Consumer medicine information

ENTECAVIR APOTEX

Entecavir monohydrate

BRAND INFORMATION

Brand name

Entecavir APOTEX Tablets

Active ingredient

Entecavir monohydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using ENTECAVIR APOTEX.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about entecavir. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is Entecavir APOTEX tablets. It contains the active ingredient entecavir and belongs to a group of medicines called antiviral medicines.

It is used to treat chronic hepatitis B virus infection in adults 16 years or older.

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

This medicine is available only with a doctor's prescription.

How it works

Infection by the hepatitis B virus can lead to damage to the liver. Entecavir 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 is when taken for long periods.

There is no evidence that this medicine is addictive.

Use in children

This medicine should not be used in children under 16 years as safety and effectiveness have not been established.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You are hypersensitive to, or have had an allergic reaction to, entecavir or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • problems with your kidneys
  • hepatitis C or D
  • you have received a liver transplant
  • you have HIV and you are not currently receiving HIV treatment. Entecavir may affect your HIV which could impact on future treatment options for HIV.
  1. You are currently pregnant or you plan to become pregnant. Experience is limited with the use of entecavir in pregnant women. Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.
  2. You are currently breastfeeding or you plan to breast-feed. It is not known whether entecavir passes into breast milk. Do not take this medicine whilst breastfeeding.
  3. You are lactose intolerant. Entecavir tablets contain lactose.
  4. You are planning to have surgery or an anaesthetic.
  5. You are currently receiving or are planning to receive dental treatment.
  6. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Medicines excreted by the kidney or which affect kidney function may interact with entecavir. Patients should be monitored closely for adverse events when entecavir is taken with such medicines.

If you are taking any of these medicines you may need a different dose or you may need to take different medicines.

Other medicines not stated above may also interact with entecavir.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

The usual dose of entecavir is 0.5mg or 1mg once a day.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

How to take it

Swallow the tablet whole with a glass of water.

When to take it

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

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

How long to take it for

Entecavir helps control your condition but does not cure it. Therefore you must continue taking entecavir for as long as your doctor tells you to.

Entecavir 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 without discussing it with your doctor. If entecavir is stopped suddenly, 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.

Make sure you have enough to last over weekends and holidays, or until you next see your doctor.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses.

This may increase the chance of you experiencing side effects. It is very important not to miss your doses of entecavir. If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breastfeeding or are planning to breast-feed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Go to your doctor regularly for a check-up.

Your doctor may want to do tests to make sure the medicine is working and to prevent side effects.

When your treatment with entecavir is stopped, your doctor will continue to monitor you and take blood tests for several months.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

There is no evidence that entecavir 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.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking entecavir or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Tell your doctor if you notice any of the following:

  • diarrhoea
  • indigestion
  • tiredness
  • headache.

Some people who have taken entecavir or medicines like entecavir 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 generally involved patients who were seriously ill due to their liver disease or other medical condition.

Tell your doctor as soon as possible if you notice 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.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious signs or symptoms of liver problems and you may need urgent medical attention or hospitalisation:

  • 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.

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to entecavir, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 30°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it.

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 this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What Entecavir APOTEX Tablet looks like

0.5mg tablet: white colored, triangular shaped film coated tablets, engraved "APO" on one side and "0.5" over "ENT" on the other side.

It is available in blister pack of 30 tablets.

1.0mg tablet: pink colored, triangular shaped film coated tablets, engraved "APO" on one side and "1" over "ENT" on the other side

It is available in blister pack of 30 tablets.

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains 0.5 mg and 1.0mg of entecavir monohydrate as the active ingredient.

It also contains the following inactive ingredients:

  • lactose
  • cellulose-microcrystalline
  • copovidone
  • crospovidone
  • magnesium stearate
  • hypromellose
  • hydroxypropylcellulose
  • macrogol 8000
  • titanium dioxide
  • iron oxide red (1.0mg only)
  • purified water.

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

Entecavir APOTEX 0.5mg tablet (blister pack): AUST R 217581

Entecavir APOTEX 1.0mg tablet (blister pack): AUST R 217583.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was last updated in:
March 2016

BRAND INFORMATION

Brand name

Entecavir APOTEX Tablets

Active ingredient

Entecavir monohydrate

Schedule

S4

 

Name of the medicine

Entecavir monohydrate.

Excipients.

Lactose, microcrystalline cellulose, copovidone, crospovidone, magnesium stearate, hypromellose, hydroxypropylcellulose, macrogol 8000, titanium dioxide and iron oxide red (1.0 mg only).

Description

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.
CAS Registry Number: 209216-23-9.
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.
Each tablet contains entecavir (as monohydrate) as the active ingredient. In addition, each tablet contains the following inactive ingredients: lactose, microcrystalline cellulose, copovidone, crospovidone, magnesium stearate, hypromellose, hydroxypropylcellulose, macrogol 8000, titanium dioxide and iron oxide red (1.0 mg only).

Pharmacology

Pharmacological actions.

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, ß, δ and ε 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 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 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 1). 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 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 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.

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 (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 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 Cmax 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 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.

Elimination.

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.
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 and during Entecavir therapy in liver transplant recipients receiving cyclosporine or 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 is not a substrate, inhibitor, or inducer of the 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 pharmacokinetics 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 Interactions with Other Medicines).
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 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 coinfected 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 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-αtreatment. 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 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. Ninetyeight 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.
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-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-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 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. Ninetyeight 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 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 6. Table 7 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-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-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 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 seroconversion 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 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 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.

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 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 9.
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 Precautions, Co-infection 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 were 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 lamivudine-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 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 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. (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, Hepatic impairment and Pharmacology, Special populations: Hepatic impairment and Post-liver transplant).

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 120.35 mg of lactose in each 0.5 mg daily dose and 204.70 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.
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, Use in pregnancy).

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)
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.

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 be taken in dose selection, and it may be useful to monitor renal function (see Dosage and Administration, Renal impairment).

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, rats), 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

Medicinal products.

Since entecavir monohydrate is predominantly eliminated by the kidney (see Pharmacology, Pharmacokinetics: Elimination), co-administration with medicinal products that reduce renal function or compete for active tubular secretion may increase serum concentrations of either medicinal product. Co-administration of entecavir monohydrate with either lamivudine, adefovir dipivoxil or tenofovir disoproxil fumarate resulted in no significant drug interactions. The effects of co-administration 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 co-administered with such medicinal products (see also Drug interactions under Pharmacology, Pharmacokinetics).

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.

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.
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 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 (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.

Patients with decompensated liver disease.

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

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 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), the adverse event and 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 in 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 (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 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.

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 overdose, contact the Poisons Information Centre on 131 126 (Australia).

Presentation

Entecavir APOTEX tablets are intended for oral administration.
Each tablet contains 0.5 mg or 1.0 mg of entecavir (as monohydrate) as the active ingredient.

0.5 mg tablet.

White colored, triangular shaped film coated tablets, engraved ‘”APO” on one side and “0.5” over “ENT” on the other side.
Blister Pack (Aluminium/Aluminium) of 30 tablets (AUST R 217581).

1 mg tablet.

Pink colored, triangular shaped film coated tablets, engraved ‘”APO” on one side and “1” over “ENT” on the other side.
Blister Pack (Aluminium/Aluminium) of 30 tablets (AUST R 217583).
Not all strengths may be available.

Storage

Store below 30°C in original package.

Poison Schedule

S4.