Date of approval.
Date of revision.
Entecavir Dispersible Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
Warnings
Severe acute worsening 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 hepatitis B antiviral therapy 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 when treated with entecavir 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 Dispersible Tablets
English name: Entecavir Dispersible Tablets
Hanyu Pinyin: Entikawei Fensanpian
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
This product is white or off-white tablet.
Indications】
It is indicated for the treatment of chronic adult hepatitis B with active viral replication, persistent elevation of serum alanine aminotransferase (ALT) or histological indication of active liver lesions.
It is also indicated for the treatment of pediatric patients aged 2 to <18 years with nucleoside priming for chronic HBV infection in compensated liver disease with evidence of active viral replication and persistently elevated serum ALT levels or histologic evidence of moderate to severe inflammation and/or fibrosis. For its specific use, see [Dosage].
Specification
0.5mg
Dosage]
Patients should take this product under the supervision of an experienced physician.
This product should be taken on an empty stomach (at least 2 hours before or after a meal).
Recommended Dosage.
Adults
Take 0.5mg (one capsule) orally once daily. 1 mg (two capsules) once daily for patients who develop viremia or lamivudine resistance mutations while on lamivudine therapy.
Children
Treatment decisions for pediatric patients should carefully consider the needs of the individual patient 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.
In pediatric patients with HBeAg-positive chronic hepatitis B compensated liver disease, serum ALT elevation should persist for at least 6 months prior to treatment; in HBeAg-negative pediatric patients, at least 12 months.
The daily dose for patients weighing 32.6 kg or more should be 0.5 mg of this product administered with or without food. Patients weighing less than 32.6 kg should use an oral solution.
Duration of treatment in pediatric patients
The optimal duration of therapy 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 absence of efficacy. Serum ALT and HBV DNA levels should be followed regularly after discontinuation of therapy (see [Warnings] and [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 primary treatment patients with lamivudine treatment failure ≥ 50 0.5 mg once daily 1 mg once daily 30 – 49 0.25 mg once daily
or
0.5 mg once every 48 hours 0.5 mg once daily 10 – 29 0.15 m once daily, g once daily
or
0.5 mg once every 72 hours 0.3 mg once daily
or
0.5 mg once every 48 hours< 10
Hemodialysis or CAPD** 0.05 mg once daily
or
0.5 mg once every 5-7 days 0.1 mg once daily
OR
0.5 mg once 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 for this product and its relationship to long-term treatment outcomes, such as cirrhosis and hepatocellular carcinoma, are not known.
[Adverse reactions].
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.
Adult patients
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. In studies controlled with lamivudine, the adverse events and abnormal laboratory tests were similar for entecavir and 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 the four studies, 1% of entecavir-treated patients and 4% of lamivudine-treated patients withdrew from the studies due to adverse events and abnormal laboratory test indices.
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 Patients on initial treatment with nucleoside analogsb Patients with treatment failure with lamivudinec Entecavir lamivudine Entecavir lamivudine 0.5 mg 100 mg 1 mg 100 mg n=679 n=668 n=183 n=190 Any grade 2 to 4
Adverse eventsa 15% 18% 22% 23% Gastrointestinal Diarrhea<1%01%0 Dyspepsia<1%<1%1%0 Nausea<1%<1%<1%2% Vomiting<1%<1%<1%<1%0 General Fatigue1%1% 3% 3% Neurological Headache2% 2% 4% 1% Dizziness<1%< ;1%0 1% Drowsiness<1%<1%0 0 Psychiatric Insomnia<1%<1%0 <1%a
Includes adverse events that are likely, probable, related, or unclear whether they are related to treatment. b AI463022 and AI463027 studies. c
Includes AI463026 and AI463014, 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 once daily of lamivudine for 52 weeks.
Abnormal laboratory tests in foreign clinical trials
Table 3 compares the frequency of abnormal laboratory tests following 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 who tested nucleoside analogs for initial treatmentb Patients who failed lamivudine treatmentc Entecavir lamivudine Entecavir lamivudine 0.5 mg 100 mg 1.0 mg 100 mg n=679 n=668 n=183 n=190 Abnormalities of laboratory tests of any grade 3 to 4d35% 36% 37% 45% ALT >10x ULN and>2x baseline value 2% 4% 2% 11% ALT >5.0x ULN11% 16% 12% 24% AST>5.0x ULN5% 8% 5% 17% Albumin<2.5g/dl<1% <1% 0 2% Total bilirubin>2.5x ULN2% 2% 3% 2% Amylase³2.1x ULN2% 2% 3% 3% Lipase³2.1x ULN7% 6% 7% 7% Creatinine>3.0x ULN0 0 0 0 0 0 Confirmation 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, all indicators except albumin(<2.5g/dl), creatinine increase ≥0.5mg/dl, ALT>10x ULN and>2x baseline levels deteriorated from baseline values to grade 3 or 4 Grade b AI463022 and AI463027 Study C includes AI463026 and AI463014, a multi-country, randomized, double-blind phase II study in patients with recurrent viremia on lamivudine treatment who were either switched to once-daily dosing of three different doses of entecavir (0.1,0.5 and 1.0 mg) once daily, or continue 100 mg of lamivudine once daily for 52 weeksd
Includes routine blood, routine biochemistry, renal and liver function tests, pancreatic enzymes, and urinary routinee Grade 3=3+ substantial, ³500 mg/dL; Grade 4=4+, significant, severef Grade 3=3+ substantial; Grade 4=³4+, significant, severe, multiple
ULN:high limit of normal 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 medication for a period of time and the ALT returned to normal; this was preceded or accompanied by a decrease in 2 log values of viral load. Therefore, liver function needs to be tested regularly during the drug administration.
Exacerbation of hepatitis after discontinuation of treatment (see [WARNING])
Acute exacerbation of hepatitis symptoms or ALT reignition 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%) 0/16 a The reference value is the smallest of the last test values at baseline or at discontinuation. The median time to worsening after discontinuation was 23 weeks for entecavir-treated patients and 10 weeks for lamivudine-treated patients.
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 [cautionary note]).
Liver transplant recipient patients
In an open post-liver transplant trial, 65 subjects received entecavir treatment in which the frequency and nature of adverse events were consistent with the expected response and the known safety profile of entecavir in patients receiving liver transplantation.
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
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. This product 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
Patients with creatinine clearance <50mL/min, including those 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
A lower rate of virologic response (HBV DNA < 50 IU/ml) was observed in pediatric patients with baseline HBV DNA ≥ 8.0 log10 IU/ml. Entecavir was applied in these patients only when the potential benefit outweighed 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 under the supervision of their physician and inform him or her of any new symptoms and co-medications. 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
(see [warning statement]).
Treatment with entecavir does not reduce the risk of HBV transmission through sexual contact or contaminated blood sources. Therefore, appropriate precautions need to be taken.
Do not use if the inner package is opened or damaged.
Pregnant and lactating women]
The effects of entecavir on pregnant women have not been adequately studied. This product 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 the milk of rats. However, it remains unclear whether it is secreted in human milk, so breastfeeding is not recommended for mothers taking this product.
[Pediatric Use].
Clinical data for pediatric patients aged 2 years to <18 years were obtained from foreign clinical trials of entecavir.
[Geriatric Use].
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.
[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
This product is a guanine nucleoside analogue with inhibitory effect on 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 (EC50) required for entecavir to inhibit 50% of viral DNA synthesis was 0.004 μM. The median EC50 value for 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 1 (HIV-1) 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 other entecavir-resistant amino acids rtT184, rtS202 and/or rtM250 locus alterations in cell culture also revealed reduced susceptibility 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) site substitutions showed a further 16- to 741-fold reduction in susceptibility to entecavir compared with wild virus 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. Drug resistance was found to be mediated in cell culture by altering HBV reverse transcriptase to reduce competitive binding, and drug-resistant HBV strains had reduced replication capacity.
Clinical studies
Resistance was monitored in clinical studies in patients initially treated with entecavir 0.5 mg (nucleoside priming) 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 evidence of rtT184, rt202 and/or rtM250 entecavir resistance loci replacement genetic testing was three for up to 240 weeks of treatment with entecavir, two of which had viral breakthrough (see Table 5). 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 5: 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 resistanceb663 278 149 121 108 Number of patients with the following in a given year: Number of patients with entecavir genotypic resistancec1 1 1 0 0 Number of patients with virologic breakthroughsd due to entecavir resistancec1 0 1 0 0 Cumulative incidence: cumulative incidence of emergence of entecavir genotypic 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 of a continuation of therapy study with 1 mg entecavir, with 130/149 patients in year 3 and 1/121 patients in year 4 using 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 the table below.
Table 6: Emergence of entecavir genotypic 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 resistanceb187 146 80 52 33 Number of patients with the following in a given year: Number of patients with entecavir genotypic resistancec11 12 16 6 2 Number of patients with virologic breakthroughd due to entecavir resistancec 2e14 e13 e9 e1 e Cumulative incidence: cumulative incidence of emergence of entecavir genotype 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 48/80 patients in year 3 and 10/52 patients in year 4 of a continuation of therapy study patients, 10/52 patients in year 4 and 1/33 patients in year 5 on the entecavir-lamivudine combination (after long-term entecavir treatment) for 13, 38 and 16 weeks, respectively.
b Includes patients who have had at least one PCR HBV DNA test during treatment, which can 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 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 (18.8% cumulative incidence at 5-year follow-up). Similarly, lamivudine-treated patients who achieved HBV DNA <104 log10 copies/ml (PCR assay) at week 24 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)
Cross-resistance
Cross-resistance has been identified 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 lamivudine and telbivudine resistance site variants (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 observed at oral doses of 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 this product, suggesting that the lung tumors in mice may be species-specific. The incidence of hepatocellular tumors and mixed tumors (tumors and adenomas) 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 and mixed tumors (tumors and adenomas) increased in female rats at doses up to 24 times the human dose. 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 can predict the carcinogenic effect of this product in humans.
Pharmacokinetics
Absorption
After oral administration to healthy subjects, the product is rapidly absorbed and the peak concentration (Cmax) is reached in 0.5 to 1.5 hours. It is administered once a day and reaches steady state after 6 to 10 days, and the cumulative amount is about twice as much.
Effect of food on oral absorption
Oral administration of 0.5 mg of this product with a standard high-fat meal or a low-fat meal results in a slight delay in drug absorption (1.0 to 1.5 hours instead of 0.75 hours), a 44-46% decrease in Cmax, and an 18-20% decrease in the area under the drug-time curve (AUC). Therefore, this product 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 the product is widely distributed throughout the tissues.
In vitro studies have shown a 13% binding rate 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 indicates an effective cumulative half-life of approximately 24 hours.
The product is primarily cleared by the kidneys in its original form, with a clearance of 62-73% of the administered dose. Renal clearance is 360 to 471 mL/min and is not dependent on the administered dose, suggesting that entecavir is simultaneously secreted via glomerular filtration and reticulocytes.
Special Populations
Gender: The pharmacokinetics of this product do not vary by gender.
Ethnicity: The pharmacokinetics of this product do not vary by ethnicity.
Elderly: A study evaluating the relationship between age and the pharmacokinetics of this product (1 mg orally) showed a 29.3% increase in AUC in the elderly compared to healthy young adults, most likely due to individual differences in renal function. The dose of this drug in the elderly should be regulated with reference to the dose in 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 of this product showed a decrease in clearance with a decrease in creatinine clearance. A single dose of 1 mg of this product administered 2 hours prior to hemodialysis cleared approximately 13% of the administered dose over 4 hours of hemodialysis and only 0.3% of the administered dose over 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 this product 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 this product in the body was approximately twice that of a healthy individual with normal renal function due to altered renal function. Altered renal function is responsible for the increased concentration of this product in these patients. The pharmacokinetic interactions between this product 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 Use: No pharmacokinetic data are available on the use of this drug in children.
Storage
Seal and store in a dry place below 25°C. Short-term exposure to 25-30°C is possible.
Package
Aluminum-plastic packaging. (1) 7 tablets/plate×1 plate/box; (2) 10 tablets/plate×1 plate/box; (3) 7 tablets/plate×2 plate/box; (4) 7 tablets/plate×4 plate/box.
Expiration date】 12 months
Execution standard
Approval number】
State Drug Certificate H20100141
【Manufacturing enterprise】 【Approval number】 State Drug Administration H20100141
Enterprise Name.
Jiangxi Qingfeng Pharmaceutical Co.
Production Address.
Shahe Industrial Park, Ganzhou City, Jiangxi Province
Postal Code: 341000
Telephone number: 400-882-6066 (sales)
0797-7020096（Quality)
Fax number: 0797-7020593