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Date Printed: October 23, 2017: 07:19 AM

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09-J2000-41

Original Effective Date: 08/15/15

Reviewed: 07/13/16

Revised: 09/15/16

Subject: Cholic Acid (Cholbam®) Capsule

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates  
           

DESCRIPTION:

Cholic acid (Cholbam®) is an oral primary bile acid approved by the Food and Drug Administration (FDA) in March 2015 for pediatric patients (≥3 weeks of age) and adult patients with bile acid synthesis disorders (BASD) due to single enzyme defects (SED), and as adjunctive treatment for patients with peroxisomal disorders (PD), including Zellweger spectrum disorders, with hepatic manifestations. The FDA previously granted cholic acid orphan designation for the “treatment of inborn errors of cholesterol and bile acid synthesis and metabolism” in July 2003.

The true incidence of BASDs is unknown; however, it is believed to represent 1 to 2% of childhood cholestatic disorders with an estimated overall prevalence of 1 to 9 per 1,000,000 persons. There are at least 16 enzymes that convert cholesterol to the two primary bile acids, cholic acid and chenodeoxycholic acid. At the genetic level, 9 inborn errors in the bile acid biosynthetic pathways have been described to date, and each result in different metabolic products and clinical symptomology. In many BASDs the deficiency of primary bile acids leads to unregulated accumulation of toxic intermediate bile acids and subsequent cholestasis, neurologic disease, and/or fat malabsorption. The age of onset, specific symptoms, and rate of progression can vary greatly. Peroxisomal disorders (PD) are a heterogenous group of inborn errors of metabolism that result in impaired peroxisome function. Peroxisomes are organelles that catalyze numerous cellular processes including the final stage of bile acid synthesis. Not all PDs result in hepatic disease; neurologic dysfunction due to accumulation of very long chain fatty acids (VLCFA) is the primary clinical concern. Cholic acid works by enhancing bile flow, increasing fat and fat-soluble vitamin absorption, and providing physiologic feedback inhibition of the altered bile acid synthesis.

The FDA approval of Cholbam was primarily based on data from an 18-year, open-label, single-arm, compassionate use study (CAC-91-10-10, SED=50, PD=29), and a 21-month extension study (CAC-002-01) that included 14 new patients (SED=12, PD=2) and 31 patients (SED=21, PD=10) from CAC-91-10-10. For the SED patients, enrollment was based on presence of cholestatic liver disease and abnormal urinary bile acids by fast atom bombardment - mass spectrometry (FAB-MS) analysis. The most common SED was 3-beta-dehydrogenase deficiency. On average, SED patients were 4 years of age at the start of treatment (range of 3 weeks to 36 years) and most patients were treated with 15 mg/kg PO daily for an average of 6 years. Of 44 evaluable patients, 28 (64%) responded to cholic acid treatment. Response was determined by a combination of lab values (AST/ALT reduction, total bilirubin ≤1 mg/dL, no cholestasis on liver biopsy) and clinical outcomes (increased body weight, survival for >3 years). Survival for >3 years was reported in 67% (41 of 62) of patients, and 13 of the surviving patients lived 10 to 24 years on treatment.

For the PD patients, enrollment was based on presence of abnormal neurologic function, cholestatic liver disease, serum long-chain fatty acids test positive, and abnormal urinary bile acids by FAB-MS analysis. The most common PD was Zellweger syndrome. The majority of patients (80%) were less than 2 years of age at the start of cholic acid treatment (range of 3 weeks to 10 years), and most patients were treated for an average of 4.8 years. Of 24 evaluable patients, 11 (46%) responded to cholic acid treatment. Survival for >3 years was reported in 42% (13 of 31) of patients, and 8 of the surviving patients lived 10 to 17 years on treatment; this was not an improvement compared with historical controls.

POSITION STATEMENT:

Comparative Effectiveness

The Food and Drug Administration has deemed the drug(s) or biological product(s) in this coverage policy to be appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility is not considered medically necessary.

Initiation of cholic acid (Cholbam®) meets the definition of medical necessity for members meeting ALL of the following criteria:

1. Cholic acid is prescribed by a board-certified medical geneticist, board-certified pediatric gastroenterologist, or a board-certified gastroenterologist with experience in treating liver diseases (e.g., hepatologist)

2. The member has EITHER of the of following disorders (“a” or “b”):

a. ANY of the following bile acid synthesis disorders (BASD) due to a single enzyme defect (SED):

i. 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase (3β-HSD) deficiency

(a.k.a., 3-beta-dehydrogenase deficiency, or BAS defect type 1)

ii. Delta4-3-oxosteroid 5-beta reductase deficiency

(a.k.a., 5-beta-reductase deficiency, or BAS defect type 2)

iii. Alpha-methylacyl-CoA racemase deficiency

(a.k.a., 2-methylacyl-CoA racemase deficiency, or BAS defect type 4)

iv. Cholesterol 7-alpha-hydroxylase (CYP7A1) deficiency

v. Cerebrotendinous xanthomatosis (CTX) (i.e., sterol 27-hydroxylase deficiency)

vi. Smith-Lemli-Opitz syndrome (SLOS) (i.e., 7-dehydrocholesterol reductase (DHCR7) deficiency)

Note: Cholic acid therapy is NOT effective in the treatment of BASD due to oxysterol 7-alpha-hydroxylase deficiency (BAS defect type 3), OR amidation defects (i.e., amino acid n-acyltransferase deficiency or bile acid CoA ligase deficiency).

b. A peroxisomal disorder (PD) [e.g., Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD)] with at least ONE of the following associated clinical presentations:

i. Complications from decreased fat soluble vitamin (A, D, E, K) absorption (e.g., rickets)

ii. Manifestations of liver disease (e.g., jaundice, cholestasis, hepatomegaly)

iii. Steatorrhea

3. The member’s diagnosis is confirmed by EITHER of the following (lab documentation MUST be provided):

a. An abnormal urinary bile acid profile that is characteristic for the member’s given BASD or PD as determined fast atom bombardment-mass spectrometry (FAB-MS), electrospray ionization mass spectrometry (ESI-MS), or gas chromatography-mass spectrometry (GC-MS)

b. Molecular genetic testing showing a mutation in the specific gene known to cause the specific BASD or PD

i. 3-β-HSD deficiency: mutation in HSD3B7 gene on short arm of chromosome 16 (16p11.2)

ii. Delta4-3-oxosteroid 5-beta reductase: mutation in AKR1D1 gene located on long arm of chromosome 7 (7q33)

iii. Alpha-methylacyl-CoA racemase deficiency: mutation in AMACR gene located on short arm of chromosome 5 (5p13.2)

iv. Cholesterol 7-alpha-hydroxylase deficiency: mutations in CYP7A1 gene located on long arm of chromosome 8 (8q12.1)

v. CTX: mutation in CYP27A1 gene on the long arm of chromosome 2 (2q35)

vi. SLOS: mutation in DHCR7 gene on the long arm of chromosome 11 (11q13.4)

vii. PD – mutation in one of the various PEX genes (chromosome location varies)

4. Baseline labs (i.e., within 30 days of treatment initiation with cholic acid) for ALT, AST, and total bilirubin, AND the member’s baseline body weight have been provided.

5. The baseline labs are elevated (ALT and/or AST >50 units/L, and/or total bilirubin >1 mg/dL) indicating the presence of cholestasis

6. The dosage does NOT exceed 15 mg/kg per day (or 17 mg/kg per day if the member has concomitant familial hypertriglyceridemia) after the dosage is rounded to the nearest 50 mg, The dose must be achieved using the fewest number of capsule possible [e.g., 52 kg X 15 mg/kg = 780 mg, so max dose = 750 mg (3 X 250 mg capsules) once daily].

Duration of approval: 3 months

Continuation of cholic acid (Cholbam®) meets the definition of medical necessity when ALL of the following criteria are met:

1. The member meets ALL initiation criteria (including dosage limits), except for baseline lab elevations (initiation question #5) and the presence of clinical symptoms for members with PD (question #2bi-iii)

2. The member has had a positive response to cholic acid treatment defined as EITHER of the following (“a” or “b”) (documentation MUST be provided):

a. At least TWO of the following laboratory or biopsy criteria:

i. ALT or AST values reduced to less than 50 units/L, or pretreatment baseline levels reduced by 80% or more

ii. Total bilirubin values reduced to less than or equal to 1 mg/dL

iii. No evidence of cholestasis on liver biopsy

b. BOTH of the following:

i. Any ONE of the criteria listed above (see 2ai-iii)

ii. Body weight increased by at least 10% as compared to baseline pretreatment weight, or weight stable at greater than the 50th percentile for age and gender

Duration of approval: 12 months

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

FDA-approved

• Cholic acid is indicated for the treatment of bile acid synthesis disorders due to single enzyme defects (SEDs) and 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. Of note, the safety and effectiveness of cholic acid 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 orally once daily, or in two divided doses, with food in both pediatric patients (3 weeks or older) and adults. Due to poorer absorption, 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. 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. Treatment should be initiated and monitored by an experienced hepatologist or pediatric gastroenterologist.

Dose Adjustments

• 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

• Discontinue treatment at any time if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis.

• Discontinue treatment with cholic acid if liver function does not improve within 3 months of the start of treatment (as evidenced by ALT/AST and bilirubin reduction, or improvement on liver biopsy).

Drug Availability

• 50 mg orange capsule and 250 mg white capsule

PRECAUTIONS:

Contraindications

• None

Precautions/Warnings

• Exacerbation of Liver Impairment: Monitor liver function and discontinue if liver function worsens while on treatment.

• Pregnancy: No studies in pregnant women or animal reproduction studies have been conducted.

• 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 at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin (e.g., cholestyramine, colestipol, or colesevelam) or aluminum-based antacids.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

J8499

Prescription drug, oral, non-chemotherapeutic, Not Otherwise Specified

ICD-10 Diagnoses Codes That Support Medical Necessity (Effective 10/01/15)

E71.50

Peroxisomal disorder, unspecified

E71.510 – E71.518

Disorders of peroxisome biogenesis

E71.520 – E71.529

X-linked adrenoleukodystrophy

E71.53

Other group 2 peroxisomal disorders

E71.540 – E71.548

Other peroxisomal disorders

E78.70 – E78.79

Disorders of bile acid and cholesterol metabolism

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Part D: BCBSF has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

Medicare Advantage: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline review date.

DEFINITIONS:

None

RELATED GUIDELINES:

Genetic Testing, 05-82000-28

OTHER:

None

REFERENCES:

  1. American College of Medical Genetics and Genomics (ACMG) [Internet] Washington, DC: Association of American Medical Colleges; 2016 [cited 2016 July 22]. Available from: https://www.aamc.org/cim/specialty/list/us/339986/medical_genetics.html
  2. Bile Acid Synthesis Disorders. National Organization for Rare Disorders (NORD). 2014. Available at https://rarediseases.org/rare-diseases/bile-acid-synthesis-disorders/. Accessed: 6/10/16.
  3. Cholbam (cholic acid) [package insert]. Manchester Pharmaceuticals, Inc. San Diego, CA. March 2015.
  4. Clayton PT. Disorders of bile acid synthesis. J Inherit Metab Dis. 2011 Jun;34(3):593-604. Epub 2011 Jan 13.
  5. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2016 [cited 2016 Jun 10]. Available from: http://www.clinicalpharmacology.com/.
  6. DRUGDEX® System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2016 Jun 10]. Available from: http://www.thomsonhc.com/.
  7. Ferdinandusse S, Denis S, Faust PL, et al. Bile acids: the role of peroxisomes. J Lipid Res. 2009 Nov;50(11):2139-47. Epub 2009 Apr 8.
  8. Haas D, Gan-Schreier H, Langhans CD, et al. Differential diagnosis in patients with suspected bile acid synthesis defects. World J Gastroenterol. 2012 Mar 14;18(10):1067-76.
  9. Nie S, Chen G, Cao X, et al. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2014 Nov 26;9:179.
  10. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2016 [cited 2016 Jun 10]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.
  11. Setchell KD, Heubi JE. Defects in bile acid biosynthesis--diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2006 Jul;43 Suppl 1:S17-22.
  12. Sundaram SS, Bove KE, Lovell MA, et al. Mechanisms of disease: Inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008 Aug;5(8):456-68.
  13. Wanders RJ, Ferdinandusse S. Peroxisomes, peroxisomal diseases, and the hepatotoxicity induced by peroxisomal metabolites. Curr Drug Metab. 2012 Dec;13(10):1401-11.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 07/13/16.

GUIDELINE UPDATE INFORMATION:

08/15/15

New Medical Coverage Guideline.

11/01/15

Revision: ICD-9 Codes deleted.

08/15/16

Review and revision of guideline consisting of updating the position statement, related guidelines, and references.

09/15/16

Revision of guideline consisting of updating the position statement.

Date Printed: October 23, 2017: 07:19 AM