Entecavir Tablets Instructions

Date of approval.
Date of revision.
 Entecavir Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
Severe acute exacerbation of hepatitis B, patients with HIV and HBV co-infection, lactic acidosis with hepatomegaly
Severe acute deterioration has been reported in patients after discontinuation of hepatitis B antiviral therapy (including entecavir). Patients who discontinue antiviral therapy for hepatitis B should be monitored closely for liver function for at least several months. If necessary, antiviral therapy needs to be restarted.
Entecavir is not recommended for patients with HBV co-infection with HIV who are not on concomitant highly active antiretroviral therapy (HAART) due to the risk of HIV nucleoside reverse transcriptase inhibitor resistance with entecavir therapy in this group of patients.
Cases of lactic acidosis and severe hepatomegaly with steatosis, or even death, have been reported after nucleoside analogue therapy.
 Drug Name
Generic name: Entecavir Tablets
English name: Entecavir Tablets
Hanyu Pinyin: Entikawei Pian
Ingredients
The main ingredient of this product is entecavir.
Chemical Name: 2-Amino-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one monohydrate
Chemical structure formula.
Molecular formula: C12H15N5O3-H2O
Molecular weight: 295.3
【Properties
0.5mg: white or off-white triangular film-coated tablets, engraved with “S” on one side and “064” on the other side; white or off-white after removing the coating.
1mg: pink triangular film-coated tablets, engraved with “S” on one side and “065” on the other side; white or off-white after removing the coating.
Indications
Entecavir is indicated for the treatment of chronic adult hepatitis B (including patients with compensated and decompensated liver disease) with active viral replication, persistent elevation of serum alanine aminotransferase (ALT) or active liver histology.
It is also indicated for the treatment of pediatric patients aged 2 to <18 years with chronic HBV infection in compensated liver disease with nucleoside priming and evidence of active viral replication and persistently elevated serum ALT levels or histologic evidence of moderate to severe inflammation and/or fibrosis. See [Dosage] for its specific use.
Specification
(1) 0.5 mg (2) 1 mg    
Dosage]
Patients should take entecavir under the supervision of an experienced physician.
Entecavir should be taken on an empty stomach (at least 2 hours before or after a meal).
Recommended dose.
Adults
Oral entecavir, 0.5 mg once daily, 1 mg once daily (0.5 mg two tablets) in patients with viremia or lamivudine resistance mutations on lamivudine therapy.
For patients with decompensated liver disease, 1 mg once daily (0.5 mg two tablets).
Children
Patients weighing 32.6 kg or more should be given a daily dose of 0.5 mg as a tablet, and patients weighing greater than 10 kg and less than 32.6 kg should be given an oral solution.
Treatment decisions for pediatric patients should carefully consider individual patient needs and refer to current pediatric treatment guidelines, including valuable baseline histologic information. The long-term virologic suppression benefit of continuous therapy must be weighed against the risks of extended therapy, including the emergence of drug-resistant hepatitis B virus.
Serum ALT elevation should persist for at least 6 months prior to treatment in pediatric patients with HBeAg-positive chronic hepatitis B compensated liver disease; serum ALT elevation should persist for at least 12 months prior to treatment in HBeAg-negative pediatric patients.
Duration of treatment in pediatric patients
The optimal duration of treatment is not known. Circumstances in which treatment discontinuation may be considered according to current pediatric treatment guidelines are as follows.
Treatment in HBeAg-positive patients should be continued until at least 12 months after achieving undetectable levels of HBV DNA and HBeAg seroconversion (disappearance of HBeAg and anti-HBe positivity in 2 consecutive serum samples at least 3-6 months apart) or until HBsAg seroconversion or loss of efficacy. Serum ALT and HBV DNA levels should be followed regularly after discontinuation of therapy (see [Precautions]).
Treatment in HBeAg-negative patients should be continued until HBsAg seroconversion or until there is evidence of loss of efficacy.
Pharmacokinetic studies have not been performed in pediatric patients with renal or hepatic impairment.
Renal insufficiency
In patients with renal insufficiency, the apparent oral clearance of entecavir decreases with a decrease in creatinine clearance (see [Pharmacokinetics]). Dosing adjustments should be made in patients with creatinine clearance <50mL/min [including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) therapy]. See oral solution instructions for dosing adjustments for oral solutions. In the absence of oral solution, dose adjustments may be made as an alternative treatment by extending the dosing interval as detailed in Table 1. recommended dose adjustments are inferences based on limited data and have not been clinically evaluated for safety and efficacy. Therefore, virologic response should be closely monitored.
Table 1 Dosage in patients with renal insufficiency
 Entecavir dose* creatinine clearance (ml/min) nucleoside analogs lamivudine treatment failure in primary patients ≥ 500.5 mg once daily 1 mg once daily 30 – 490.25 mg once daily
or
0.5 mg every 48 hours 0.5 mg once daily 10 – 290.15 mg once daily
or
0.5 mg once every 72 hours 0.3 mg once daily
or
0.5 mg every 48 hours< 10
Hemodialysis or CAPD** 0.05 mg once daily
or
0.5 mg every 5-7 days 0.1 mg once daily
or
0.5 mg every 72 hours *For doses less than 0.5 mg, oral entecavir solution is recommended.
**Entecavir is applied after hemodialysis on the day of hemodialysis.
Hepatic insufficiency
No dose adjustment is required for patients with hepatic insufficiency.
Treatment period
The optimal duration of treatment with entecavir and the relationship with long-term treatment outcomes, such as cirrhosis and hepatocellular carcinoma, are not known.
[Adverse reactions].
a. Safety overview
In clinical studies in patients with compensated liver disease, common adverse reactions of varying severity that may be associated with entecavir were headache (9%), fatigue (6%), dizziness (4%), and nausea (3%). Acute episodes of hepatitis during entecavir treatment versus after discontinuation have also been reported (see [Precautions] and c. Description of selective adverse reactions).
b. List of adverse reactions
The evaluation of adverse reactions was based on four global clinical trials: AI463014, AI463022, AI463026, AI463027 and three clinical trials conducted in China (AI463012, AI463023, AI463056). In these seven studies, a total of 2596 patients with chronic hepatitis B were enrolled. Adverse events and abnormal laboratory tests were similar for entecavir and lamivudine in studies controlled with lamivudine.
In studies conducted abroad, the most common adverse events with entecavir were: headache, fatigue, dizziness, and nausea. Adverse events commonly seen in lamivudine-treated patients were: headache, fatigue, and dizziness. In each of these four studies, 1% of entecavir-treated patients and 4% of lamivudine-treated patients withdrew from the study due to adverse events and abnormal laboratory test indices.
Adverse reactions were evaluated based on post-marketing experience with pharmacovigilance and four clinical studies in which 1,720 patients with chronic hepatitis B infection and decompensated liver disease were studied with double-blind entecavir (n=862) or lamivudine (n=858) therapy for 107 weeks. In the control study, drug safety outcomes (including abnormal laboratory test indices) were similar for the three groups of entecavir 0.5 mg/day (679 HBeAg-positive or negative nucleoside analogs primed patients, median duration of treatment 53 weeks), entecavir 1.0 mg/day (183 lamivudine-resistant patients, median duration of treatment 69 weeks) and lamivudine.
All possible adverse reactions associated with entecavir treatment were classified according to body system organs. The frequencies were defined as very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1,000 to <1/100); and rare (≥ 1/10,000 to <1/1,000). Adverse reactions in each frequency group are listed in descending order of their severity.
Immune system: rare: allergic-like reactions Psychiatry: common: insomnia Neurologic: common: headache, dizziness, drowsiness Gastrointestinal: common: vomiting, diarrhea, nausea, dyspepsia Hepatobiliary: common: elevated aminotransferases Skin and subcutaneous tissue: uncommon: rash, alopecia Systemic abnormalities as well as site reactions: common: fatigue Lactic acidemia has been reported, and such conditions are usually associated with hepatic decompensation as well as Severe disease or drug use (see [Precautions]).
Treatment beyond 48 weeks: Entecavir treatment continued for a median of 96 weeks and no new safety issues were identified.
Adverse events in foreign clinical trials
Table 2 compares the differences between entecavir and lamivudine in four clinical studies. Moderate to severe adverse events and clinical adverse events that occurred during treatment that were at least potentially treatment-related were selected for comparison.
Table 2: Moderate to severe (grade 2 to 4) clinical adverse events in four two-year entecavir clinical studiesa Systemic systemic/adverse events nucleoside primary patientsb Lamivudine treatment failure patientsc Entecavir lamivudine Entecavir lamivudine 0.5 mg 100 mg 1 mg 100 mgn=679n=668n=183n=190 Any grade 2 to 4
Adverse eventsa15%18%22%23% Gastrointestinal Diarrhea<1%01%0 Indigestion<1%<1%1%0 Nausea<1%<1%<1%<1%2% Vomiting<1%<1%<1%<1%0 General Fatigue1%1%3%3% Nervous System Headache2%2%4%1% Dizziness<1%&lt ;1%01% Drowsiness<1%<1%00 Psychiatry <1% Insomnia<1%<1%0<1%a Includes adverse events that were probable, likely, related, or unclear whether they were related to the treatment approach. b Studies AI463022 and AI463027. c Includes AI463026 and AI463014. Study AI463014 was a multi-country, randomized, double-blind phase II study in patients with relapsed viremia on treatment with lamivudine who either switched to three different doses of entecavir (0.1,0.5 and 1.0 mg) once daily or continued to take 100 mg of lamivudine once daily for 52 weeks. In these studies, patients on entecavir who experienced an increase in ALT to 10 times the upper limit of normal and 2 times the baseline value during treatment usually continued the drug for a period of time and the ALT returned to normal; this was preceded or accompanied by a decrease in the 2 log values of viral load. Therefore, liver function needs to be tested regularly during the drug administration.
c. Description of selective adverse reactions
Abnormal laboratory tests: In clinical studies of patients treated with nucleoside analogues, ALT was elevated more than 3 times the baseline value in 5% of patients; in less than 1% of patients, ALT was elevated more than 2 times the baseline value, and total bilirubin exceeded 2 times the high limit of normal range (ULN) and 2 times the baseline value. Less than 1% of patients had an albumin level less than 2.5 g/dl, 2% had an amylase level greater than 3 times baseline, 11% had a lipase level greater than 3 times baseline, and less than 1% had platelets less than 50,000/mm3.
Abnormal laboratory tests in foreign clinical trials
Table 3 Frequency of abnormal laboratory tests after treatment with entecavir and lamivudine in four clinical trials.
Table 3: Abnormalities of critical laboratory tests during 2 years of treatment in four entecavir clinical trials,a patients with nucleoside primary treatment testedb patients with lamivudine treatment failurec patients with entecavir lamivudine entecavir lamivudine 0.5mg100mg1.0mg100mgn=679n=668n=183n=190 abnormalities of laboratory tests of any grade 3 to 4d35%36% 37%45%ALT>10xULN and>2xbaseline value2%4%2%11%ALT>5.0xULN11%16%12%24%AST>5.0xULN5%8%5%17%Albumin<2.5g/dl<1%<1%02%Total bilirubin>2.5x ULN2%2%3%2%Amylase³2.1xULN2%2%3%3%Lipase³2.1xULN7%6%7%7%Creatinine>3.0xULN0000confirmation of increased creatinine ≥0.5mg/dl1%1%2%1%Hyperglycemia,fasting glucose>250mg/dl2%1%3%1%Diabetes e4%3%4%6%Hematuria f9%10%9%6% platelets<50,000/mm3<1%<1%<1%<1%<1%a during treatment, except albumin (<2.5g/dl), creatinine increase ≥0.5mg/dl, ALT>10x ULN and>2x baseline levels all indicators deteriorated from baseline values up to grade 3 or 4 Grade b AI463022 and AI463027 Study C included AI463026 and AI463014, a multi-country, randomized, double-blind phase II study in patients with relapsed viremia on lamivudine treatment who either switched to once-daily dosing of three different doses of entecavir (0.1,0.5 and 1.0 mg), or continue 100 mg of lamivudine once daily for 52 weeksd including routine blood, routine biochemistry, renal and liver function tests, pancreatic enzymes, and urinary routinee Grade 3=3+ massive, ³500 mg/dL; Grade 4=4+, significant, severef Grade 3=3+ massive; Grade 4=³4+, significant, severe, multiple
ULN:high limit of normal In clinical studies of patients who failed lamivudine therapy, 4% of patients had ALT elevations above 3 times baseline values, less than 1% had ALT elevations above 2 times baseline values, and total bilirubin above 2 times ULN and 2 times baseline values. 2% of patients had amylase levels above 3 times baseline values, 18% had lipase levels above 3 times baseline values, and less than 1% had platelets less than 50,000/mm3.
Acute deterioration during treatment
In clinical studies of nucleoside primed patients, 2% of patients in the entecavir-treated group had ALT elevations above 10 times ULN versus 2 times baseline during treatment, compared with 4% in the lamivudine-treated group. In clinical studies of lamivudine-naïve patients, 2% of patients in the entecavir group had ALT elevations above 10 times ULN versus 2 times baseline, compared with 11% in the lamivudine-treated group. In the entecavir group, the median time to ALT rekindling during treatment was 4-5 weeks, and ALT usually returned to normal with continued dosing for a period of time, and was usually preceded or accompanied by a decrease in viral load of 2log10/ml or more in most cases. Regular liver function testing during treatment is recommended.
Exacerbation of hepatitis after discontinuation of treatment (see [Precautions])
Acute exacerbation of hepatitis symptoms or ALT flare-up is defined as ALT greater than 10 times the upper limit of normal and greater than 2 times the patient’s reference level (baseline value or the minimum value between the last test values at the time of discontinuation). The number of patients who experienced ALT relapse in all patients who discontinued treatment (for whatever reason) is recorded in Table 4. A subgroup of patients in these studies may be allowed to discontinue if they achieve a treatment response as defined by the protocol at or after week 52. If treatment response is not achieved and entecavir is discontinued, the probability of ALT reignition after discontinuation may be higher.
Table 4: Hepatitis worsening in nucleoside primed patients during the post-discontinuation follow-up period in studies AI463022, AI463027 and AI463026 Patients with ALT increases greater than 10 times the upper limit of normal and greater than 2 times the reference valuea Entecavir lamivudine nucleoside primed HBeAg positive 4/174 (2%) 13/147 (9%) HBeAg Negative 24/302 (8%) 30/270 (11%) Lamivudine failure 6/52 (12%) 0/16a The reference value is the smallest of the last test values at baseline or at discontinuation. The median time to progression after discontinuation was 23 weeks for entecavir-treated patients and 10 weeks for lamivudine-treated patients.
In clinical trials, entecavir treatment was discontinued only when patients achieved a pre-defined response. Therefore, if treatment is terminated without consideration of response, the proportion of ALT worsening after treatment is higher.
d. Pediatric patients
Safety data were obtained for pediatric patients treated with entecavir based on 2 ongoing clinical studies in pediatric patients aged 2 to <18 years with chronic HBV infection, a phase 2 pharmacokinetic study (study AI463028) and a phase 3 study (study AI463189). These 2 studies provided treatment experience with entecavir in 195 HBeAg-positive nucleoside primed subjects for a median duration of 99 weeks. The adverse reactions observed in pediatric subjects treated with entecavir were consistent with those observed in clinical studies of adult entecavir.
e. Other special populations
Experience in patients with decompensated liver disease: The safety of entecavir in patients with decompensated liver disease was evaluated using a non-blinded randomized comparative trial in which patients received either entecavir at 1 mg/day (n=102) or adefovir at 10 mg/day (n=89) (study number 048). In addition to the adverse reactions listed in the b. list of adverse reactions, one new adverse reaction [decrease in blood bicarbonate (2%)] was identified in patients receiving treatment with entecavir up to 48 weeks. The cumulative mortality rate in the study was 23% (23/102) and the cause of death was generally liver-related, consistent with the expected cause of death in this population. The cumulative incidence of hepatocellular liver cancer (HCC) in the study was 12% (12/102). Serious adverse events were generally liver-related, with a cumulative frequency of 69% in the study. Patients with high baseline CTP scores were at higher risk of developing serious adverse events (see [Precautions]).
Abnormal laboratory tests: In 48 weeks of treatment with entecavir in patients with decompensated liver disease, no patients experienced an ALT elevation greater than 10 times the ULN and 2 times the baseline value. 1% of patients had an ALT elevation greater than 2 times the baseline value with total bilirubin greater than 2 times the ULN and 2 times the baseline value. 30% of patients had an albumin level less than 2.5 g/dl, 10% had a lipase level greater than 3 times the Baseline values, and 20% of patients had platelets less than 50,000/mm3.
Experience in patients co-infected with HIV: The safety profile of entecavir in a limited number of HIV/HBV co-infected patients on lamivudine-containing HAART (highly active antiretroviral therapy) therapy is similar to that in patients infected with HBV only ([Caution]).
Gender/Age: The safety profile of entecavir did not show significant differences related to gender (approximately 25% women in clinical studies) or age (approximately 5% of patients were over 65 years of age).
Reporting of suspected adverse reactions: There is an important role for the reporting of suspected adverse reactions after drug approval. Adverse reaction reporting facilitates ongoing monitoring of the benefit/risk balance of a drug. Healthcare professionals are required to report all suspected adverse reactions.
Co-infection with HIV and HBV
A similar safety profile was observed in the AI463038 double-blind study in HBV co-infected HIV patients treated with entecavir 1 mg (N=51) or placebo (N=17) for 24 weeks in both groups and was similar to that observed in patients not co-infected with HIV (see [Caution]).
Liver transplant recipient patients
In an open post-liver transplant trial, 65 subjects were treated with entecavir in which the frequency and nature of adverse events were consistent with the expected response and the known safety profile of entecavir in patients who received liver transplants.
Decompensated liver disease
Study AI463048 was a randomized, open study comparing entecavir 1 mg once daily with adefovir 10 mg once daily for up to 48 weeks of treatment in adult subjects with chronic HBV infection who had evidence of hepatic decompensation (defined as a Child-Turcotte-Pugh (CTP) score of 7 or greater). Among the 102 subjects receiving entecavir, regardless of causality to the study drug, the most common adverse events that occurred during 48 weeks of treatment included peripheral edema (16%), ascites (15%), fever (14%), hepatic encephalopathy (10%), and upper respiratory tract infection (10%). Clinical adverse reactions observed over 48 weeks that are not listed in Table 2 included a decrease in blood bicarbonate (2%) and renal failure (<1%).
Eighteen of 102 subjects (18%) treated with entecavir and 18 of 89 subjects (20%) treated with adefovir died during the first 48 weeks of treatment. Most deaths (11 in the entecavir group and 16 in the adefovir group) were due to liver-related causes, such as liver failure, hepatic encephalopathy, hepatorenal syndrome, and upper gastrointestinal bleeding. incidence of hepatocellular carcinoma (HCC) within 48 weeks: 6% (6/102) in subjects treated with entecavir and 8% (7/89) in subjects treated with adefovir. Five percent of subjects in both groups discontinued treatment within 48 weeks due to adverse events.
No subjects in either treatment group experienced an on-treatment liver function reignition (ALT > 2x baseline and >10x upper limit of normal) within 48 weeks. Confirmed serum creatinine elevations of 0.5 mg/dL occurred in 11 of 102 (11%) subjects treated with entecavir and 11 of 89 (13%) subjects treated with adefovir over 48 weeks.
In clinical trials conducted in China, the most common adverse events with entecavir were elevated ALT, fatigue, dizziness, nausea, abdominal pain, abdominal discomfort, epigastric pain, liver discomfort, myalgia, insomnia, and rubella. These adverse events were mostly mild to moderate. In controlled trials with lamivudine, the incidence of adverse events with entecavir was comparable to that of lamivudine.
Post-marketing Adverse Reactions
The following adverse reactions have been reported in post-marketing clinical use of entecavir. Given that the adverse reactions were spontaneously reported in unknown numbers, the frequency of the adverse reactions or the causal relationship with entecavir exposure cannot be reliably assessed.
Immune system dysregulation: anaphylactic-like reactions.
Adverse reactions in the skin and subcutaneous tissues: alopecia, rash.
Metabolic and nutritional disorders: lactic acidosis has been reported, mostly associated with hepatic dysfunction or other severe disease or drug exposure. Patients with hepatic decompensation are at higher risk of lactic acidosis.
Hepatobiliary system abnormalities: elevated aminotransferases.
[Contraindicated].
Contraindicated in patients with hypersensitivity to entecavir or any component of the formulation.
Precautions]
Warnings
1. Severe acute deterioration of hepatitis B
Severe acute exacerbation of hepatitis B has been reported in patients after discontinuation of hepatitis B antiviral therapy (including entecavir). Patients who discontinue antiviral therapy for hepatitis B should be monitored closely for liver function for at least several months. If necessary, antiviral therapy needs to be restarted.
2. Co-infection with HIV
Entecavir has not been evaluated in patients with HBV co-infection with HIV and not receiving effective HIV therapy. Limited clinical experience suggests that entecavir has the potential to develop resistance to HIV nucleoside reverse transcriptase inhibitors if used in patients with chronic hepatitis B co-infection with HIV who are not on anti-HIV therapy. Therefore, entecavir is not recommended for patients with HBV co-infection with HIV who are not on highly active antiretroviral therapy (HAART). All patients should be tested for HIV antibodies before starting entecavir therapy. Studies of entecavir for the treatment of HIV infection have not been performed; therefore, entecavir is not recommended for anti-HIV therapy.
3. lactic acidosis and severe hepatomegaly with steatosis
Cases of lactic acidosis and hepatomegaly with steatosis, or even death, have been reported after treatment with nucleoside analogs alone or in combination with antiretroviral drugs. Most of the patients who had these events were women. Obesity and prolonged use of nucleoside analogs may be risk factors for such adverse events. Any patient with these risk factors should take special care when using nucleoside analogs for the treatment of liver disease; however, such events have also occurred in patients without these risk factors.
Lactic acidosis has been reported in patients receiving entecavir therapy, mostly associated with hepatic decompensation or other severe disease or drug exposure. The risk of lactic acidosis is higher in patients with hepatic decompensation. Entecavir should be withheld if there are clinical or laboratory findings suggesting that they have developed lactic acidosis or significant hepatotoxicity (which may include hepatomegaly and steatosis, even if aminotransferases are not significantly elevated).
Precautions.
In patients with renal insufficiency
Creatinine clearance<50mL/min, including patients on hemodialysis or CAPD, are advised to adjust the dose of entecavir administered (see [DOSAGE AND ADMINISTRATION]).
Liver Transplant Recipient Patients
The safety and efficacy of entecavir in the treatment of liver transplant recipients is unknown. If a liver transplant recipient is considered to be in need of entecavir therapy who has received or is receiving immunosuppressive agents that may affect renal function, such as: cyclosporine or tacrolimus, renal function should be closely monitored prior to and during entecavir administration. (See [Pharmacokinetics])
Special considerations for patients with drug resistance and lamivudine treatment failure
Mutations in the lamivudine resistance site in the polymerase region of HBV may lead to secondary mutations, including mutations in sites associated with entecavir resistance.
A small number of patients who fail lamivudine treatment have mutations in the entecavir resistance-associated loci rtT184, rtS202, and rtM250 at baseline. Patients with lamivudine resistance had a higher risk of subsequent entecavir resistance than patients without lamivudine resistance. In lamivudine treatment failure studies, the cumulative incidence of entecavir genotypic resistance was 6%, 15%, 36%, 47% and 51% after 1, 2, 3, 4 and 5 years of entecavir treatment, respectively.
Pediatric patients
The virologic response rate (HBV DNA < 50 IU/ml) observed in pediatric patients with baseline HBV DNA ≥ 8.0 log10 IU/ml was low. Entecavir should be used in these patients only if the potential benefit outweighs the risk to the child (e.g., drug resistance). Because some pediatric patients may require long-term, or even lifelong, treatment for chronic active hepatitis B, consider the impact of entecavir on future treatment options.
Information for patients
Patients should take entecavir as directed by their physician and inform them of any new symptoms and coadministration. Patients should be informed that liver disease can sometimes worsen if the drug is discontinued, so treatment should be changed under the direction of the physician.
Patients will need to be tested for HIV antibodies before starting entecavir therapy. Patients should be informed that entecavir may increase the chance of resistance to HIV drug therapy if they are infected with HIV and are not receiving effective HIV drug therapy.
Treatment with entecavir does not reduce the risk of HBV transmission via sexual contact or contaminated blood sources. Therefore, appropriate protective measures need to be taken.
Do not use if the inner package is opened or broken.
Pregnant women and nursing mothers]
The effects of entecavir on pregnant women have not been adequately studied. Entecavir should be used only when the potential risk benefit to the fetus has been adequately weighed.
There is no information to suggest that entecavir can affect mother-to-child transmission of HBV; therefore, appropriate interventions should be taken to prevent HBV infection in the newborn.
Entecavir is secreted from rat milk. However, it remains unclear whether it is secreted in human milk, so breastfeeding is not recommended for mothers taking entecavir.
[Pediatric Use].
Clinical data for pediatric patients aged 2 years to <18 years were obtained from foreign clinical trials of entecavir.
Dosage for Elderly Patients
It is not clear how older patients respond differently to entecavir than younger patients because there were not enough older patients aged 65 years and older to participate in clinical studies of entecavir. Other reports of clinical trials have not found differences between older and younger patients. Entecavir is primarily excreted by the kidneys, and the risk of possible toxic reactions is higher in patients with renal impairment. Because most elderly patients have decreased renal function, care should be taken in the selection of drug doses and in monitoring renal function.
Drug Interactions]
Metabolism of entecavir was evaluated in in vivo and in vitro tests. Entecavir is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system. At concentrations up to approximately 10,000-fold in humans, entecavir does not inhibit any of the major human CYP450 enzymes: 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1. at concentrations up to approximately 340-fold in humans, entecavir does not induce the human CYP450 enzymes: 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. while administration of drugs that are metabolized by inhibition or induction of the CYP450 system has no effect on the pharmacokinetics of entecavir. Also, concomitant administration of entecavir had no effect on the pharmacokinetics of known CYP substrates.
When the interactions of entecavir with lamivudine, adefovir and tenofovir were studied, no alteration in the steady-state pharmacokinetics of either entecavir or the drugs with which it interacted was found.
Because entecavir is primarily cleared by the kidney, administration of drugs that reduce renal function or compete for secretion via the active glomerulus may increase the blood levels of both drugs. Concomitant administration of entecavir with lamivudine, adefovir, and tenofovir does not cause significant drug interactions. The interaction of concomitant entecavir with other drugs that are cleared by the kidneys or are known to affect renal function has not been studied. Patients should be closely monitored for adverse reactions when taking entecavir concomitantly with such drugs.
Pediatric Patients
Drug interactions have been studied in adults only.
[Drug overdose].
There have been no reports of overdose with entecavir. No increase in the occurrence of adverse events has been observed after a single dose of up to 40 mg or multiple doses of 20 mg/day for 14 consecutive days in a healthy population. If an overdose occurs, patients must be monitored for indicators of toxicity and standard supportive therapy must be administered if necessary.
A single dose of 1 mg entecavir was followed by 4 hours of hemodialysis to clear approximately 13% of entecavir.
Pharmacology and Toxicology
Pharmacological effects
Microbiology
Mechanism of action
Entecavir is a guanine nucleoside analogue that inhibits the hepatitis B virus (HBV) polymorphic enzyme. It can become an active triphosphate by phosphorylation, and the half-life of triphosphate in cells is 15 hours. By competing with deoxyguanine triphosphate, the natural substrate of HBV polymutase, entecavir triphosphate inhibits all three activities of the viral polymutase (reverse transcriptase): (1) initiation of HBV polymutase; (2) formation of the negative strand of reverse transcription of pregenomic mRNA; and (3) synthesis of the positive strand of HBV DNA. Entecavir triphosphate is a weak inhibitor of cellular alpha, beta, and delta DNA multimerases and mitochondrial gamma DNA multimerase, with Ki values ranging from 18 to greater than 160 μM.
Antiviral activity
In human HepG2 cells transfected with wild-type hepatitis B virus, the concentration required to inhibit 50% of viral DNA synthesis (EC50) was 0.004 μM. The median EC50 value of entecavir against lamivudine-resistant virus strains (rtL180M, rtM204V) was 0.026 μM (range 0.01 to 0.059 μM).
In the in vitro HBV co-administration analysis, no antagonistic effect of abacavir, desoxymyel, lamivudine, stavudine, tenofovir or zidovudine on the anti-HBV activity of entecavir was found over a wide range of concentrations. In an in vitro HIV antiviral assay, entecavir remained unaffected by the anti-HIV effects of these six nucleoside reverse transcriptase inhibitors (NRTIs) or emtricitabine at micromolar concentrations.
Anti-HIV viral activity
A comprehensive analysis of the inhibitory activity of entecavir against a group of laboratory isolates as well as a clinically isolated strain of human immunodeficiency virus type I (HIV-I) yielded EC50 values ranging from 0.026 to >10 mM under different cellular and experimental conditions; lower EC50 values were observed when viral levels were reduced. In cell culture, entecavir at micromolar concentration levels selected out the M184I site displacement of HIV reverse transcriptase, and inhibition was confirmed at high entecavir concentration levels. HIV variants containing M184V site substitution lost sensitivity to entecavir.
Drug resistance
Cell culture
Lamivudine-resistant strains with rtM204I/V and rtL180M site substitutions in the reverse transcriptase region (LVDr) showed an 8-fold decrease in susceptibility to entecavir compared to HBV wild strains. Combination of additional entecavir-resistant amino acids rtT184, rtS202 and/or rtM250 locus alterations was also found in cell culture to have reduced sensitivity to entecavir. Clinical isolates combining additional (rtT184A,C,F,G,I,L,M or S; rtS202 C,G or I; and/or rtM 250I, L or V) locus substitutions showed a further 16- to 741-fold reduction in susceptibility to entecavir compared with wild strains. Viral strains with rtT184,rtS202 and rtM250 entecavir resistance site substitutions alone had only a modest effect on entecavir susceptibility, and no reduction in susceptibility was observed in more than 1000 patients without lamivudine resistance site substitutions. Resistance was found to be mediated in cell culture by altering HBV reverse transcriptase to reduce competitive binding, with resistant HBV strains having diminished replication capacity. Lamivudine-resistant strains containing rtL180M plus rtM204V combined with amino acid replacement rtA181C resulted in a 16- to 122-fold reduction in phenotypic susceptibility to entecavir.
Clinical studies
Resistance monitoring was performed in clinical studies in patients initially treated with entecavir 0.5 mg (nucleoside, primary treatment) or 1 mg (lamivudine failure) and who had on-treatment HBV DNA PCR test values at or after 24 weeks of treatment.
Nucleoside primed patients: The number of patients in the nucleoside primed patient study with up to 240 weeks of entecavir treatment found to have evidence of rtT184, rt202, and/or rtM250 entecavir resistance loci replacement genetic testing was three, two of which had viral breakthrough (see Table 15). Displacement of these loci was found to occur with entecavir resistance only on the basis of the presence of lamivudine resistance loci (rtM204V and rtL180M).
Table 15: Emergence of entecavir genotypic resistance in nucleoside primed patients treated for 5 years 1 year 2 years 3 yearsa 4 yearsa 5 yearsa Number of patients treated and monitored for resistanceb663278149121108 Number of patients with the following in a given year: Number of patients with emergence of entecavir genotypic resistancec1 1 100 Number of patients with virologic breakthroughsd due to entecavir resistancec 10100 Cumulative incidence: Cumulative incidence of emergence of entecavir genotype resistancec 0.2% 0.5% 1.2% 1.2% 1.2% Incidence of virologic breakthroughd due to entecavir resistancec 0.2% 0.2% 0.8% 0.8% 0.8%a Results reflect 147/149 patients in year 3 and all patients in years 4 and 5 in a continuation of therapy study Efficacy with 1 mg entecavir in 130/149 patients in year 3 and 1/121 patients in year 4 with the entecavir-lamivudine combination (after long-term entecavir treatment) for 20 weeks and 1 week, respectively.
b Includes patients who had at least one PCR HBV DNA test during treatment, which could be performed at 24 weeks or from 24 to 58 weeks (year 1), 58 to 102 weeks (year 2), 102 to 156 weeks (year 3), 156 to 204 weeks (year 4), or 204 to 252 weeks (year 5).
c Patients also had LVDr locus substitution.
d PCR assay for HBV DNA rise from nadir ³ 1 log10 , confirmed by serial assays or assay values obtained at the end of the time window. Patients who failed lamivudine treatment: 10 of 187 (5%) of baseline viral isolates from patients who failed lamivudine with entecavir treatment and were monitored for resistance were found to have pre-existing entecavir resistance site replacement, indicating that prior lamivudine treatment was able to select for these resistance sites and were present at low levels prior to entecavir treatment. At 240 weeks of treatment, viral breakthrough (≥1 log10 elevation over the lowest detection value) occurred in 3 of 10 patients. The occurrence of entecavir resistance in the study of patients who failed lamivudine at 240 weeks of treatment is summarized in Table 16.
Table 16: Emergence of entecavir genotype resistance in lamivudine treatment-naïve patients treated for 5 years 1 year 2 years 3 yearsa 4 yearsa 5 yearsa Number of patients treated and monitored for resistanceb187146805233 Patients with the following in a given year: Number of patients with entecavir genotype resistancec11121662 Patients with virologic breakthroughsd due to entecavir resistancec Number 2e14 e13 e9 e1 e Cumulative incidence: cumulative incidence of emergence of entecavir genotypic resistancec6.2%15%36.3%46.6%51.45% Incidence of virologic breakthrough d due to entecavir resistancec1.1% e10.7%e27%e41.3%e43.6%ea Results reflect a continuation of treatment study in 48/80 patients in year 3 and 10/80 patients in year 4. 13 weeks, 38 weeks and 16 weeks of entecavir-lamivudine combination (after long-term entecavir treatment) for 48/80 patients in year 3, 10/52 patients in year 4 and 1/33 patients in year 5, respectively.
b Includes patients who have had at least one PCR HBV DNA test during treatment, which may be performed at 24 weeks or at 24 to 58 weeks (year 1), 58 to 102 weeks (year 2), 102 to 156 weeks (year 3), 156 to 204 weeks (year 4), or 204 to 252 weeks (year 5).
c Patients also had LVDr locus substitution.
d PCR for HBV DNA rise from nadir ³ 1 log10 , confirmed by serial testing or assay values obtained at the end of the time window.
e ETVr was present in any year and virologic breakthrough was present in a given year. Among lamivudine-treated patients who failed at baseline HBV DNA <107 log10 copies/mL, 64% (9/14) patients achieved HBV DNA <300 copies/mL at week 48. the incidence of genotypic entecavir resistance was lower in these 14 patients compared to the overall study population (cumulative incidence of 18.8% at 5-year follow-up). Similarly, patients who achieved HBV DNA <104 log10 copies/mL (PCR assay) at week 24 with lamivudine treatment failure had a lower incidence of resistance compared to those who did not (17.6% [n=50] vs. 60.5% [n=135] cumulative incidence at 5 years).
Combined analysis of phase 2 and phase 3 clinical studies
In a pooled analysis of post-approval entecavir resistance data from 17 phase 2 and phase 3 clinical studies, the entecavir treatment-associated resistance site variant rtA181C was detected in 5 of 1461 subjects during entecavir treatment and only when the lamivudine resistance-associated site variant rtL180M plus rtM204V was present.
Cross-resistance
Cross-resistance has been found in nucleoside antihepatitis B virus drugs. In cellular assays, entecavir was found to inhibit HBV DNA synthesis 8 to 30-fold less than wild strains of hepatitis B virus containing the lamivudine and telbivudine resistance site variant (rtM204I/V±rtL180M). rtM204I/V±rtL180M, rtL80I/V, or rtV173L site substitution variants were associated with lamivudine and tebivudine resistance, also resulted in reduced phenotypic sensitivity to entecavir. In cell culture, entecavir was found to be 0.3- and 1.1-fold less susceptible to recombinant hepatitis B virus with rtN236T or rtA181V adefovir resistance site substitutions, respectively. The efficacy of entecavir in treating HBV with adefovir resistance site substitution has not been confirmed in clinical studies. Virus strains isolated from patients who failed both lamivudine and entecavir were found to be susceptible to adefovir in cell culture, but remained resistant to lamivudine.
Toxicological studies
Genotoxicity
In experiments with human lymphocytes in culture, entecavir was found to be an inducer of chromosome breakage. Entecavir was found not to be a mutation inducer in Ames assays (using S. typhi, Escherichia coli, with or without metabolic activators), gene mutation assays, and Syrian hamster embryo cell transfection assays. Entecavir was also negative in transoral administration micronucleus assays and DNA repair assays in rats.
Reproductive toxicity
In a reproductive toxicity study, entecavir was administered for 4 weeks at doses up to 30 mg/kg, and no effects on fertility were observed in male and female rats at doses exceeding 90 times the maximum recommended human dose of 1.0 mg/day. In toxicological studies with entecavir, degenerative changes of the vas deferens were found in rodents and dogs at doses up to 35 times or more the human dose. In monkey experiments, no testicular alterations were found.
In reproductive toxicity studies in rats and rabbits, no embryonic or maternal toxicity was found when oral entecavir was administered at doses up to 200 and 16 mg/kg/day, i.e., 28 times (for rats) and 212 times (for rabbits) the maximum human dose of 1.0 mg/day. In rat experiments, toxic effects of entecavir in embryo-fetal rats (resorption), reduced body weight, abnormal tail and spine morphology and reduced levels of ossification (vertebrae, toes and phalanges), and additional lumbar vertebrae and ribs were observed when female rats were dosed at doses equivalent to 3100 times the human dose. In rabbit experiments, toxic effects (resorption), reduced levels of ossification (hyoid bone), and an increased incidence of the 13th rib were observed in female rabbits dosed at 883 times the human dose of 1.0 mg/day. In a study of oral entecavir in pre- and postnatal rats, no effect on offspring was found at doses greater than 94 times the human dose of 1.0 mg/day.
Entecavir is secreted from rat milk.
Carcinogenicity
In long-term carcinogenicity studies of oral entecavir in mice and rats, drug exposure was approximately 42 times (rats) and 35 times (mice) the maximum recommended human dose (1.0 mg/day), respectively. In the above-mentioned studies, positive results for entecavir carcinogenicity were observed.
In mouse tests, the incidence of lung adenomas increased in male and female mice at doses up to 3 to 40 times the human dose. The incidence of lung tumors increased in male and female mice at doses up to 40 times the human dose. The incidence of lung adenomas and tumors increased in male mice at doses up to 3 times the human dose, and in male mice at doses up to 40 times the human dose. Lung cell hyperplasia followed by lung tumors was observed in mice, but no lung cell hyperplasia was observed in rats, dogs and monkeys given entecavir, suggesting that lung tumors in mice may be species-specific. The incidence of hepatocellular tumors with mixed tumors (tumors and adenomas) was increased in male mice at doses up to 42 times the human dose. The incidence of vascular tumors (including angiosarcoma of the ovary, uterus and spleen) was increased in female mice at doses up to 40 times the human dose. In rats, the incidence of hepatocellular adenomas was increased in female rats at doses up to 24 times the human dose, as was the incidence of mixed tumors (tumors and adenomas). Gliomas were found in male and female rats at doses up to 35 and 24 times the human dose, respectively. Dermal fibromas were found in female rats at doses up to 4 times the human dose.
It is not clear whether the results of the rodent carcinogenicity test of entecavir can predict the carcinogenic effect of entecavir in humans.
Pharmacokinetics
Absorption
After oral administration to healthy subjects, entecavir is rapidly absorbed and reaches peak concentration (Cmax) in 0.5 to 1.5 hours. Steady state is achieved after 6 to 10 days of once-daily dosing, and the cumulative amount is approximately twice as high.
Effect of food on oral absorption
Oral administration of 0.5 mg entecavir with a standard high-fat or low-fat meal results in a slight delay in drug absorption (1.0 to 1.5 hours instead of 0.75 hours), a 44% to 46% decrease in Cmax, and an 18% to 20% decrease in the area under the drug-time curve (AUC). Therefore, entecavir should be taken on an empty stomach (at least 2 hours before or after a meal).
Distribution
Pharmacokinetic data indicate that the apparent volume of distribution exceeds the volume of systemic fluid, suggesting that entecavir is widely distributed throughout the tissues.
In vitro studies have shown that entecavir is 13% bound to human plasma proteins.
Metabolism and clearance
No oxidized or acetylated metabolites of entecavir were observed following administration of 14C-labeled entecavir to humans and rats, but small amounts of the phase II metabolites glucuronide conjugates and sulfate conjugates were observed. Entecavir is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system.
After peak plasma concentrations are reached, blood concentrations decline in a biexponential manner, taking approximately 128 to 149 hours to reach terminal clearance half-life. The drug accumulation index is approximately two times the once-daily dose, which suggests an effective cumulative half-life of approximately 24 hours.
Entecavir is primarily cleared by the kidneys in its native form, with a clearance of 62% to 73% of the administered dose. Renal clearance ranged from 360 to 471 mL/min and was not dependent on the dose administered, suggesting that entecavir is cleared by both glomerular filtration and net tubular secretion.
Special Populations
Gender
The pharmacokinetics of entecavir do not vary by gender.
Ethnicity
There were no significant racial differences in the pharmacokinetic profile of entecavir. A single-arm, open trial evaluated the safety and efficacy of entecavir 0.5 mg once daily in HBeAg-positive or negative, nucleoside primed, black/African American (n=40) and Hispanic (n=6) subjects infected with chronic HBV. In this trial, 76% of subjects were male, mean age was 42 years, 57% were HBeAg-positive, mean baseline HBV DNA was 7.0 log10 IU/mL, and mean baseline ALT was 162 U/L. At week 48 of treatment, 32 of 46 subjects (70%) had HBV DNA <50 IU/mL (approximately 300 copies/mL). ALT normalization (≤1 × ULN) occurred in 31 of 46 subjects (67%), and HBeAg serologic conversion occurred in 12 of 26 HBeAg-positive subjects (46%). The safety data were similar to those observed in larger controlled clinical trials.
Older adults
A study evaluating the relationship between age and entecavir pharmacokinetics (oral entecavir 1 mg) showed an elevated AUC of 29.3% in older adults compared to healthy younger adults, most likely due to individual differences in renal function. For dosing in the elderly, see Dose Modification in Patients with Renal Insufficiency.
Renal insufficiency
In patients with varying degrees of renal insufficiency (without chronic hepatitis B virus infection), including those treated with hemodialysis or CAPD, pharmacokinetic results following a single dose of 1 mg entecavir showed a decrease in clearance with a decrease in creatinine clearance. A single dose of 1 mg entecavir administered 2 hours prior to hemodialysis cleared approximately 13% of the administered dose at 4 hours of hemodialysis and only approximately 0.3% of the administered dose at 7 days of CAPD treatment. Entecavir should be administered after hemodialysis.
Hepatic insufficiency
The pharmacokinetics of entecavir after a single dose of 1 mg was studied in patients with moderate and severe hepatic insufficiency (Child-Pugh classification B or C) (excluding patients with chronic hepatitis B virus infection), and the pharmacokinetics of entecavir in patients with hepatic insufficiency were similar to those of healthy control patients. Therefore, there is no need to adjust the dose of entecavir administered in patients with hepatic insufficiency.
After liver transplantation
The safety and efficacy of entecavir in liver transplant patients is not known. In a small study of HBV-infected liver transplant patients treated with stable doses of cyclosporine A (n=5) or tacrolimus (n=4), the total amount of entecavir in the body was approximately twice that of healthy individuals with normal renal function due to altered renal function. The altered renal function is responsible for the increased concentration of entecavir in these patients. The pharmacokinetic interactions between entecavir and cyclosporine A or tacrolimus have not been formally evaluated.
In liver transplant recipient patients who have been or are being treated with immunosuppressive agents that may affect renal function, e.g., cyclosporine A or tacrolimus, renal function should be closely monitored prior to and during treatment with entecavir (see Dosage Adjustment for Patients with Renal Insufficiency under [DOSAGE AND ADMINISTRATION]).
Pediatric Dosing
Pediatric Population: Entecavir steady-state pharmacokinetics were evaluated in 24 nucleoside primed, 19 HBeAg-positive, 2 to <18-year-old, compensated liver disease subjects on prior lamivudine therapy (study AI463028). Nucleoside primed subjects received oral entecavir 0.015 mg/kg to a maximum dose of 0.5 mg once daily, and entecavir exposure was similar to that achieved in adults with oral dosing of 0.5 mg once daily. The Cmax, AUC (0-24) and Cmin of these subjects were 6.31 ng/ml, 18.33 ng h/ml and 0.28 ng/ml, respectively. exposure to entecavir 0.030 mg/kg up to a maximum dose of 1.0 mg once daily in previously lamivudine-treated subjects was similar to the exposure achieved in adults with 1.0 mg once daily. similar to that achieved in adults with 1.0 mg once daily. The Cmax, AUC (0-24) and Cmin of these subjects were 14.48 ng/ml, 38.58 ng∙h/ml and 0.47 ng/ml, respectively.
Storage】Sealed and stored in a dry place below 25°C. It can be exposed to 15-30°C for a short time.
Package】High density polyethylene bottle for oral solid medicine: 30 tablets per bottle.
Expiration date】36 months
【Execution standard
Approval number】
【Drug marketing license holder
Company Name: Zhejiang Huahai Pharmaceutical Co.
Production Address: Flood Bridge, Linhai City, Zhejiang Province
Postal code: 317024
Telephone number: 0576-85010288
Fax number: 0576-85016013
Manufacturer
Company name: Zhejiang Huahai Pharmaceutical Co.
Production Address: Flood Bridge, Linhai City, Zhejiang Province
Postal Code: 317024
Telephone number: 0576-85010288
Fax number: 0576-85016013
Web address: www.huahaipharm.com