ENTECAVIR VIATRIS

MIMS Revision Date: 01 December 2022

1 Name of Medicine

Entecavir (as monohydrate).

2 Qualitative and Quantitative Composition

Each Entecavir Viatris tablet contains 0.5 mg or 1 mg of 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

Entecavir Viatris 0.5 mg. A white, film-coated, round, biconvex, beveled edge tablet debossed with 'M' on one side of the tablet and 'EV1' on the other side.
Entecavir Viatris 1 mg. A white, film-coated, round, biconvex, beveled edge tablet debossed with 'M' on one side of the tablet and 'EV2' on the 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 (LVD^R 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 haemodialysis 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

Entecavir is contraindicated in patients with previously demonstrated hypersensitivity to entecavir or any component of the product. See Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Coinfection with HIV. Therapy with entecavir is not recommended for HIV/HBV coinfected 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.
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 Section 4.8 Adverse Effects (Undesirable Effects)). The majority of post-treatment exacerbations appear to be self limited. However, severe exacerbations, including fatalities, may occur. Hepatic function should be monitored closely for at least several months after discontinuation. If appropriate, resumption of hepatitis B therapy may be warranted.
Use in renal impairment. Dosage adjustment of entecavir is recommended for patients with renal impairment who have creatinine clearance < 50 mL/min (see Section 4.2 Dose and Method of 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 postoperative 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 retransplantation. 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 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 ciclosporine or tacrolimus (see Section 4.2 Dose and Method of Administration, Hepatic impairment; Section 5.2 Pharmacokinetic Properties, Hepatic impairment and Postliver 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 Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.8 Adverse Effects (Undesirable Effects)).
Coinfection with hepatitis C or D. There are no data on the efficacy of entecavir in patients coinfected 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 medicinal product contains 62.5 mg of lactose monohydrate in each 0.5 mg daily dose and 125 mg of lactose monohydrate 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.
Effects on laboratory tests. No data available.
Patient information. A consumer medicine information leaflet for Entecavir Viatris 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.

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), coadministration with medicinal products that reduce renal function or compete for active tubular secretion may increase serum concentrations of either medicinal product. Coadministration of entecavir with either lamivudine, adefovir dipivoxil or tenofovir disoproxil fumarate resulted in no significant drug interactions. The effects of coadministration 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 coadministered with such medicinal products.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility. Male and female rat fertility was unaffected by drug exposures (AUC) up to approximately 160 (male) and 230 (female) times that in humans treated with a daily dose of 1 mg. Testicular seminiferous tubule degeneration or germinal epithelial maturation arrest was observed in long-term rodent studies, at drug exposures that were ≥ 10 (mice) and 29 (rats) times the human value, and in dog studies at exposures > 379 times the human value. No testicular changes were evident in monkeys at exposures up to 114 times the clinical exposure.
Use in pregnancy. (Category B3)
Category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
There are no adequate and well controlled studies in pregnant women. Entecavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
There are no data on the effect of entecavir on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
In animal experiments, embryofetal development was unaffected at drug exposures (AUC) of up to 23 (rats) and 175 (rabbits) times the maximum human exposure (1 mg daily dose). Slightly increased resorptions occurred in rats at a maternotoxic dose resulting in a higher drug exposure (150 times the human value), while embryofetal development was severely retarded at a maternotoxic dose resulting in a drug exposure > 2500 times the human value; tail and vertebral malformations were observed. A drug exposure 730 times the maximum human value resulted in increased resorptions and incomplete fetal hyoid ossification in rabbits, in the absence of maternal toxicity. Rat offspring development was unaffected at drug exposures approximately 230 times the human value, when mothers were treated from early gestation to the end of lactation.
Pregnancy registry. To monitor maternal fetal outcomes of pregnant women exposed to entecavir, a pregnancy registry has been established. Physicians are encouraged to register patients by calling 1-800-067-567.
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 breastfeed if they are taking entecavir.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Assessment of adverse reactions is based on four clinical studies in which 1720 patients with chronic HBV infection received double blind treatment with entecavir 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 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 2.

Laboratory findings. Table 3 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 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.
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 5. The cumulative rates of discontinuation for adverse events and on study cumulative rates of death and hepatocellular carcinoma (HCC) are also shown in Table 5.
Causes of death in study AI463048 were generally liver related, as expected in this population. The time to onset of HCC or death (whichever occurred first) was comparable in the two treatment groups.
Laboratory test abnormalities reported through week 48 in study AI463048 are listed in Table 6.
Patients coinfected with HIV. Patients coinfected 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 coinfected patients who are not concurrently receiving effective HIV treatment (see Section 4.4 Special Warnings and Precautions for Use, Coinfection 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.
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 haemodialysis 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 pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir-TP Ki 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 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 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 from 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.
Lamivudine-resistant strains harbouring rtL180M plus rtM204V in combination with amino acid substitution rtA181C conferred 16- to 122-fold reductions in entecavir phenotypic susceptibility.
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 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 Section 5.1 Pharmacodynamic Properties, Clinical trials) who failed to achieve the study defined complete response by week 96 were offered continued entecavir treatment in a rollover study. Participants received 1 mg entecavir once daily for up to an additional 96 weeks. Genotypic analysis of clinical samples from lamivudine refractory patients identified emerging entecavir resistance substitutions in 11/187 patients in year 1, 12/146 patients in year 2, 16/80 patients in year 3, 6/52 patients in year 4 and 2/33 patients in year 5 (see Table 8). Results in Table 8 reflect the use of combination entecavir 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.
Integrated analysis of phase 2 and 3 clinical studies. In a post-approval integrated analysis of entecavir resistance data from 17 Phase 2 and 3 clinical studies, an emergent entecavir resistance-associated substitution rtA181C was detected in 5 out of 1461 (0.3%) subjects during treatment with entecavir. This substitution was detected only in the presence of lamivudine-associated substitutions rtL180M plus rtM240V.
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 naïve patients with compensated liver disease. Outcomes at 48 weeks. HBeAg positive. Study AI463022 was a multinational, randomized, double blind study of entecavir tablets 0.5 mg once daily versus lamivudine 100 mg once daily for 52 weeks in 709 (of 715 randomized) nucleoside naïve patients with chronic hepatitis B infection and detectable HBeAg. The mean age of patients was 35 years (range 16 to 78), and 75% were male; 57% were Asian, 40% were Caucasian, and 13% had previously received interferon-α treatment. At baseline, patients had a mean Knodell necroinflammatory score of 7.8, mean serum HBV DNA level as measured by Roche COBAS Amplicor PCR assay of 9.66 log₁₀ copies/mL, and mean serum ALT level of 143 U/L. Response was assessed at week 52 based on test results obtained at the week 48 visit. Ninety six percent of patients had a baseline liver biopsy, paired samples were collected for 89% of patients.
HBeAg negative (anti-HBe positive/HBV DNA positive). Study AI463027 was a multinational, randomized, double blind study of entecavir tablets 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 precore or core promoter mutants). The mean age of patients was 44 years (range 18 to 77), and 76% were male. Thirty nine percent were Asian and 58% were Caucasian; 13% had previously received interferon-α treatment. At baseline, patients had a mean Knodell necroinflammatory score of 7.8, mean serum HBV DNA level as measured by Roche COBAS Amplicor PCR assay of 7.58 log₁₀ copies/mL, and mean serum ALT level of 142 U/L. Ninety eight percent of patients had a baseline liver biopsy, and 89% had a biopsy at week 48; paired samples were collected for 88% of patients. Response was assessed at week 52 based on test results obtained at the week 48 visit. In studies AI463022 and AI463027, entecavir 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 a 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 LVD^R 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 serocoversion at the end of dosing.
Post-treatment follow-up: of the 22/141 (16%) lamivudine refractory patients who met response criteria (HBV DNA < 0.7 mEq/mL on bDNA assay and loss of HBeAg) while receiving entecavir, 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.
Outcomes of long-term follow-up study. Study AI463080 was a randomized, global, observational, open-label Phase 4 study to assess long-term risks and benefits of entecavir (0.5 mg/day or 1 mg/day) treatment as compared to other standard of care hepatitis B virus nucleoside analogies (nucs) in subjects with chronic HBV (CHB) infection.
A total of 12,378 patients with CHB were treated with ETV (n=6,216) or other standard of care HBV nucleoside (acid) treatment (non-ETV) (n=6,162). The patients were evaluated at baseline and subsequently twice a year (every 6 months) on clinical outcome events (COEs) for up to 10 years during the study. The principal COEs assessed in the study were overall malignant neoplasms, liver-related HBV disease progression, non-HCC malignant neoplasms, HCC, non-HCC HBV disease progression, and deaths, including liver-related deaths. The study data showed that ETV was not significantly associated with an increased risk of malignant neoplasms compared to use of other standard of care HBV nucs, as assessed by either the composite endpoint of overall malignant neoplasms or the individual endpoint of non-HCC malignant neoplasm. The most commonly reported malignancy was HCC followed by gastrointestinal malignancies with colorectal and gastric cancers representing the majority of the observed tumour types within the gastrointestinal system in both ETV and non-ETV groups. The data also showed that long-term ETV use was not associated with a lower occurrence of HBV disease progression or a lower rate of death overall.
There were significant population changes over the long-term follow-up period and more frequent post-randomisation treatment changes in the non-ETV group were noted. The study was underpowered to demonstrate a difference in the non-HCC malignancy rate because of the overall lower than expected background rate.
The principal COE assessment is shown in Table 13:
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 14.
HIV/HBV coinfected patients. Study AI463038 was a randomized, double blind, placebo controlled study of entecavir versus placebo in 68 patients coinfected 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 15.
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 coinfected patients who are not concurrently receiving effective HIV treatment (see Section 4.4 Special Warnings and Precautions for Use, Coinfection with HIV).
Liver transplant recipients. The safety and efficacy of entecavir 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.

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 solution.
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).
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 biexponential 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 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 haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Results are shown in Table 16.

Dosage adjustment is recommended for patients with a creatinine clearance < 50 mL/min, including patients on haemodialysis or CAPD. (See Section 4.2 Dose and Method of Administration, Renal impairment.)
Following a single 1 mg dose of entecavir, haemodialysis 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 haemodialysis.
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.
Postliver transplant. Entecavir exposure in HBV infected liver transplant recipients on a stable dose of ciclosporine 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 ciclosporine 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 and Excretion). The pharmacokinetics of entecavir 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.
The steady-state pharmacokinetics of entecavir and coadministered drug were not altered in interaction studies of entecavir with each of the following: lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (also 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 ciclosporine A (n = 5) or tacrolimus (n = 4) therapy did not affect the pharmacokinetics of entecavir (see Section 5.2 Pharmacokinetic Properties, Special populations, Postliver transplant). The effect of entecavir on the pharmacokinetics of ciclosporine 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, rates), vascular tumours (mice, rats) salivary duct adenoacanthomas (mice), kidney oncocytoma and malignant mesenchymal tumours (rats), and Zymbal's gland carcinomas (rats; no human counterpart). With the exception of the mouse lung tumours, disruption of cellular deoxyribonucleotide triphosphated (dNTP) pools is likely a significant factor in the carcinogenicity of entecavir, 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 (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

6 Pharmaceutical Particulars

6.1 List of Excipients

Entecavir film-coated tablets are available for oral administration in strengths of 0.5 mg and 1 mg of entecavir. Entecavir 0.5 mg and 1 mg film-coated tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, magnesium stearate, and Opadry white YS-1R-7003 (ARTG PI No. 1625).

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.

6.5 Nature and Contents of Container

Entecavir Viatris 0.5 mg. Blister pack (PA/Al/PVC/Al) of 30 tablets; bottle (HDPE bottle with PP screw cap) of 30 tablets.
Entecavir Viatris 1 mg. Blister pack (PA/Al/PVC/Al) of 30 tablets; bottle (HDPE bottle with PP screw cap) of 30 tablets.
Some strengths, pack sizes and/or pack types may not be marketed.
Australian register of therapeutic goods (ARTG). AUST R 220088 - Entecavir Viatris entecavir (as monohydrate) 1 mg film coated tablets bottle.
AUST R 220090 - Entecavir Viatris entecavir (as monohydrate) 0.5 mg film coated tablets blister pack.
AUST R 220091 - Entecavir Viatris entecavir (as monohydrate) 1 mg film coated tablets blister pack.
AUST R 220093 - Entecavir Viatris entecavir (as monohydrate) 0.5 mg film coated tablets bottle.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it 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 crystalline 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.
CAS number. 209216-23-9.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Date of First Approval

18 April 2016

Date of Revision

03 November 2022

Summary Table of Changes