Ocaliva
Generic Name: obeticholic acid
Dosage Form: tablet, film coated
Indications and Usage for Ocaliva
Ocaliva® 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) [see Clinical Studies (14)].
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.
Ocaliva Dosage and Administration
Dosage Regimen
Starting Dosage
The
recommended starting dosage of Ocaliva is 5 mg orally once daily in adult
patients who have not achieved an adequate biochemical response to an
appropriate dosage of UDCA for at least 1 year or are intolerant to UDCA [see Clinical Studies (14)].
Dosage Titration
If an
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 the dosage of Ocaliva to 10 mg once daily [see Clinical Pharmacology (12.2), Clinical Studies (14)].
Maximum Dosage
The
maximum recommended dosage of Ocaliva is 10 mg once daily [see Warnings and Precautions (5.1)].
Management of Patients with Intolerable Pruritus on
Ocaliva
For
patients with intolerable pruritus on Ocaliva, consider one or more of the
following:
· Add an antihistamine or bile acid binding resin [see Dosage and Administration (2.4), Clinical Studies (14)].
· Reduce the dosage of Ocaliva to:
o 5 mg every other day, for patients intolerant to 5 mg
once daily.
o 5 mg once daily, for patients intolerant to 10 mg
once daily.
· Temporarily interrupt Ocaliva dosing for up to 2
weeks followed by restarting at a reduced dosage.
Increase
the dosage of Ocaliva to 10 mg once daily, as tolerated, to achieve optimal
response.
Consider
discontinuing Ocaliva treatment in patients who continue to experience
persistent, intolerable pruritus.
Dosage Adjustment in Hepatic Impairment
Treatment
with Ocaliva in patients with moderate and severe hepatic impairment should be
initiated and monitored by a healthcare provider with experience managing PBC.
The
recommended starting dosage of Ocaliva for moderate (Child-Pugh Class B) and
severe (Child-Pugh Class C) hepatic impairment is 5 mg once weekly. If an
adequate reduction in ALP and/or total bilirubin has not been achieved after 3
months of Ocaliva 5 mg once weekly, and the patient is tolerating the drug,
increase the dosage of Ocaliva to 5 mg twice weekly (at least three days apart)
and subsequently to 10 mg twice weekly (at least three days apart) depending on
response and tolerability [see Use in Specific Populations (8.6)].
Monitor
patients during treatment with Ocaliva for the occurrence of liver-related
adverse reactions [see Warnings and Precautions (5.1)]. Weigh the potential risks against the benefits of
continuing treatment with Ocaliva in patients who have experienced clinically
significant liver-related adverse reactions.
Administration Instructions
· Take Ocaliva with or without food.
· For patients 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 [see Drug Interactions (7.1), Clinical Studies (14)].
Dosage Forms and Strengths
Ocaliva
is available as:
· 5 mg tablet: Off white to yellow, round tablet
debossed with "INT" on one side and "5" on the other side.
· 10 mg tablet: Off white to yellow, triangular tablet
debossed with "INT" on one side and "10" on the other side.
Contraindications
Ocaliva
is contraindicated in patients with complete biliary obstruction.
Warnings and Precautions
Liver-Related Adverse Reactions
In two
3-month, placebo-controlled clinical trials a dose-response relationship was
observed for the occurrence of liver-related adverse reactions including
jaundice, worsening ascites and primary biliary cholangitis flare with dosages
of Ocaliva of 10 mg once daily to 50 mg once daily (up to 5-times the highest
recommended dosage), as early as one month after starting treatment with
Ocaliva [see Overdosage (10)].
In a
pooled analysis of three placebo-controlled trials in patients with PBC, the
exposure-adjusted incidence rates for all serious and otherwise clinically
significant liver-related adverse reactions, and isolated elevations in liver
biochemical tests, per 100 patient exposure years (PEY) were: 5.2 in the
Ocaliva 10 mg group (highest recommended dosage), 19.8 in the Ocaliva 25 mg
group (2.5 times the highest recommended dosage) and 54.5 in the Ocaliva 50 mg
group (5 times the highest recommended dosage) compared to 2.4 in the placebo
group.
Monitor
patients during treatment with Ocaliva for elevations in liver biochemical
tests and for the development of liver-related adverse reactions. Weigh the
potential risks against the benefits of continuing treatment with Ocaliva in
patients who have experienced clinically significant liver-related adverse
reactions. The maximum recommended dosage of Ocaliva is 10 mg once daily [see Dosage and Administration (2.1)]. Adjust the dosage for patients with moderate or
severe hepatic impairment [see Dosage and Administration (2.3)].
Discontinue
Ocaliva in patients who develop complete biliary obstruction [see Contraindications (4)].
Severe Pruritus
Severe
pruritus was reported in 23% of patients in the Ocaliva 10 mg arm, 19% of
patients in the Ocaliva titration arm, and 7% of patients in the placebo arm in
Trial 1, a 12-month double-blind randomized controlled trial of 216
patients [see Adverse Reactions (6.1)]. Severe pruritus was defined as intense or
widespread itching, interfering with activities of daily living, or causing
severe sleep disturbance, or intolerable discomfort, and typically requiring
medical interventions. In the subgroup of patients in the Ocaliva titration arm
who increased their dosage from 5 mg once daily to 10 mg once daily after 6
months of treatment (n=33), the incidence of severe pruritus was 0% from Months
0 to 6 and 15% from Months 6 to 12. The median time to onset of severe pruritus
was 11, 158, and 75 days for patients in the Ocaliva 10 mg, Ocaliva titration,
and placebo arms, respectively.
Management
strategies include the addition of bile acid resins or antihistamines, Ocaliva
dosage reduction, and/or temporary interruption of Ocaliva dosing [see Dosage and Administration (2.2)].
Reduction in HDL-C
Patients
with PBC generally exhibit hyperlipidemia characterized by a significant
elevation in total cholesterol primarily due to increased levels of high
density lipoprotein-cholesterol (HDL-C). In Trial 1, dose-dependent reductions
from baseline in mean HDL-C levels were observed at 2 weeks in Ocaliva-treated
patients, 20% and 9% in the 10 mg and titration arms, respectively, compared to
2% in the placebo arm. At month 12, the reduction from baseline in mean HDL-C
level was 19% in the Ocaliva 10 mg arm, 12% in the Ocaliva titration arm, and
2% in the placebo arm. Nine patients in the Ocaliva 10 mg arm, 6 patients in
the Ocaliva titration arm, versus 3 patients in the placebo arm had reductions
in HDL-C to less than 40 mg/dL.
Monitor
patients for changes in serum lipid levels during treatment. For patients who
do not respond to Ocaliva after 1 year at the highest recommended dosage that
can be tolerated (maximum of 10 mg once daily), and who experience a reduction
in HDL-C, weigh the potential risks against the benefits of continuing
treatment.
Adverse Reactions
The
following clinically significant adverse reactions are described elsewhere in
labeling:
· Liver-Related Adverse Reactions [see Warnings and Precautions (5.1)]
· Severe Pruritus [see Warnings and Precautions (5.2)]
· Reduction in HDL-C [see Warnings and Precautions (5.3)]
Clinical Trials Experience
Because
clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to
rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
A total
of 432 patients with PBC were studied in three double-blind placebo-controlled
trials. Of these patients, 290 were treated with Ocaliva for at least 6 months,
232 were treated for at least 12 months, and 70 were treated for at least 2
years. There were 131 patients who received Ocaliva 10 mg once daily and 70 who
received Ocaliva 5 mg once daily.
In Trial
1, 216 patients were randomized (1:1:1) to receive either:
· Ocaliva 10 mg once daily for the entire 12 months of
the trial (n=73);
· Ocaliva titration (5 mg once daily for the initial 6
months, with the option to increase to 10 mg once daily for the last 6 months,
in patients who were tolerating Ocaliva, but had ALP 1.67-times ULN or greater,
and/or total bilirubin greater than ULN, or less than 15% ALP reduction)
(n=70); or
· placebo (n=73).
During
the trial, Ocaliva or placebo was administered in combination with UDCA in 93%
of patients and as monotherapy in 7% of patients who were unable to tolerate
UDCA. The overall discontinuation rate was 12% in the Ocaliva 10 mg arm, 10% in
the Ocaliva titration arm, and 4% in the placebo arm.
The
recommended starting dosage of Ocaliva is 5 mg orally once daily for 3 months
with titration to 10 mg once daily based upon tolerability and response [see Dosage and Administration (2.1)]. Initiation of therapy with Ocaliva 10 mg once
daily is not recommended due to an increased risk of pruritus.
The most
common adverse reactions in Trial 1 occurring in at least 5% of patients in
either Ocaliva treatment arm and at an incidence at least 1% higher than the
placebo treatment arm are shown in Table 1.
Table 1: Most Common Adverse Reactions in Adult Patients with PBC in
Trial 1 by Treatment Arm with or without UDCA*
|
|
|
Placebo
N = 73
%
|
|
Adverse
Reaction†
|
Ocaliva 10 mg
N = 73
%
|
Ocaliva Titration‡
N = 70
%
|
|
*
In the trial
there were 16 patients (7%) who were intolerant and did not receive
concomitant UDCA: 6 patients (8%) in the Ocaliva 10 mg arm, 5 patients (7%)
in the Ocaliva titration arm, and 5 patients (7%) in the placebo arm.
†
Occurring in
greater than or equal to 5% of patients in either Ocaliva treatment arm and
at an incidence greater than or equal to1% higher than in the placebo
treatment arm.
‡
Patients
randomized to Ocaliva titration received Ocaliva 5 mg once daily for the
initial 6 month period. At Month 6, patients who were tolerating Ocaliva, but
had an ALP 1.67-times ULN or greater, and/or total bilirubin greater than
ULN, or less than 15% ALP reduction were eligible for titration from 5 mg
once daily to 10 mg once daily for the final 6 months of the trial.
§
Includes skin
eruptions, prurigo, pruritus, pruritus generalized, eye pruritus, ear
pruritus, anal pruritus, vulvovaginal pruritus, and rash pruritic.
¶
Includes
fatigue, tiredness and asthenia.
#
Includes
abdominal pain upper, abdominal pain, abdominal discomfort, abdominal pain
lower, abdominal tenderness, and gastrointestinal pain.
Þ
Includes
urticaria, rash, rash macular, rash papular, rash maculo-papular, heat rash,
urticaria cholinergic.
ß
Includes
dizziness, syncope, presyncope.
à
Includes thyroxine free decreased, blood thyroid
stimulating hormone increased, hypothyroidism.
|
|
Pruritus§
|
70
|
56
|
38
|
|
Fatigue¶
|
25
|
19
|
15
|
|
Abdominal pain
and discomfort#
|
10
|
19
|
14
|
|
RashÞ
|
10
|
7
|
8
|
|
Arthralgia
|
10
|
6
|
4
|
|
Oropharyngeal
pain
|
8
|
7
|
1
|
|
Dizzinessß
|
7
|
7
|
5
|
|
Constipation
|
7
|
7
|
5
|
|
Peripheral Edema
|
7
|
3
|
3
|
|
Palpitations
|
7
|
3
|
1
|
|
Pyrexia
|
7
|
0
|
1
|
|
Thyroid function
abnormalityà
|
4
|
6
|
3
|
|
Eczema
|
3
|
6
|
0
|
Liver-Related Adverse Reactions
In Trial
1, the following serious or otherwise clinically significant liver-related
adverse reactions were reported at the recommended dosage of Ocaliva: one
patient in the Ocaliva 10 mg treatment arm experienced ascites; one patient in
the Ocaliva titration treatment arm experienced two episodes of ascites and
four episodes of hepatic encephalopathy; one patient in the placebo treatment
arm experienced variceal bleeding.
Pruritus
Approximately
60% of patients had a history of pruritus upon enrollment in Trial 1.
Treatment-emergent pruritus, including all the terms described in Table 1,
generally started within the first month following the initiation of treatment
with Ocaliva.
The
incidence of pruritus was higher in patients who started on Ocaliva 10 mg once
daily relative to the Ocaliva titration arm, 70% and 56%, respectively.
Discontinuation rates due to pruritus were also higher in patients who started
on Ocaliva 10 mg once daily relative to the Ocaliva titration arm, 10% and 1%, respectively.
The
number of patients with pruritus who required an intervention (e.g., dosage
adjustment, treatment interruption, or initiation of bile acid binding resin or
antihistamine) was 30 of 51 patients (59%) in the Ocaliva 10 mg arm, 24 of 39
patients (62%) in the Ocaliva titration arm, and 14 of 28 patients (50%) in the
placebo arm.
Drug Interactions
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 [see Dosage and Administration (2.4)].
Warfarin
The
International Normalized Ratio (INR) decreased following coadministration of
warfarin and Ocaliva [see Clinical Pharmacology (12.3)]. Monitor INR and adjust the dosage of warfarin, as
needed, to maintain the target INR range when co-administering Ocaliva and
warfarin.
CYP1A2 Substrates with Narrow Therapeutic Index
Obeticholic
acid may increase the exposure to concomitant drugs that are CYP1A2
substrates [see Clinical Pharmacology (12.3)]. Therapeutic monitoring of CYP1A2 substrates with a
narrow therapeutic index (e.g. theophylline and tizanidine) is recommended when
co-administered with Ocaliva.
USE IN SPECIFIC POPULATIONS
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 [see Data below].
The
estimated background risks of major birth defects and miscarriage for the
indicated population are unknown. In theU.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.
Data
Animal Data
In an
embryo-fetal development study in rats, obeticholic acid was administered
orally during the period of organogenesis at doses of 5, 25, and 75 mg/kg/day.
At 25 mg/kg/day (a dose that produced systemic exposures approximately 13 times
those in humans at the MRHD of 10 mg), there was no maternal or developmental
toxicity. At 75 mg/kg/day (approximately 40 times the human exposure at the
MRHD), decreased fetal body weights and increased numbers of early or late
resorptions and nonviable fetuses were observed. In maternal animals,
mortality, fetal loss, decreased body weight and food consumption as well as
decreased body weight gain were observed at 75 mg/kg/day. Thus, the
developmental toxicity observed at this dose may be secondary to maternal
toxicity. In rabbits, obeticholic acid was administered orally during the
period of organogenesis at doses of 3, 9, and 20 mg/kg/day. Obeticholic acid
administered at doses up to 20 mg/kg/day (approximately 6 times the human
exposure at the MRHD) was not teratogenic and did not produce any evidence of
fetal harm.
In a pre-
and post-natal development study, administration of obeticholic acid in rats
during organogenesis through lactation at doses of 5, 25, and 40 mg/kg/day did
not produce effects on pregnancy, parturition or postnatal development at any
dose (the 40 mg/kg/day dose is approximately 21 times the human exposure at the
MRHD).
Obeticholic
acid exposure margins were calculated using systemic exposure (AUC) values of
obeticholic acid plus obeticholic acid's active metabolite conjugates
(tauro-obeticholic acid and glyco-obeticholic acid) in animals (at the
indicated doses) and in humans at the MRHD of 10 mg.
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.
Pediatric Use
The
safety and effectiveness of Ocaliva in pediatric patients have not been
established.
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.
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) [see Clinical Pharmacology (12.3)].
Monitor
patients during treatment with Ocaliva for elevations in liver biochemical
tests and for the development of liver-related adverse reactions [see Warnings and Precautions (5.1)]. Dosage adjustment of Ocaliva is recommended for
patients with moderate and severe hepatic impairment [see Dosage and Administration (2.3)]. No dosage adjustment is needed in patients with
mild hepatic impairment (Child-Pugh Class A).
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 [see Warnings and Precautions (5.1)].
In the
case of overdosage, patients should be carefully observed and supportive care
administered, as appropriate.
Ocaliva Description
Ocaliva
is a farnesoid X receptor (FXR) agonist. Chemically, obeticholic acid is
3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid. It is a white to off-white powder. It is soluble in methanol, acetone and
ethyl acetate. Its solubility in water is pH dependent. It is slightly soluble
at low pH and very soluble at high pH. Its chemical formula is C26H44O4, the molecular weight is 420.63 g/mol and the chemical structure
is:
Ocaliva
tablets are supplied in 5 mg and 10 mg strengths for oral administration. Each
tablet contains obeticholic acid as the active ingredient and the following
inactive ingredients: microcrystalline cellulose, sodium starch glycolate, and
magnesium stearate. The film coating is Opadry II (Yellow) containing polyvinyl
alcohol-part hydrolyzed, titanium dioxide, macrogol (polyethylene glycol 3350),
talc, and iron oxide yellow.
Ocaliva - Clinical Pharmacology
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.
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 [see Dosage and Administration (2.1), Clinical Studies (14)].
Pharmacodynamic Markers
In Trial
1, administration of Ocaliva 10 mg once daily was associated with a 173%
increase in concentrations of FGF-19, an FXR-inducible enterokine involved in
bile acid homeostasis, from baseline to Month 12. Concentrations of cholic acid
and chenodeoxycholic acid were reduced 2.7 micromolar and 1.4 micromolar,
respectively, from baseline to Month 12. The clinical relevance of these
findings is unknown.
Cardiac Electrophysiology
At a dose
of 10-times the maximum recommended dose, Ocaliva does not prolong the QT
interval to any clinically relevant extent.
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 [see Dosage and Administration (2.4)].
Following
multiple-dose administration of Ocaliva 5, 10, and 25 mg once daily (2.5 times
the highest recommend dosage) for 14 days, systemic exposures of obeticholic
acid increased dose proportionally. Exposures to glyco-obeticholic acid and
tauro-obeticholic acid, and total obeticholic acid (the sum of obeticholic acid
and its two active conjugates) increased more than proportionally with dose.
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.
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. The metabolite-to-parent ratios of the glycine and
taurine conjugates of obeticholic acid were 13.8 and 12.3 respectively, after
daily administration. An additional third obeticholic acid metabolite,
3-glucuronide, was formed but was considered to have minimal pharmacologic
activity.
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
Age, Sex Race/Ethnicity: Based on population pharmacokinetic analysis,
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 by
1.1-, 4- and 17-fold, respectively, compared to subjects with normal hepatic
function following single-dose administration of 10 mg Ocaliva [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].
Drug Interaction Studies
Effect of Obeticholic Acid on Other Drugs
Based
on in vitro studies, obeticholic acid can
inhibit CYP3A4. However, an in vivo study
indicated no inhibition of CYP3A4 by obeticholic acid at the recommended dose
of Ocaliva. Obeticholic acid is not expected to inhibit CYPs 2B6, 2C8, 2C9,
2C19, and 2D6, or induce CYPs 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4 at the
recommended dose of Ocaliva. Down-regulation of mRNA was observed in a
concentration-dependent fashion for CYP1A2 and CYP3A4 by obeticholic acid and
its glycine and taurine conjugates.
In vitro studies
suggest that there is potential for obeticholic acid and its glycine and
taurine conjugates to inhibit OATP1B1 and OATP1B3 (the clinical significance of
which is unknown), but not P-gp, BCRP, OAT1, OAT3, OCT2, and MATE transporters,
at the recommended dose of Ocaliva.
Warfarin: Concomitant administration of 25 mg warfarin as a single
dose with Ocaliva 10 mg once daily resulted in 13% increase in systemic
exposure to S-warfarin and 11% decrease in maximum INR [see Drug Interactions (7.2)].
Caffeine (CYP1A2 substrate): Concomitant administration of 200 mg caffeine
as a single dose with Ocaliva 10 mg once daily resulted in a 42% increase in
plasma AUC and 6% increase in Cmax of
caffeine [see Drug Interactions (7.3)].
Omeprazole (CYP2C19 substrate): Concomitant administration of 20 mg omeprazole
as a single dose with Ocaliva 10 mg once daily resulted in a 32% increase in
AUC and a 33% increase in Cmax of
omeprazole. The clinical significance is unknown.
No
clinically relevant interactions were seen when the following drugs were
administered as single doses concomitantly with Ocaliva 10 mg once daily:
Midazolam 2 mg (CYP3A4 substrate): 2% increase in AUC and Cmax of
midazolam.
Dextromethorphan 30 mg (CYP2D6 substrate): 11% decrease in AUC and 12% decrease in Cmax of dextromethorphan.
Digoxin 0.25 mg (P-gp substrate): 1% increase in AUC and 3% decrease in Cmax of digoxin.
Rosuvastatin 20 mg (BCRP, OATP1B1, OATP1B3
substrate): 22%
increase in AUC and a 27% increase in Cmax of
rosuvastatin.
Effect of Other Drugs on Obeticholic Acid
In vitro data
suggest that obeticholic acid is not metabolized to any significant extent by
CYP450 enzymes.
Proton Pump Inhibitors (omeprazole): Concomitant administration of 20 mg omeprazole
once daily with Ocaliva 10 mg once daily resulted in a less than 1.2-fold
increase in obeticholic acid exposure. This increase is not expected to be
clinically relevant. Concomitant administration of 40 mg omeprazole once daily
with Ocaliva 10 mg once daily was not studied.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenic
potential of obeticholic acid was assessed in carcinogenicity studies of up to
2 years in duration in mice and rats. In mice, there were no drug-related
neoplastic findings at doses up to 25 mg/kg/day obeticholic acid, a dose that
produced systemic exposures approximately 12 times those in humans at the MRHD
of 10 mg. In rats, obeticholic acid was administered at doses of 2, 7, and 20
mg/kg/day. At 20 mg/kg/day (approximately 12 times the human exposure at the
MRHD), obeticholic acid caused an increase in the incidence of benign granulosa
cell tumors in the ovaries and benign granular cell tumors in the cervix and
vagina of female rats. There were no drug-related neoplastic findings in male
rats.
Obeticholic
acid was not genotoxic in the Ames test, a human peripheral blood lymphocyte
chromosomal aberration test, and a mouse micronucleus test. The glycine
conjugate of obeticholic acid was also not genotoxic in an Ames test and human
peripheral blood lymphocyte chromosome aberration test. The taurine conjugate
of obeticholic acid was not genotoxic in an Ames test, and was negative in a
human peripheral blood lymphocyte chromosomal aberration test in the presence
of metabolic activation; the findings of the chromosomal aberration assay in
the absence of metabolic activation were inconclusive.
Obeticholic
acid, administered at oral doses of 5, 25 and 50 mg/kg/day to male rats for 28
days before mating and throughout the mating period, and to female rats from 14
days before mating through mating and until gestation day 7, did not alter male
or female fertility or early embryonic development at any dose (the 50
mg/kg/day dose is approximately 13 times the human exposure at the MRHD).
Clinical Studies
The
recommended starting dosage of Ocaliva is 5 mg orally once daily for 3 months
with titration to 10 mg once daily based upon tolerability and response [see Dosage and Administration (2.1)]. Initiation of therapy with a starting dosage
Ocaliva 10 mg once daily is not recommended due to an increased risk of
pruritus [see Adverse Reactions (6.1)].
Trial 1
was a randomized, double-blind, placebo-controlled, 12-month trial which
evaluated the safety and efficacy of Ocaliva in 216 patients with PBC who were
taking UDCA for at least 12 months (on a stable dosage for at least 3 months),
or who were unable to tolerate UDCA and did not receive UDCA for at least 3
months. Patients were included in the trial if the ALP was 1.67-times upper
limit of normal (ULN) or greater and/or if total bilirubin was greater than
1-times ULN but less than 2-times ULN. Patients were excluded from the trial if
they had other liver disease, presence of clinically significant hepatic
decompensation events (i.e., portal hypertension and its complications,
cirrhosis with complications, or hepato-renal syndrome), severe pruritus, or
Model for End Stage Liver Disease (MELD) score of 15 or greater.
Patients
were randomized (1:1:1) to receive either Ocaliva 10 mg once daily for the
entire 12 months of the trial, (n=73); Ocaliva titration (5 mg once daily for
the initial 6 months, with the option to increase to 10 mg once daily for the
last 6 months if the patient was tolerating Ocaliva but had ALP 1.67-times ULN
or greater, and/or total bilirubin greater than ULN, or less than 15% ALP
reduction) (n=70); or placebo (n=73). Ocaliva or placebo was administered in
combination with UDCA in 93% of patients during the trial and as monotherapy in
7% of patients who were unable to tolerate UDCA.
The
primary endpoint was a responder analysis at Month 12, where response was
defined as a composite of three criteria: ALP less than 1.67-times the ULN,
total bilirubin less than or equal to ULN, and an ALP decrease of at least 15%.
The ULN for ALP was defined as 118 U/L for females and 124 U/L for males. The
ULN for total bilirubin was defined as 1.1 mg/dL for females and 1.5 mg/dL for
males.
The study
population was 91% female and 94% white. The mean age was 56 years (range 29 to
86 years). The mean baseline ALP concentration was 323.2 U/L, corresponding to
2.74-times ULN. Approximately 29% of the patients had ALP concentration levels
greater than 3-times the ULN. The mean baseline total bilirubin concentration
was 0.65 mg/dL, and was less than or equal to the ULN in 92% of the enrolled
patients. Distribution of patients byRotterdamdisease stage criteria at baseline is shown in Table 2. Cirrhosis was present
at baseline in 4 patients (5%) in the Ocaliva 10 mg arm, 7 patients (10%) in
the Ocaliva titration arm, and 9 patients (12%) in the placebo arm.
Table 2:RotterdamDisease Stage Criteria at Baseline in Trial 1 by Treatment Arm with or
without UDCA *
|
|
Disease Stage†
|
Ocaliva 10 mg
(N=73)
|
Ocaliva Titration
(N=70)
|
Placebo
(N=73)
|
|
Percentages are
based on non-missing values for each time point.
|
|
*
In the trial
there were 16 patients (7%) who were intolerant and did not receive
concomitant UDCA: 6 patients (8%) in the Ocaliva 10 mg arm, 5 patients (7%)
in the Ocaliva titration arm, and 5 patients (7%) in the placebo arm.
†
Early: normal total bilirubin and normal albumin
(values less than or equal to ULN and greater than or equal to the lower
limit of normal (LLN), respectively), Moderately advanced: abnormal total
bilirubin or abnormal albumin, Advanced: abnormal total bilirubin and abnormal
albumin. Total bilirubin ULN: 1.1 mg/dL (females) and 1.5 mg/dL (males).
Albumin LLN: 35 g/L (females and males).
|
|
Early, n (%)
|
66 (90)
|
64 (91)
|
65 (89)
|
|
Moderately
Advanced, n (%)
|
7 (10)
|
6 (9)
|
8 (11)
|
|
Advanced, n (%)
|
0 (0)
|
0 (0)
|
0 (0)
|
Table 3
shows the percentage of patients by treatment arm in Trial 1 who achieved a
response to the primary composite endpoint at Month 12, and to the individual
components of the primary endpoint (i.e., ALP less than 1.67-times the ULN,
total bilirubin less than or equal to ULN, and an ALP decrease of at least
15%). A total of 33 patients in the Ocaliva titration arm, who did not achieve
a response at 6 months and tolerated Ocaliva, had their dosage increased from 5
mg once daily to 10 mg once daily. Of these 33 patients, 13 (39%) achieved the
primary composite endpoint at 12 months.
Table 3: Percentage of Adult Patients with PBC Achieving the Primary
Composite Endpoint at Month 12 in Trial 1 by Treatment Arm with or without
UDCA*
|
|
|
Ocaliva
10 mg
(N = 73)
|
Ocaliva
Titration†
(N = 70)
|
Placebo
(N = 73)
|
|
*
In the trial
there were 16 patients (7%) who were intolerant and did not receive
concomitant UDCA: 6 patients (8%) in the Ocaliva 10 mg arm, 5 patients (7%)
in the Ocaliva titration arm, and 5 patients (7%) in the placebo arm.
†
Patients
randomized to Ocaliva titration received Ocaliva 5 mg for the initial 6 month
period. At Month 6, patients who were tolerating Ocaliva, but had an ALP
1.67-times ULN or greater, and/or total bilirubin greater than ULN, or less
than 15% ALP reduction were eligible for titration from 5 mg once daily to 10
mg once daily for the final 6 months of the trial.
‡
Percentage of
patients achieving a response, defined as an ALP less than 1.67-times the
ULN, total bilirubin less than or equal to the ULN, and an ALP decrease of at
least 15%. Missing values were considered a non-response. The exact test was
used to calculate the 95% CIs.
§
p<0.0001 for
Ocaliva titration and Ocaliva 10 mg arms versus placebo. P-values are
obtained using the Cochran–Mantel–Haenszel General Association test
stratified by intolerance to UDCA and pretreatment ALP greater than 3-times
ULN and/or AST greater than 2-times ULN and/or total bilirubin greater than
ULN.
¶
Response rates
were calculated based on the observed case analysis (i.e., [n=observed
responder]/[N=ITT population]); percentage of patients with Month 12 values
are 86%, 91% and 96% for the Ocaliva 10 mg, Ocaliva titration and placebo
arms, respectively.
#
The mean baseline total bilirubin value was 0.65
mg/dL, and was less than or equal to the ULN in 92% of the enrolled patients.
|
|
Primary Composite Endpoint‡
|
|
|
|
|
Responder
rate, (%)§
[95% CI]
|
48
[36, 60]
|
46
[34, 58]
|
10
[4, 19]
|
|
Components of Primary Endpoint¶
|
|
ALP
less than 1.67-times ULN, n (%)
|
40 (55)
|
33 (47)
|
12 (16)
|
|
Decrease
in ALP of at least 15%, n (%)
|
57 (78)
|
54 (77)
|
21 (29)
|
|
Total
bilirubin less than or equal to ULN#, n (%)
|
60 (82)
|
62 (89)
|
57 (78)
|
Mean Reduction in ALP
Figure 1
shows the mean reductions in ALP in Ocaliva-treated patients compared to
placebo. Reductions were observed as early as Week 2, plateaued by Month 3 and
were maintained through Month 12 for patients who were maintained on the same
dosage throughout 12 months. Although Trial 1 studied titration at 6 months,
these data are supportive of titration of Ocaliva after 3 months [see Dosage and Administration (2.1)]. For patients in the Ocaliva titration arm whose
Ocaliva dosage was increased from 5 mg once daily to 10 mg once daily,
additional reductions in ALP were observed at Month 12 in the majority of
patients [see Clinical Pharmacology (12.2)].
|
Figure 1:
Mean ALP over 12 Months in Trial 1 by Treatment Arm with or without UDCAa
|
|
a
In the trial
there were 16 patients (7%) who were intolerant and did not receive
concomitant UDCA: 6 patients (8%) in the Ocaliva 10 mg arm, 5 patients (7%)
in the Ocaliva titration arm, and 5 patients (7%) in the placebo arm.
b
Patients randomized to Ocaliva titration received
Ocaliva 5 mg once daily for the initial 6 month period. At Month 6, patients
who were tolerating Ocaliva, but had an ALP 1.67-times ULN or greater, and/or
total bilirubin greater than ULN, or less than 15% ALP reduction were
eligible for titration from 5 mg once daily to 10 mg once daily for the final
6 months of the trial.
|
|
|
Mean Reduction in GGT
The mean
(95% CI) reduction in gamma-glutamyl transferase (GGT) was 178 (137, 219) U/L
in the Ocaliva 10 mg arm, 138 (102, 174) U/L in the Ocaliva titration arm, and
8 (-32, 48) U/L in the placebo arm.
Ocaliva Monotherapy
Fifty-one
PBC patients with baseline ALP 1.67-times ULN or greater and/or total bilirubin
greater than ULN were evaluated for a biochemical response to Ocaliva as
monotherapy (24 patients received Ocaliva 10 mg once daily and 27 patients
received placebo) in a pooled analysis of data from Trial 1 and from a
randomized, double-blind, placebo-controlled, 3-month trial. At Month 3, 9
(38%) Ocaliva-treated patients achieved a response to the composite endpoint,
compared to 1 (4%) placebo-treated patient. The mean (95% CI) reduction in ALP
in Ocaliva-treated patients was 246 (165, 327) U/L compared to an increase of
17 (-7, 42) U/L in the placebo-treated patients.
How Supplied/Storage and Handling
Ocaliva
tablets are packaged in a 40 mL high density polyethylene bottle closed with a
33 mm polypropylene child resistant cap containing an induction seal. Each
bottle contains 30 tablets.
5 mg Tablets
Ocaliva
tablets are available as off-white to yellow, round tablets debossed with INT
on one side and 5 on the other side. Each tablet contains 5 mg of obeticholic
acid.
· NDC 69516-005-30 5
mg tablets in a bottle (30 count)
10 mg Tablets
Ocaliva
tablets are available as off-white to yellow, triangular tablets debossed with
INT on one side and 10 on the other side. Each tablet contains 10 mg of
obeticholic acid.
· NDC 69516-010-30 10
mg tablets in a bottle (30 count)
Storage and Handling
Store at
20°C-25°C (68°F-77°F); excursions permitted to 15°C- 30°C (59°F -86°F) [See USP
Controlled Room Temperature].
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 [see Warnings and Precautions (5.1)].
· Advise patients who develop symptoms of complete
biliary obstruction to report to their healthcare provider immediately [see Contraindications (4)].
Severe Pruritus
· Advise patients to contact their healthcare provider
if they experience pruritus or an increase in the severity of pruritus [see Warnings and Precautions (5.2)].
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 (5.3)].
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 [see Drug Interactions (7.1)].
Ocaliva
is a registered trademark of Intercept Pharmaceuticals, Inc.
Distributed
by:
Intercept
Pharmaceuticals, Inc.
New York,
NY 10001
PRINCIPAL DISPLAY PANEL - 5 mg Tablet Bottle Label
NDC 69516-005-30
Rx only
Ocaliva®
(obeticholic acid) tablets
5 mg
30
tablets
Intercept
PRINCIPAL DISPLAY PANEL - 10 mg Tablet Bottle Label
NDC 69516-010-30
Rx only
Ocaliva®
(obeticholic acid) tablets
10 mg
30
tablets
Intercept
|
Ocaliva obeticholic acid tablet, film coated
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:69516-005
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
Obeticholic Acid (Obeticholic Acid)
|
Obeticholic
Acid
|
5 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
Sodium Starch Glycolate Type A Potato
|
|
|
Magnesium stearate
|
|
|
Polyvinyl Alcohol, Unspecified
|
|
|
Titanium dioxide
|
|
|
Polyethylene glycol 3350
|
|
|
Talc
|
|
|
Ferric Oxide Yellow
|
|
|
|
Product
Characteristics
|
|
Color
|
YELLOW
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
8mm
|
|
Flavor
|
|
Imprint Code
|
INT;5
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:69516-005-30
|
30 TABLET, FILM
COATED in 1 BOTTLE, PLASTIC
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA207999
|
05/27/2016
|
|
|
|
Ocaliva obeticholic acid tablet, film coated
|
|
Product Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:69516-010
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
Obeticholic Acid (Obeticholic Acid)
|
Obeticholic
Acid
|
10 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
Sodium Starch Glycolate Type A Potato
|
|
|
Magnesium stearate
|
|
|
Polyvinyl Alcohol, Unspecified
|
|
|
Titanium dioxide
|
|
|
Polyethylene glycol 3350
|
|
|
Talc
|
|
|
Ferric Oxide Yellow
|
|
|
|
Product
Characteristics
|
|
Color
|
YELLOW
|
Score
|
no score
|
|
Shape
|
TRIANGLE
|
Size
|
8mm
|
|
Flavor
|
|
Imprint Code
|
INT;10
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:69516-010-30
|
30 TABLET, FILM
COATED in 1 BOTTLE, PLASTIC
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA207999
|
05/27/2016
|
|
|
|
Labeler - Intercept Pharmaceuticals Inc (966658416)
|
Revised: 07/2017
Intercept
Pharmaceuticals Inc
