Consumer medicine information

Entecavir RBX

Entecavir

BRAND INFORMATION

Brand name

Entecavir RBX

Active ingredient

Entecavir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Entecavir RBX.

What is in this leaflet

Read this leaflet carefully before taking ENTECAVIR RBX. This leaflet answers some common questions about ENTECAVIR RBX.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ENTECAVIR RBX against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What ENTECAVIR RBX is used for

ENTECAVIR RBX contains entecavir (as monohydrate) and belongs to a group of medicines called antiviral medicines.

ENTECAVIR RBX is used to treat adults infected with hepatitis B virus.

How ENTECAVIR RBX Works

Infection by the hepatitis B virus can lead to damage to the liver.

ENTECAVIR RBX reduces the amount of virus in your body, and has been shown to improve the condition of the liver.

It is not known how safe ENTECAVIR RBX is when taken for long periods.

Your doctor may have prescribed ENTECAVIR RBX for another reason. Ask your doctor if you have any questions about why ENTECAVIR RBX has been prescribed for you.

ENTECAVIR RBX is not addictive. This medicine is available only with a doctor's prescription.

ENTECAVIR RBX is not recommended for use in children under 16 years, as there have been no studies of its effects in children.

Before you take ENTECAVIR RBX

It is important that you check the information below before you take ENTECAVIR RBX.

When you must not take ENTECAVIR RBX

You must not take ENTECAVIR RBX if you have a history of severe allergic reactions to ENTECAVIR RBX or to any of the ingredients listed at the end of this leaflet. Symptoms of a severe allergic reaction may include; chills, fever, fast heart beat, wheezing or coughing, difficulty breathing, dizziness, flushing, sweating and swelling of the face, tongue or other parts of the body.

Do not use ENTECAVIR RBX after the expiry date printed on the back of the pack. If this medicine is taken after the expiry date has passed, it may not work as well.

Do not take ENTECAVIR RBX if the packaging is torn or shows signs of tampering.

Before you start to take ENTECAVIR RBX

It is important to remain under the care of your doctor during ENTECAVIR RBX therapy and after stopping ENTECAVIR RBX.

You should report any new symptoms, medications or any other aspects affecting your health to your doctor. Your hepatitis B virus infection may get worse if you stop taking ENTECAVIR RBX. If your doctor advises you to stop ENTECAVIR RBX, they will monitor your health and perform regular blood tests to monitor your liver.

Tell your doctor if you:

  1. have allergies to:
  • any other medicines you have been given or purchased
  • substances such as foods, preservatives or dyes;
Symptoms of a severe allergic reaction may include; chills, fever, fast heart beat, wheezing or coughing, difficulty breathing, dizziness, flushing, sweating and swelling of the face, tongue or other parts of the body.
  1. are pregnant or intend to become pregnant.
Experience is limited with the use of ENTECAVIR RBX in pregnant women. Therefore, it should not be used during pregnancy unless it is clearly needed. If there is an urgent need to consider ENTECAVIR RBX during pregnancy, your doctor will discuss with you the benefits and risks of taking it.
  1. are breast feeding or planning to breast-feed.
It is not known whether ENTECAVIR RBX passes into breast milk. Therefore to avoid possible side effects in the nursing infant, mothers should stop breastfeeding if they are taking ENTECAVIR RBX.
  1. currently experience or have experienced any medical conditions especially any problems with your kidneys.
  2. have HIV and you are not currently on HIV treatment.
ENTECAVIR RBX is not recommended in patients who have both HIV and Hepatitis B and who are not currently receiving anti-HIV treatment. ENTECAVIR RBX may affect your HIV virus which could impact on future treatment options for HIV.
  1. are lactose intolerant. ENTECAVIR RBX tablets contain lactose.

If you have not told your doctor about any of the above, tell them before you use ENTECAVIR RBX.

Taking other medicines

Tell your doctor if you are taking other medicines, including vitamin supplements, herbal preparations or any medicines you buy with or without a prescription from your pharmacy, supermarket or health food shop.

Your doctor and pharmacist may have more information on medicines to be careful with, or to avoid while taking ENTECAVIR RBX.

How to take ENTECAVIR RBX

ENTECAVIR RBX should be given only when prescribed by your doctor.

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

How much to take

The usual dose of ENTECAVIR RBX is 0.5 mg (one white tablet) or 1 mg (one pink tablet) once a day.

If you have a medical problem with your kidneys your doctor may need to change how often you take your ENTECAVIR RBX tablets.

Your doctor will tell you what dose to take and how often you should take your ENTECAVIR RBX tablets.

Please talk to your doctor or pharmacist for more information.

How to take it

Swallow the tablet whole with a glass of water. The dose of ENTECAVIR RBX should be taken on an empty stomach.

When to take ENTECAVIR RBX

ENTECAVIR RBX may be taken at any time of day provided it is taken on an empty stomach. Empty stomach means at least 2 hours before or 2 hours after a meal.

Talk to your doctor or pharmacist to work out when it is best for you to take your dose of ENTECAVIR RBX.

How long to take it

ENTECAVIR RBX helps control your condition but does not cure it. Therefore you must take ENTECAVIR RBX every day as directed by your doctor. Continue taking ENTECAVIR RBX for as long as your doctor tells you to.

Your doctor has prescribed ENTECAVIR RBX to prevent hepatitis B virus from further damaging your liver.

ENTECAVIR RBX is a very important treatment that can improve the inflammation and scar tissue caused by the hepatitis B virus in your liver and may reduce the chance of developing cirrhosis, liver failure and liver cancer.

It is extremely important that you do not stop taking ENTECAVIR RBX without discussing it with your doctor. If ENTECAVIR RBX is suddenly stopped, the hepatitis B virus can become very active again and lead to sudden development of severe liver failure. There is a high risk of dying if liver failure develops and liver transplantation may be necessary to save your life.

It is important to take ENTECAVIR RBX every day or as directed by your doctor, to not miss medicine doses, and to make sure you have enough supply until you next see your doctor.

Do not stop taking ENTECAVIR RBX or change the dose unless asked to do so by your doctor, even if you feel better, as it can be very dangerous.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take the next dose when you are meant to.

Otherwise take it as soon as you remember, and then go back to taking it as you would normally.

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect. If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints and inform your doctor that you have missed a dose. It is very important not to miss your doses of ENTECAVIR RBX.

If you take too much (overdose)

Immediately call your doctor or the Poisons Information Centre on 13 11 26 or go to the Accident and Emergency Centre at your nearest hospital if you or anyone else takes too much ENTECAVIR RBX. Do this even if there are no signs of discomfort or poisoning.

While you are using ENTECAVIR RBX

Things you must do

  • If you become pregnant while taking ENTECAVIR RBX, tell your doctor immediately.
  • If you are about to start taking any new medicines, tell your doctor and pharmacist that you are taking ENTECAVIR RBX. ENTECAVIR RBX may interfere with the medicine you are taking.
  • If you are about to have any medical tests, tell your doctor that you are taking ENTECAVIR RBX. ENTECAVIR RBX may interfere with the results of these tests.
  • If you plan to have surgery, tell your doctor or dentist that you are taking ENTECAVIR RBX.

Things you must not do

  • Do not give ENTECAVIR RBX to anyone else, even if they have the same condition as you.
  • Do not use ENTECAVIR RBX to treat any other complaints unless your doctor tells you to.
  • Do not stop taking ENTECAVIR RBX or lower the dosage without checking with your doctor. Your hepatitis may worsen after stopping treatment.

Things to be careful of

  • Be careful driving or operating machinery until you know how ENTECAVIR RBX affects you.
    Some patients taking ENTECAVIR RBX have experienced dizziness. It is not known if this was caused by ENTECAVIR RBX. Make sure you know how you react to ENTECAVIR RBX before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy.
  • Make sure that you visit your doctor regularly throughout your entire course of treatment with ENTECAVIR RBX.
    When your treatment with ENTECAVIR RBX is stopped, your doctor will continue to monitor you and take blood tests for several months.
  • There is no evidence that ENTECAVIR RBX reduces the risk of infecting others with hepatitis B through sexual contact or body fluids (including blood contamination).
    Therefore it is important to take appropriate precautions to prevent others being infected with hepatitis B. Talk to your doctor about safe sexual practices that protect your partner. Never share needles. Do not share personal items that can have blood or bodily fluids on them, like toothbrushes and razor blades. A vaccine is available to protect those at risk of becoming infected with hepatitis B.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ENTECAVIR RBX. ENTECAVIR RBX helps most people with hepatitis B infection but it may have unwanted side effects in some people. Ask your doctor or pharmacist to answer any questions you may have.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. Some very important side effects are listed below.

Tell your doctor immediately, or go to accident and emergency at your nearest hospital if you notice any of the following signs of a sudden life-threatening allergic reaction:
chills, fever, fast heart beat, wheezing or coughing, difficulty breathing, dizziness, flushing, sweating and swelling of the face, tongue or other parts of the body.

Some people who have taken ENTECAVIR RBX or medicines like ENTECAVIR RBX have developed a serious condition called lactic acidosis. Lactic acidosis is a serious medical emergency that can cause death. Lactic acidosis must be treated in the hospital. Reports of lactic acidosis with ENTECAVIR RBX generally involved patients who were seriously ill due to their liver disease or other medical condition.

Call your healthcare provider right away if you get any of the following signs or symptoms of lactic acidosis:
Feeling very weak or tired, unusual muscle pain, trouble breathing, stomach pain with nausea and vomiting, feeling cold (especially in your arms and legs), feeling dizzy or light-headed, fast or irregular heartbeat.

Some people who have taken medicines like ENTECAVIR RBX have developed serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Hepatomegaly with steatosis is a serious medical emergency that can cause death.

Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:
Your skin or the white part of your eyes turns yellow (jaundice), urine turns dark, bowel movements (stools) turn light in colour, you don't feel like eating food for several days or longer, nausea, lower stomach pain. You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight, or have been taking medicines, like ENTECAVIR RBX, for a long time.

The most common side-effects are diarrhoea, indigestion, tiredness and headache.

This is not a complete list of side effects, other side effects not listed above may also occur in some patients.

Tell your doctor if you notice anything that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them or only some of them.

After using ENTECAVIR RBX

Storage

Store ENTECAVIR RBX tablets in a cool dry place where the temperature stays below 25°C.

Keep your tablets in the blister pack until it is time to take one. If you take the tablets out of the pack they may not keep as well.

Do not store ENTECAVIR RBX or any other medicine in the bathroom or near the kitchen sink. Do not leave it in the car. Heat and dampness can destroy some medicines.

Do not keep ENTECAVIR RBX tablets where children can reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking ENTECAVIR RBX, or the tablets have passed their expiry date, ask your pharmacist what to do with what is left over.

Product Description

What it looks like

ENTECAVIR RBX tablets come in two types:

  • ENTECAVIR RBX 0.5 mg tablets are white to off-white, triangular shaped film coated tablets, debossed with ‘RL1’ on one side and plain on other side
  • ENTECAVIR RBX 1 mg tablets are light pink to pink, triangular shaped film coated tablets, debossed with ‘RL2’ on one side and plain on other side

Ingredients

Each tablet contains:

Active ingredients:

  • ENTECAVIR RBX0.5 mg tablet - 0.5 mg of entecavir (as monohydrate) per tablet
  • ENTECAVIR RBX1 mg tablet - 1 mg of entecavir (as monohydrate) per tablet

Other ingredients:

Lactose monohydrate, povidone, crospovidone, microcrystalline cellulose and magnesium stearate. The 0.5 mg tablet coating contains hypromellose, titanium dioxide, macrogol 400 and polysorbate 80. The 1 mg tablet coating contains hypromellose, titanium dioxide, macrogol 400, polysorbate 80 and iron oxide red.

Registration Numbers

ENTECAVIR RBX 0.5 mg tablets
blister pack 30’s AUST R 256612

ENTECAVIR RBX 0.5 mg tablets
bottle pack 30’s & 500’s AUST R 256632

ENTECAVIR RBX 1 mg tablets
blister pack 30’s AUST R 256652

ENTECAVIR RBX 1 mg tablets
bottle pack 30’s & 500’s AUST R 256672

Not all pack sizes and presentations are marketed in Australia.

Sponsored by

Sun Pharma ANZ Pty Ltd
Macquarie Park NSW 2113
Australia
[email protected]
Tel: 1800 726 229

Date of preparation: January 2019

This information in no way replaces the advice of your doctor or pharmacist.

Published by MIMS April 2019

BRAND INFORMATION

Brand name

Entecavir RBX

Active ingredient

Entecavir

Schedule

S4

 

1 Name of Medicine

Entecavir monohydrate.

6.7 Physicochemical Properties

Chemical Name: 2-amino-1,9-dihydro-9- [(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate.
Molecular Formula: C12H15N5O3.H2O.
Molecular Weight: 295.3.
Entecavir monohydrate is a white to off-white powder. It is 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. The partition coefficient logP is -0.81, -1.4 and the pKa in strongest acid is 8 and strongest basic is 2.77.

Chemical structure.


CAS number.

209216-23-9.

2 Qualitative and Quantitative Composition

Each tablet contains 0.5 mg or 1 mg entecavir (a monohydrate).
Excipients with known effects: lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Entecavir RBX 0.5 mg film-coated tablet is white to white-off, triangular shaped film coated tablet, debossed with 'RL1' on one side and plain on other side.
Entecavir RBX 1 mg film-coated tablet is light pink to pink, triangular shaped film coated tablet, debossed with 'RL2' on one side and plain on other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Entecavir monohydrate, is a guanosine nucleoside analogue with selective activity against hepatitis B virus (HBV).

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 no significant accumulation beyond initial plateau levels. By competing with the 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 nanoM. Entecavir monohydrate-TP is a weak inhibitor of cellular DNA polymerases α, β, delta and epsilon with Ki values of 18 to 40 microM. It did not inhibit mitochondrial γ polymerase (Ki > 160 microM) 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 microM in human HepG2 cells transfected with wild-type HBV. IC50 values for entecavir monohydrate against lamivudine-resistant HBV ranged from 0.029-0.061 microM.

Resistance in vitro.

There was reduced susceptibility to entecavir monohydrate when LVDR substitutions (M204I/V ± L180M) were present. Entecavir monohydrate inhibited the replication of LVDR 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 log10 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 Section 5.1 Pharmacodynamic Properties, 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 105 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 7 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 7). These substitutions were observed only in the presence of LVDr substitutions (rtM204V and rtL180M).

Lamivudine-refractory studies.

Participants treated with entecavir monohydrate 1 mg once daily in lamivudine-refractory studies (see Section 5.1 Pharmacodynamic Properties, 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 8). Results in Table 8 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 187 lamivudine-refractory patients indicates that prior lamivudine treatment can 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.

Clinical trials.

The safety and efficacy of entecavir monohydrate 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 monohydrate 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 monohydrate 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 log10 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 monohydrate 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 log10 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 monohydrate 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 9. Biochemical, virologic, and serologic outcome measures are shown in Table 10.
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.
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 log10 copies/human genome equivalents (approximately 8-fold reduction) for entecavir monohydrate-treated patients (n=159) and -0.7 log10 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 log10 copies/HGEq (approximately 3-fold reduction) in each treatment group (n=107 for entecavir monohydrate-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 monohydrate in 286 (of 293 randomized) patients with lamivudine-refractory chronic hepatitis B infection. Patients receiving lamivudine at study entry either switched to entecavir monohydrate 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 LVDR 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 log10 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.
In Study AI463026, entecavir monohydrate was superior to lamivudine on the coprimary endpoints of 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 11. Table 12 shows biochemical, virologic, and serologic endpoints.
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.
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 log10 copies/HGEq (approximately 4-fold reduction) for entecavir monohydrate-treated patients (n=74) and 0.0 log10 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 monohydrate-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 monohydrate is unknown. According to protocol mandated criteria in the Phase 3 clinical trials, participants discontinued entecavir monohydrate 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 and 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.

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). 55 of 57 (96%) of these patients had Histologic Improvement (a ≥ 2-point decrease in 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 monohydrate 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 monohydrate, adefovir dipivoxil, or tenofovir disoproxil fumarate). At baseline, patients had a mean serum HBV DNA by PCR of 7.83 log10 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 monohydrate in this study was 1 mg once daily. Entecavir monohydrate 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 13.

HIV/HBV co-infected patients.

Study AI463038 was a randomized, double-blind, placebo-controlled study of entecavir monohydrate 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 monohydrate 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 monohydrate. At baseline, patients had a mean serum HBV DNA level by PCR of 9.13 log10 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 14.
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 log10 copies/mL (n=43); 4/51 (8%) patients had HBV DNA < 300 copies/mL by PCR; and 13/35 (37%) patients with abnormal ALT at baseline had ALT normalisation. Entecavir monohydrate has not been evaluated in HIV/HBV co-infected patients who are not concurrently receiving effective HIV treatment (see Section 4.4 Special Warnings and Precautions for Use, Coinfection with HIV).

Liver transplant recipients.

The safety and efficacy of entecavir monohydrate 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 monohydrate 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 monohydrate.

5.2 Pharmacokinetic Properties

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 (Cmax) 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. Cmax and trough plasma concentration (Ctrough) at steady-state were 4.2 and 0.3 nanogram/mL, respectively, for a 0.5 mg dose, and 8.2 and 0.5 nanogram/mL, respectively, for a 1 mg dose. In healthy participants, the bioavailability of the tablet was 100% relative to the oral solution1. 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 Cmax of 44-46%, and a decrease in AUC of 18-20%. Therefore, entecavir monohydrate should be administered on an empty stomach (at least 2 hours before a meal and at least 2 hours after a meal) (see Section 4.2 Dose and Method of 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 is not a substrate, inhibitor, or inducer of the CYP450 enzyme system. At 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 14C-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.
1Entecavir oral solution is unavailable in this brand, however is available in other brands.

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 15.
Dosage adjustment is recommended for patients with a creatinine clearance < 50 mL/min, including patients on hemodialysis or CAPD (see Section 4.2 Dose and Method of 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 monohydrate 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 and during entecavir monohydrate therapy in liver transplant recipients receiving cyclosporine or tacrolimus, renal function should be carefully evaluated (see Section 4.2 Dose and Method of Administration, Renal impairment).

Paediatrics.

Pharmacokinetic studies have not been conducted in children.

Drug interactions.

Entecavir monohydrate is not a substrate, inhibitor, or inducer of the CYP450 enzyme system (see Section 5.2 Pharmacokinetic Properties, Metabolism and Excretion). 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
A pilot study in nine HBV-infected liver transplant recipients suggested that concurrent cyclosporine A (n=5) or tacrolimus (n=4) therapy did not affect the pharmacokinetics of entecavir monohydrate (see Section 5.2 Pharmacokinetic Properties, Special populations, Post-liver transplant). The effect of entecavir monohydrate on the pharmacokinetics of cyclosporine A or tacrolimus is unknown.

5.3 Preclinical Safety Data

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 microgram/mL) and mouse L5178Y+/- lymphoma cell (> 28 microgram/mL) assays, with evidence that the L5178Y+/- cell response was related to perturbation of 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 1 mg dose. The doses in rats achieved exposure multiples relative to the human 1 mg 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Entecavir monohydrate 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.

4.3 Contraindications

Entecavir RBX is contraindicated in patients with previously demonstrated hypersensitivity to entecavir monohydrate or any component of the product.

4.4 Special Warnings and Precautions for Use

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 monohydrate (see Section 4.8 Adverse Effects (Undesirable Effects)). The majority of post-treatment exacerbations 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.

Liver transplant recipients.

Limited data are available on the safety and efficacy of entecavir monohydrate 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 monohydrate 1 mg once daily post-transplant. On treatment, 15 subjects (23%) had liver-related adverse events of interest: fourteen subjects had ascites (22%) and 1 subject each had 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 monohydrate (see Section 5.1 Pharmacodynamic Properties, Clinical trials.)
Renal function should be carefully monitored before and during entecavir monohydrate therapy in liver transplant recipients receiving an immunosuppressant that may affect renal function such as cyclosporine or tacrolimus (see Section 4.2 Dose and Method of Administration, Hepatic impairment; Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment and Post-liver transplant).

Decompensated liver disease.

A study of entecavir monohydrate at a dose of 1 mg once daily has been conducted in patients with decompensated liver disease (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials).

Co-infection with hepatitis C or D.

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

Lactose.

This medicinal product contains 112.5 mg of lactose in each 0.5 mg daily dose and 225 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 RBX is available for patient information.
Patients should remain under the care of a physician while taking entecavir monohydrate. They should discuss any new symptoms or concurrent medications with their physician.
Patients should be advised to take entecavir monohydrate 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.
Patients should be advised that treatment with entecavir monohydrate has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Use in renal impairment.

Dosage adjustment of entecavir monohydrate is recommended for patients with renal impairment who have creatinine clearance < 50 mL/min (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

Clinical studies of entecavir monohydrate 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 be taken in dose selection, and it may be useful to monitor renal function (see Section 4.2 Dose and Method of Administration, Renal impairment).

Paediatric use.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Medicinal products.

Since entecavir monohydrate is predominantly eliminated by the kidney (see Section 5.2 Pharmacokinetic Properties, 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 or tenofovir disoproxil fumarate resulted in no 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 monohydrate is coadministered with such medicinal products.

4.6 Fertility, Pregnancy and Lactation

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.
(Category B3)
There are no adequate and well-controlled studies in pregnant women. Entecavir monohydrate 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.
To monitor maternal-fetal outcomes of pregnant women exposed to entecavir monohydrate, physicians are encouraged to report all patients taking Entecavir RBX during pregnancy to Sun Pharma by calling 1800 726 229.
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 monohydrate.

4.8 Adverse Effects (Undesirable 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 monohydrate 0.5 mg/day (n = 679), entecavir monohydrate 1 mg/day (n = 183), or lamivudine (n = 858) for up to 107 weeks. The safety profiles of entecavir monohydrate and lamivudine were comparable in these studies. Among entecavir monohydrate-treated patients, the most common adverse events of any severity with at least a possible relation to entecavir monohydrate 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 monohydrate was compared to lamivudine are presented in Table 2.

Laboratory findings.

Table 3 shows laboratory findings from four double-blind, lamivudine-controlled clinical studies in which 679 nucleoside-naive patients received entecavir monohydrate 0.5 mg once daily for a median of 53 weeks and 183 lamivudine-refractory patients received entecavir monohydrate 1 mg for a median of 69 weeks.
Among entecavir monohydrate-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 log10/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 monohydrate (see Section 4.4 Special Warnings and Precautions for Use). 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 monohydrate is presented in Table 4.

Patients with decompensated liver disease.

Clinical adverse reactions observed through Week 48 in Study AI463048 in which entecavir monohydrate 1 mg once daily was compared with adefovir dipivoxil in patients with chronic hepatitis B infection and decompensated liver disease are listed in Table 5. The cumulative rates of discontinuation for adverse events and on-study cumulative rates of death and hepatocellular carcinoma (HCC) are also shown in Table 5.
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 6.

Patients co-infected with HIV.

Patients co-infected with HBV and human immunodeficiency virus (HIV) who experienced recurrence of HBV viremia while receiving a lamivudine-containing highly active antiretroviral regimen were treated with their lamivudine-containing regimen (lamivudine dose, 300 mg/day) and either entecavir monohydrate 1 mg once daily or placebo. After 24 weeks of double-blind therapy and a mean of 17 weeks of open-label therapy (where all patients received entecavir monohydrate), the adverse event and laboratory abnormality profiles were similar for the entecavir monohydrate and placebo treatment groups. Entecavir monohydrate has not been evaluated in HIV/HBV co-infected patients who are not concurrently receiving effective HIV treatment (see Section 4.4 Special Warnings and Precautions for Use, Co-infection with HIV).

Postmarketing experience.

The following events have been identified during postapproval use of entecavir monohydrate. 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 in association with hepatic decompensation, other serious medical conditions or drug exposures.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems

4.2 Dose and Method of Administration

Recommended dosage.

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

Renal impairment.

In patients with renal impairment, the apparent oral clearance of entecavir monohydrate decreased as creatinine clearance decreased (see Section 5.2 Pharmacokinetic Properties, Special populations). Dosage adjustment of Entecavir RBX is recommended for patients with creatinine clearance < 50 mL/min, including patients on hemodialysis or CAPD, as shown in Table 1.

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.
1Entecavir Oral Solution is unavailable in this brand, however is available in other brands.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

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 overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, povidone, crospovidone, microcrystalline cellulose and magnesium stearate.
The 0.5 mg tablet coating is OPDARY complete film coating system 13B58802 WHITE (PI12811).
The 1 mg tablet coating is OPARDY complete film coating system 13B84610 Pink (PI 106175). The OPADRY complete film coating system WHITE contains hypromellose, titanium dioxide, macrogol 400 and polysorbate 80, and the Pink contains all of the above in addition to iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutics Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Entecavir RBX tablets.

Store below 25°C. Store in original package.

6.5 Nature and Contents of Container

Entecavir RBX 0.5 mg tablets.

PA/Al/PVC/Al Blister Packs 30's: AUST R 256612.

Entecavir RBX 0.5 mg tablets.

HDPE Bottle Packs 30’s and 500's*: AUST R 256632.

Entecavir RBX 1 mg tablets.

PA/Al/PVC/Al Blister Packs 30's: AUST R 256652.

Entecavir RBX 1 mg tablets.

HDPE Bottle Packs 30's and 500's*: AUST R 256672.
*For dispensing only. This pack is not to be supplied to a patient.
Not all pack sizes and presentations are marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be dispose of by taking to your local pharmacy.

Summary Table of Changes