Glossary

Key terminology for bile acid synthesis disorders and Zellweger spectrum disorders


Adjunctive therapy
Any accessory treatment used in combination to enhance primary treatment.1

Alanine transaminase test
The alanine transaminase/aminotransferase test, also known as ALT, is one of a group of tests known as liver function tests (or LFTs) and is used to monitor damage to the liver.2

Aspartate transaminase test
The aspartate transaminase/aminotransferase test measures levels of AST, an enzyme released into the blood when certain organs or tissues, particularly the liver and heart, are injured.2

Bile
Bile is a fluid that contains water, certain minerals, and other materials including bile salts, lipids, cholesterol, and an orange-yellow pigment (bilirubin). Bile aids in digestion and absorption of dietary fats, vitamins, and other nutrients and it aids in the elimination of excess cholesterol, bilirubin, waste, and toxins from the body.3,4

Bile acids
Bile acids are compounds that aid in digestion and absorption of dietary fats, vitamins, and other nutrients and in the elimination of excess cholesterol, bilirubin, waste, and toxins from the body.3,4

Bile Acid Synthesis Disorders
A rare group of inherited disorders of the enzymes that make bile acids.4

Cholestasis
When bile flow is reduced or stopped.3

Cholic acid
One of the primary bile acids. It helps with fat absorption and cholesterol excretion.4

Enzyme
A biological substance that produces changes seen in natural processes (such as digestion).5

Gamma glutamyltransferase test
A blood test that measures GGT and is used to detect liver cell dysfunction. It accurately indicates cholestasis and/or biliary obstruction.2,6

Infantile Refsum Disease
A disorder affecting peroxisomal biogenesis belonging to the family of Zellweger spectrum disorders. Infantile Refsum disease (IRD) is not as devastating. Patients generally have longer survival, and sometimes live into their adult life.7,8

Jaundice
Jaundice is a condition in which a person's skin and the whites of the eyes are discolored yellow due to an increased level of bile pigments in the blood resulting from liver disease.3

Liver Function Test
A group of blood tests that detect inflammation and damage to the liver. They can also check how well the liver is working.2

Neonatal Adrenoleukodystrophy
A disorder affecting peroxisomal biogenesis belonging to the family of Zellweger spectrum disorders. Patients affected with this disorder may live to school age.7,8

Peroxisome
Specialized compartments of cells that contain enzymes important for the final steps in bile acid production.7,9

Steatorrhea
The excretion of abnormal quantities of fat with the feces owing to reduced absorption of fat by the intestine.3

Zellweger Spectrum Disorders
A spectrum of disorders ranging in severity from severe to moderate to mild caused by defects in peroxisomal biogenesis.7,9,10

Zellweger Syndrome
A disorder affecting peroxisomal biogenesis belonging to the family of Zellweger Spectrum Disorders. Zellweger Syndrome is the most severe form of Zellweger Spectrum Disorders. Zellweger Syndrome is often fatal within the first 1-2 years of life. For these patients, early diagnosis and treatment for liver problems are offered as an approach to help relieve the symptoms that are part of the liver disease.7,9,10

1. National Cancer Institute. NCI Dictionary of Cancer Terms: Adjunct therapy. http://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=467826/. Accessed January 22, 2016. 2. Liver function tests. WebMD website. http://www.webmd.boots.com/a-to-z-guides/liver-function-tests?page=2&print=true#/. Accessed November 3, 2015. 3. Heubi JE. http://rarediseases.org/rare-diseases/bile-acid-synthesis-disorders/. Accessed January 19, 2016. 4. Heubi JE, Setchell K, Bove KE. Inborn errors of bile acid metabolism. Semin Liver Dis. 2007;27(3):282-294. 5. Merriam Webster Dictionary: Enzyme. http://www.merriam-webster.com/dictionary/enzyme. Accessed January 22, 2016. 6. Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2004;39:115-128. 7. Braverman NE, D’Agostino MD, Maclean GE. Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev. 2013;17:187-196. 8. CHOLBAM® (cholic acid) capsules, for oral use [prescribing information]. San Diego, CA: Retrophin, Inc.; March 2015. 9. Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of Disease: inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008;5(8):456-468. 10. Poll-The BT, Gartner J. Clinical diagnosis, biochemical findings and MRI spectrum of perioxisomal disorders. Biochim Biophys Acta. 2012;1822:1421-1429.

Indication and Usage
CHOLBAM® is a bile acid indicated for:

  • Treatment of bile acid synthesis disorders due to single enzyme defects
  • Adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders in patients who show signs and symptoms of liver disease, steatorrhea (fatty stools), or complications from decreased fat soluble vitamins absorption (A, D, E, K)

Limitation of Use:
The safety and effectiveness of CHOLBAM® on extrahepatic manifestations of bile acid synthesis disorders due to single enzyme defects or peroxisomal disorder including Zellweger spectrum disorders have not been established.

Important Safety Information
Warnings and Precautions—Exacerbation of Liver Impairment

  • Monitor liver function and discontinue CHOLBAM® (cholic acid) in patients who develop worsening of liver function while on treatment.
  • Monitor AST, ALT, GGT, alkaline phosphatase, bilirubin, and international normalized ratio (INR) every month for the first 3 months, every 3 months for the next 9 months, every 6 months during the next 3 years and annually thereafter. Administer the lowest dose that effectively maintains liver function.
  • Discontinue CHOLBAM® if liver function does not improve within 3 months of starting treatment, if complete biliary obstruction develops, or if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis; continue to monitor liver function and consider restarting at a lower dose when parameters return to baseline.

Adverse Reactions
In the CHOLBAM® clinical trials, diarrhea was the most common adverse reaction in approximately 2% of the patient population. All other adverse reactions are less than or equal to 1% of the patient population.

Drug Interaction

  • Bile Salt Efflux Pump (BSEP) Inhibitors (eg, cyclosporine): Avoid concomitant use; if concomitant use is necessary, monitor serum transaminases and bilirubin.
  • 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.

Pregnancy
No studies in pregnant women or animal reproduction studies have been conducted with CHOLBAM®. Women who become pregnant during CHOLBAM® treatment are encouraged to call 1-844-202-6262.

Lactation
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.

Overdosage
In the event of overdose (elevated GGT and ALT), the patient should be monitored and treated symptomatically.

Elevated 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.

Please see full prescribing information for CHOLBAM® (cholic acid) 50 mg and 250 mg capsules.

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.