DRUG INTERACTIONS

 

 Warfarin: Potential for decreased INR; monitor INR and adjust the dosage

 of warfarin, as needed, to maintain the target INR range. 

 

 CYP1A2 Substrates with Narrow Therapeutic Index (e.g., theophylline

 and tizanidine): 

 Potential for increased exposure to CYP1A2 substrates; monitor drug

 concentrations of CYP1A2 substrates with narrow therapeutic index. 

DRUG INNOVATION - NOVEL DRUG APPROVALS FOR 2016

 

No    Drug Name   Active Ingredient   Approval Date   FDA-Approved use

                                                                                         on Approval date

 

11.   Ocaliva          Obeticholic acid       5/27/2016             To treat rare, chronic liver                                                                                                               disease                                                                                                                                                                                                                                                                                           Press Rlease                                                                                                      

  Approved by FDA  on 5/27/2016  (Ref- FDA approved List- 2016)    

 

 

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                                                                                                                                            

                                                                                               

 INDICATIONS AND USAGE

 

OCALIVA, a farnesoid X receptor (FXR) agonist, is indicated for the treatment

 of primary biliary c h o l a n g i t i s (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. 

 

                                                                                                                  

 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. 

 

CONTRAINDICATIONS

 

Patients with complete biliary obstruction 

 

 WARNINGS AND PRECAUTIONS

 

 Liver-Related Adverse Reactions: 

 Monitor for elevations in liver  biochemical tests and development of

 liver-related adverse reactions; weigh the potential risk against the benefits 

 of continuing treatment. Do not exceed 10 mg once daily. 

 Adjust the dosage for patients with moderate or severe hepatic impairment.

 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. 

 

INDICATIONS AND USAGE

 

OCALIVA, a farnesoid X receptor (FXR) agonist, is indicated for the treatment

 of primary biliary c h o l a n g i t i s (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

 

Starting Dosage: The recommended starting dosage of OCALIVA 

 is  5 mg orally once daily in adults who have not achieved an adequate

 response to an appropriate dosage of UDCA for at least 1 year or are 

 intolerant to UDCA. 

 

 Dosage Titration: If adequate reduction in ALP and/or total bilirubin has

 not been achieved after 3 months of OCALIVA 5 mg once daily and the 

patient is tolerating OCALIVA, increase dosage to 10 mg once daily. 

 

 Maximum Dosage: 10 mg once daily 

 

 Management of Patients with Intolerable Pruritus: 

See full prescribing information for management options. 

 

Hepatic Impairment: See full prescribing information for dosage

 adjustment in patients with moderate or severe hepatic impairment

 (Child-Pugh Class B or C). 

 

Administration Instructions

 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 

 

 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.

.

 In the case of overdosage, patients should be carefully observed and 

 supportive care administered, as appropriate.

 

 PATIENT COUNSELING INFORMATION

 

 Liver-Related Adverse Reactions

 Advise patients to report any symptoms of worsening of liver disease to their

 healthcare provider immediately and that they may need to  undergo laboratory

 testing periodically while on OCALIVA treatment to assess liver function .

 

 Advise patients who develop symptoms of complete biliary obstruction to report 

 to their healthcare provider immediately.

 

Severe Pruritus

 Advise patients to contact their healthcare provider if they experience pruritus 

 or an increase in the severity of pruritus.

 

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.

 

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 trademark of Intercept Pharmaceuticals, Inc.

Distributed by:

Intercept Pharmaceuticals, Inc.

 

New York, NY 10011

 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. 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.

 

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.

 

After daily administration of obeticholic acid, there was accumulation

 of the glycine and taurine conjugates of obeticholic acid, which have

 in vitro pharmacological activities similar to the parent drug, obeticholic acid.

 

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. 

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 f

or 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 mothers 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

 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) 

 

 Monitor patients during treatment with OCALIVA for elevations in liver 

 biochemical tests and for the development of liver-related adverse

 reactions 

 

 Dosage adjustment of OCALIVA is recommended for patients with

 moderate and severe hepatic impairment.

 

 No dosage adjustment is needed in patients with mild hepatic

 impairment (Child-Pugh Class A).

 

6. 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.

.

 In the case of overdosage, patients should be carefully observed and 

 supportive care administered, as appropriate.