for greater than years on treatment or aliveat the end of Trial 2. met at least two laboratory criteria and were alive atthe last follow-up; or. met at least one laboratory criterion, had increased bodyweight and were alive at the last follow-up.. Case SeriesA published report of case series described 15 patients with SEDs;thirteen were diagnosed with 3-HSD deficiency and two with AKR1D1deficiency by mass spectrometry and gene sequencing. All patientswere treated with cholic acid with median duration of treatmentof 12.4 years (range 5.6 to 15 years). Therapy started at medianage of 3.9 years (range 0.3 to 13.1 years). The mean dose at the startof cholic acid treatment was 13 mg/kg and the mean dose at last followup was mg/kg. Eight patients were initially treated with oral ursodeoxycholicacid prior to receiving diagnosis of bile acid synthesis defect,after which they were switched to cholic acid. Initial signs andsymptoms included jaundice, hepatosplenomegaly, steatorrhea, or symptomsrelated to deficiency of fat-soluble vitamin (K, or E).Of the patients who receivedursodeoxycholic acid initially, the six with 3-HSD deficiency demonstratedmild clinical improvement. Following treatment with cholic acid,all patients experienced resolution of their pre-existing jaundiceand steatorrhea, and all but one experienced resolution of hepatosplenomegaly. Weight and height improved, and sexual maturation progressed normallyin all patients. Liver biopsies were performed in 14 patients afterat least years of cholic acid treatment and all showed resolutionof cholestasis. In one patient with 3-HSD deficiency, biliary bileacid analysis while on cholic acid therapy showed enrichment of thebile with cholic acid.. 14.2 Peroxisomal Disordersincluding Zellweger Spectrum Disorders. The effectiveness of CHOLBAM at dosageof 10 to 15 mg/kg per day in patients with PDs including Zellwegerspectrum disorders was assessed in patients in the same trials describedin section 14.1. Trial treated 29 patients with PDs over an 18-year period.Trial treated new patients along with 10 patients whorolled over from Trial (n=12 total). Efficacy data are availablefrom Trial for 21 months of treatment.Additional efficacy data were obtained from published casereports of patients.Enrollment criteria inTrials and were based on abnormal urinary bile acids analysisby FAB-MS and neurologic exam. Most patients received concomitantDHA (docosahexaenoic acid) and Vitamins A, D, E, and K. Documentationof adherence to treatment, concomitant medications, and response totreatment were incomplete during Trial 1.. Trial treated 29 patients with PDs over an 18-year period.. Trial treated new patients along with 10 patients whorolled over from Trial (n=12 total). Efficacy data are availablefrom Trial for 21 months of treatment.. Additional efficacy data were obtained from published casereports of patients.. Trials and 2The majority of patients (80%, 25/31) wereless than years of age at the start of CHOLBAM treatment (range3 weeks to 10 years). The majority of patients were treated for anaverage of 254 weeks (4.8 years). Sufficient data were available to assessbaseline liver function and effects of CHOLBAM treatment in 23 patientsin Trial and in one new patient in Trial 2. responder analysiswas performed in the patients who had received at least one dose ofCHOLBAM and had sufficient data available to assess baseline liverimpairment.Responseto CHOLBAM treatment was assessed by the following laboratory criteria:ALT or AST values reduced to less than 50 U/L, or baselinelevels reduced by 80%;total bilirubin values reduced to less than or equal to1 mg/dL; andno evidence of cholestasis on liver biopsy;and the following clinicalcriteria:body weight increased by 10% or stable at greater than the50th percentile; andsurvival for greater than years on treatment or aliveat the end of Trial 2CHOLBAM responders weredefined as patients who either:met at least two laboratory criteria and were alive atthe last follow-up; ormet at least one laboratory criterion, had increased bodyweight and were alive at the last follow-up.Overall, 11 of 24 patients(46%) were responders. The breakdown by disorder is as follows:Table 5: Response to CHOLBAM Treatment by Type of PeroxisomalDisorders including Zellweger Spectrum DisordersPeroxisomal DisorderResponders/Number Treated(%)Neonatal Adrenoleukodystropyhy3/6 (50%)Generalized Peroxisomal Disorder1/1 (100%)Refsum Disease3/4 (75%)Zellweger Syndrome3/8 (38%)Peroxisomal Disorder, Type Unknown1/5 (20%)Among responsive patientswith PDs, 38% of the responders met the two clinical criteria plus1 to laboratory criteria and 63% met the weight criteria. Therewere no PD patients that underwent liver transplant.No evidence of improvement in survival overthat seen in historical controls could be demonstrated from the datapresented. Overall, 13 of 31 patients (42%) survived greater than3 years from the time of trial entry. Eight of these 13 patients (62%)survived 10 to 17 years on treatment.Nine patients had both pre- and post-treatmentliver biopsies. One patient showed improvement in histology, whilethe majority of patients remained unchanged. Two patients demonstratedworsening histology, which was consistent with worsening of otherliver laboratory parameters (bilirubin, serum transaminase values).CHOLBAMs effects on extrahepaticmanifestations of PDs including Zellweger spectrum disorders, suchas neurologic symptoms have not been established.One patient, who did not have cholestasison pre-treatment liver biopsy, developed cholestasis on treatmentwith CHOLBAM and subsequently died.. ALT or AST values reduced to less than 50 U/L, or baselinelevels reduced by 80%;. total bilirubin values reduced to less than or equal to1 mg/dL; and. no evidence of cholestasis on liver biopsy;. body weight increased by 10% or stable at greater than the50th percentile; and. survival for greater than years on treatment or aliveat the end of Trial 2. met at least two laboratory criteria and were alive atthe last follow-up; or. met at least one laboratory criterion, had increased bodyweight and were alive at the last follow-up.. Case ReportsIn case reports from the literature, 6-month-oldpatient with Zellweger syndrome treated with combination of cholicand chenodeoxycholic acids experienced normalization of serum transaminasesand bilirubin, improvement in liver histology, reduced serum and urinaryatypical bile acid intermediates, and improvement in steatorrhea andgrowth. Two patients with Zellweger syndrome treated with oral bileacids showed decreased serum transaminases.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None 4).

DESCRIPTION SECTION.

11 DESCRIPTION. Cholic acid is bile acid producedby the liver where it is synthesized from cholesterol. The chemicalformula is 24H 40O 5, the molecular weight is 408.57 and the chemical structureis: Cholic acid is white to off-white powder. It is practically insoluble in water and in 0.1 HCl at 20C andis sparingly soluble in 0.1 NaOH at 20C. It is soluble in glacialacetic acid, alcohols, and acetone. saturated solution in waterat 20C has pH of 4.4.CHOLBAM capsules contain 50 mg or 250 mg of cholic acid as the activeingredient in size Swedish orange or size white opaque gelatincapsules, respectively. Inactive ingredients in CHOLBAM include silicifiedmicrocrystalline cellulose, magnesium stearate, and hard gelatin capsules.The size shells contain gelatin, red iron oxide and titanium dioxide,and the size shells contain gelatin and titanium dioxide. CHOLBAMis administered orally.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage is 10 to 15 mg/kg once daily or intwo divided doses, in pediatric patients and adults. See prescribinginformation for weight-based dosing tables. 2.1) The recommended dosage in patients with concomitant familialhypertriglyceridemia is 11 to 17 mg/kg once daily or in two divideddoses and is adjusted based on clinical response 2.1) Monitor AST, ALT, GGT, alkaline phosphatase, bilirubin andINR every month for the first months, every months for the next9 months, every months during the next three years and annuallythereafter. Administer the lowest dose that effectively maintainsliver function. 2.2) Discontinue CHOLBAM if liver function does not improve within3 months of starting treatment, if complete biliary obstruction develops,or if there are persistent clinical or laboratory indicators of worseningliver function or cholestasis; continue to monitor liver functionand consider restarting at lower dose when parameters return tobaseline. 2.2, 5.1) Administration Instructions:Take with food. 2.3) Do not crush or chew the capsules. For patients unable toswallow the capsules, the capsules can be opened and the contentsmixed with drink/food 2.3) The recommended dosage is 10 to 15 mg/kg once daily or intwo divided doses, in pediatric patients and adults. See prescribinginformation for weight-based dosing tables. 2.1) The recommended dosage in patients with concomitant familialhypertriglyceridemia is 11 to 17 mg/kg once daily or in two divideddoses and is adjusted based on clinical response 2.1) Monitor AST, ALT, GGT, alkaline phosphatase, bilirubin andINR every month for the first months, every months for the next9 months, every months during the next three years and annuallythereafter. Administer the lowest dose that effectively maintainsliver function. 2.2) Discontinue CHOLBAM if liver function does not improve within3 months of starting treatment, if complete biliary obstruction develops,or if there are persistent clinical or laboratory indicators of worseningliver function or cholestasis; continue to monitor liver functionand consider restarting at lower dose when parameters return tobaseline. 2.2, 5.1) Take with food. 2.3) Do not crush or chew the capsules. For patients unable toswallow the capsules, the capsules can be opened and the contentsmixed with drink/food 2.3) 2.1 Dosage Regimen for Bile Acid Synthesis Disorders Due to SEDsand PDs Including Zellweger Spectrum Disorders. The recommended dosage of CHOLBAMis 10 to 15 mg/kg administered orally once daily, or in two divideddoses, in pediatric patients and in adults.Tables and show the number of capsulesthat should be administered daily to approximate dosage of 10 mg/kg/dayand 15 mg/kg/day, respectively, using the available 50 mg and 250mg capsules alone or in combination.Table 1: Number of CHOLBAM Capsules Needed to Achieve aRecommended Dosage of 10 mg/kg/day10 mg/kg/day DosageBody Weight (kg)Number of 50 mg capsulesNumber of 250 mg capsules4 to 6107 to 102011 to 153016 to 204021 to 250126 to 301131 to 352136 to 403141 to 454146 to 500251 to 551256 to 602261 to 653266 to 704271 to 750376 to 8013Table 2: Number of CHOLBAM Capsules Needed to Achieve aRecommended Dosage of 15 mg/kg/day15 mg/kg/day DosageBody Weight (kg)Number of 50 mg capsulesNumber of 250 mg capsules4 to 5106 to 92010 to 133014 to 164017 to 190120 to 231124 to 262127 to 293130 to 334134 to 360237 to 391240 to 432244 to 463247 to 494250 to 530354 to 561357 to 592360 to 633364 to 664367 to 690470 to 731474 to 762477 to 79348044Patients with newly diagnosed,or family history of, familial hypertriglyceridemia may have poorabsorption of CHOLBAM from the intestine and require 10% increasein the recommended dosage to account for losses due to malabsorption.The recommended dosage of CHOLBAM in patients with concomitant familialhypertriglyceridemia is 11 to 17 mg/kg orally once daily, or in twodivided doses. Adequacy of the dosage regimen can be determined bymonitoring the patients clinical response including steatorrhea andlaboratory values of serum transaminases, bilirubin, and prothrombintime/international normalized ratio (PT/INR).. 2.2 Treatment Monitoring. Treatment with CHOLBAM shouldbe initiated and monitored by an experienced hepatologist or pediatricgastroenterologist.Monitor serum aspartate aminotransferase (AST), serum alanine aminotransferase(ALT), serum gamma glutamyltransferase (GGT), alkaline phosphatase,bilirubin, and INR every month for the first months, every monthsfor the next months, every months during the subsequent threeyears, and annually thereafter. Monitor more frequently during periodsof rapid growth, concomitant disease, and pregnancy. Administer thelowest dose of CHOLBAM that effectively maintains liver function [see Warnings and Precautions (5.1)] Discontinue treatmentwith CHOLBAM if liver function does not improve within months ofthe start of treatment or if complete biliary obstruction develops.Discontinue treatment with CHOLBAMat any time if there are persistent clinical or laboratory indicatorsof worsening liver function or cholestasis [see Warnings and Precautions (5.1)] Concurrent elevations of serumGGT and serum ALT may indicate CHOLBAM overdose see Overdosage (10)]. Continue to monitorlaboratory parameters of liver function and consider restarting ata lower dose when the parameters return to baseline. Assessment of serum or urinary bile acidlevels using mass spectrometry is used in the diagnosis of bile acidsynthesis disorders due to SEDs and PDs including Zellweger spectrumdisorders. The utility of bile acid measurements in monitoring theclinical course of patients and in decisions regarding dose adjustmenthas not been demonstrated.. 2.3 Administration Instructions. Take CHOLBAM with food. Take CHOLBAM at least hour before or to hours (orat as great an interval as possible) after bile acid binding resinor aluminum-based antacid. Do not crush or chew the capsules. For patients unable to swallow the capsules, open thecapsules and mix the contents with infant formula or expressed breastmilk (for younger children), or soft food such as mashed potatoesor apple puree (for older children and adults) in order to mask anyunpleasant taste: Hold the capsule over the prepared liquid/food, gently twistopen, 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 softfood such as mashed potatoes or apple puree.Stir for 30 seconds.The capsule contents will remain as fine granules in themilk or food and will not dissolve.Administer the mixture immediately Take CHOLBAM with food.. Take CHOLBAM at least hour before or to hours (orat as great an interval as possible) after bile acid binding resinor aluminum-based antacid.. Do not crush or chew the capsules.. For patients unable to swallow the capsules, open thecapsules and mix the contents with infant formula or expressed breastmilk (for younger children), or soft food such as mashed potatoesor apple puree (for older children and adults) in order to mask anyunpleasant taste: Hold the capsule over the prepared liquid/food, gently twistopen, 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 softfood such as mashed potatoes or apple puree.Stir for 30 seconds.The capsule contents will remain as fine granules in themilk or food and will not dissolve.Administer the mixture immediately Hold the capsule over the prepared liquid/food, gently twistopen, 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 softfood such as mashed potatoes or apple puree.. Stir for 30 seconds.. The capsule contents will remain as fine granules in themilk or food and will not dissolve.. Administer the mixture immediately.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Exacerbation of Liver Impairment [see Warningsand Precautions (5.1)] Advise patients that they will need to undergo laboratorytesting periodically while on treatment to assess liver function.Advise patients that CHOLBAM may worsen liver impairmentand that they should immediately report to their health care providerany symptoms associated with liver impairment (e.g., yellowing ofthe skin or the whites of the eye, dark or tea-colored urine, painon the right side of stomach, bleeding or bruising occurs more easilythan normal, or increased lethargy). Advise patients that they will need to undergo laboratorytesting periodically while on treatment to assess liver function.. Advise patients that CHOLBAM may worsen liver impairmentand that they should immediately report to their health care providerany symptoms associated with liver impairment (e.g., yellowing ofthe skin or the whites of the eye, dark or tea-colored urine, painon the right side of stomach, bleeding or bruising occurs more easilythan normal, or increased lethargy). Administration [see Dosage and Administration(2.3)] Advise patients:to take CHOLBAM with food.to take CHOLBAM at least one hour before or to hoursafter taking bile acid binding resin or an aluminum-based antacid.not to crush or chew the capsules.for infants and children who cannot swallow capsules, thecapsules can be opened and the contents mixed with either infant formulaor expressed breast milk (for younger children), or soft food suchas 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 twistopen, and allow the contents to fall into the liquid/food.Mix the entire capsule contents with one or two tablespoonfuls(15 mL to 30 mL) of infant formula, expressed breast milk, or softfood such as mashed potatoes or apple puree.Stir for 30 seconds.The capsule contents will remain as fine granules in themilk or food and will not dissolve.Administer the mixture immediately. to take CHOLBAM with food.. to take CHOLBAM at least one hour before or to hoursafter taking bile acid binding resin or an aluminum-based antacid.. not to crush or chew the capsules.. for infants and children who cannot swallow capsules, thecapsules can be opened and the contents mixed with either infant formulaor expressed breast milk (for younger children), or soft food suchas 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 twistopen, and allow the contents to fall into the liquid/food.Mix the entire capsule contents with one or two tablespoonfuls(15 mL to 30 mL) of infant formula, expressed breast milk, or softfood such as mashed potatoes or apple puree.Stir for 30 seconds.The capsule contents will remain as fine granules in themilk or food and will not dissolve.Administer the mixture immediately. Hold the capsule over the prepared liquid/food, gently twistopen, and allow the contents to fall into the liquid/food.. Mix the entire capsule contents with one or two tablespoonfuls(15 mL to 30 mL) of infant formula, expressed breast milk, or softfood such as mashed potatoes or apple puree.. Stir for 30 seconds.. The capsule contents will remain as fine granules in themilk or food and will not dissolve.. Administer the mixture immediately.. Pregnancy Registry [see Use in SpecificPopulations (8.1)] Inform patients about the pregnancy surveillanceprogram that monitors pregnancy outcomes in women exposed to CHOLBAMduring pregnancy.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Cholic acid is primary bileacid synthesized from cholesterol in the liver. In bile acid synthesisdisorders due to SEDs in the biosynthetic pathway, and in PDs includingZellweger spectrum disorders, deficiency of primary bile acids leadsto unregulated accumulation of intermediate bile acids and cholestasis. Bile acids facilitate fat digestion and absorption by forming mixedmicelles and facilitate absorption of fat-soluble vitamins in theintestine.Endogenousbile acids including cholic acid enhance bile flow and provide thephysiologic feedback inhibition of bile acid synthesis. The mechanismof action of cholic acid has not been fully established; however,it is known that cholic acid and its conjugates are endogenous ligandsof the nuclear receptor, farnesoid receptor (FXR). FXR regulatesenzymes and transporters that are involved in bile acid synthesisand in the enterohepatic circulation to maintain bile acid homeostasisunder normal physiologic conditions.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis,Mutagenesis, Impairment of Fertility. Carcinogenicity, genetic toxicology, andnonclinical fertility studies have not been performed with cholicacid.. 13.2 Animal Toxicology and/or Pharmacology. In the PEX2 -/- mouse model of peroxisomal disorders, feeding with combinationof cholic acid and ursodeoxycholic acid normalized 24 bile acid concentrations in bile to that of untreated control animals. Although growth was only mildly improved, there was near completenormalization of stool fat content, resolution of steatorrhea, andimproved survival. Bile acid feeding reduced the number of cholestaticdeposits in bile ducts and alleviated cholangitis but exacerbatedthe degree of hepatic steatosis and mitochondrial and cellular damagein the peroxisome-deficient livers of these animals.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Concurrent elevations of serumGGT and ALT may indicate CHOLBAM overdose. If an overdose is suspected,discontinue CHOLBAM and treat symptoms. Continue to monitor laboratoryparameters of liver function and consider restarting at lower dosewhen the parameters return to baseline [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 50 mg Capsule Bottle Label. NDC 45043- 001-02 90 capsules Cholbam(TM) (cholic acid) capsules 50 mgRx OnlyManufactured for: Manchester Pharmaceuticals, Inc., San Diego, CA 92130 Manufactured by: Patheon France SA 38300 Bourgoin-Jallieu, France For product information please call 844-246-5226.. PRINCIPAL DISPLAY PANEL 50 mg Capsule Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectivenessof CHOLBAM have been established in pediatric patients weeks ofage and older for the treatment of bile acid synthesis disorders dueto SEDs and for adjunctive treatment of patients with PDs includingZellweger spectrum disorders who exhibit manifestations of liver disease,steatorrhea, or complications from decreased fat-soluble vitamin absorption [see Clinical Studies (14)].

PHARMACOKINETICS SECTION.

12.2 Pharmacokinetics. Orally administered cholic acid is subjectto the same metabolic pathway as endogenous cholic acid.Cholic acid is absorbed by passivediffusion along the length of the gastrointestinal tract. Once absorbed,cholic acid enters into the bodys bile acid pool and undergoes enterohepaticcirculation mainly in conjugated forms.In the liver, cholic acid is conjugatedwith glycine or taurine by bile acid-CoA synthetase and bile acid-CoA:aminoacid N-acetyltransferase. Conjugated cholic acid is actively secretedinto bile by the BSEP, and then released into the small intestines,along with other components of bile.Conjugated cholic acid is mostly re-absorbedin the ileum mainly by the apical-sodium-dependent-bile acid transporter,passed back to the liver by transporters including sodium-taurocholatecotransporting polypeptide and organic anion transport protein andenters another cycle of enterohepatic circulation. Any conjugatedcholic acid not absorbed in the ileum passes into the colon wheredeconjugation and 7-dehydroxylation are mediated by bacteria to formcholic acid and deoxycholic acid, which may be re-absorbed in thecolon or excreted in the feces. The loss of cholic acid is compensatedby de-novo synthesis of cholic acids from cholesterol to maintainthe bile acid pool in healthy subjects.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy surveillance programthat monitors pregnancy outcomes in women exposed to CHOLBAM duringpregnancy [COCOA Registry (ChOlbam: Child and mOthers heAlth)]. Women who become pregnant during CHOLBAM treatment are encouragedto enroll. Patients or their health care provider should call 1-844-20C-OCOAor 1-844-202-6262 to enroll. Risk SummaryNo studies in pregnant women or animal reproductionstudies have been conducted with CHOLBAM. Limited published case reports discuss pregnanciesin women taking cholic acid for 3-HSD deficiency resulting in healthyinfants. These reports may not adequately inform the presence or absenceof drug-associated risk with the use of CHOLBAM during pregnancy. The background risk of major birth defects and miscarriage for theindicated population is unknown. However, the background risk inthe U.S. general population of major birth defects is 2-4% and ofmiscarriage is 15-20% of clinically recognized pregnancies.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Exacerbation of Liver Impairment 5.1) 10/2020.

SPL UNCLASSIFIED SECTION.

1.1 Bile Acid SynthesisDisorders due to Single Enzyme Defects. CHOLBAM is indicated for the treatment ofbile acid synthesis disorders due to single enzyme defects (SEDs).

STORAGE AND HANDLING SECTION.

Storage and HandlingStore at 20C-25C(69F-77F), excursions permitted between 15C-30C (59F-86F). [seeUSP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy surveillance programthat monitors pregnancy outcomes in women exposed to CHOLBAM duringpregnancy [COCOA Registry (ChOlbam: Child and mOthers heAlth)]. Women who become pregnant during CHOLBAM treatment are encouragedto enroll. Patients or their health care provider should call 1-844-20C-OCOAor 1-844-202-6262 to enroll. Risk SummaryNo studies in pregnant women or animal reproductionstudies have been conducted with CHOLBAM. Limited published case reports discuss pregnanciesin women taking cholic acid for 3-HSD deficiency resulting in healthyinfants. These reports may not adequately inform the presence or absenceof drug-associated risk with the use of CHOLBAM during pregnancy. The background risk of major birth defects and miscarriage for theindicated population is unknown. However, the background risk inthe U.S. general population of major birth defects is 2-4% and ofmiscarriage is 15-20% of clinically recognized pregnancies.. 8.2 Lactation. Risk SummaryEndogenous cholic acid is present in humanmilk. Clinical lactation studies have not been conducted to assessthe presence of CHOLBAM in human milk, the effects of CHOLBAM on thebreastfed infant, or the effects of CHOLBAM on milk production. Thereare no animal lactation data and no data from case reports availablein the published literature. The developmental and health benefitsof breastfeeding should be considered along with the mothers clinicalneed for CHOLBAM and any potential adverse effects on the breastfedinfant from CHOLBAM or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectivenessof CHOLBAM have been established in pediatric patients weeks ofage and older for the treatment of bile acid synthesis disorders dueto SEDs and for adjunctive treatment of patients with PDs includingZellweger 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 CHOLBAMdid not include any patients aged 65 years and over. It is not knownif elderly patients respond differently from younger patients.. 8.6Hepatic Impairment. Discontinue treatment with CHOLBAMif liver function does not improve within months of the start oftreatment.Discontinuetreatment with CHOLBAM at any time if there are clinical or laboratoryindicators of worsening liver function or cholestasis see Warnings and Precautions (5.1), Overdosage (10), and Nonclinical Toxicology(13.2) ]. Continue to monitor laboratory parametersof liver function and consider restarting at lower dose when theparameters return to baseline.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Exacerbation of LiverImpairment: Monitor liver function. Discontinue CHOLBAMif liver function worsens while on treatment. 5.1) 5.1Exacerbation of LiverImpairment. In clinical trials, evidence of liver impairment was present beforetreatment with CHOLBAM in approximately 86% (44/51) of patients withbile 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 PD) with liver impairment at baselineexperienced worsening serum transaminases, elevated bilirubin values,or worsening cholestasis on liver biopsy following treatment. Fiveadditional patients (2 SED and PD) who did not have baseline cholestasisexperienced exacerbation of their liver disease while on treatment.In patients with cirrhosis, cases of severe hepatotoxicity have alsobeen observed following postmarket use of Cholbam Exacerbation ofliver impairment by CHOLBAM in these patients cannot be ruled out.Six patients with SEDs underwentliver transplant, including four patients diagnosed with AKR1D1 deficiency,one with 3-HSD deficiency, and one with CYP7A1 deficiency.Concurrent elevations ofserum GGT and ALT may indicate CHOLBAM overdose [see Dosage and Administration (2.2) and Overdosage (10)] Monitor liver function and discontinue CHOLBAMin patients who develop worsening of liver function while on treatment.Discontinue treatment with CHOLBAM at any time if there are clinicalor laboratory indicators of worsening liver function or cholestasis [see Dosage and Administration (2.2)].