ENTECAVIR

Main information

  • Trade name:
  • ENTECAVIR MYLAN entecavir monohydrate 0.5 mg film coated tablets bottle
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ENTECAVIR MYLAN entecavir monohydrate 0.5 mg film coated tablets bottle
    Australia
  • Language:
  • English

Other information

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization number:
  • 220093
  • Last update:
  • 08-10-2017

Public Assessment Report

Public Summary

Summary for ARTG Entry:

220093

ENTECAVIR MYLAN entecavir monohydrate 0.5 mg film coated tablets bottle

ARTG entry for

Medicine Registered

Sponsor

Alphapharm Pty Ltd

Postal Address

PO Box R1462,ROYAL EXCHANGE, NSW, 1225

Australia

ARTG Start Date

18/04/2016

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. ENTECAVIR MYLAN entecavir monohydrate 0.5 mg film coated tablets bottle

Product Type

Single Medicine Product

Effective date

12/07/2017

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

Entecavir is indicated for the treatment of chronic hepatitis B virus infection in adults 16 years or older with evidence of active liver inflammation.

This indication is based on histologic, virologic, biochemical and serological responses in nucleoside-treatment naïve and lamividine-resistant adult

patients with HBeAg-positive or HBeAg-negative chronic HBV infection with compensated liver disease.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Bottle

HDPE

24 Months

Store below 25

degrees Celsius

Not recorded

Store in Original

Container

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

Components

1. ENTECAVIR MYLAN entecavir monohydrate 0.5 mg film coated tablets bottle

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

A white, film-coated, round, biconvex, beveled edge tablet debossed with

'M' on one side of the tablet and 'EV1' on the other side.

Active Ingredients

entecavir monohydrate

.5 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 26.11.2017 at 02:51:44 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics

ENTECAVIR MYLAN

Entecavir monohydrate

PRODUCT INFORMATION

NAME OF THE MEDICINE

Active ingredient

Entecavir monohydrate

Chemical name

2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-

methylenecyclopentyl]-6H-purin-6-one, monohydrate

Structural formula

Molecular formula

Molecular weight

295.3

CAS Registry no.

209216-23-9

DESCRIPTION

Entecavir

monohydrate

white to

off-white crystalline powder. It

slightly soluble in

water (2.4

mg/mL), and the pH of the saturated solution in water is 7.9 at 25° + 0.5°C.

Entecavir film-coated tablets are available for oral administration in strengths of 0.5 mg and 1 mg of entecavir

monohydrate. Entecavir monohydrate 0.5 mg and 1 mg film-coated tablets contain the following inactive

ingredients: lactose, microcrystalline cellulose, crospovidone, magnesium stearate, and Opadry White YS-1R-

7003 (ARTG No. 1625).

PHARMACOLOGY

Pharmacodynamics

Mechanism of action - Entecavir monohydrate is a guanosine nucleoside analogue with activity against HBV

polymerase. It is phosphorylated to the active triphosphate (TP) form, which has an intracellular half-life of 15

hours. Intracellular TP levels are directly related to extracellular entecavir monohydrate concentrations, with

significant

accumulation

beyond

initial

plateau

levels.

competing

with

natural

substrate

deoxyguanosine-TP, entecavir monohydrate-TP inhibits all 3 functional activities of the viral polymerase: (1)

priming of the HBV polymerase, (2) reverse transcription of the negative strand from the pregenomic

messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir monohydrate-TP Ki value

for inhibition of HBV DNA polymerase is 1.2 nM. Entecavir monohydrate-TP is a weak inhibitor of cellular

DNA polymerases α, β, δ and ε with Ki values of 18 to 40 µM. It did not inhibit mitochondrial γ polymerase

(Ki>160μM) and did not affect the mitochondrial DNA content of human hepatoma cells in vitro. Entecavir

monohydrate inhibited HBV DNA synthesis at a concentration of 0.004 μM in human HepG

cells transfected

ENTECAVIR MYLAN – PRODUCT INFORMATION

2

with wild-type HBV. IC

values for entecavir monohydrate against lamivudine-resistant HBV ranged from

0.029-0.061 μM.

Resistance in vitro - There was reduced susceptibility to entecavir monohydrate when LVD

substitutions

(M204I/V + L180M) were present. Entecavir monohydrate inhibited the replication of LVD

HBV at 8-fold

higher concentrations than that for the wild-type virus in cell-based studies. At extracellular concentrations

representative of plasma levels achieved with 1 mg dosing, intracellular entecavir monohydrate-TP levels

would be expected to surpass those needed to inhibit the enzyme activity of lamivudine-resistant HBV

polymerases. Recombinant viruses encoding adefovir-resistant substitutions at either rtN236T or rtA181V

remained fully susceptible to entecavir monohydrate.

Clinical resistance - Genotyping was performed on paired baseline and on-treatment samples from all

continuously treated patients with PCR detectable HBV DNA (

300 copies/mL) at Week 48, 96, 144, 192

and 240 or at the end of dosing to identify any novel or known resistance substitutions that emerged during

entecavir therapy. Virologic breakthrough (

1 log

increase above nadir in HBV DNA by PCR) due to

resistance to entecavir monohydrate requires the existence of primary lamivudine resistance substitutions

(M204I/V ± L180M) along with an additional substitution at residues T184, S202, and/or M250 of the

polymerase protein.

Nucleoside-naive studies: Patients in nucleoside-naive studies received 0.5 mg entecavir monohydrate for up to

96 weeks (see CLINICAL TRIALS). Study participants who failed to achieve the study-defined complete

response by Week 96 were offered continued entecavir monohydrate treatment in a rollover study. Complete

response for HBeAg positive was <0.7 MEq/mL (approximately 7 x 10

copies/mL) serum HBV DNA and

HBeAg loss and, for HBeAg negative, was <0.7 MEq/mL HBV DNA and ALT normalisation.

By week 96, evidence of emerging amino acid substitution rtS202G with rtM204V and rtL180M was detected

in the HBV of 2 subjects and 1 of them experienced virologic rebound (

1 log10 increased above nadir). In

addition, emerging amino acid substitution at rtM204I/V and rtL180M, rtL80I or rtV173L, which conferred

decreased phenotypic susceptibility to entecavir in the absence of rtT184, rtS202 or rtM250 changes, were

detected in the HBV of 3 subjects who experienced virologic rebound.

Results in Table 1 reflect use of a 1 mg dose of entecavir monohydrate for 147 of 149 patients in Year 3 and

121 patients in Year 4, 108 patients in Year 5 and of combination entecavir monohydrate plus lamivudine

therapy (followed by long-term entecavir monohydrate monotherapy) for a median of 20 weeks for 130 of 149

patients in Year 3 and for 1 week for 1 of 121 patients in Year 4 in the rollover study. Through Week 240 in

nucleoside-naive studies, genotypic evidence of ETVr substitutions at rtT184, rtS202, or rtM250 was identified

in 3 patients treated with entecavir monohydrate, 2 of whom experienced virologic breakthrough (see table).

These substitutions were observed only in the presence of LVDr substitutions (rtM204V and rtL180M).

Table 1. Genotypic Resistance to Week 240, Nucleoside-Naive Patients

Year 1

Year 2

Year 3

a

Year 4

a

Year 5

a

Patients treated and monitored for

resistance

Patients in specific year with:

emerging genotypic entecavir

resistance

genotypic entecavir resistance

with

virologic breakthrough

Cumulative probability of:

emerging genotypic entecavir resistance

0.2%

0.5%

1.2%

1.2%

1.2%

ENTECAVIR MYLAN – PRODUCT INFORMATION

3

genotypic entecavir resistance

with

0.2%

0.2%

0.8%

0.8%

0.8%

virologic breakthrough

Results reflect use of a 1 mg dose of entecavir monohydrate for 147 patients in Year 3 and all patients in Years 4 and

5 and of combination of entecavir monohydrate-lamivudine therapy (followed by long-term entecavir therapy) for a

median of 20 weeks for 130 patients in Year 3 and for 1 week for 1 patient in Year 4 in a rollover study.

Includes patients with at least one on-therapy HBV DNA measurement by PCR at or after Week 24 through Week 58

(year 1), after Week 58 through Week 102 (year 2), after Week 102 through Week 156 (year 3), after week 156

through week 204 (Year 4), or after week 204 through week 252 (Year 5).

Entecavir monohydrate resistance substitutions at residues rtT184, rtS202, or rtM250. Patients also have lamivudine

resistance substitutions (rtM204V and rtL180M).

≥ 1 log

increase above nadir in HBV DNA by PCR, confirmed with successive measurements or at the end of the

windowed time point.

Lamivudine-refractory

studies:

Participants

treated

with

entecavir

monohydrate

once

daily

lamivudine-refractory studies (see CLINICAL TRIALS) who failed to achieve the study-defined complete

response by Week 96 were offered continued entecavir treatment in a rollover study. Participants received 1

mg entecavir once daily for up to an additional 96 weeks. Genotypic analysis of clinical samples from

lamivudine-refractory patients identified emerging entecavir resistance substitutions in 11/187 patients in Year

1, 12/146 patients in Year 2, 16/80 patients in Year 3, 6/52 patients in Year 4 and 2/33 patients in Year 5 (see

Table 2). Results in Table 2 reflect the use of combination entecavir monohydrate plus lamivudine therapy

(followed by long-term entecavir monohydrate monotherapy) for a median of 13 weeks for 48 of 80 patients in

Year 3, for a median of 38 weeks for 10 of 52 patients in Year 4 and for 16 weeks for 1 of 33 patients in Year 5

in the rollover study. The presence of entecavir resistance substitutions at baseline in isolates from 10 (5%) of

lamivudine-refractory

patients

indicates

that

prior

lamivudine

treatment

select

these

resistance

substitutions and that they can exist at a low frequency before entecavir monohydrate treatment. Three of the

10 patients experienced virologic breakthrough in the 240 weeks of follow-up.

Table 2. Genotypic Entecavir Resistance to Week 240, Lamivudine-Refractory Patients

Results reflect use of combination entecavir-lamivudine therapy (followed by long-term entecavir therapy) for a

median of 13 weeks for 48 patients in Year 3, a median of 38 weeks for 10 patients in Year 4, and for 16 weeks in 1

patient in Year 5 in a rollover study.

Includes patients with at least one on-therapy HBV DNA measurement by PCR at or after week 24 through week 58

(Year 1), after week 58 through week 102 (Year 2), after week 102 through week 156 (Year 3), after week 156

through week 204 (Year 4), or after week 204 through week 252 (Year 5).

Entecavir resistance substitutions at residues rtT184, rtS202, or rtM250. Patients also had lamivudine resistance

substitutions (rtM204V/I ± rtL180M).

≥1 log

increase above nadir in HBV DNA by PCR, confirmed with successive measurements or at the end of the

windowed time point.

Entecavir resistance substitutions occurring in any year; virologic breakthrough in specified year.

Year 1

Year 2

Year 3

a

Year 4

a

Year 5

a

Patients treated and monitored for

resistance

Patients in specific year with:

emerging genotypic entecavir

resistance

genotypic entecavir resistance

with

virologic breakthrough

Cumulative probability of:

emerging genotypic entecavir resistance

genotypic entecavir resistance

with

virologic breakthrough

ENTECAVIR MYLAN – PRODUCT INFORMATION

4

Pharmacokinetics

Absorption

In healthy participants, entecavir monohydrate was rapidly absorbed with peak plasma concentrations occurring

between 0.5 and 1.5 hours. There was a dose-proportionate increase in peak plasma concentration (C

) and

area under the concentration-time curve (AUC) values following multiple doses ranging from 0.1 to 1 mg.

Steady-state was achieved after 6-10 days of once-daily dosing with approximately 2-fold accumulation. C

and trough plasma concentration (C

trough

) at steady-state were 4.2 and 0.3 ng/mL, respectively, for a 0.5 mg

dose, and 8.2 and 0.5 ng/mL, respectively, for a 1 mg dose. In healthy participants, the bioavailability of the

tablet was 100% relative to the oral solution. The oral solution and tablet may be used interchangeably.

Oral administration of entecavir monohydrate 0.5 mg with a standard high-fat meal (945 kcal, 54.6 g fat) or a

light meal (379 kcal, 8.2 g fat) resulted in a minimal delay in absorption (1-1.5 hour fed vs. 0.75 hour fasted), a

decrease in C

of 44-46%, and a decrease in AUC of 18-20%. Therefore, entecavir should be administered on

an empty stomach (at least 2 hours before a meal and at least 2 hours after a meal) (see DOSAGE AND

ADMINISTRATION).

Distribution

The estimated volume of distribution for entecavir monohydrate was in excess of total body water, suggesting

that it has good penetration into tissues. Protein binding to human serum protein in vitro was approximately

13%.

Metabolism

Entecavir

monohydrate

substrate,

inhibitor,

inducer

CYP450

enzyme

system.

concentrations approximately 10,000-fold higher than those obtained in humans, entecavir monohydrate

inhibited none of the major human CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1. At

concentrations approximately 340-fold higher than those observed in humans, entecavir monohydrate did not

induce the human CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. Following administration of

entecavir monohydrate in humans and rats, no oxidative or acetylated metabolites and minor amounts of the

phase II metabolites glucuronide and sulfate conjugates were observed.

Excretion

After reaching peak levels, entecavir monohydrate plasma concentrations decreased in a bi-exponential manner

with a terminal elimination half-life of approximately 128-149 hours. The observed drug accumulation index is

approximately 2-fold with once-daily dosing, suggesting an effective accumulation half-life of about 24 hours.

Entecavir monohydrate is predominantly eliminated by the kidney with urinary recovery of unchanged drug at

steady-state ranging from 62% to 73% of the dose. Renal clearance is independent of dose and ranges between

360 and 471 mL/min suggesting that entecavir monohydrate undergoes both glomerular filtration and net

tubular secretion.

Special Populations

Gender/race

The pharmacokinetic profile of entecavir monohydrate does not vary by gender or race.

Elderly

The pharmacokinetic profile of entecavir monohydrate does not vary by age.

Renal impairment

The pharmacokinetics of entecavir monohydrate following a single 1 mg dose were studied in patients (without

chronic hepatitis B infection) with selected degrees of renal impairment, including patients whose renal

impairment was managed by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Results are

shown in Table 3.

ENTECAVIR MYLAN – PRODUCT INFORMATION

5

Table 3.

Pharmacokinetic Parameters of Entecavir monohydrate in Participants with Selected

Degrees of Renal Impairment

Renal Function Group

Baseline Creatinine Clearance (mL/min)

Unimpaired

Mild

Moderate

Severe

Severe

Managed with

Severe

Managed

>80

>50-≤80

30-50

<30

Hemodialysis

with CAPD

(n=6)

(n=6)

(n=6)

(n=6)

(n=6)

(n=4)

(ng/mL)

10.4

10.5

15.3

15.4

16.6

(CV%)

(30.7)

(37.2)

(22.7)

(33.8)

(56.4)

(29.7)

(0-T)

27.9

51.5

69.5

145.7

233.9

221.8

(ng•hr/mL)

(25.6)

(22.8)

(22.7)

(31.5)

(28.4)

(11.6)

(CV)

CLR (mL/min)

383.2

197.9

135.6

40.3

(SD)

(101.8)

(78.1)

(31.6)

(10.1)

CLT/F (mL/min)

588.1

309.2

226.3

100.6

50.6

35.7

(SD)

(153.7)

(62.6)

(60.1)

(29.1)

(16.5)

(19.6)

CLR=renal clearance; CLT/F=apparent oral clearance.

Dosage adjustment is recommended for patients with a creatinine clearance <50 mL/min, including patients on

hemodialysis or CAPD. (See DOSAGE AND ADMINISTRATION: Renal Impairment.)

Following a single 1 mg dose of entecavir monohydrate, hemodialysis removed approximately 13% of the

entecavir monohydrate dose over 4 hours and CAPD removed approximately 0.3% of the dose over 7 days.

Entecavir monohydrate should be administered after hemodialysis.

Hepatic impairment

The pharmacokinetics of entecavir monohydrate following a single 1 mg dose were studied in patients (without

chronic hepatitis B infection) with moderate and severe hepatic impairment. The pharmacokinetics of entecavir

monohydrate were similar between hepatically impaired patients and healthy control participants; therefore, no

dosage adjustment of entecavir is recommended for patients with hepatic impairment.

Post-liver transplant

Entecavir monohydrate exposure in HBV-infected liver transplant recipients on a stable dose of cyclosporine A

(n=5) or tacrolimus (n=4) was approximately 2-fold the exposure in healthy participants with normal renal

function. Altered renal function contributed to the increase in entecavir monohydrate exposure in these

patients.

Before

during

entecavir

therapy

liver

transplant

recipients

receiving

cyclosporine

tacrolimus, renal function should be carefully evaluated (see DOSAGE AND ADMINISTRATION: Renal

Impairment).

Paediatrics

Pharmacokinetic studies have not been conducted in children.

Drug Interactions

Entecavir

monohydrate

substrate,

inhibitor,

inducer

CYP450

enzyme

system

(see

PHARMACOLOGY: Metabolism and Elimination). The pharmacokinetics of entecavir monohydrate are

unlikely to be affected by coadministration with agents that are either metabolized by, inhibit, or induce the

CYP450 system. Likewise, the pharmacokinetics of known CYP substrates are unlikely to be affected by

coadministration of entecavir monohydrate.

The steady-state pharmocokinetics of entecavir monohydrate and coadministered drug were not altered in

interaction studies of entecavir monohydrate with each of the following:

lamivudine,

adefovir dipivoxil,

tenofovir disoproxil fumarate (see also PRECAUTIONS: Drug Interactions).

ENTECAVIR MYLAN – PRODUCT INFORMATION

6

A pilot study in nine HBV-infected liver transplant recipients suggested that concurrent cyclosporine A (n=5)

tacrolimus

(n=4)

therapy

affect

pharmacokinetics

entecavir

monohydrate

(see

PHARMACOLOGY: Special Populations - Post-Liver Transplant). The effect of entecavir monohydrate on

the pharmacokinetics of cyclosporine A or tacrolimus is unknown.

CLINICAL TRIALS

The safety and efficacy of entecavir were evaluated in three active-controlled trials on five continents. These

studies included 1633 patients 16 years of age or older with chronic hepatitis B infection (serum HBsAg-

positive for at least 6 months) accompanied by evidence of viral replication (detectable serum HBV DNA, as

measured by the bDNA hybridization or PCR assay). Patients had persistently elevated ALT levels ≥1.3 times

the upper limit of normal (ULN) and chronic inflammation on liver biopsy compatible with a diagnosis of

chronic viral hepatitis. The safety and efficacy of entecavir were also evaluated in an active-controlled study of

191 HBV-infected patients with decompensated liver disease and in a study of 68 patients co-infected with

HBV and HIV.

Nucleoside-Naive Patients With Compensated Liver Disease

Outcomes at 48 weeks

HBeAg-positive

Study AI463022 was a multinational, randomized, double-blind study of entecavir tablets 0.5 mg once daily

versus lamivudine 100 mg once daily for 52 weeks in 709 (of 715 randomized) nucleoside-naive patients with

chronic hepatitis B infection and detectable HBeAg. The mean age of patients was 35 years (range 16 to 78),

and 75% were male; 57% were Asian, 40% were Caucasian, and 13% had previously received interferon-α

treatment. At baseline, patients had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA

level as measured by Roche COBAS Amplicor

PCR assay of 9.66 log

copies/mL, and mean serum ALT

level of 143 U/L. Response was assessed at Week 52 based on test results obtained at the Week 48 visit.

Ninety-six percent of patients had a baseline liver biopsy, paired samples were collected for 89% of patients.

HBeAg-negative (anti-HBe positive/HBV DNA positive)

Study AI463027 was a multinational, randomized, double-blind study of entecavir tablets 0.5 mg once daily

versus lamivudine 100 mg once daily for 52 weeks in 638 (of 648 randomized) nucleoside-naive patients with

HBeAg-negative (HBeAb-positive) chronic hepatitis B infection (presumed to have pre-core or core-promoter

mutants). The mean age of patients was 44 years (range 18 to 77), and 76% were male. Thirty-nine percent

were Asian and 58% were Caucasian; 13% had previously received interferon-α treatment. At baseline,

patients had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA level as measured by

Roche COBAS Amplicor PCR assay of 7.58 log

copies/mL, and mean serum ALT level of 142 U/L. Ninety-

eight percent of patients had a baseline liver biopsy, and 89% had a biopsy at Week 48; paired samples were

collected for 88% of patients. Response was assessed at Week 52 based on test results obtained at the Week 48

visit. In Studies AI463022 and AI463027, entecavir was superior to lamivudine on the primary efficacy

endpoint of Histologic Improvement, defined as ≥2-point reduction in Knodell Necroinflammatory Score with

no worsening in Knodell Fibrosis Score at Week 48. Histologic Improvement and change in Ishak Fibrosis

Score are shown in Table 4. Biochemical, virologic, and serologic outcome measures are shown in Table 5.

ENTECAVIR MYLAN – PRODUCT INFORMATION

7

Table 4.

Histologic Improvement and Change in Ishak Fibrosis Score at Week 48, Nucleoside-

Naive

Patients in Studies AI463022 and AI463027

Patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥2).

In these analyses, missing or inadequate biopsies at Week 48 were classified “no improvement.”

≥2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis

Score.

p<0.01.

p<0.05.

For Ishak Fibrosis Score, improvement = ≥1-point decrease from baseline and worsening = ≥1-point increase from

baseline.

Not significant.

CI = confidence interval.

Table 5.

Biochemical, Virologic, and Serologic Endpoints at Week 48, Nucleoside-Naive Patients in

Studies AI463022 and AI463027

Study AI463022 (HBeAg-Positive)

Study AI463027 (HBeAg-Negative)

Entecavir

0.5

mg

Lami-

vudine

100 mg

Difference

Entecavir-

lamivudine

Entecavir

0.5

mg

Lami-

vudine

100 mg

Difference

Entecavir-

lamivudine

n=314

a

n=314

a

(95% CI)

b

n=296

a

n=287

a

(95% CI)

b

Histologic Improvement (Knodell Scores)

Improvement

9.9%

(2.6%,

17.2%)

9.6%

(2.0%,

17.3%)

No improvement

Ishak Fibrosis Score

Improvement

3.2%

(-4.4%,

10.7%)

-1.8%

(-9.7%, 6.0%)

No change

Worsening

Missing Week

48 biopsy

Study AI463022 (HBeAg-Positive)

Study AI463027 (HBeAg-Negative)

Entecavir

0.5 mg

Lami-

vudine

100 mg

Difference

Entecavir-

lamivudine

Entecavir

0.5 mg

Lami-

vudine

100 mg

Difference

Entecavir-

lamivudine

n=354

n=355

(95% CI)

n=325

n=313

(95% CI)

ALT normalisation

(≤1 X ULN)

HBV DNA

8.4%

(1.3%,

15.4%)

6.9%

(0.2%, 13.7

Mean change

from baseline by

(log

copies/mL)

-6.86

-5.39

-1.52%

(-1.8, -1.3

-5.04

-4.53

-0.43%

(-0.6, -0.3

Proportion

undetectable (<300

copies/mL) by

30.3%

(23.3%, 37.3%

18.3%

(12.3, 24.2

<0.7 MEq/mL by

bDNA

25.6%

(19.8%, 31.4%

5.9%

(1.8%, 10.1%

ENTECAVIR MYLAN – PRODUCT INFORMATION

8

p<0.05.

Roche COBAS Amplicor PCR assay.

p<0.0001.

At Week 24, HBV DNA < 300 copies/mL by PCR was observed in 42% of entecavir-treated patients and 25% of

lamivudine-treated patients (p<0.0001) in Study AI463022 and 74% of entecavir-treated patients and 62% of

lamivudine-treated patients (p = 0.0013) in Study AI463027.

Quantiplex bDNA assay.

p<0.01.

CI = confidence interval

Responses for patients with baseline Knodell Fibrosis Scores of 4 (cirrhosis) were comparable to overall

responses

efficacy

outcome

measures

(all

patients

compensated

liver

disease).

Histologic

Improvement was independent of baseline HBV DNA or ALT levels.

Covalently closed circular deoxyribonucleic acid (cccDNA) is a stable genomic form of nuclear HBV DNA

that serves as an hepatic reservoir of virus, provides the template for HBV transcription, and contributes to viral

persistence and relapse. For a subset of patients with paired liver samples in Study AI463022, the mean change

from baseline in hepatic cccDNA at Week 48 was -0.9 log

copies/human genome equivalents (approximately

8-fold reduction) for entecavir-treated patients (n=159) and -0.7 log

copies/HGEq (approximately 5-fold

reduction) for lamivudine-treated patients (n=146). In Study AI463027, the mean change from baseline in

hepatic cccDNA at Week 48 was -0.5 log

copies/HGEq (approximately 3-fold reduction) in each treatment

group (n=107 for entecavir-treated patients and n=104 for lamivudine-treated patients).

Lamivudine-Refractory Patients

Outcomes at 48 weeks

Study AI463026 was a multinational, randomized, double-blind study of entecavir in 286 (of 293 randomized)

patients with lamivudine-refractory chronic hepatitis B infection. Patients receiving lamivudine at study entry

either switched to entecavir 1 mg once daily (with neither a washout nor an overlap period) or continued on

lamivudine 100 mg for 52 weeks. The mean age of patients was 39 years (range 16 to 74), and 76% were male;

37% were Asian and 62% were Caucasian. Eighty-five percent had LVD

mutations at baseline. Patients had a

mean Knodell Necroinflammatory Score of 6.5, mean serum HBV DNA level as measured by Roche COBAS

Amplicor PCR assay of 9.36 log

copies/mL, and mean serum ALT level of 128 U/L. Response was assessed

at Week 52 based on test results obtained at the Week 48 visit. Ninety-eight percent of patients had a baseline

liver biopsy, and 88% had a biopsy at Week 48; paired samples were collected for 87% of patients.

Study

AI463026,

entecavir

superior

lamivudine

coprimary

endpoints

Histologic

Improvement (using the Knodell Score at Week 48) and Composite Endpoint (proportion of patients with HBV

DNA <0.7 MEq/mL by bDNA assay and ALT <1.25 X ULN at Week 48). These results and change in Ishak

Fibrosis Score are shown in Table 6. Table 7 shows biochemical, virologic, and serologic endpoints.

Table 6.

Histologic Improvement, Change in Ishak Fibrosis Score, and Composite Endpoint at

Week 48, Lamivudine-Refractory Patients in Study AI463026

a

Entecavir

1

mg

Lamivudine

100 mg

Difference Entecavir-

lamivudine

(97.5% CI)

n=124

a

n=116

a

Histologic Improvement (Knodell Scores)

Improvement

27.3%

(13.6%, 40.9

No improvement

Ishak Fibrosis Score

Improvement

17.5%

Loss of HBeAg

HBeAg

seroconversion

ENTECAVIR MYLAN – PRODUCT INFORMATION

9

No change

(6.8%, 28.2

Worsening

Missing Week

48 biopsy

Composite Endpoint

h

n=141

n=145

50.5%

(40.4%, 60.6

Patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥2).

≥2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis

Score.

In this analysis, missing or inadequate biopsies at Week 48 were classified “no improvement.”

p<0.0001.

For Ishak Fibrosis Score, improvement = ≥1-point decrease from baseline and worsening = ≥1-point increase from

baseline.

p<0.01.

95% confidence interval.

Composite Endpoint (a coprimary endpoint) was defined as HBV DNA <0.7 MEq/mL by bDNA assay and

normalisation of serum ALT (<1.25 X ULN) at Week 48.

CI = confidence interval

Table 7.

Biochemical, Virologic, and Serologic Endpoints at Week 48, Lamivudine-Refractory

Patients in Study AI463026

Entecavir

1

mg

Lamivudine

100 mg

Difference Entecavir-lamivudine

n=141

n=145

(95% CI)

ALT normalisation

(≤1 X ULN)

45.8%

(35.9%, 55.8

HBV DNA

Mean change from

baseline by PCR

(log

copies/mL)

-5.11

-0.48

-4.39

(-4.8, -4.0)

Proportion undetectable

(<300 copies/mL)

by PCR

17.8%

(11.0%, 24.5%)

<0.7 MEq/mL by

bDNA

60.4%

(51.8%, 69.1

Loss of HBeAg

HBeAg

seroconversion

p<0.0001.

Roche COBAS Amplicor PCR assay.

At Week 24, HBV DNA <300 copies/mL by PCR was observed in 7% of entecavir-treated patients and no lamivudine-

treated patients (p=0.0011).

Quantiplex bDNA assay.

CI = confidence interval.

In Study AI463026, responses for patients with baseline Knodell Fibrosis Scores of 4 (cirrhosis) were

comparable to overall responses on all efficacy outcome measures (all patients had compensated liver disease).

Histologic Improvement was independent of baseline HBV DNA or ALT levels.

ENTECAVIR MYLAN – PRODUCT INFORMATION

10

For a subset of patients with paired liver samples in Study AI463026, the mean change from baseline in hepatic

cccDNA at Week 48 was -0.6 log

copies/HGEq (approximately 4-fold reduction) for entecavir-treated

patients (n=74) and 0.0 log

copies/HGEq for lamivudine-treated patients (n=59).

Health-related quality of life (HRQoL) was assessed in Study AI463026 using the standardized and validated

EQ-5D instrument developed by the EurolQol group. After 48 weeks of therapy, entecavir-treated patients

experienced significantly less worsening compared to lamivudine-treated patients in the dimensions of mobility,

self care, and pain/discomfort.

Outcomes Beyond 48 Weeks

The optimal duration of therapy with entecavir is unknown. According to protocol mandated criteria in the

Phase 3 clinical trials, participants discontinued entecavir or lamivudine treatment after 52 weeks according to a

definition of response based on HBV virologic suppression (<0.7 mEq/mL by bDNA assay) and either loss of

HBeAg in HBeAg-

positive participants, or ALT < 1.25 X ULN in HBeAg-negative participants at Week 48.

Participants who achieved virologic suppression but did not have serologic response (HBeAg-positive) or did

not achieve ALT< 1.25 X ULN (HBeAg-negative) continued blinded dosing until 96 weeks or until the

response criteria were met. These protocol-specific participant management guidelines are not intended as

guidance for clinical practice.

Nucleoside-naïve HBeAg-positive

Among

nucleoside-naïve

HBeAg-positive

participants

(Study

AI463022),

243/354

(69%)

entecavir

monohydrate-treated

participants

164/355

(46%)

lamivudine-treated

participants

continued

blinded

treatment for up to 96 weeks. Of those continuing blinded treatment in year 2, 180/243 (74%) entecavir

monohydrate-treated participants and 60/164 (37%) lamivudine-treated participants achieved HBV DNA < 300

copies/mL by PCR at the end of dosing; 193/243 (79%) entecavir monohydrate-treated participants achieved

ALT ≤ 1 X ULN compared to 112/164 (68%) lamivudine-treated participants. The number of participants with

virologic response but not serologic response who achieved a loss of HBeAg at the end of dosing in the second

year of blinded treatment was 37/243 (15%) for entecavir monohydrate and 28/164 (17%) for lamivudine. The

proportion who achieved HBeAg seroconversion was 26/243 (11%) for entecavir and 20/164 (12%) for

lamivudine.

Post-treatment follow-up: Among nucleoside-naïve HBeAg-positive participants, 111/354 (31%) entecavir

monohydrate-treated participants and 93/355 (26%) lamivudine-treated participants met the definition of

response at end of dosing, discontinued study drugs, and were followed off-treatment for up to 24 weeks. In

this cohort, 34/111 (31%) entecavir monohydrate-treated patients and 27/93 (29%) lamivudine-treated patients

had HBV DNA < 300 copies/mL by PCR at the end of follow-up. At the end of follow-up, 78/111 (70%) of the

entecavir group and 59/93 (63%) of the lamivudine group recorded ALT ≤ 1 X ULN.

Nucleoside-naïve HBeAg-negative

Among

nucleoside-naïve,

HBeAg-negative

participants

(Study

AI463027),

26/325

(8%)

entecavir

monohydrate-treated participants and 28/313 (9%) lamivudine-treated participants continued blinded treatment

for up to 96 weeks. In the cohorts continuing treatment, 22/26 entecavir monohydrate-treated and 16/28

lamivudine-treated participants had HBV DNA <300 copies/mL by PCR; 7 entecavir monohydrate-treated and

6 lamivudine-treated patients had ALT ≤ 1 X ULN at the end of dosing (up to 96 weeks).

Post-treatment follow-up: Among the nucleoside-naïve, HBeAg-negative participants, 286/325 (88%) treated

with entecavir monohydrate and 253/313 (81%) treated with lamivudine met the definition of response at end

of dosing, discontinued study drugs and were followed off-treatment for up to 24 weeks. In this cohort, 7/286

(2%) entecavir monohydrate-treated patients and 10/253 (4%) lamivudine-treated patients had HBV DNA <

300 copies/mL by PCR at the end of follow-up. At the end of follow-up 129/286 (45%) in the entecavir group

and 85/253 (34%) in the lamivudine group recorded ALT ≤ 1 X ULN.

ENTECAVIR MYLAN – PRODUCT INFORMATION

11

Liver biopsy results: 57 patients from the pivotal nucleoside-naïve studies AI463022 (HBeAg positive) and

AI463027 (HBeAg negative) who enrolled in a long-term rollover study were evaluated for long-term liver

histology outcomes. All 57 patients had both an evaluable baseline and long-term biopsy, with a median

duration of entecavir monohydrate therapy of 280 weeks (approximately 6 years).

(96%)

these

patients

Histologic

Improvement

2-point

decrease

Knodell

necroinflammatory score from baseline with no worsening of the Knodell fibrosis score), and 50 of 57 (88%)

had a ≥ 1-point decrease in Ishak fibrosis score. Of the 43 patients with a baseline Ishak fibrosis score of ≥ 2,

25 (58%) had a ≥ 2-point decrease. All (10/10) patients with advanced fibrosis or cirrhosis at baseline (Ishak

fibrosis score of 4.5 or 6) had a ≥1-point decrease (median decrease from baseline of 1.5 points). At the time of

the long-term biopsy, 57 (100%) of patients had HBV DNA < 300 copies/mL and 49 (86%) had serum ALT ≤ 1

X ULN.

Lamivudine-Refractory: Among lamivudine-refractory participants (Study AI463026), 77/141 (55%) in the

entecavir monohydrate-treated group and 3/145 (2%) in the lamivudine-treated group continued blinded

treatment for up to 96 weeks. In the entecavir monohydrate-treated cohort, 31/77 (40%) achieved HBV DNA <

300 copies/mL, 62/77 (81%) had ALT ≤ 1 X ULN and 8/77 (10%) demonstrated HBeAg serocoversion at the

end of dosing.

Post-treatment follow-up: Of the 22/141 (16%) lamivudine-refractory patients who met response criteria (HBV

DNA < 0.7 mEq/mL on bDNA assay and loss of HBeAg) while receiving entecavir monohydrate, 5/22 (23%)

had HBV DNA <300 copies/mL by PCR and 12/22 (55%) had ALT ≤ 1 X ULN at the end of follow-up.

Special Populations

Patients with Decompensated Liver Disease

Study AI463048 was a randomized, open-label study of entecavir versus adefovir dipivoxil in 191 (of 195

randomised) patients with HBeAg-positive or –negative chronic HBV infection and evidence of hepatic

decompensation, defined as Child-Turcotte-Pugh (CTP) score of 7 or higher. Patients were either HBV-

treatment naïve or pretreated (excluding pretreatment with entecavir, adefovir dipivoxil, or tenofovir disoproxil

fumarate). At baseline, patients had a mean serum HBV DNA by PCR of 7.83 log

copies/mL and mean ALT

level of 100 U/L; 54% of patients were HBeAg-positive; 35% had genotypic evidence of lamivudine resistance.

The baseline mean CTP score was 8.6. The dose of entecavir in this study was 1 mg once daily. Entecavir was

superior to adefovir dipivoxil on the primary efficacy endpoint of mean change from baseline in serum HBV

DNA by PCR at Week 24. Results for selected study endpoints at Weeks 24 and 48 are shown in Table 8.

Table 8. Selected Endpoints at Weeks 24 and 48, Patients with Decompensated Liver Disease, Study

AI463048.

Week 24 Week 48

Entecavir 1 mg

(n=100)

Adefovir

Dipivoxil 10 mg

(n=91)

Entecavir 1mg

(n=100)

Adefovir

Dipivoxil 10 mg

(n=91)

HBV DNA

Proportion

undetectable (<300

copies/mL)

49%*

57%*

Mean change from

baseline (log

copies/mL)

-4.48*

-3.40

-4.66

-3.90

ENTECAVIR MYLAN – PRODUCT INFORMATION

12

Stable or improved

CTP score

Model for End-

Stage Liver Disease

(MELD)

score

Mean change from

baseline

-2.0

-0.9

-2.6

-1.7

HBsAg loss

Normalisation of:

ALT (≤1 X ULN)

46/78 (59%)*

28/71 (39%)

49/78 (63%)*

33/71 (46%)

Albumin (≥1 X

LLN)

20/82 (24%)

14/69 (20%)

32/82 (39%)

20/69 (29%)

Bilirubin (≤1 X

ULN)

12/75 (16%)

10/65 (15%)

15/75 (20%)

18/65 (28%)

Prothrombin time

(≤1 X ULN)

9/95 (9%)

6/82 (7%)

8/95 (8%)

7/82 (9%)

Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL).

Defined as decrease or no change from baseline in CTP score

Baseline mean MELD score was 17.1 for ETV and 15.3 for adefovir dipivoxil.

Denominator is patients with abnormal values at baseline

* p<0.05

ULN = upper limit of normal, LLN = lower limit of normal

HIV/HBV Co-infected Patients

Study AI463038 was a randomized, double-blind, placebo-controlled study of entecavir versus placebo in

68 patients co-infected with HIV and HBV who were lamivudine refractory (experienced recurrence of

HBV viremia while receiving a lamivudine-containing HAART [highly active antiretroviral therapy]

regimen). Patients continued their lamivudine-containing HAART regimen (lamivudine dose 300 mg/day)

and were assigned to add either entecavir 1 mg once daily (51 patients) or placebo (17 patients) for 24

weeks followed by an open-label phase for an additional 24 weeks where all patients received entecavir.

At baseline, patients had a mean serum HBV DNA level by PCR of 9.13 log

copies/mL. Most patients

were HBeAg-positive at baseline, with a mean baseline ALT level of 71.5 U/L. Biochemical and virologic

endpoints at Week 24 are shown in Table 9.

Table 9. Biochemical and Virologic Endpoints at Week 24, Study AI463038

Entecavir 1 mg

a

Placebo

a

Difference entecavir-

Placebo

n=51

n=17

(95% CI)

HBV DNA (by PCR assay

Proportion undetectable (<300

copies/mL)

3/51 (6%)

5.9% (-0.6, 12.3)

Mean change from baseline (log

copies/mL)

-3.65

(n=48)

+0.11

(n=16)

-3.75

(-4.47, -3.04)

ALT normalisation (

1x ULN)

12/35 (34%)

1/12 (8%)

26.0

(3.8, 48.1)

ENTECAVIR MYLAN – PRODUCT INFORMATION

13

All patients also received a lamivudine-containing HAART regimen.

Roche COBAS Amplicor PCR assay.

p<0.0001.

p = 0.08

At the end of the open-label phase (Week 48), the mean change from baseline HBV DNA by PCR for patients

originally assigned to entecavir monohydrate was -4.20 log

copies/mL (n=43); 4/51 (8%) patients had HBV

<300

copies/mL

PCR;

13/35

(37%)

patients

with

abnormal

baseline

normalisation. Entecavir monohydrate has not been evaluated in HIV/HBV co-infected patients who are not

concurrently receiving effective HIV treatment (see PRECAUTIONS - Coinfection with HIV).

Liver Transplant Recipients

The safety and efficacy of entecavir 1 mg once daily were assessed in a single-arm, open label study in 65

patients who received a liver transplant for complications of chronic HBV infection and had HBV DNA <172

IU/mL (approximately 1000 copies/mL) at the time of transplant. The study population was 82% male, 39%

Caucasian, and 37% Asian, with a mean age of 49 years; 89% of patients had HBeAg-negative disease at the

time of transplant. Of the 61 patients who where evaluable for efficacy (received entecavir for at least 1

month), 60 also received hepatitis B immune globulin as part of the post-transplant prophylaxis regimen. At

Week 72 post-transplant, none of the evaluable patients had HBV recurrence [defined as HBV DNA ≥50

IU/mL (approximately 300 copies/mL)] by last-observation-carried forward analysis.

The frequency and nature of adverse events in this study were consistent with those expected in patients who

have received a liver transplant and the known safety profile of entecavir.

INDICATIONS

Entecavir is indicated for the treatment of chronic hepatitis B virus infection in adults 16 years or older with

evidence of active liver inflammation.

This indication is based on histologic, virologic, biochemical and serological responses in nucleoside-treatment

naïve and lamividine-resistant adult patients with HBeAg-positive or HBeAg-negative chronic HBV infection

with compensated liver disease.

CONTRAINDICATIONS

Entecavir is contraindicated in patients with previously demonstrated hypersensitivity to entecavir monohydrate

or any component of the product.

PRECAUTIONS

Co-infection with HIV

Therapy with entecavir monohydrate is not recommended for HIV/HBV co-infected patients who are not

receiving highly active antiretroviral therapy. There is a potential for the development of HIV resistance

if entecavir monohydrate is used to treat chronic hepatitis B infection in patients with untreated HIV

infection.

Lactic acidosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use

of nucleoside analogues alone or in combination with antiretrovirals.

Exacerbations of hepatitis after discontinuation of treatment

Acute exacerbation of hepatitis has been reported in patients who have discontinued hepatitis B therapy,

including therapy with entecavir (see ADVERSE EFFECTS). The majority of post-treatment exacerbations

ENTECAVIR MYLAN – PRODUCT INFORMATION

14

appear to be self-limited. However, severe exacerbations, including fatalities, may occur. Hepatic function

should be monitored closely for at least several months after discontinuation. If appropriate, resumption of

hepatitis B therapy may be warranted.

Patients with renal impairment

Dosage adjustment of entecavir is recommended for patients with renal impairment who have creatinine

clearance < 50 mL/min (see DOSAGE AND ADMINISTRATION).

Liver transplant recipients

Limited data are available on the safety and efficacy of entecavir in liver transplant recipients. In a single-arm,

open-label study, patients who had HBV DNA less than 172 IU/mL at the time of transplant were treated with

entecavir 1 mg once daily post-transplant. On treatment, 15 subjects (23%) had liver-related adverse events of

interest:

fourteen

subjects

ascites

(22%)

subject

each

bacterial

peritonitis,

hepatic

encephalopathy, and recurrent HCC. In 12 of the 15 subjects, all liver-related events occurred during the first

30 days post-transplant, and were considered post-operative complications. During the first 30 days post-

transplant, 18 of 65 treated subjects (28%) or 8 of 61 evaluable subjects (13%) had episodes of acute liver

rejection with 1 subject who required re-transplantation. None of the 61 evaluable patients had virologic

recurrence. The frequency and nature of adverse events and acute liver rejection in this study were consistent

with those expected in patients who have received a liver transplant and the known safety profile of entecavir.

(See CLINICAL TRIALS.)

Renal function should be carefully monitored before and during entecavir therapy in liver transplant recipients

receiving an immunosuppressant that may affect renal function such as cyclosporine or tacrolimus (see

DOSAGE

AND ADMINISTRATION: Patients with hepatic impairment

and PHARMACOLOGY:

Patients with hepatic impairment and Liver transplant recipients).

Decompensated liver disease

A study of entecavir at a dose of 1 mg once daily has been conducted in patients with decompensated liver

disease (see CLINICAL TRIALS and ADVERSE EFFECTS).

Co-infection with hepatitis C or D

There are no data on the efficacy of entecavir in patients co-infected with hepatitis C or D.

Lactose

This medicinal product contains 62.5 mg of lactose in each 0.5 mg daily dose and 125 mg of lactose in each

1 mg daily dose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency of

glucose-galactose malabsorption should not take this medicine.

Patient information

A Consumer Medicine Information Leaflet for entecavir is available for patient information.

Patients should remain under the care of a physician while taking entecavir. They should discuss any new

symptoms or concurrent medications with their physician.

Patients should be advised to take entecavir on an empty stomach (at least 2 hours before and at least 2 hours

after a meal).

Patients should be informed that deterioration of liver disease may occur in some cases if treatment is

discontinued, and that they should discuss any change in regimen with their physician.

ENTECAVIR MYLAN – PRODUCT INFORMATION

15

Patients should be advised that treatment with entecavir has not been shown to reduce the risk of transmission

of HBV to others through sexual contact or blood contamination (see PRECAUTIONS: Labor and Delivery).

Effects on Fertility

Male and female rat fertility was unaffected by drug exposures (AUC) up to approximately 160 (male) and 230

(female) times that in humans treated with a daily dose of 1 mg. Testicular seminiferous tubule degeneration or

germinal epithelial maturation arrest was observed in long-term rodent studies, at drug exposures that were ≥ 10

(mice) and 29 (rats) times the human value, and in dog studies at exposures >379 times the human value. No

testicular changes were evident in monkeys at exposures up to 114 times the clinical exposure.

Use in Pregnancy (Category B3)

Drugs which have been taken by only a limited number of pregnant women and women of childbearing age,

without an increase in the frequency of malformation or other direct or indirect harmful effects on the human

fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal

damage, the significance of which is considered uncertain in humans.

There are no adequate and well-controlled studies in pregnant women. Entecavir should be used during

pregnancy only if the potential benefit justifies the potential risk to the fetus.

There are no data on the effect of entecavir monohydrate on transmission of HBV from mother to infant.

Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.

In animal experiments, embryofetal development was unaffected at drug exposures (AUC) of up to 23 (rats)

and 175 (rabbits) times the maximum human exposure (1 mg daily dose). Slightly increased resorptions

occurred in rats at a maternotoxic dose resulting in a higher drug exposure (150 times the human value), while

embryofetal development was severely retarded at a maternotoxic dose resulting in a drug exposure >2500

times the human value; tail and vertebral malformations were observed. A drug exposure 730 times the

maximum human value resulted in increased resorptions and incomplete fetal hyoid ossification in rabbits, in

the absence of maternal toxicity. Rat offspring development was unaffected at drug exposures approximately

230 times the human value, when mothers were treated from early gestation to the end of lactation.

Pregnancy

Registry:

monitor

maternal-fetal

outcomes

pregnant

women

exposed

entecavir

monohydrate, a Pregnancy Registry has been established. Physicians are encouraged to register patients by

calling 1-800-067-567.

Use in Lactation

Entecavir monohydrate and/or its conjugate metabolites are excreted in the milk of rats. It is not known

whether excretion occurs in human milk. Mothers should be instructed not to breast-feed if they are taking

entecavir.

Paediatric Use

Safety and effectiveness of entecavir in paediatric patients below the age of 16 years have not been established.

Use in the Elderly

Clinical studies of entecavir did not include sufficient numbers of participants aged 65 years and over to

determine whether they respond differently from younger participants. Other reported clinical experience has

not identified differences in responses between the elderly and younger patients. Entecavir monohydrate is

substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with

impaired renal function. Because elderly patients are more likely to have decreased renal function, care should

taken

dose

selection,

useful

monitor

renal

function

(see

DOSAGE

AND

ADMINISTRATION: Renal Impairment).

ENTECAVIR MYLAN – PRODUCT INFORMATION

16

Genotoxicity

Entecavir monohydrate was not genotoxic in in vitro assays for bacterial gene mutation, cell transformation and

DNA repair, or in an in vivo micronucleus assay for clastogenicity. High concentrations were clastogenic in

vitro in human lymphocyte (>10 μg/mL) and mouse L5178Y

lymphoma cell (>28 μg/mL) assays, with

evidence

that

L5178Y

cell

response

related

perturbation

cellular

deoxyribonucleotide

triphosphate pools.

Carcinogenicity

Two year carcinogenicity studies with entecavir monohydrate were conducted in mice and rats. In mice,

entecavir monohydrate was administered orally at 4 dosage levels representing exposure multiples of 1, 2.4, 10

and 34 times human exposure at the 1mg dose. The doses in rats achieved exposure multiples relative to the

human 1mg dose of <0.3, 0.3, 3.9 and 29 times and 0.3, 0.6,

3.6 and 20 times in males and females,

respectively. Increases in the incidence of lung tumours were observed in male and female mice at exposures

≥2.4 times that in humans. Mechanistic studies suggest the lung tumours are likely to be species-specific to

mice and probably not relevant to humans. In male rats, entecavir monohydrate caused pancreatic acinar cell

hyperplasia and adenomas at ≥3.9 times human exposure. An increase in skin fibromas was seen in female rats

at ≥3.6 times the exposure in humans at 1 mg/day. The incidence of microglial tumours was increased in rats at

and above 0.3 times the exposures in humans at 1 mg/day, reaching statistical significance at 20 times human

exposure. Other tumours, which were observed only at exposures ≥20 times the exposure in humans at 1

mg/day, included hepatocellular adenomas and/or carcinomas (mice, rates), vascular tumours (mice, rats)

salivary duct adenoacanthomas (mice), kidney oncocytoma and malignant mesenchymal tumours (rats), and

Zymbal’s gland carcinomas (rats; no human counterpart). With the exception of the mouse lung tumours,

disruption of cellular deoxyribonucleotide triphosphated (dNTP) pools is likely a significant factor in the

carcinogenicity of entecavir monohydrate, which involves a threshold mechanism. These tumours were

generally late appearing and required long term exposure. Based on animal data, an increased risk of cancer in

humans treated with entecavir monohydrate for an extended period cannot be excluded.

INTERACTIONS WITH OTHER MEDICINES

Medicinal products: Since entecavir monohydrate is predominantly eliminated by the kidney (see Excretion),

coadministration with medicinal products that reduce renal function or compete for active tubular secretion may

increase serum concentrations of either medicinal product. Coadministration of entecavir monohydrate with

either

lamivudine,

adefovir

dipivoxil

tenofovir

disoproxil

fumarate

resulted

significant

drug

interactions. The effects of coadministration of entecavir monohydrate with other medicinal products that are

excreted renally or affect renal function have not been evaluated. Patients should be monitored closely for

adverse events when entecavir is coadministered with such medicinal products.

ADVERSE EFFECTS

Assessment of adverse reactions is based on four clinical studies in which 1720 patients with chronic HBV

infection received double-blind treatment with entecavir 0.5 mg/day (n = 679), entecavir 1 mg/day (n = 183), or

lamivudine (n = 858) for up to 107 weeks. The safety profiles of entecavir and lamivudine were comparable in

these studies. Among entecavir-treated patients, the most common adverse events of any severity with at least

a possible relation to entecavir were headache (9%), fatigue (6%), dizziness (4%) and nausea (3%).

In these clinical studies, the 594 entecavir monohydrate-treated patients who received blinded therapy for more

than 52 weeks reported adverse reactions similar in nature and severity to those reported during the first 52

weeks of treatment.

Clinical trials adverse events

Selected clinical adverse events of moderate-severe intensity and considered at least possibly related to

treatment occurring during therapy in four clinical studies in which entecavir was compared to lamivudine are

presented in Table 10.

ENTECAVIR MYLAN – PRODUCT INFORMATION

17

Table 10.

Selected Clinical Adverse Events

a

of Moderate-Severe Intensity

(Grades 2-4) Reported in Four Entecavir monohydrate Clinical Trials

Nucloside-Naive

b

Lamivudine-Refractory

c

Body System/

Adverse Event

Entecavir

0.5 mg

n=679

Lamivudine

100 mg

n=668

Entecavir

1 mg

n=183

Lamivudine

100 mg

n=190

Gastrointestinal

Diarrhea

<1%

Dyspepsia

<1%

<1%

Nausea

<1%

<1%

<1%

Vomiting

<1%

<1%

<1%

General

Fatigue

Nervous System

Headache

Dizziness

<1%

<1%

Somnolence

<1%

<1%

Psychiatric

Insomnia

<1%

<1%

<1%

Includes events of possible, probable, certain or unknown relationship to treatment regimen.

Studies AI463022 and AI463027.

Includes Study AI463206 and the entecavir 1-mg and lamivudine treatment arms of Study AI463014 a Phase 2

multinational, randomized, double-blind study of three doses of entecavir (0.1, 0.5, and 1 mg) once daily versus

continued lamivudine 100 mg once daily for up to 52 weeks in patients who experienced recurrent viremia on

lamivudine therapy.

Laboratory findings

Table 11 shows laboratory findings from four double-blind, lamivudine-controlled clinical studies in which 679

nucleoside-naive patients received entecavir 0.5 mg once daily for a median of 53 weeks and 183 lamivudine-

refractory patients received entecavir 1 mg for a median of 69 weeks.

Table 11.

Selected Laboratory Abnormalities Reported During Treatment in Four Clinical

Trials

Nucleoside-Naive

a

Lamivudine-Refractory

b

Test

Entecavir 0.5 mg

n=679

Entecavir 1 mg

n=183

ALT

>10 X ULN and >2 X baseline

ALT

>3 X baseline

ALT

>2 X baseline and total bilirubin >2 X

ULN and >2 X baseline

<1%

<1%

Albumin

<2.5 g/dL

<1%

Amylase

>3 X baseline

Lipase

>3 X baseline

Platelets

<50,000/mm

<1%

<1%

Median duration of therapy was 53 weeks.

Median duration of therapy was 69 weeks

ULN=upper limit of normal.

ENTECAVIR MYLAN – PRODUCT INFORMATION

18

Among entecavir-treated patients in these studies, on-treatment ALT elevations >10 X ULN and >2 X baseline

generally resolved with continued treatment. A majority of these exacerbations were associated with a >2

/mL reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of

hepatic function is recommended during treatment.

ALT Flares after discontinuation of treatment: Acute exacerbations of hepatitis have been reported in

patients who have discontinued anti-HBV therapy, including therapy with entecavir (see PRECAUTIONS).

The frequency of exacerbations of hepatitis or ALT flare (defined as ALT >10 X ULN and 2 X the patient’s

reference level) during off-treatment follow-up in clinical studies with entecavir is presented in Table 12.

Table 12.

ALT

Flares

During

Off-Treatment

Follow-up

in

Studies

AI463022,

AI463026,

and

AI463027.

Patients with ALT Elevations >10 X ULN and >2 X Reference

a

Entecavir

Lamivudine

Nucleoside-naive

28/476 (6%)

43/417 (10%)

HBeAg-positive

4/174 (2%)

13/147 (9%)

HBeAg-negative

24/302 (8%)

30/270 (11%)

Lamivudine-refractory

6/52 (12%)

0/16

Reference is the minimum of the baseline or last measurement at end of dosing. Median time to off-treatment

exacerbation was 23 weeks for entecavir-treated patients and 10 weeks for Lamivudine-treated patients.

Patients with Decompensated Liver Disease

Clinical adverse reactions observed through Week 48 in Study AI463048 in which entecavir 1mg once daily

was compared with adefovir dipivoxil in patients with chronic hepatitis B infection and decompensated liver

disease are listed in Table 13. The cumulative rates of discontinuation for adverse events and on-study

cumulative rates of death and hepatocellular carcinoma (HCC) are also shown in Table 13.

Table 13

Selected Safety Outcomes in Study AI463048

Entecavir

1 mg

n=102

Adefovir dipivoxil

10 mg

n=89

Clinical Adverse Events

a

of Moderate-Severe Intensity (grades 2-4) Through Week 48

Body System/

Adverse Event

Gastrointestinal Disorders

Vomiting

<1%

Diarrhea

Investigations

Blood bicarbonate decreased

Nervous System Disorders

Dizziness

Headache

Renal and Urinary Disorders

Renal failure

<1%

General Disorders and

Administration Site

Conditions

Fatigue

<1%

Discontinuation for Adverse Event

(cumulative)

ENTECAVIR MYLAN – PRODUCT INFORMATION

19

Deaths (cumulative)

HCC (cumulative)

Includes events of possible, probable, certain or unknown relationship to treatment regimen.

Causes of death in Study AI463048 were generally liver-related, as expected in this population. The time

to onset of HCC or death (whichever occurred first) was comparable in the two treatment groups.

Laboratory test abnormalities reported through week 48 in study AI463048 are listed in Table 14.

Table 14.

Selected Laboratory Abnormalities Reported Through Week 48 in Study AI463048

Test

Entecavir 1 mg

n=102

ALT

>10 X ULN and >2 X baseline

ALT

>2 X baseline and total bilirubin >2 X

ULN and >2 X baseline

Albumin

<2.5 g/dL

Lipase

>3 X baseline

Platelets

<50,000/mm

ULN = upper limit of normal

Patients co

-infected with HIV: Patients co-infected with HBV and human immunodeficiency virus (HIV)

experienced

recurrence

viremia

while

receiving

lamivudine-containing

highly

active

antiretroviral regimen were treated with their lamivudine-containing regimen (lamivudine dose, 300 mg/day)

and either entecavir 1 mg once daily or placebo. After 24 weeks of double-blind therapy and a mean of 17

weeks

open-label

therapy

(where

patients

received

entecavir),

adverse

event

laboratory

abnormality profiles were similar for the entecavir and placebo treatment groups. Entecavir has not been

evaluated in HIV/HBV co-infected patients who are not concurrently receiving effective HIV treatment (see

PRECAUTIONS - Co-infection with HIV).

Postmarketing Experience

The following events have been identified during postapproval use of entecavir. Because reports are voluntary

from

a population of unknown size, an estimate of frequency cannot be made.

Immune system disorders:

anaphylactoid reaction

Skin and subcutaneous tissue disorders:

alopecia, rash.

Hepatobiliary disorders:.

increased transaminases

Metabolism and nutrition disorders:

Lactic

acidosis,

often

association

with

hepatic

decompensation, other serious medical conditions or drug

exposures.

DOSAGE AND ADMINISTRATION

Recommended Dosage

Entecavir should be taken orally, on an empty stomach (at least 2 hours after a meal and 2 hours before the next

meal).

The recommended oral dose of entecavir in adults and adolescents older than 16 years is 0.5 mg once daily. For

lamivudine-refractory patients [history of hepatitis B viremia while receiving lamivudine therapy or known

lamivudine resistance (LVD

commonly called YMDD mutations)], the recommended dose is 1 mg once daily.

ENTECAVIR MYLAN – PRODUCT INFORMATION

20

Renal Impairment

In patients with renal impairment, the apparent oral clearance of entecavir monohydrate decreased as creatinine

clearance decreased (see PHARMACOLOGY: Special Populations). Dosage adjustment of entecavir is

recommended for patients with creatinine clearance <50 mL/min, including patients on hemodialysis or CAPD,

as shown in Table 15.

Table 15.

Recommended Dosage of Entecavir in Patients with Renal Impairment

Creatinine Clearance (mL/min)

Nucleoside Naïve

Lamivudine Refractory

≥50

0.5 mg once daily

1.0 mg once daily

30 to < 50

0.25 mg once daily*

or

0.5 mg every 48 hours

0.5 mg once daily

or

1.0 mg every 48 hours

10 to < 30

0.15 mg once daily*

or

0.5 mg every 72 hours

0.3 mg once daily*

or

1.0 mg every 72 hours

< 10

0.05 mg once daily*

or

0.5 mg every 5-7 days

0.1 mg once daily*

or

1.0 mg every 5-7 days

Haemodialysis or CAPD **

0.05 mg once daily*

or

0.5 mg every 5-7 days

0.1 mg once daily*

or

1.0 mg every 5-7 days

* For doses < 0.5mg entecavir Oral Solution is recommended. Do not split tablets.

** On haemodialysis days, administer after haemodialysis

Hepatic Impairment

No dosage adjustment is necessary for patients with hepatic impairment.

Duration of Therapy

The optimal duration of treatment with entecavir monohydrate for patients with chronic hepatitis B infection

and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma

are unknown.

OVERDOSAGE

There is limited experience of entecavir monohydrate overdosage reported in patients. Healthy participants

who received single entecavir monohydrate doses up to 40 mg or multiple doses up to 20 mg/day for up to 14

days had no increase in or unexpected adverse events. If overdose occurs, the patient must be monitored for

evidence of toxicity, and standard supportive treatment applied as necessary.

Following a single 1-mg dose of entecavir monohydrate, a 4-hour hemodialysis session removed approximately

13% of the entecavir monohydrate dose.

For information on the management of overdosage, contact the Poison Information Centre on 13 11 26

(Australia).

PRESENTATION AND STORAGE CONDITIONS

ENTECAVIR MYLAN

0.5 mg

A white, film-coated, round, biconvex, beveled edge tablet debossed with ‘M’

on one side of the tablet and ‘EV1’ on the other side. Blister pack

(PA/Al/PVC/Al) of 30 tablets; Bottle (HDPE bottle with PP screw cap) of 30

tablets.

ENTECAVIR MYLAN

A white, film-coated, round, biconvex, beveled edge tablet debossed with ‘M’

on one side of the tablet and ‘EV2’ on the other side. Blister pack

ENTECAVIR MYLAN – PRODUCT INFORMATION

21

1 mg

(PA/Al/PVC/Al) of 30 tablets; Bottle (HDPE bottle with PP screw cap) of 30

tablets.

NAME AND ADDRESS OF THE SPONSOR

Alphapharm Pty Limited

Level 1, 30 The Bond

30-34 Hickson Road

Millers Point NSW 2000

ABN 93 002 359 739

www.alphapharm.com.au

POISON SCHEDULE OF THE MEDICINE

S4 (Prescription Only Medicine)

DATE

OF

FIRST

INCLUSION

IN

THE

AUSTRALIAN

REGISTER

OF

THERAPEUTIC GOODS (the ARTG)

18/04/2016

EntecavirMylan_pi\APR16/00

30-10-2018

EU/3/18/2076 (Orphan Europe S.A.R.L.)

EU/3/18/2076 (Orphan Europe S.A.R.L.)

EU/3/18/2076 (Active substance: Glycine, L-alanine, L-arginine, L-aspartic acid, L-cysteine, L-cystine, L-glutamic acid, L-histidine, L-lysine monohydrate, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, taurine) - Orphan designation - Commission Decision (2018)7277 of Tue, 30 Oct 2018 European Medicines Agency (EMA) procedure number: EMA/OD/100/18

Europe -DG Health and Food Safety

27-7-2018

EU/3/16/1635 (Leadiant GmbH)

EU/3/16/1635 (Leadiant GmbH)

EU/3/16/1635 (Active substance: N-acetyl-D-mannosamine monohydrate) - Transfer of orphan designation - Commission Decision (2018)5053 of Fri, 27 Jul 2018 European Medicines Agency (EMA) procedure number: EMA/OD/228/15/T/01

Europe -DG Health and Food Safety

12-6-2018

EU/3/10/811 (Celgene Europe B.V.)

EU/3/10/811 (Celgene Europe B.V.)

EU/3/10/811 (Active substance: N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino] benzenesulfonamide dihydrochloride monohydrate) - Transfer of orphan designation - Commission Decision (2018)3809 of Tue, 12 Jun 2018 European Medicines Agency (EMA) procedure number: EMA/OD/092/10/T/03

Europe -DG Health and Food Safety

12-6-2018

EU/3/10/810 (Celgene Europe B.V.)

EU/3/10/810 (Celgene Europe B.V.)

EU/3/10/810 (Active substance: N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino] benzenesulfonamide dihydrochloride monohydrate) - Transfer of orphan designation - Commission Decision (2018)3808 of Tue, 12 Jun 2018 European Medicines Agency (EMA) procedure number: EMA/OD/084/10/T/03

Europe -DG Health and Food Safety

12-6-2018

EU/3/10/794 (Celgene Europe B.V.)

EU/3/10/794 (Celgene Europe B.V.)

EU/3/10/794 (Active substance: N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino] benzenesulfonamide dihydrochloride monohydrate) - Transfer of orphan designation - Commission Decision (2018)3803 of Tue, 12 Jun 2018 European Medicines Agency (EMA) procedure number: EMA/OD/069/10/T/03

Europe -DG Health and Food Safety