ENTECAVIR APO

MIMS Revision Date: 01 May 2026

1 Name of Medicine

Entecavir monohydrate.

2 Qualitative and Quantitative Composition

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

3 Pharmaceutical Form

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

4 Clinical Particulars

4.1 Therapeutic 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.

4.2 Dose and Method of Administration

Recommended dosage. Entecavir should be taken orally, on an empty stomach (at least 2 hours after a meal and at least 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 decreased as creatinine clearance decreased (see Section 5.2 Pharmacokinetic Properties, 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 1.

Hepatic impairment. No dosage adjustment is necessary for patients with hepatic impairment.
Duration of therapy. The optimal duration of treatment with entecavir for patients with chronic hepatitis B infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.

4.3 Contraindications

This medicine is contraindicated in patients with previously demonstrated hypersensitivity to entecavir or any component of the product.

4.4 Special Warnings and Precautions for Use

Co-infection with human immunodeficiency virus (HIV). Therapy with entecavir is not recommended for HIV/hepatitis B virus (HBV) co-infected patients who are not receiving highly active antiretroviral therapy. There is a potential for the development of HIV resistance if entecavir is used to treat chronic hepatitis B infection in patients with untreated HIV infection.
Before initiating entecavir therapy, HIV antibody testing should be recommended to all patients.
HIV/HBV co-infected patients receiving concomitant antiretroviral therapy. Entecavir has been studied in 68 adults with HIV/HBV co-infection receiving a lamivudine-containing HAART regimen (see Section 5.1 Pharmacodynamic Properties, Clinical trials). No data are available on the efficacy of entecavir in HBeAg-negative patients co-infected with HIV. There are limited data on patients co-infected with HIV who have low CD₄ cell counts (< 200 cells/mm³).
Lactic acidosis and severe hepatomegaly with steatosis. 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.
As entecavir is a nucleoside analogue, this risk cannot be excluded. Treatment with nucleoside analogues should be discontinued when rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown aetiology occur. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, might be indicative of lactic acidosis development. Severe cases, sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic steatosis, renal failure and higher levels of serum lactate. Caution should be exercised when prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease. These patients should be followed closely.
To differentiate between elevations in aminotransferases due to response to treatment and increases potentially related to lactic acidosis, physicians should ensure that changes in ALT are associated with improvements in other laboratory markers of chronic hepatitis B.
Resistance and specific precaution for lamivudine-refractory patients. Mutations in the HBV polymerase that encode lamivudine-resistance substitutions may lead to the subsequent emergence of secondary substitutions, including those associated with entecavir associated resistance (ETVr). In a small percentage of lamivudine refractory patients, ETVr substitutions at residues rtT184, rtS202 or rtM250 were present at baseline. Patients with lamivudine-resistant HBV are at higher risk of developing subsequent entecavir resistance than patients without lamivudine resistance. The cumulative probability of emerging genotypic entecavir resistance after 1, 2, 3, 4 and 5 years treatment 5 in the lamivudine-refractory studies was 6%, 15%, 36%, 47% and 51%, respectively. Virological response should be frequently monitored in the lamivudine-refractory population and appropriate resistance testing should be performed. In patients with a suboptimal virological response after 24 weeks of treatment with entecavir, a modification of treatment should be considered (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.1 Pharmacodynamic Properties). When starting therapy in patients with a documented history of lamivudine-resistant HBV, combination use of entecavir plus a second antiviral agent (which does not share cross-resistance with either lamivudine or entecavir) should be considered in preference to entecavir monotherapy.
Pre-existing lamivudine-resistant HBV is associated with an increased risk for subsequent entecavir resistance regardless of the degree of liver disease; in patients with decompensated liver disease, virologic breakthrough may be associated with serious clinical complications of the underlying liver disease. Therefore, in patients with both decompensated liver disease and lamivudine-resistant HBV, combination use of entecavir plus a second antiviral agent (which does not share cross-resistance with either lamivudine or entecavir) should be considered in preference to entecavir monotherapy.
Exacerbations of hepatitis. Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients as serum HBV DNA levels decline (see Section 4.8 Adverse Effects (Undesirable Effects)). Among entecavir-treated patients on-treatment exacerbations had a median time of onset of 4-5 weeks. In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with advanced liver disease or cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.
Acute exacerbation of hepatitis has also been reported in patients who have discontinued hepatitis B therapy (see Section 4.8 Adverse Effects (Undesirable Effects)). Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported. Among entecavir-treated nucleoside naive patients, post-treatment exacerbations had a median time to onset of 23-24 weeks, and most were reported in HBeAg negative patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be warranted.
Use in renal impairment. Dosage adjustment of entecavir monohydrate is recommended for patients with renal impairment who have creatinine clearance < 50 mL/min including patients on hemodialysis or CAPD (continuous ambulatory peritoneal dialysis; see Section 4.2 Dose and Method of Administration). The proposed dose modifications are based on extrapolation of limited data, and their safety and effectiveness have not been clinically evaluated. Therefore, virological response should be closely monitored.
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 hepatocellular carcinoma (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 therapy in liver transplant recipients receiving an immunosuppressant that may affect renal function such as ciclosporin or tacrolimus (see Section 4.2 Dose and Method of Administration, Hepatic impairment; Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment, 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 A higher rate of serious hepatic adverse events (regardless of causality) has been observed in patients with decompensated liver disease, in particular in those with Child-Turcotte-Pugh (CTP) class C disease, compared with rates in patients with compensated liver function. Also, patients with decompensated liver disease may be at higher risk for lactic acidosis and for specific renal adverse events such as hepatorenal syndrome. Therefore, clinical and laboratory parameters should be closely monitored in this patient population (also 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 in patients co-infected with hepatitis C or D.
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 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).
Lactose. This medicine contains 112.5 mg of lactose in each 0.5 mg daily dose and 225 mg of lactose in each 1 mg daily dose. These tablets should be used with caution in patients with lactose intolerance. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency of glucose-galactose malabsorption should not take this medicine.
Effects on laboratory tests. No data available.
Patient information. A Consumer Medicine Information leaflet for this medicine 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 Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Medicinal products. Since entecavir is predominantly eliminated by the kidney (see Section 5.2 Pharmacokinetic Properties, Excretion), 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 with either lamivudine, adefovir dipivoxil or tenofovir disoproxil fumarate resulted in no significant drug interactions. The effects of co-administration of entecavir 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.

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.
Use in pregnancy. (Category B3)
There are no adequate and well-controlled studies in pregnant women. Given that the potential risks to the developing fetus are unknown, women of childbearing potential should use effective contraception. Entecavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
There is no research on the labour and delivery in pregnant women and no data on the effect of entecavir 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 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.

4.7 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. However, dizziness, fatigue and somnolence are common side effects which may impair the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Assessment of adverse reactions is based on four clinical studies in which 1,720 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 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%). Exacerbations of hepatitis during and after discontinuation of entecavir therapy have also been reported.
In these clinical studies, the 594 entecavir-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-naïve 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.
Exacerbations 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 is presented in Table 4.
In the clinical trials entecavir treatment was discontinued if patients achieved a prespecified response. If treatment is discontinued without regard to treatment response, the rate of post-treatment ALT flares could be higher.
Other special populations. 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 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 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 Section 4.4 Special Warnings and Precautions for Use, Co-infection with human immunodeficiency virus (HIV)).
Gender/age. There was no apparent difference in the safety profile of entecavir with respect to gender or age.
Post-marketing experience. The following events have been identified during post-approval use of entecavir. Because reports are voluntary from a population of unknown size, an estimate of frequency cannot be made.
Gastrointestinal disorders. Upper abdominal pain, pancreatitis.
Blood and lymphatic system disorders. Leukopenia, neutropenia, platelet count decreased.
Immune system disorders. Hypersensitivity and drug hypersensitivity including 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 www.tga.gov.au/reporting-problems.

4.9 Overdose

There is limited experience of entecavir overdosage reported in patients. Healthy participants who received single entecavir 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, a 4-hour hemodialysis session removed approximately 13% of the entecavir dose.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action. Entecavir 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 concentrations, with no significant accumulation beyond initial plateau levels. By competing with the natural substrate deoxyguanosine-TP, entecavir-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 pre-genomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir-TP K_i value for inhibition of HBV DNA polymerase is 1.2 nanoM. Entecavir-TP is a weak inhibitor of cellular DNA polymerases α, β, δ and ε with K_i values of 18 to 40 microM. It did not inhibit mitochondrial γ polymerase (K_i > 160 microM) and did not affect the mitochondrial DNA content of human hepatoma cells in vitro. Entecavir inhibited HBV DNA synthesis at a concentration of 0.004 microM in human HepG2 cells transfected with wild-type HBV. IC₅₀ values for entecavir against lamivudine-resistant HBV ranged 0.029-0.061 microM.
Resistance in vitro. There was reduced susceptibility to entecavir when LVD^R substitutions (M204I/V ± L180M) were present. Entecavir inhibited the replication of LVD^R 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-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.
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 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-naïve studies. Patients in nucleoside-naïve studies received 0.5 mg entecavir 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 for 147 of 149 patients in Year 3 and 121 patients in Year 4, 108 patients in Year 5 and of combination entecavir plus lamivudine therapy (followed by long-term entecavir 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-naïve studies, genotypic evidence of ETVr substitutions at rtT184, rtS202 or rtM250 was identified in 3 patients treated with entecavir, 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 1 mg once daily in lamivudine-refractory studies (see Clinical trials, below) 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 plus lamivudine therapy (followed by long-term entecavir 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 treatment. Three of the 10 patients experienced virologic breakthrough in the 240 weeks of follow-up.
Clinical trials. The safety and efficacy of entecavir were evaluated in three active-controlled trials on five continents. These studies included 1,633 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-naïve 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-naïve patients with chronic hepatitis B infection and detectable HBeAg. The mean age of patients was 35 years (range: 16-78) 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 0.5 mg once daily versus lamivudine 100 mg once daily for 52 weeks in 638 (of 648 randomized) nucleoside-naïve 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: 18-77) 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 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-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: 16-74), 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 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-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-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-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-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 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-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-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-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-treated and 16/28 lamivudine-treated participants had HBV DNA < 300 copies/mL by PCR; 7 entecavir-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 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-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 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-treated group and 3/145 (2%) in the lamivudine-treated group continued blinded treatment for up to 96 weeks. In the entecavir-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 pre-treated (excluding pre-treatment 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 monohydrate 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 13.
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 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 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 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 human immunodeficiency virus (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 monohydrate.

5.2 Pharmacokinetic Properties

Absorption. In healthy participants, entecavir was rapidly absorbed with peak plasma concentrations occurring between 0.5 and 1.5 hours. There was a dose-proportionate increase in peak plasma concentration (C_max) and area under the concentration-time curve (AUC) values following multiple doses ranging from 0.1 to 1 mg. Steady-state was achieved after 6-10 days of once-daily dosing with approximately 2-fold accumulation. C_max and trough plasma concentration (C_trough) 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 solution². The oral solution and tablet may be used interchangeably.
Oral administration of entecavir 0.5 mg with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in a minimal delay in absorption (1-1.5 hour fed vs. 0.75 hour fasted), a decrease in C_max 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 Section 4.2 Dose and Method of Administration).
² Entecavir oral solution is unavailable in this brand, however is available in other brands.
Distribution. The estimated volume of distribution for entecavir 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 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 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 did not induce the human CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5 and 2B6. Following administration of ¹⁴C-entecavir 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 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 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 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 does not vary by age.
Renal impairment. The pharmacokinetics of entecavir 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, hemodialysis removed approximately 13% of the entecavir dose over 4 hours and CAPD removed approximately 0.3% of the dose over 7 days. Entecavir should be administered after hemodialysis.
Hepatic impairment. The pharmacokinetics of entecavir 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 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 exposure in HBV-infected liver transplant recipients on a stable dose of ciclosporin 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 exposure in these patients. Before and during entecavir therapy in liver transplant recipients receiving ciclosporin 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 is not a substrate, inhibitor or inducer of the CYP450 enzyme system (see Section 5.2 Pharmacokinetic Properties, Metabolism, Excretion, above). The pharmacokinetics of entecavir are unlikely to be affected by co-administration 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 co-administration of entecavir.
The steady-state pharmacokinetics of entecavir and co-administered 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 ciclosporin A (n = 5) or tacrolimus (n = 4) therapy did not affect the pharmacokinetics of entecavir (see Section 5.2 Pharmacokinetic Properties, Special populations, Post-liver transplant). The effect of entecavir on the pharmacokinetics of ciclosporin A or tacrolimus is unknown.

5.3 Preclinical Safety Data

Genotoxicity. Entecavir 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 were conducted in mice and rats. In mice, entecavir 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 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, 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 for an extended period cannot be excluded.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, povidone, crospovidone, microcrystalline cellulose and magnesium stearate. The 0.5 mg tablet coating is Opadry complete film coating system 13B58802 White (which contains hypromellose, titanium dioxide, macrogol 400 and polysorbate 80). The 1 mg tablet coating is Opadry complete film coating system 13B84610 Pink (which contains hypromellose, titanium dioxide, macrogol 400, polysorbate 80 and 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 Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Store in original package.

6.5 Nature and Contents of Container

Blister pack (PA/Al/PVC/Al) of 30s.
0.5 mg tablets - AUST R 256432; 1 mg tablets - AUST R 256492.

6.6 Special Precautions for Disposal

Unused or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

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 log P is -0.81, -1.4 and the pKa in strongest acid is 8 and strongest basic is 2.77.
CAS number. 209216-23-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Date of First Approval

19 May 2016

Date of Revision

01 April 2026

Summary Table of Changes