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Entecavir

(en te' ka veer)

Molecule Info

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WARNING

SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS 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.

Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if Entecavir is used to treat chronic hepatitis B virus (HBV) infection in patients with HIV infection that is not being treated. Therapy with Entecavir is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART).

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals.

Content & Description

Entecavir (Monohydrate) 0.5 & 1mg.

Tablets may also contain: Lactose monohydrate, microcrystalline cellulose, crospovidone, povidone and magnesium stearate. The tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400, polysorbate 80 (0.5-mg tablet only) and iron oxide red (1-mg tablet only).
Entecavir is a guanosine nucleoside analogue with selective activity against hepatitis B virus (HBV). Entecavir is 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate. Its molecular formula is C12H15N5O3·H2O, which corresponds to a molecular weight of 295.3.
Entecavir is a white to off-white powder. It is slightly soluble in water (2.4 mg/mL), and the pH of the saturated solution in water is 7.9 at 25°±0.5°C.

Indication(s) Treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
This indication is based on histologic, virologic, biochemical, and serologic responses after 1 year of treatment in nucleoside-treatment-naive and lamivudine-resistant adult patients with HBeAg-positive or HBeAg-negative chronic HBV infection with compensated liver disease and on more limited data in adult patients with HIV/HBV co-infection who have received prior lamivudine therapy.
Dosage & Administration

Recommended Dosage: Adults and Adolescents ≥16 years: Chronic Hepatitis B Virus Infection in Nucleoside - Treatment-Naive: 0.5 mg once daily.
Adults and Adolescents ≥16 years with a History of Hepatitis B Viremia While Receiving Lamivudine or Known Lamivudine Resistance Mutations: 1 mg once daily.
Entecavir 0.5 mg can take with meal. Entecavir 1 mg should be administered on an empty stomach (at least 2 hrs after a meal or 2 hrs before the next meal or morning or bedtime).
Patients with renal impairment: In patients with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased. Dosage adjustment is recommended for patients with creatinine clearance <50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).
Nucleoside treatment-naive
CrCl 30 to less than 50 mL/min: 0.25 mg orally once a day or 0.5 mg orally every 48 hours
CrCl 10 to less than 30 mL/min: 0.15 mg orally once a day or 0.5 mg orally every 72 hours
CrCl less than 10 mL/min: 0.05 mg orally once a day or 0.5 mg orally every 7 days

Lamivudine-refractory, known lamivudine or telbivudine resistance mutations, or decompensated liver disease
CrCl 30 to less than 50 mL/min: 0.5 mg orally once a day or 1 mg orally every 48 hours
CrCl 10 to less than 30 mL/min: 0.3 mg orally once a day or 1 mg orally every 72 hours
CrCl less than 10 mL/min: 0.1 mg orally once a day or 1 mg orally every 7 days

The once-daily dosing regimen is preferred.
Hepatic impairment: No dose adjustment to patients with hepatic impairment.

Duration of Therapy: The optimal duration of treatment with Entecavir for patients with chronic hepatitis B infection and the relationship between treatment and long-term outcomes eg, cirrhosis and hepatocellular carcinoma are unknown.

Administration:

0.5-mg tab: Should be taken with food. 1-mg tab: Should be taken on an empty stomach.: Take on an empty stomach at least 2 hr after a meal & 2 hr before the next meal.

Overdose There is no experience of entecavir overdosage reported in patients. Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase in or unexpected adverse events. If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Following a single 1-mg dose of entecavir, a 4-hr hemodialysis session removed approximately 13% of the entecavir dose.
Contraindications Patients with known hypersensitivity to entecavir or any component of the medication.
Warning Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals.
Exacerbations of Hepatitis B After Discontinuation of Treatment: 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 Exacerbations of Hepatitis After Discontinuation of Treatment under Adverse Reactions).
Special Precautions

General: Renal Impairment: Dosage adjustment of Entecavir is recommended for patients with a creatinine clearance <50 mL/min, including patients on hemodialysis or CAPD (see Renal Impairment under Dosage & Administration).
Liver Transplant Recipients: The safety and efficacy of Entecavir in liver transplant recipients 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 eg, cyclosporine or tacrolimus, renal function must be carefully monitored both before and during treatment with entecavir.
Information for Patients: Patients should remain under the care of a physician while taking Entecavir. They should discuss any new symptoms or concurrent medications with their physician.
Patients should be advised to take entecavir on an empty stomach (at least 2 hrs after a meal and 2 hrs before the next meal).
Patients should be informed that deterioration of liver disease may occur in some cases if treatment is discontinued, and that they should discuss any change in regimen with their physician.
Patients should be advised that treatment with entecavir has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Long-term oral carcinogenicity studies of entecavir in mice and rats were carried out at exposures up to approximately 42 times (mice) and 35 times (rats) those observed in humans at the highest recommended dose of 1 mg/day. In mouse and rat studies, entecavir was positive for carcinogenic findings.
In mice, lung adenomas were increased in males and females at exposures 3 and 40 times those in humans. Lung carcinomas in both male and female mice were increased at exposures 40 times those in humans. Combined lung adenomas and carcinomas were increased in male mice at exposures 3 times and in female mice at exposures 40 times those in humans. Tumor development was preceded by pneumocyte proliferation in the lung, which was not observed in rats, dogs, or monkeys administered entecavir, supporting the conclusion that lung tumors in mice may be a species-specific event. Hepatocellular carcinomas were increased in males and combined liver adenomas and carcinomas were also increased at exposures 42 times those in humans. Vascular tumors in female mice (hemangiomas of ovaries and uterus and hemangiosarcomas of spleen) were increased at exposures 40 times those in humans. In rats, hepatocellular adenomas were increased in females at exposures 24 times those in humans; combined adenomas and carcinomas were also increased in females at exposures 24 times those in humans. Brain gliomas were induced in both males and females at exposures 35 and 24 times those in humans. Skin fibromas were induced in females at exposures 4 times those in humans.
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
Entecavir was clastogenic to human lymphocyte cultures. Entecavir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation, a mammalian-cell gene mutation assay, and a transformation assay with Syrian hamster embryo cells. Entecavir was also negative in an oral micronucleus study and an oral DNA repair study in rats. In reproductive toxicology studies, in which animals were administered entecavir at up to 30 mg/kg for up to 4 weeks, no evidence of impaired fertility was seen in male or female rats at systemic exposures >90 times those achieved in humans at the highest recommended dose of 1 mg/day. In rodent and dog toxicology studies, seminiferous tubular degeneration was observed at exposures ≥35 times those achieved in humans. No testicular changes were evident in monkeys.

Drug Interactions - Since entecavir is primarily eliminated by the kidneys, so the generic drug entecavir with impairment of renal function or excretion of drugs active competition with entecavir in renal tubules may increase serum concentrations of entecavir or of the generic drug. 
- The concomitant use of entecavir with lamivudine, adefovir or tenofovir disoproxil fumarate dipovoxil not cause significant drug interactions. The resulting shared with the drug entecavir is excreted through the kidneys or are known to affect renal function is not evaluated, so patients should be monitored closely for adverse effects of drugs when entecavir is used in conjunction with this kind of medicine.
Adverse Drug Reaction(s)

General

The most common side effects reported in patients with chronic hepatitis B virus (HBV) infection and compensated liver disease during clinical trials have included headache, fatigue, dizziness, and nausea. One percent of patients discontinued treatment due to side effects or laboratory abnormalities (compared to 4% of lamivudine-treated patients).

The most common side effects reported in patients with chronic HBV infection and evidence of hepatic decompensation (n=102) through Week 48 of a study have included peripheral edema, ascites, pyrexia, hepatic encephalopathy, and upper respiratory infection. Eighteen percent of patients treated with entecavir died during the first 48 weeks of therapy (compared to 20% of adefovir-treated patients). The majority of deaths (11 of 18 entecavir-treated patients and 16 of 18 adefovir-treated patients) were due to liver-related causes such as hepatic failure, hepatic encephalopathy, hepatorenal syndrome, and upper gastrointestinal hemorrhage. Five percent of patients discontinued entecavir or adefovir due to a side effect through 48 weeks of therapy.

Hepatic

Hepatic side effects have included elevated ALT (greater than 10 times ULN and greater than 2 times baseline: 2%; greater than 5 times ULN: up to 12%) and total bilirubin (greater than 2.5 times ULN; up to 3%). Elevated AST and ALT flares have also been reported. Hepatic encephalopathy (10%) and deaths due to liver-related causes (such as hepatic failure, hepatic encephalopathy, and hepatorenal syndrome) have been reported in entecavir-treated patients with hepatic decompensation. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside/nucleotide analogs alone or in combination with other antiretroviral agents. Severe acute exacerbations of hepatitis have been reported in patients with hepatitis B after discontinuation of entecavir. Increased transaminases have been reported during postmarketing experience.

Posttreatment exacerbations of hepatitis or ALT flare, as defined by ALT greater than 10 times ULN and greater than 2 times baseline, have been reported in patients who discontinued treatment at or after 52 weeks after achieving a defined treatment response (nucleoside-naive HBeAg-positive, 2%; nucleoside-naive HBeAg-negative, 8%; lamivudine-refractory, 12%). The median time to exacerbation was 23 to 24 weeks. The rate may be higher in patients who discontinue entecavir without regard to treatment response.

Other

Other side effects of moderate to severe intensity (Grade 2 to 4) have included fatigue (up to 3%). Fever, accidental injury, influenza, and back pain have also been reported. Peripheral edema (16%), ascites (15%), and pyrexia (14%) have been reported in entecavir-treated patients with hepatic decompensation.

Metabolic

Metabolic side effects have included elevated lipase (greater than or equal to 2.1 times ULN; 7%), fasting hyperglycemia (greater than 250 mg/dL; up to 3%), elevated alkaline phosphatase, and elevated amylase. Decreased blood bicarbonate has been reported in 2% of entecavir-treated patients with hepatic decompensation. Lactic acidosis has been reported during postmarketing experience.

Genitourinary

Genitourinary side effects have included hematuria (Grade 3 to 4; 9%), glycosuria (Grade 3 to 4; 4%), and dysuria.

Renal

Renal side effects have included confirmed creatinine increases of 0.5 mg/dL or more (up to 2%). A confirmed increase in serum creatinine of 0.5 mg/dL (11%) and renal failure (less than 1%) have been reported in entecavir-treated patients with hepatic decompensation.

Respiratory

Respiratory side effects have included upper respiratory tract infection, cough, nasopharyngitis, and rhinitis. Upper respiratory infection has been reported in 10% of entecavir-treated patients with hepatic decompensation.

Gastrointestinal

Gastrointestinal side effects of moderate to severe intensity (Grade 2 to 4) have included diarrhea (up to 1%), dyspepsia (up to 1%), nausea (less than 1%), and vomiting (less than 1%). Abdominal pain (unspecified) and upper abdominal pain have also been reported. Deaths due to gastrointestinal hemorrhage were reported in entecavir-treated patients with hepatic decompensation.

Oncologic

Oncologic side effects have included malignant neoplasms occurring at a rate of 8.4 per 1000 patient-years. Hepatocellular carcinoma has been reported in 6% of entecavir-treated patients with hepatic decompensation.

Nervous system

Nervous system side effects of moderate to severe intensity (Grade 2 to 4) have included headache (up to 4%), dizziness (less than 1%), and somnolence (less than 1%).

Hematologic

Hematologic side effects have included decreased albumin (less than 2.5 g/dL) and platelets (less than 50,000/mm3) in less than 1% of patients.

Immunologic

Immunologic side effects have included anaphylactoid reaction during postmarketing experience.

Psychiatric

Psychiatric side effects of moderate to severe intensity (Grade 2 to 4) have included insomnia (less than 1%).

Musculoskeletal

Musculoskeletal side effects have included arthralgia and myalgia.

Dermatologic

Dermatologic side effects have included erythema. Rash and alopecia have been reported during postmarketing experience.

Hypersensitivity

Hypersensitivity side effects have included photosensitivity with lethargy in at least one patient, which resolved after stopping entecavir.

Pharmacology

Microbiology: Mechanism of Action: Entecavir, a guanosine nucleoside analogue with activity against HBV polymerase, is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hrs. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all 3 activities of the HBV polymerase (reverse transcriptase): Base priming; reverse transcription of the negative strand from the pregenomic messenger RNA; and synthesis of the positive strand of HBV DNA. Entecavir triphosphate has an inhibition constant (Ki) for HBV DNA polymerase of 0.0012 micromolar. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β, and δ and mitochondrial DNA polymerase gamma with Ki values ranging from 18 to >160 micromolar.
Antiviral Activity: Entecavir inhibited HBV DNA synthesis (50% reduction, EC50) at a concentration of 0.004 micromolar in human HepG2 cells transfected with wild-type HBV. The median EC50 value for entecavir against lamivudine-resistant HBV (rtL180M, rtM204V) was 0.026 micromolar (range 0.01-0.059 micromolar). In contrast, no clinically relevant activity was noted against human immunodeficiency virus (HIV) type 1 (EC50 value >10 micromolar) grown in cell culture.
Daily or weekly entecavir treatment significantly reduced viral DNA levels (4-8 log10) in 2 relevant animal models, woodchucks chronically infected with woodchuck hepatitis virus (WHV) and ducks infected with duck HBV. Long-term studies in woodchucks demonstrated that oral weekly dosing of 0.5 mg/kg entecavir (equivalent to the 1-mg human dose) maintained viral DNA levels at undetectable levels (<200 copies/mL by PCR) for up to 3 years in 3 of 5 woodchucks. No entecavir resistance changes were detected in the HBV polymerase in any of the treated animals for up to 3 years of treatment.
The co-administration of HIV nucleoside reverse transcriptase inhibitors (NRTIs) with 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 vitro, abacavir, didanosine, lamivudine, stavudine, tenofovir, or zidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range of concentrations. In HIV antiviral assays, entecavir was not antagonistic to the in vitro anti-HIV activity of these 6 NRTIs at >4 times the Cmax of entecavir.
Resistance: In Vitro: In cell-based assays, 8- to 30-fold reductions in entecavir phenotypic susceptibility were observed for lamivudine-resistant strains. Further reductions (>70-fold) in entecavir phenotypic susceptibility required the presence of primary lamivudine resistance amino acid substitutions (rtL180M and/or rtM204V/I) along with additional substitutions at residues rtT184, rtS202, or rtM250, or a combination of these substitutions with or without an rtI169 substitution in the HBV polymerase.
Clinical Studies: Nucleoside-Naive Patients: Eighty-one percent of HBV chronically infected nucleoside-naive patients receiving entecavir 0.5 mg once daily achieved a reduction in viral load to <300 copies/mL at 48 weeks. Genotypic analysis of serum HBV DNA from nucleoside-naive HBeAg-positive (Study AI463022; n=219) or HBeAg-negative (Study AI463027; n=211) patients detected no genotypic changes in the HBV polymerase associated with phenotypic resistance to entecavir at week 48. No genotypic or phenotypic evidence of entecavir resistance was detected in the 2 patients who experienced a confirmed virologic rebound (≥1 log increase from nadir) in Study AI463022.
Lamivudine-Refractory Patients: Twenty-two percent of lamivudine-refractory patients with chronic HBV infection achieved HBV DNA levels <300 copies/mL at week 48 on entecavir 1 mg once daily. Genotypic analysis of clinical samples from those patients with detectable viral DNA identified 7% (13/189) with evidence of emerging entecavir resistance-associated substitutions at rtI169, rtT184, rtS202, and/or rtM250 by week 48 when preexisting lamivudine resistance mutations rtL180M and/or rtM204V/I were present. Of the 13 patients with genotypic resistance, 3 experienced virologic rebound (≥1 log increase from nadir) by week 48, with the majority of these 13 patients experiencing virologic rebound beyond week 48.
Description of Clinical Studies: The safety and efficacy of Entecavir were evaluated in three Phase 3 active-controlled trials. These studies included 1633 patients ≥16 years with chronic hepatitis B infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of viral replication (detectable serum HBV DNA, as measured by the bDNA hybridization or PCR assay). Patients had persistently elevated ALT levels ≥1.3 times the upper limit of normal (ULN) and chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. The safety and efficacy of Entecavir were also evaluated in a study of 68 patients co-infected with HBV and HIV.
Nucleoside-Naive Patients With Compensated Liver Disease: HBeAg-Positive: Study AI463022 was a multinational, randomized, double-blind study of Entecavir 0.5 mg once daily versus lamivudine 100 mg once daily for 52 weeks in 709 (of 715 randomized) nucleoside-naive patients with chronic hepatitis B infection and detectable HBeAg. The mean age of patients was 35 years, 75% were male, 57% were Asian, 40% were Caucasian, and 13% had previously received interferon-α. At baseline, patients had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 9.66 log10 copies/mL, and mean serum ALT was 143 U/L. Paired, adequate liver biopsy samples were available for 89% of patients.
HBeAg-Negative (Anti-HBe Positive/HBV DNA Positive): Study AI463027 was a multinational, randomized, double-blind study of Entecavir 0.5 mg once daily versus lamivudine 100 mg once daily for 52 weeks in 638 (of 648 randomized) nucleoside-naive patients with HBeAg-negative (HBeAb-positive) chronic hepatitis B infection. The mean age of patients was 44 years, 76% were male, 39% were Asian, 58% were Caucasian, and 13% had previously received interferon-α. At baseline, patients had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 7.58 log10 copies/mL, and mean serum ALT level was 142 U/L. Paired, adequate liver biopsy samples were available for 88% of patients.
In Studies AI463022 and AI463027, Entecavir was superior to lamivudine on the primary efficacy endpoint of Histologic Improvement, defined as ≥2-point reduction in Knodell Necroinflammatory Score with no worsening in Knodell Fibrosis Score at week 48, and on the secondary efficacy measures of reduction in viral load and ALT normalization. 
Histologic Improvement was independent of baseline levels of HBV DNA or ALT.
Lamivudine-Refractory Patients: Study AI463026 was a multinational, randomized, double-blind study of Entecavir in 286 (of 293 randomized) patients with lamivudine-refractory chronic hepatitis B infection. Patients receiving lamivudine at study entry either switched to Entecavir 1 mg once daily (with neither a washout nor an overlap period) or continued on lamivudine 100 mg for 52 weeks. The mean age of patients was 39 years, 76% were male, 37% were Asian, 62% were Caucasian, and 52% had previously received interferon-α. The mean duration of prior lamivudine therapy was 2.7 years, and 85% had lamivudine resistance mutations at baseline by an investigational line probe assay. At baseline, patients had a mean Knodell Necroinflammatory Score of 6.5, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 9.36 log10 copies/mL, and mean serum ALT level was 128 U/L. Paired, adequate liver biopsy samples were available for 87% of patients.
Entecavir was superior to lamivudine on the coprimary endpoint of Histologic Improvement (using the Knodell Score at week 48). Histologic Improvement was independent of baseline levels of HBV DNA or ALT.

Post-Treatment Follow-Up: The optimal duration of therapy with Entecavir is unknown. According to protocol-mandated criteria in the phase 3 clinical trials, patients discontinued Entecavir or lamivudine treatment after 52 weeks according to a definition of response based on HBV virologic suppression (<0.7 mEq/mL by bDNA assay) and loss of HBeAg (in HBeAg-positive patients) or ALT normalization (<1.25 X ULN, in HBeAg-negative patients) at week 48. For the 21% of nucleoside-naive, HBeAg-positive Entecavir-treated patients who met response criteria, response was sustained throughout the 24-week post-treatment follow-up period in 82%. For the 85% of nucleoside-naive, HBeAg-negative Entecavir-treated patients who met response criteria, response was sustained throughout the 24-week post-treatment follow-up period in 48%. Few lamivudine-refractory patients met the response criteria and were eligible to discontinue treatment. These protocol-specified patient management guidelines are not intended as guidance for clinical practice.
Special Populations: Study AI463038 was a randomized, double-blind, placebo-controlled study of Entecavir versus placebo in 68 patients co-infected with HIV and HBV who experienced recurrence of HBV viremia while receiving a lamivudine-containing highly active antiretroviral (HAART) regimen. Patients continued their lamivudine-containing HAART regimen (lamivudine dose 300 mg/day) and were assigned to add either Entecavir 1 mg once daily (51 patients) or placebo (17 patients) for 24 weeks followed by an open-label phase for an additional 24 weeks where all patients received Entecavir. At baseline, patients had a mean serum HBV DNA level by PCR of 9.13 log10copies/mL. Ninety-nine percent of patients were HBeAg-positive at baseline, with a mean baseline ALT level of 71.5 U/L. Median HIV RNA level remained stable at approximately 2 log10 copies/mL through 24 weeks of blinded therapy. There are no data in patients with HIV/HBV co-infection who have not received prior lamivudine therapy.
Cross-Resistance: Cross-resistance has been observed among HBV nucleoside analogues. In cell-based assays, entecavir had 8- to 30-fold less inhibition of replication of HBV containing lamivudine resistance mutations rtL180M and/or rtM204V/I than of wild-type virus. Recombinant HBV genomes encoding adefovir resistance-associated substitutions at either rtN236T or rtA181V remained susceptible to entecavir. HBV isolates from lamivudine-refractory patients failing entecavir therapy were susceptible in vitro to adefovir but retained resistance to lamivudine.
Pharmacokinetics: The single- and multiple-dose pharmacokinetics of entecavir were evaluated in healthy subjects and patients with chronic hepatitis B infection.
Absorption: Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hrs. Following multiple daily doses ranging from 0.1-1 mg, Cmax and area under the concentration-time curve (AUC) at steady state increased in proportion to dose. Steady state was achieved after 6-10 days of once-daily administration with approximately 2-fold accumulation. For a 0.5-mg oral dose, Cmax at steady state was 4.2 ng/mL and trough plasma concentration (Ctrough) was 0.3 ng/mL. For a 1-mg oral dose, Cmax was 8.2 ng/mL and Ctrough was 0.5 ng/mL.
In healthy subjects, the bioavailability of the tablet was 100% relative to the oral solution. The oral solution and tablet may be used interchangeably.
Effects of Food on Oral Absorption: Oral administration of entecavir 0.5 mg with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in a delay in absorption (1-1.5 hrs fed vs. 0.75 hr fasted), a decrease in Cmax of 44-46%, and a decrease in AUC of 18-20%. Therefore, Entecavir should be administered on an empty stomach (at least 2 hrs after a meal and 2 hrs before the next meal).
Distribution: 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 approximately 13%.
Metabolism and Elimination: Following administration of 14C-entecavir in humans and rats, no oxidative or acetylated metabolites were observed. Minor amounts of phase II metabolites (glucuronide and sulfate conjugates) were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P-450 (CYP-450) enzyme system (see Interactions).
After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128-149 hrs. The observed drug accumulation index is approximately 2-fold with once-daily dosing, suggesting an effective accumulation half-life of approximately 24 hrs.
Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady state ranging from 62-73% of the administered dose. Renal clearance is independent of dose and ranges from 360-471 mL/min suggesting that entecavir undergoes both glomerular filtration and net tubular secretion (see Interactions).
Special Populations: Gender: There are no significant gender differences in entecavir pharmacokinetics.
Race: There are no significant racial differences in entecavir pharmacokinetics.
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 Entecavir should be based on the renal function of the patient, rather than age (see Renal Impairment under Dosage & Administration).
Pediatrics: Pharmacokinetic studies have not been conducted in children.
Renal Impairment: The pharmacokinetics of entecavir following a single 1-mg dose were studied in patients (without chronic hepatitis B infection) with selected degrees of renal impairment, including patients whose renal impairment was managed by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). 

Dosage adjustment is recommended for patients with a creatinine clearance <50 mL/min, including patients on hemodialysis or CAPD. (See Renal Impairment under Dosage & Administration).
Following a single 1-mg dose of entecavir administered 2 hrs before the hemodialysis session, hemodialysis removed approximately 13% of the entecavir dose over 4 hrs. CAPD removed approximately 0.3% of the dose over 7 days. Entecavir should be administered after hemodialysis.
Hepatic Impairment: The pharmacokinetics of entecavir following a single 1-mg dose were studied in patients (without chronic hepatitis B infection) with moderate or severe hepatic impairment (Child-Pugh Class B or C). The pharmacokinetics of entecavir were similar between hepatically impaired patients and healthy control subjects; therefore, no dosage adjustment of Entecavir is recommended for patients with hepatic impairment.
Post-Liver Transplant: The safety and efficacy of Entecavir 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 with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these patients. The potential for pharmacokinetic interactions between entecavir and cyclosporine A or tacrolimus was not formally evaluated. Renal function must be carefully monitored both before and during treatment with Entecavir in liver transplant recipients who have received or are receiving an immunosuppressant that may affect renal function eg, cyclosporine or tacrolimus (see Renal Impairment under Dosage & Administration).
Drug Interactions (see also Interactions): The metabolism of entecavir was evaluated in in vitro and in vivo studies. Entecavir is not a substrate, inhibitor, or inducer of the CYP-450 enzyme system. At concentrations up to approximately 10,000-fold higher than those obtained in humans, entecavir inhibited none of the major human CYP-450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1. At concentrations up to approximately 340-fold higher than those observed in humans, entecavir did not induce the human CYP-450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6 (see Metabolism and Elimination). The pharmacokinetics of entecavir are unlikely to be affected by co-administration with agents that are either metabolized by, inhibit, or induce the CYP-450 system. Likewise, the pharmacokinetics of known CYP substrates are unlikely to be affected by co-administration of entecavir.
The steady-state pharmacokinetics of entecavir and co-administered drug were not altered in interaction studies of entecavir with lamivudine, adefovir dipivoxil, and tenofovir disoproxil fumarate.

Pharmacokinetics:

• Absorption

- concentrations of entecavir peak plasma in healthy subjects obtained in about 0.5-1.5 hours after ingestion. 
- The effect of food on oral absorption: Oral 0.5 mg entecavir with a normal diet or a high-fat snacks leads to slow absorption (1.0-1.5 hours fed vs. 0.75 stomach on an empty stomach) makes decreased C max and AUC 44% -46% 18% ​​-20%. 

• Distribution : - Based on the analysis of entecavir pharmacokinetics following oral dosing, the apparent volume of distribution was estimated to be more than the sum of body water, suggesting that entecavir is more distributed in tissues. - In vitro , approximately 13% of entecavir linked to human serum proteins. 

• Metabolism and excretion : Not seen as oxidative metabolites or acetylation in humans after ingestion of 14 C-entecavir. Observed negligible amounts of phase II metabolites (glucuronide conjugate materials and sulfates). Entecavir is not a substrate, inhibitor or an inducible enzyme system cytochrome P450 (CYP450). After reaching peak concentration, entecavir plasma concentrations decreased exponentially with a half level 2 finally discharged approximately 128-149 hours. Drug accumulation index is observed to be nearly double dose 1 time / day, indicating accumulation half-life is approximately 24 hours really. Entecavir is excreted primarily through the kidneys with no transfer of drugs goods recovered in the urine in the steady state from 62% -73% of the administered dose. Renal clearance is not dependent on the administered dose and ranged from 360-471 ml / min, suggesting that entecavir undergoes both glomerular filtration and tubule secretion.

Pregnancy Category (FDA) and use in Specific Population

Use in pregnancy: 

Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Reproduction studies have been performed in rats and rabbits at orally administered doses up to 200 and 16 mg/kg/day and showed no embryotoxicity or maternal toxicity at systemic exposures approximately 28 and 212 times those achieved at the highest recommended dose of 1 mg/day in humans. In rats, maternal toxicity, embryo-fetal toxicity (resorptions), lower fetal body weights, tail and vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs were observed at exposures 3100 times those in humans. In rabbits, embryo-fetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at exposures 883 times those in humans. In a peri-postnatal study, no adverse effects on offspring were seen with entecavir administered orally to rats at exposures >94 times those in humans. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Entecavir should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits.
Labor and Delivery: There are no studies in pregnant women and no data on the effect of Entecavir on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
Use in lactation: Entecavir is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Mothers should be instructed not to breastfeed if they are taking Entecavir.
Use in children: Safety and effectiveness of entecavir in pediatric patients <16 years have not been established.
Use in the elderly: Clinical studies of Entecavir did not include sufficient numbers of subjects ≥65 years to determine whether they respond differently from younger subjects. Entecavir is substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Renal Impairment under Dosage & Administration).
Use in Racial/Ethnic Groups: Clinical studies of Entecavir did not include sufficient numbers of subjects from some racial/ethnic minorities (black/African American, Hispanic) to determine whether they respond differently to treatment with the drug. There are no significant racial differences in entecavir pharmacokinetics.

ATC Classification J05AF10 - entecavir; Belongs to the class of nucleoside and nucleotide reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.

Brand/Product Info


Total Products : 10          
Brand Name Manufacturer/Marketer Composition Dosage Form Pack Size & Price
Barcavir 0.5 Incepta Pharmaceuticals Limited Entecavir 0.5 mg Tablet Tablet 10x1's:MRP 480 Tk
Barcavir 1 Incepta Pharmaceuticals Limited Entecavir 1 mg Tablet Tablet 10x1's:MRP 900 Tk
CAVIR 0.5 Square Pharmaceuticals Ltd. Entecavir 0.5mg Tablet 2x5's: 481.40 MRP
CAVIR 1 Square Pharmaceuticals Ltd. Entecavir 1mg Tablet 1x5's: 451.35 MRP
CAVIRAL Beacon Pharmaceuticals Limited Entecavir INN 0.5mg Tablet 10's: 600.00 MRP
ENTAVIR Drug International Ltd Entecavir INN 0.5mg Tablet 10's: 600.00 MRP
ENVIRAL Opsonin Pharma Limited Entecavir INN 0.5mg & 1mg Tablet 10's each: 481.80 & 903.40 MRP
ENVIRAL Solution Opsonin Pharma Limited Entecavir INN 0.25mg/5ml Oral Solution 100ml: 301.14 MRP
TECAVIR Aristopharma Ltd. Entecavir INN 0.5mg & 1mg Tablet 10's each: 600.00 & 1000.00 MRP
TEVIRAL ACI Ltd. Entecavir INN 0.5mg & 1mg Tablet 10's each: 481.80 & 900.00 MRP

Gen. MedInfo

IMPORTANT WARNING:

Entecavir can cause serious or life-threatening damage to the liver and a condition called lactic acidosis (a buildup of acid in the blood). inform your doctor if you drink or have ever drunk large amounts of alcohol, if you use or have ever used injectable street drugs, and if you have or have ever had cirrhosis (scarring) of the liver or any liver disease other than hepatitis B. If you experience any of the following symptoms, call your doctor immediately: yellowing of the skin or eyes; dark-colored urine; light-colored bowel movements; difficulty breathing; stomach pain or swelling; nausea; vomiting; unusual muscle pain; loss of appetite for at least several days; lack of energy; extreme weakness or tiredness; feeling cold, especially in the arms or legs; dizziness or lightheadedness; or fast or irregular heartbeat.

Do not stop taking entecavir without talking to your doctor. When you stop taking entecavir, your hepatitis may get worse. This is most likely to happen during the first several months after you stop taking entecavir. Take entecavir exactly as directed. Be careful not to miss doses or run out of entecavir. Refill your prescription at least 5 days before you expect that you will need the new supply of medication. If you experience any of the following symptoms after you stop taking entecavir, call your doctor immediately: extreme tiredness, weakness, nausea, vomiting, loss of appetite, yellowing of the skin or eyes, dark-colored urine, light-colored bowel movements, or muscle or joint pain.

If you have human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) that is not being treated with medications and you take entecavir, your HIV infection may become more difficult to treat. inform your doctor if you have HIV or AIDS or if there is a chance that you have been exposed to HIV. Your doctor may test you for HIV infection before you begin treatment with entecavir and at any time during your treatment if there is a chance that you have been exposed to HIV. Entecavir will not treat HIV infection.

Keep all appointments with your doctor and the laboratory before, during, and for a few months after your treatment with entecavir. Your doctor will order certain tests to check your body's response to entecavir during this time.

Talk to your doctor about the risks of taking entecavir.

Why is Entecavir prescribed?

Entecavir is used to treat chronic (long-term) hepatitis B infection (swelling of the liver caused by a virus) in people who have liver damage. Entecavir is in a class of medications called nucleoside analogs. It works by decreasing the amount of hepatitis B virus (HBV) in the body. Entecavir does not cure HBV and may not prevent complications of chronic hepatitis B such as cirrhosis of the liver or liver cancer. Entecavir does not prevent the spread of HBV to other people.

How should Entecavir be used?

Entecavir comes as a tablet and solution (liquid) to take by mouth. It is usually taken once a day on an empty stomach, at least 2 hours after a meal and at least 2 hours before the next meal. Take entecavir at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take entecavir exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

To use the entecavir solution, follow these steps:

  1. Hold the spoon that came with your medication upright and slowly fill it with entecavir solution up to the mark that matches your dose.

  2. Hold the spoon with the volume marks facing you and check to see that the top of the liquid is level with the mark that matches your dose.

  3. Swallow the medication right from the measuring spoon. Do not mix the medication with water or any other liquid.

  4. Rinse the spoon with water after each use, and allow it to air dry.

  5. Put the spoon in a safe place where it will not get lost because you will need to use it every time you take your medication. If you do lose the dosing spoon, call your doctor or pharmacist.

Other uses for Entecavir

Entecavir may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions to follow?

Before taking entecavir,

  • inform your doctor if you are allergic to entecavir, or any other medications, or any of the ingredients in entecavir tablets or solution. Ask your pharmacist for a list of the ingredients.
  • inform your doctor what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: aminoglycoside antibiotics such as amikacin, gentamicin, kanamycin, neomycin, paromomycin, streptomycin, and tobramycin; amphotericin B; medications to prevent rejection of a transplanted organ such as cyclosporine (Neoral, Sandimmune) or tacrolimus (Prograf); probenecid; or vancomycin. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • inform your doctor if you have had a liver transplant (surgery to replace a diseased liver) or if you have or have ever had kidney disease.
  • inform your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking entecavir, call your doctor. Do not breast-feed while you are taking entecavir.
  • if you are having surgery, including dental surgery, inform the doctor or dentist that you are taking entecavir.

What special dietary instructions to follow?

Unless your doctor informs you otherwise, continue your normal diet.

What to do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

What side effects can Entecavir cause?

Entecavir may cause side effects. inform your doctor if this symptom is severe or does not go away:

  • headache

Some side effects can be serious. If you experience any of the symptoms listed in the IMPORTANT WARNING section, call your doctor immediately.

Entecavir may cause other side effects. Call your doctor if you have any unusual problems while using Entecavir.

In case of emergency/overdose

In case of overdose, consult your doctor. If the victim has collapsed or is not breathing, consult local medical emergency services.

What other information to know?

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your response to Entecavir.

Do not let anyone else use your medication. If you still have symptoms and need further treatment, consult your doctor.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Ref:  U.S. National Library of Medicine.


This information is provided for reference only and not a replacement for and should only be used in conjunction with full consultation with a registered medical practitioner. It may not contain all the available information you require and cannot substitute professional medical care, nor does it take into account all individual circumstances. Although great effort has been made to ensure content accuracy, mph-bd shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise.

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