ENTEKOR 0.5 MG
WARNING: SEVERE ACUTE EXAGERBATIONS OF HEPATITIS B.PATIENT CO-INFECTED WITH HIV AND HBV and LACTIC ACIDOSIS AND HEPATOMEGALY.
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued Anti-hepatitis B therapy, including entecavir.Hepatic function should be monitored closely with both Clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate Initiation of anti-hepatitis B therapy may be warranted [see WARNINGS AND PRECAUTIONS]
Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus.) nucleoside reverse transcriptase inhibitors if ENTEKOR is used to treat chronic hepatitis B virus (HBV) infection in patients with HIV infection that is not being treated. Therapy with ENTEKOR is not recommended for HIV/HBV co-infected patients who are not also Receiving highly active antiretroviral therapy (HEART) [see WARNING AND PRECAUTIONS].Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretroviral [see WARNING AND PRECAUTIONS].
Each film-coated tablet contains.
Colour: Titanium Dioxide IP & Red Oxide of Iron
Oral film-coated tablet
Entecavir is an antiviral drug. Entecavir a guanosine nucleoside analog with activity against HBV reverse transriptase (rt).is efficiently phosphorylated to the active triphosphate form which has an intracellular half-life functionally inhibits all three activities of the HBV reserve transcriptase:
(1) Base priming. (2) Reverse transcnption of the negative stand from the pregenomic messenger RNA and (3) synthesis of the positive stand of HBV DNA Entecavir in phosphate is a weak inhibitor Of cellular DNA polymerases α β and δ and mitochondrial DNA polymerase gamma with K, values Raining from 18 to<160 Tm. Antiviral Activity. Entecavir inhibited HBV DNA synthesis (50% Reduction, EC) at a concentration of 0.004 ΓM in human HepG2 cells transfected with wild-type HBV.The median EC value for Entecavir against Lamivudine-resistant HBV (rtl 180M,Tm204v) Was 0.026 ΓM.(range 0.010 to 0.059 ΓM) The co-administration of HIV nucleoside/ nucleotide Reverse transcriptase inhibitors (NRTIs) wlth entecavir is unlikely to reduce the antiviral efficacy of Entecavir against HBV or of any of these agents against HIV, in HBV combination assays in cell culture, Abacavir, Didanosine, Lamivudine, Stavudine, Tenfovir or Zidovudine were not antagonistic to the cell culture anti-HIV activity of these six NRTIs or emtricitabine at concentrations greater than 100 time C max of Entecavir using 1 mg dose.
Antiviral Activity against HIV
Analysis of the inhibitory activity of Entecavir 0.5mg against a panel of laboratory and clinical HIV type 1(HIV-1) isolates using a variety of cells and assay conditions yielded EC50 values ranging from 0.026 to >10 ΓM; the lower EC50 values were observed when decreased levels of virus were Used in the assay. in cell culture, Entecavir selected for an M1841 substitution in HIV variants Containing the M184V substitution showed loss of susceptibility to entecavir.
The single- and multiple-dose pharmacokinetics of Entecavir were evaluated in healthy subjects And subjects with chronic HBV infection. Absorption. Following oral administration in healthy Subjects, Entecavir peak plasma concentration occurred between 0.5 and 1.5 hours. Following Multiple daily doses ranging from 0.1to 1.0 mg. CMAX and area under the concentration-time curve (AUC) at steady state increased in proportion to dose. Steady state was achieved after 6 to 10 days of once-daily administration with approximately 2-fold accumulation. for a 0.5 mg oral Dose, CMAX at steady state was 4.2ng/ML.and trough plasma concentration (C1rough) was 0.3 ng/ML.for a 1mg oral dose. CMAX at steady state was 4.2ng/ML and trough plasma concentration( CMAX ) was 0.3 ng/ml for a 1 mg oral dose CMAX was 8.2ng/ml and C1rough was 0.5ng.ml. Effects of Food on Oral Absorption: Oral administration of 0.5 mg of Entecavir with a Standard high-fat meal (945 kcal,54.6 g fat)or a light meal(379 kcal.8.2 g fat) resulted in a delay In absorption (1.0-1.5 hours fed versus 0.75 hours fasted).a decrease in AUC of 18-20%[see DOSAGE ANDADMINISTRATION].
Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that entecavir is extensively Distributed into tissues. Binding of entecavir to human serum proteins in vitro was approximate 13%.
Metabolism and Elimination:
Following administration of 14C-entecavir in humans and rats, no oxidative of acetylated metabolism were observed. Minor amounts of phase II metabolites (glucuronide and sulfate Conjugates) were observed entecavir is not a substrate, inhibitor, or include the cytochrome P450 (CYP450) enzyme system [see Drug Interactions].
After reaching peak concentration entecavir plasma concentrations decreased in a biexponential manner with a terminal elimination half-life of approximately 128-149 hours. The observed drug accumulation index is approximately 2-fold with once-daily dosing. Suggesting an Effective accumulation half-life of approximately 24 hours.
Entecavir is predominantly eliminated by the kidney, with a unary recovery of the unchanged drug at steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent of dose and ranges from 360 to 471 ml/min, suggesting that entecavir undergoes both glomerular filtration and net tubular secretion [see Drug Interactions.]
Gender: there are no significant gender differences in entecavir pharmacokinetic.
Race: There no significant racial differences in entecavir pharmacokinetic.
Elderly: the effect of age on the pharmacokinetics of entecavir was evaluated following administration of a single 1 mg oral dose in healthy young and elderly volunteers. Entecavir AUC was 29.3% greater in elderly subjects compared to young subjects. The disparity in exposure between elderly and young subjects was most likely attributable to differences in renal function. Dosage adjustment of ENTEKOR Tablets should be based on the renal function of the patient, rather than age [see DOSAGE AND ADMINISTRATION].
Pediatrics: pharmacokinetic studies have not been conducted in children.
Renal impairment: the pharmacokinetics of entecavir following a single 1mg dose were studied in subjects (without chronic HBV infection) with selected degrees of renal impairment. Including subjects whose renal impairment was managed by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).Results are shown in Table 1 [see DOSAGE AND ADMINISTRATION].
Table 1: Pharmacokinetic Parameters in Subjects with Selected Degrees of Renal function
Renal Function Group
Baseline Creatinine Clearance (ml/min)
Unimpaired Mild Moderate Severe Severe Severe
>80 >50 to 30 to 50 <30 managed Managed
n=6 <-80 n=6 n=6 with with n=6 hemodialysis CAPD n=6 n=4
Cmax (ng/ml) 8.1 10.4 10.5 15.3 15.4 16.6
(CV%) (30.7) (37.2) (22.7) (33.8) (56.4) (29.7)
AUC(0-T) 27.09 51.5 69.5 145.7 233.9 221.8
(ng*/ml) (25.6) (22.8) (22.7) (31.5) (28.4) (11.6)
CLR 383.2 197.9 135.6 40.03 NA NA
(ML/MIN) (101.8) (78.01) (31.6) (10.1)
CLT/F 588.1 309.2 226.3 100.6 50.6 35.7
(ML//MIN)(SD) (153.7) (62.6) (60.1) (29.01) (16.5) ( 19.6)
*Dosed immediately following hemodialysis.
CLR = Renal clearance: CLT/F= Apparent oral clearance.
Following a single 1 mg dose of entecavir administered 2 hours before the hemodialysis session. Hemodialysis. removed approximate 13% of the entecavir dose over 4 hours. CAPD removed approximately 0.3% of the dose over 7 days (see DOSAGE AND ADMINISTRATION). Hepatic impairment. The pharmacokinetics of entecavir following single 1 mg dose was studied in subjects (without chronic HBV infection).with moderate so severe hepatic impairment (child-pugh class B or C).The pharmacokinetics of entecavir was similar between hepatically impairment and healthy control subjects: therefore. No dosage adjustment of ENTEKOR Tablets is recommended for patients with hepatic impairment. Post-liver Transplant: the safety and efficacy of ENTEKOR tablets in liver transplant recipients are unknown, however, in a small pilot study of entecavir use in HBV-infected liver transplant recipients on a stable dose of cyclosporine A (n=5) or tacrolimus (n=4) Entecavir exposure was approximately 2 fold the exposure in healthy subjects. The potential for pharmacokinetic interactions between entecavir and cyclosporine A or tacrolimus was not formally evaluated.
ENTEKOR Tablets (entecavir) are indicated for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent efevations in serum aminotransferance (ALT or AST) or histologically active disease.
The following points should be considered when initiating therapy with entecavir.
*the indication is based on histologic, virologic biochemical. And serologic responses in nucleoside-treatment-naïve and lamivudine-resistant adult subjects with HBeAg-positive or MBeAg-negative chronic HBV infection and decompensated liver disease (see UNDESSIRABLE EFFECTS).*Virologic.biochemical.serologic and safety data are available for a limited number of adult subjects with HIV/HBV co-infection who have received prior lamivudine therapy (see WARNING AND PRECAUTIONS)
DOSAGE AND ADMINISTRATION:
ENTEKOR Tablets should be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal.
Compensated Liver Disease: The Recommended dose entecavir for chronic hepatitis B virus infection in nucleoside treatment-naïve adult and adolescents 16 years of age and older is 0.5 gm once daily.
Decompensated liver Disease: The Recommended dose of entecavir for chronic hepatitis B virus infection in an adult with a decompensated liver disease is 1 mg once daily.
Duration of therapy:
The optimal duration of treatment with entecavir for patients with chronic hepatitis B virus infection and the relationship between treatment and long-term outcomes such as chronic and hepatocellular carcinoma are unknown.
In subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased. Dosage adjustment is recommended for patients with creatinine clearance less than 50ml/min. including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) as shown in table 2the once-daily dosing regimens are preferred.
Severe acute exacerbations of Hepatitis B: Severe acute exacerbations of Hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy. Including Entecavir hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
Patients co-infected with HIV and HBV: Entecavir has not been evaluated in HIV/HBV co-infected patients who were not simultaneously. Receiving effective HIV treatment. Limited clinical experience suggests there is a potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors if entecavir is used to treat chronic HBV infection in patients with HIV infection that not being treated. Therefore therapy with entecavir is not recommended antibody testing should be offered to all patients. entecavir has not been studied as a treatment for HIV infection and is not recommended for this use.
Lactic acidosis and severe nucleoside with steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of this case has been in a woman. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analog to any patient with known risk factors for liver disease, however, cases have also been reported in patients with no known risk factors. Treatment with Entecavir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.
Renal impairment: Dosage adjustment of entecavir is recommended for patients with creatinine clearance less than 50ml/min. including patients on hepatomegaly or CAPD [see DOSAGE AND ADMINSTRATION].
Liver transplant reciplents: The safety and efficacy of entecavir in liver transplant reciplents are unknown. If entecavir treatment is determined to be necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosponne or tacrolimus, renal function must be carefully monitored both before and during treatment with entecavir [see DOSAGE AND ADMINISTRATIONS]
Entecavir is not a substrate inhibitor or inducer of the CYP450 enzyme system. The pharmacokinetics of entecavir is unlikely to be affected by co-administration with an agent that is either metabolized by, inhibit. Or induce the CYP450 system. Likewise, the pharmacokinetics of known CYP substrates is unlikely to be affected by co-administration of entecavir. Since entecavir is primarily eliminated by the kidneys, co-administration of entecavir with a drug that reduces renal function or competes for active tubular secretion may increase the serum concentration of either entecavir or the co-administrated drug. Co-administration of entecavir with lamivudine adefovir dipivoxil or tenofovir disoproxil fumarate did not result in signification drug interactions. The effects of co-administration of ENTEKOR Tablets with other drugs that are really eliminated or are known to affect renal function have not been evaluated. And patients should be monitored closely for an adverse event when ENTEKOR Tablets is co-administered with such drug.
This is a limited experience of Entecavir overdosage reported in patients. Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20mg/day for up 14 days had no increase in or unexpected adverse events. If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Following a single 1 mg dose of Entecavir, a 4-hour hemodialysis session removed approximate 13% of the entecavir dose.
STORAGE AND HANDLING INSTRUCTION: Store below 30*C protect from light & moisture
ENTEKOR 0.5 mg Tablets Blister of 10 Tablets