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. (

BRIEF SUMMARY

CHOLI ACID- (Mar 2015)

Indn-   to treat pediatric adult patient with bile acid synthesis                                                   disorders due to  enzyme  defects

Comp-      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

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

CI-  None 

WARNINGS AND PRECAUTIONS-

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

Pat Infrm

 Advise patients that CHOLBAM may worsen liver impairment and that they should immediately report to their health care provider any symptoms associated with liver impairment (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown [tea colored], pain on the right side of stomach, bleeding or bruising occurs more easily than normal, or increased lethargy) 

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Novel Drug Approvals for 2015

1.Name                        CHOLBAM

2.Active ingredient-    Cholic acid defects

3. Indication-            to treat pediatric adult patient with bile acid synthesis                                                   disorders due to  enzyme  defects

Date of Approval       3/17/2015

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                             CHOLBAM® safely and effectively.

See full prescribing information for CHOLBAM. CHOLBAM (cholic acid) capsules, for oral use

Initial U.S. Approval: 2015

INDICATIONS AND USAGE--

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

 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

 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.

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.

CONTRAINDICATIONS-

 None 

WARNINGS AND PRECAUTIONS-

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

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.

 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

 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. 

PATIENT COUNSELING INFORMATION-

Exacerbation of Liver Impairment ? Advise patients that they will need to undergo laboratory testing periodically while on treatment to assess liver function.

 Advise patients that CHOLBAM may worsen liver impairment and that they should immediately report to their health care provider any symptoms associated with liver impairment (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown [tea colored], pain on the right side of stomach, bleeding or bruising occurs more easily than normal, or increased lethargy) 

Advise patients:

to take CHOLBAM with food.

 to take CHOLBAM at least one hour before or 4 to 6 hours after taking a bile acid binding resin or an aluminum-based antacid.

 not to crush or chew the capsules. ? for infants and children who cannot swallow 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 tablespoonfuls (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. Pregnancy Registry: Advise patients there is a pregnancy surveillance program that monitors pregnancy outcomes in women exposed to CHOLBAM during pregnancy [see Use in Specific Populations (8.1)]

. CHOLBAM® is a registered trademark of Asklepion Pharmaceuticals LLC Revised: March 2015

Manufactured by: Patheon France SA 38300 Bourgoin-Jallieu, France Manufactured for: Asklepion Pharmaceuticals LLC Baltimore, MD 21202 For further information, please call Asklepion Pharmaceuticals LLC at 410-545-0494

CLINICAL PHARMACOLOGY

1 Mechanism of Action

Cholic acid is a primary bile acid synthesized from cholesterol in the liver. In bile acid synthesis disorders due to SEDs in the biosynthetic pathway, and in PDs including Zellweger spectrum disorders, deficiency of primary bile acids leads to unregulated accumulation of intermediate bile acids and cholestasis. Bile acids facilitate fat digestion and absorption by forming mixed micelles, and facilitate absorption of fat-soluble vitamins in the intestine

 Endogenous bile acids including cholic acid enhance bile flow and provide the physiologic feedback inhibition of bile acid synthesis.

3. Pharmacokinetics Orally administered cholic acid is subject to the same metabolic pathway as endogenous cholic acid. Cholic acid is absorbed by passive diffusion along the length of the gastrointestinal tract.

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.

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.

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.

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.

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.

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 

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.

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 

 OVERDOSAGE 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.

In the event of overdose the patient should be monitored and treated symptomatically.