Brand Information

Strength	Rate	Packing Style
mg	0.00	unit

Drug Interaction:

DRUG INTERACTIONS

1.Bile Acid Binding Resins-

Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of OCALIVA.

If taking a bile acid binding resin, take OCALIVA at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as great an interval as possible

2. Warfarin-

The International Normalized Ratio (INR) decreased following coadministration of warfarin and OCALIVA . Monitor INR and adjust the dosage of warfarin, as needed, to maintain the target INR range when co-administering OCALIVA and warfarin.

3.CYP1A2 Substrates with Narrow Therapeutic Index -

Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates.

Therapeutic monitoring of CYP1A2 substrates with a narrow therapeutic index (e.g. theophylline and tizanidine) is recommended when co-administered with OCALIVA.

4.Inhibitors of Bile Salt Efflux Pump-

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 including taurine conjugate of obeticholic acid in the liver and result in clinical symptoms.

If concomitant use is deemed necessary, monitor serum transaminases and bilirubin.

Indication:

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

OCALIVA® safely and effectively. See full prescribing information for OCALIVA. OCALIVA® (obeticholic acid) tablets, for oral use

Initial U.S. Approval: 2016

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN INCORRECTLY DOSED PBC PATIENTS WITH CHILD-PUGH CLASS B OR C OR DECOMPENSATED CIRRHOSIS See full prescribing information for complete boxed warning

• In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with primary biliary cholangitis (PBC) with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when OCALIVA was dosed more frequently than recommended.

• The recommended starting dosage of OCALIVA is 5 mg once weekly for patients with Child-Pugh Class B or C hepatic impairment or a prior decompensation event.

RECENT MAJOR CHANGES

Boxed Warning 01/2018

Dosage and Administration 01/2018

Warnings and Precautions 01/2018

INDICATIONS AND USAGE

OCALIVA, a farnesoid X receptor (FXR) agonist, is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.

This indication is approved under accelerated approval based on a reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATION

Important Dosage and Administration Instructions (

• Prior to starting OCALIVA in patients with suspected cirrhosis, use the nomogram to calculate Child-Pugh classification (A, B, or C) and determine the appropriate starting dose

Proprietary Name- CHOLBAM

Established Name- Cholic Acid

Applicant- Askelpion Pharmaceuticals LLC

Indication- For the treatment of Bile acid synthesis disorders due to

Single Enzyme Defects and as Adjunctive treatment of

Paroxisomal Disorders in patients Zellweger Spectrum

Disorders in patients who exhibit manifestations of Liver

Disease Steratorrhea or Complications from decreased

Fat Slouble Vitamin Absorption

Approval Date- 3/17/2015

Approved by U.S.FDA on 30-06-2015 (Ref- FDA approved List- 2015)

NEW MOLECULAR ENTITY AND NEW THERAPEUTIC BIOLOGICAL

PRODUCTS APPROVED FOR 2015

Certain drugs are classified as New molecular Emtities- NME- for FDA review

Many of these products contain active moieties that have not been approved

by FDA previously, either as a single ingredient or as part of a combination

products; these products frequently provide important new therapies for the

patients.

Some drugs are characterized as NMEs for administrative purposes ,but

nonetheless contain certain active moieties in products that have been

previously approved by FDA. For example, CDER classifies biological

products submitted in an application under section 351(a) of the Public

Service Act as NME for purposes of FDA review, regardless of whether

the agency previously approved a related active moiety in a different

product.

FDAs classification of a drug as an -NME- for review purposes is distinct

from FDAs determination of whether a drug is a - New Chemical Entity or - NCE-

within the meaning of the Federal Food,Drug, and Cosmetic Act

No.10

Drug Name - Cholic acid

Active Ingredient- Cholbam

Date of approval - 3/17/2015

FDA-approved use - To treat pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects, and for patients with peroxisomal disorders

Approved by US FDA on 3/17/2015- (Ref- FDA approved List- 2015)

Adverse Reaction:

ADVERSE REACTIONS

Most common adverse reactions (= 5%) are:

pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema.

Contra-Indications:

CONTRAINDICATIONS

Patients with complete biliary obstruction

WARNINGS AND PRECAUTIONS

• Hepatic Decompensation and Failure in Incorrectly Dosed PBC Patients with Child-Pugh Class B or C or Decompensated Cirrhosis:

Routinely monitor patients for progression of PBC disease, including liver-related complications, with laboratory and clinical assessments.

Dosage adjustment, interruption, or discontinuation may be required. Discontinue in patients who develop complete biliary obstruction.

• Severe Pruritus:

Management strategies include the addition of bile acid binding resins or antihistamines; OCALIVA dosage reduction and/or temporary dosing interruption.

• Reduction in HDL-C:

Monitor for changes in serum lipid levels during treatment.

Dosages/ Overdosage Etc:

INDICATIONS AND USAGE

OCALIVA, a farnesoid X receptor (FXR) agonist, is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.

This indication is approved under accelerated approval based on a reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATION

Important Dosage and Administration Instructions

• Prior to starting OCALIVA in patients with suspected cirrhosis, use the nomogram to calculate Child-Pugh classification (A, B, or C) and determine the appropriate starting dose

•Monitoring for Safety, Treatment Discontinuation

• Routinely monitor all patients for progression of PBC disease.

• Reduce the dosing frequency for patients who progress from Child-Pugh Class A to Child-Pugh Class B or C.

• Closely monitor patients at an increased risk of hepatic decompensation. • Interrupt treatment in patients with laboratory or clinical evidence of worsening liver function indicating risk of decompensation, and monitor liver function.

• Consider discontinuing OCALIVA in patients who experience clinically significant liver-related adverse reactions. Management of Patients with Intolerable Pruritus

• See full prescribing information for management options.

• Take with or without food.

• For patients taking bile acid binding resins, take OCALIVA at least 4 hours before or 4 hours after taking a bile acid binding resin, or at as great an interval as possible.

DOSAGE FORMS AND STRENGTHS

Tablets: 5 mg, 10 mg

Patient Information:

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Hepatic Decompensation and Failure in Incorrectly Dosed PBC Patients with Child-Pugh Class B or C or Decompensated Cirrhosis

• Instruct patients and caregivers to immediately contact their healthcare provider if they experience: o Symptoms of disease progression or worsening liver function, such as ascites, jaundice, gastrointestinal bleeding or worsening of hepatic encephalopathy. Symptoms of complete biliary obstruction

• Instruct patients and caregivers to immediately contact their healthcare provider if they experience severe or persistent non-specific signs and symptoms of impaired health: nausea, vomiting, abdominal pain, diarrhea, weight loss, fever and chills, worsening or new fatigue, weakness, loss of appetite or dehydration.

• Inform patients that they will need to undergo laboratory testing periodically while on OCALIVA treatment to assess liver function.

Severe Pruritus

• Advise patients to contact their healthcare provider if they experience new onset or worsening severe pruritus [see Warnings and Precautions (5.3)].

Reduction in HDL-C

• Advise patients that they may need to undergo laboratory testing to check for changes in lipid levels while on treatment with OCALIVA [see Warnings and Precautions (5.4)]. Administration

Advise patients to take:

• OCALIVA with or without food.

• OCALIVA at least 4 hours before or 4 hours after taking a bile acid binding resin, or at as great an interval as possible

OCALIVA is a registered trademark of Intercept Pharmaceuticals, Inc.

Distributed by:

Intercept Pharmaceuticals, Inc.

New York

Pharmacology/ Pharmacokinetics:

CLINICAL PHARMACOLOGY

1. Mechanism of Action

Obeticholic acid is an agonist for FXR, a nuclear receptor expressed in the liver and intestine. FXR is a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways.

FXR activation decreases the intracellular hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol as well as by increased transport of bile acids out of the hepatocytes.

These mechanisms limit the overall size of the circulating bile acid pool while promoting choleresis, thus reducing hepatic exposure to bile acids.

2. Pharmacodynamics

Dose Titration -

In Trial 1, ALP reduction was observed to plateau at approximately 3 months in most patients treated with OCALIVA 5 mg once daily. Increasing the dosage of OCALIVA to 10 mg once daily based on tolerability and response provided additional reduction in ALP in the majority of patients

3. Pharmacokinetics-

Absorption

Following multiple oral doses of OCALIVA 10 mg once daily, peak plasma concentrations (Cmax) of obeticholic acid occurred at a median time (Tmax) of approximately 1.5 hours.

The median Tmax for both the glyco-and tauro-conjugates of obeticholic acid was 10 hours. Coadministration with food did not alter the extent of absorption of obeticholic acid.

Distribution

Human plasma protein binding of obeticholic acid and its conjugates is greater than 99%. The volume of distribution of obeticholic acid is 618 L. The volumes of distribution of glyco-and tauro-obeticholic acid have not been determined.

Elimination Metabolism-

Obeticholic acid is conjugated with glycine or taurine in the liver and secreted into bile. These glycine and taurine conjugates of obeticholic acid are absorbed in the small intestine leading to enterohepatic recirculation.

The conjugates can be deconjugated in the ileum and colon by intestinal microbiota, leading to the conversion to obeticholic acid that can be reabsorbed or excreted in feces, the principal route of elimination.

Excretion

After administration of radiolabeled obeticholic acid, about 87% of the dose was excreted in feces through biliary secretion. Less than 3% of the dose was excreted in the urine with no detection of obeticholic acid.

Specific Populations Body weight, Age, Sex Race/Ethnicity:

Based on population pharmacokinetic analysis, body weight was a significant predictor of obeticholic acid pharmacokinetics with lower obeticholic acid exposure expected with higher body weight.

The body weight effect is not expected to cause a meaningful impact on efficacy. The pharmacokinetics of obeticholic acid would not be expected to be altered based on age, sex, or race/ethnicity.

Renal Impairment:

Obeticholic acid has not been studied in patients with moderate and severe renal impairment (estimated glomerular filtration rate [eGFR] less than 60 mL/min/1.73 m2). In the population pharmacokinetic analysis, an eGFR greater than 50 mL/min/1.73 m2 did not have a meaningful effect on the pharmacokinetics of obeticholic acid and its conjugated metabolites.

Hepatic Impairment:

Obeticholic acid is metabolized in the liver. In subjects with mild, moderate and severe hepatic impairment (Child-Pugh Class A, B, and C, respectively), the mean AUC of total obeticholic acid increased 1.1-, 4-and 17-fold, respectively, compared to subjects with normal hepatic function following single-dose administration of 10 mg OCALIVA

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Pregnancy and lactation:

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-

The limited available human data on the use of obeticholic acid during pregnancy are not sufficient to inform a drug-associated risk.

In animal reproduction studies, no developmental abnormalities or fetal harm was observed when pregnant rats or rabbits were administered obeticholic acid during the period of organogenesis at exposures approximately 13 times and 6 times human exposures, respectively, at the maximum recommended human dose (MRHD) of 10 mg

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown.

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

2. Lactation Risk Summary

There is no information on the presence of obeticholic acid in human milk, the effects on the breast-fed infant or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for OCALIVA and any potential adverse effects on the breastfed infant from OCALIVA or from the underlying maternal condition.

3.Pediatric Use

The safety and effectiveness of OCALIVA in pediatric patients have not been established.

4.Geriatric Use-

Of the 201 patients in clinical trials of OCALIVA who received the recommended dosage (5 mg or 10 mg once daily), 41 (20%) were 65 years of age and older, while 9 (4%) were 75 years of age and older.

No overall differences in safety or effectiveness were observed between these subjects and subjects less than 65 years of age, but greater sensitivity of some older individuals cannot be ruled out.

5.Hepatic Impairment-

Hepatic decompensation and failure, in some cases fatal, have been reported postmarketing in PBC patients with decompensated cirrhosis or Child-Pugh B or C hepatic impairment when OCALIVA was dosed more frequently than recommended.

In PBC clinical trials, a dose-response relationship was observed for the occurrence of liver-related adverse reactions with OCALIVA

Plasma exposure to obeticholic acid and its active conjugates, increases significantly in patients with moderate to severe hepatic impairment (Child-Pugh Classes B and C)

Prior to the initiation of OCALIVA determine the patient’s Child-Pugh classification to determine the starting dosage. Re-evaluate the dosing regimen periodically during treatment.

Dosage adjustment is required in patients with Child-Pugh Class B and C.

Routinely monitor patients for progression of PBC disease with laboratory and clinical assessments. Dosage adjustment, interruption or discontinuation may be required

OVERDOSAGE

In PBC patients who received OCALIVA 25 mg once daily (2.5 times the highest recommended dosage) or 50 mg once daily (5 times the highest recommended dosage), a dose-dependent increase in the incidence of liver-related adverse reactions, including elevations in liver biochemical tests, ascites, jaundice, portal hypertension, and primary biliary cholangitis flare, was reported.

Serious liver-related adverse reactions have been reported postmarketing in PBC patients with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when OCALIVA was dosed more frequently than the recommended starting dosage of 5 mg once weekly

In the case of overdosage, patients should be carefully observed and supportive care administered, as appropriate.

.

CHOLBAM*

Drug Interaction

Indication

Adverse Reaction

Contra-Indications

Dosages/ Overdosage Etc

Patient Information

Pharmacology/ Pharmacokinetics

Pregnancy and lactation