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entecavir 1 mg tablet generic baraclude

Out of Stock Manufacturer AMNEAL PHARMACE 65162044903
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Uses

Chronic Hepatitis B Virus Infection

Entecavir is used for the treatment of chronic hepatitis B virus (HBV) infection in adults and pediatric patients 2 years of age and older with evidence of active HBV replication and either persistent elevations in serum aminotransferase (ALT or AST) concentrations or histologic evidence of active liver disease.

The indication for use of entecavir in adults is based on clinical trial data in adults and adolescents 16 years of age or older with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic HBV infection with compensated liver disease who were nucleoside-naive (had not previously received treatment with nucleoside antivirals) or had lamivudine-refractory HBV; although most study patients had compensated liver disease, a limited number had decompensated liver disease. The indication for use of the drug in pediatric patients is based on clinical trial data in nucleoside-naive pediatric patients 2 years of age and older and in a limited number of lamivudine-experienced patients with HBeAg-positive chronic HBV infection and compensated liver disease.

Entecavir has not been evaluated for the treatment of chronic HBV infection in patients with human immunodeficiency virus (HIV) coinfection who were not receiving antiretroviral therapy; the drug should not be used for the treatment of HBV infection in such patients.(See HBV-infected Individuals Coinfected with HIV under Warning/Precautions: Warnings, in Cautions.)

Only limited data are available regarding the efficacy and safety of entecavir for the treatment of HBV infection in liver transplant recipients. (See Liver Transplant Recipients under Uses: Chronic Hepatitis B Infection and see Liver Transplant Recipients under Warnings/Precautions: Warnings, in Cautions.)

The goal of antiviral therapy in patients with chronic HBV infection is to decrease the morbidity and mortality related to the infection (e.g., cirrhosis, hepatic failure, hepatocellular carcinoma). Sustained suppression of HBV replication has been associated with normalization of serum ALT concentrations, loss of HBeAg with or without detection of antibody to HBeAg (anti-HBe), and improvement in liver histology. Currently available therapies for chronic HBV infection (e.g., adefovir, entecavir, lamivudine, telbivudine, tenofovir alafenamide, tenofovir disoproxil fumarate [tenofovir DF], interferon alfa, peginterferon alfa) are used in an attempt to provide an immunologic cure (HBsAg loss and sustained HBV DNA suppression), but cannot provide a virologic cure (eradication of HBV).

Treatment of chronic HBV infection is complex and evolving, and specialized references and experts should be consulted. Information from the American Association for the Study of Liver Diseases (AASLD) regarding management of chronic HBV infection, including recommendations for initial treatment, is available at https://www.aasld.org.

HBeAg-Positive Adults

Efficacy of entecavir for the management of HBeAg-positive chronic HBV infection was evaluated in a phase III, randomized, double-blind, active-controlled study (AI463022) in nucleoside-naive adults with active HBV replication (median baseline serum HBV DNA levels 9.66 log10 copies/mL), persistent elevations in serum ALT concentrations (mean serum ALT of 143 IU/L), and histologic evidence of active liver disease (mean Knodell necroinflammatory score of 7.8). Seventy-five percent of patients in the study were male, 57% were Asian, 40% were Caucasian, and 13% had prior treatment with interferon alfa.

Data analysis at 48 weeks indicated that 72% of patients who received entecavir in a dosage of 0.5 mg daily had histologic improvement (defined as a reduction of at least 2 points in the Knodell necroinflammatory score with no concurrent worsening of the Knodell fibrosis score) compared with 62% of those who received lamivudine in a dosage of 100 mg daily. Sixty-eight percent of patients receiving entecavir (0.5 mg daily) had normal serum ALT concentrations (i.e., biochemical response) at week 48 compared with 60% of those receiving lamivudine (100 mg daily). In addition, the mean decrease in serum HBV DNA levels from baseline was 6.86 log10 copies/mL at week 48 in those receiving entecavir compared with a decrease of 5.39 log10 copies/mL in those receiving lamivudine. Sixty-seven percent of patients who received entecavir had undetectable levels of serum HBV DNA (defined as less than 300 copies/mL by a polymerase chain reaction [PCR] assay) at week 48 compared with 36% of those who received lamivudine. Seroconversion to anti-HBe also occurred in 21 or 18% of patients who received entecavir or lamivudine, respectively. The optimal duration of therapy with entecavir is not known. According to the study protocol, patients who met the response criteria (determined at 48 weeks based on HBV virologic suppression [less than 0.7 MEq/mL by bDNA assay] and loss of HBeAg [in HBeAg-positive patients] or ALT normalization [less than 1.25 times the upper limit of normal in HBeAg-negative patients]) discontinued therapy at week 52 while patients who did not meet the response criteria continued treatment through week 96 or until they met the response criteria. Twenty-one percent of patients treated with entecavir who met the response criteria discontinued entecavir at 52 weeks per protocol; 82% of these patients maintained such a response during an additional 24 weeks of post-treatment follow-up. Approximately 69% of patients treated with entecavir continued treatment for up to 96 weeks; 74% of these patients had undetectable levels of serum HBV DNA after the last dose of the drug and 79% had normal ALT concentrations. Seroconversion to anti-HBe occurred in 11% of patients receiving entecavir.

HBeAg-Negative Adults

Efficacy of entecavir for the management of HBeAg-negative, anti-HBe- and HBV-DNA-positive chronic HBV infection was evaluated in a phase III, randomized, double-blind, active-controlled study (AI463027) in nucleoside-naive adults with active HBV replication (median baseline serum HBV DNA levels 7.58 log10 copies/mL by a PCR-based assay), persistent elevations in serum ALT concentrations (mean serum ALT of 142 IU/L), and histologic evidence of active liver disease (mean Knodell necroinflammatory score of 7.8). Seventy-six percent of patients in the study were male, 58% were Caucasian, 39% were Asian, and 13% had prior treatment with interferon alfa.

Data analysis at 48 weeks indicated that 70% of patients who received entecavir (0.5 mg daily) had histologic improvement (defined as a reduction of at least 2 points in the Knodell necroinflammatory score with no concurrent worsening of the Knodell fibrosis score) compared with 61% of those who received lamivudine (100 mg daily). Serum ALT concentrations also normalized at week 48 in 78% of patients who received entecavir compared with 71% of those who received lamivudine. In addition, the mean decrease in serum HBV DNA levels from baseline was 5.04 log10 copies/mL at week 48 in patients receiving entecavir compared with a mean decrease of 4.53 log10 copies/mL in those receiving lamivudine. Ninety percent of patients who received entecavir had undetectable levels of serum HBV DNA (defined as less than 300 copies/mL by PCR assay) at week 48 compared with 72% of those who received lamivudine. Eighty-five percent of patients treated with entecavir met the response criteria (determined at 48 weeks based on HBV virologic suppression [less than 0.7 MEq/mL by bDNA assay] and loss of HBeAg) and discontinued entecavir at 52 weeks per protocol; very few of these patients had undetectable levels of serum HBV DNA and 46% of patients maintained normal ALT concentrations during an additional 24 weeks of follow-up.

Adults with Lamivudine-refractory HBV

Entecavir has been evaluated for the treatment of lamivudine-refractory chronic HBV infection in a phase III, randomized, double-blind, active-controlled study (AI463026) in adults with active HBV replication (median baseline serum HBV DNA levels 9.36 log10 copies/mL), persistent elevations in serum ALT concentrations (mean serum ALT of 128 IU/L), and histologic evidence of compensated liver disease (mean Knodell necroinflammatory score of 6.5). Seventy-six percent of patients in the study were male, 37% were Asian, 62% were Caucasian, and 52% had prior treatment with interferon alfa.

Patients in the study had previously received lamivudine therapy for a mean duration of 2.7 years and lamivudine-resistant mutations were identified at baseline in 85% of patients. Patients were randomized to switch (without a washout or an overlap period) from lamivudine to entecavir (1 mg daily) or to continue lamivudine (100 mg daily) for 52 weeks. Data analysis at 48 weeks indicated that 55% of patients switched to entecavir had histologic improvement (defined as a reduction of at least 2 points in the Knodell necroinflammatory score with no concurrent worsening of the Knodell fibrosis score) compared with 28% of those who continued to receive lamivudine. Sixty-one percent of patients receiving entecavir had normal serum ALT concentrations (i.e., biochemical response) at week 48 compared with 15% of those receiving lamivudine. In addition, the mean decrease in serum HBV DNA levels from baseline was 5.11 log10 copies/mL at week 48 in those receiving entecavir compared with a decrease of 0.48 log10 copies/mL in those receiving lamivudine. Nineteen percent of patients who received entecavir had undetectable levels of serum HBV DNA (defined as less than 300 copies/mL by PCR assay) at week 48 compared with 1% of those who received lamivudine. Seroconversion to anti-HBe occurred in 8 or 3% of patients who received entecavir or lamivudine, respectively. Approximately 55% of patients treated with entecavir continued treatment for up to 96 weeks; 40% of these patients had undetectable levels of serum HBV DNA, 81% had normal ALT concentrations, and 10% achieved seroconversion.

Adults with Decompensated Liver Disease

Entecavir has been evaluated for the treatment of chronic HBV infection in patients with decompensated liver disease in a randomized, open-label study (AI463048). The study included 191 adults with HBeAg-positive or HBeAg-negative chronic HBV infection and evidence of hepatic decompensation (Child-Turcotte-Pugh score of 7 or higher) (mean age 52 years, 74% male, 54% Asian, 33% Caucasian, 5% black, baseline HBV DNA levels 7.83 log10 copies/mL, mean ALT concentration 100 U/L, 54% HBeAg-positive, 35% with evidence of lamivudine resistance, baseline mean Child-Turcotte-Pugh score 8.6). Patients were randomized to receive entecavir 1 mg once daily or adefovir dipivoxil 10 mg once daily. At 48 weeks, 57 or 20% of patients receiving entecavir or adefovir dipivoxil, respectively, achieved undetectable levels of HBV DNA (less than 300 copies/mL [the lower limit of quantification]) and 61 or 67% of patients, respectively, had stable or improved Child-Turcotte-Pugh scores.

HBeAg-Positive Pediatric Patients

Efficacy, safety, and pharmacokinetics of entecavir in pediatric patients were initially evaluated in 53 pediatric patients 2 years to less than 18 years of age with chronic HBV infection (HBeAg-positive) with compensated liver disease and elevated ALT concentration (study AI463028); 24 patients were treatment-naive and 19 patients were previously treated with lamivudine (lamivudine-experienced). Nucleoside-naive (had not previously received treatment with nucleoside antivirals) patients received entecavir in a dosage of 0.015 mg/kg (up to 0.5 mg) once daily and lamivudine-experienced patients received 0.03 mg/kg (up to 1 mg) once daily. At 48 weeks, 58 or 47% of treatment-naive or lamivudine-experienced patients, respectively, achieved HBV DNA levels less than 50 IU/mL; ALT concentrations normalized in 83 or 95% of patients, respectively.

Efficacy and safety of entecavir in pediatric patients were confirmed in an ongoing randomized, placebo-controlled, double-blind study (AI463189) in 180 pediatric patients 2 years to less than 18 years of age who were nucleoside-naive with HBeAg-positive chronic HBV infection, compensated liver disease, and elevated ALT concentrations (mean HBV DNA levels 8.1 log10 IU/mL, mean ALT concentrations 103 U/L). Patients were randomized in a 2:1 ratio to receive entecavir in a dosage of 0.015 mg/kg (up to 0.5 mg) once daily or placebo. At 48 weeks, 24% of patients receiving entecavir met the composite primary efficacy end point of HBeAg seroconversion and serum HBV DNA levels less than 50 IU/mL. An HBV DNA level less than 50 IU/mL was achieved in 46 or 2% of patients receiving entecavir or placebo, respectively; ALT normalization and HBeAg seroconversion were attained in 67 or 24%, respectively, of patients receiving entecavir compared with 22 or 12%, respectively, of patients receiving placebo.

HBV-infected Individuals Coinfected with HIV

Efficacy of entecavir for the treatment of chronic HBV infection in HIV-infected patients was evaluated in a phase III, randomized, double-blind, active-controlled study (AI463038) in patients receiving highly active antiretroviral therapy (HAART) that included lamivudine. These HIV-infected patients had recurrent HBV viremia (99% were HBeAg-positive), active HBV replication (median baseline serum HBV DNA levels 9.13 log10 copies/mL), and persistent elevations in serum ALT concentrations (mean serum ALT of 71.5 IU/L). Patients continued HAART (including lamivudine 300 mg daily) and were randomized to receive concurrent therapy with entecavir (1 mg daily) or placebo for 24 weeks followed by an additional 24-week open-label period during which all patients received entecavir (1 mg daily).

Analysis of limited data at 24 weeks indicated that 6% of patients who received entecavir in conjunction with lamivudine-containing HAART had undetectable levels of serum HBV DNA (defined as less than 300 copies/mL by PCR assay) compared with 0% of those who received placebo and lamivudine-containing HAART. Thirty-four percent of patients receiving the regimen that included entecavir had normal serum ALT concentrations (i.e., biochemical response) at week 24 compared with 8% of those who did not receive entecavir. In addition, the mean decrease in serum HBV DNA levels from baseline was 3.65 log10 copies/mL at week 24 in those receiving the regimen that included entecavir compared with an increase of 0.11 log10 copies/mL in those receiving a lamivudine-containing HAART regimen alone. Median serum HIV-1 RNA levels remained stable at approximately 2 log10/mL during the 24-week blinded study period.

HBV-infected patients coinfected with HIV often have higher HBV viral loads, more rapid disease progression, and an increased risk of HBV-related liver complications and death than those not infected with HIV. Decisions regarding when to initiate treatment of HBV and which HBV treatment regimen to use in HIV-infected patients must be individualized and such patients should be treated in consultation with an expert.

Entecavir should not be used for the treatment of HBV infection in HIV-infected patients who are not receiving antiretroviral therapy. Although the drug has not been systematically evaluated in HIV-infected patients with HBV who were not receiving concomitant antiretroviral therapy, limited clinical experience suggests there is a potential for development of HIV resistance in such patients.(See HBV-infected Individuals Coinfected with HIV under Warning/Precautions: Warnings, in Cautions.)

Liver Transplant Recipients

Efficacy and safety of entecavir in liver transplant recipients were evaluated in a single-arm, open-label trial that included 65 patients who received a liver transplant for complications of chronic HBV infection. Patients had HBV DNA levels less than 172 IU/mL and 89% had HBeAg-negative disease at the time of transplant; mean age was 49 years, 82% were male, 39% were white, and 37% were Asian. All patients received entecavir 1 mg once daily in addition to usual posttransplant management, including hepatitis B immune globulin (HBIG). Of the 53 patients who completed the trial and had HBV DNA levels tested at or after 72 weeks of posttransplant treatment, all achieved HBV DNA levels less than 50 IU/mL. Of the 61 evaluable patients, all lost HBsAg posttransplant and 2 patients experienced recurrence of measurable HBsAg without recurrence of HBV viremia.

Dosage and Administration

Administration

Entecavir is administered orally.

Because presence of food in the GI tract may decrease the rate and extent of absorption, entecavir should be administered on an empty stomach at least 2 hours before or 2 hours after meals.

The oral solution should be administered using the oral dosing spoon according to the patient instructions provided by the manufacturer. The oral solution contains 0.05 mg of entecavir per mL and should not be diluted or mixed with water or any other liquid.

Dosage

Adult Dosage

Chronic Hepatitis B Virus Infection

For the treatment of chronic hepatitis B virus (HBV) infection in nucleoside-naive (have not previously received treatment with nucleoside antivirals) adults with compensated liver disease, the recommended dosage of entecavir is 0.5 mg once daily. Adults with compensated liver disease and a history of HBV viremia while receiving lamivudine or with HBV known to have lamivudine- or telbivudine-associated resistance mutations (rtM204I/V +/- rtL180M, rtL80I/V, or rtV173L) should receive entecavir in a dosage of 1 mg once daily.

For the treatment of HBV infection in adults with decompensated liver disease, the recommended dosage of entecavir is 1 mg once daily.

The optimal duration of entecavir therapy in patients with chronic HBV infection is not known.

Pediatric Dosage

Chronic Hepatitis B Virus Infection

Dosage of entecavir for the treatment of chronic HBV infection in pediatric patients 2 years of age and older weighing at least 10 kg is based on weight. (See Table 1.) For patients weighing 30 kg or less, entecavir oral solution should be used.

Table 1: Dosage of Entecavir for Treatment of HBV Infection in Pediatric Patients 2 Years of Age or Older Weighing 10 kg or More[1 ]
Body Weight Dosage of Oral Solution Containing 0.05 mg/mL in Treatment-naive Patients Dosage of Oral Solution Containing 0.05 mg/mL in Lamivudine-experienced Patients
10-11 kg 0.15 mg (3 mL) once daily 0.3 mg (6 mL) once daily
>11 to 14 kg 0.2 mg (4 mL) once daily 0.4 mg (8 mL) once daily
>14 to 17 kg 0.25 mg (5 mL) once daily 0.5 mg (10 mL) once daily
>17 to 20 kg 0.3 mg (6 mL) once daily 0.6 mg (12 mL) once daily
>20 to 23 kg 0.35 mg (7 mL) once daily 0.7 mg (14 mL) once daily
>23 to 26 kg 0.4 mg (8 mL) once daily 0.8 mg (16 mL) once daily
>26 to 30 kg 0.45 mg (9 mL) once daily 0.9 mg (18 mL) once daily
>30 kg 0.5 mg (10 mL) once daily 1 mg (20 mL) once daily

Treatment-naive pediatric patients weighing more than 30 kg may receive 0.5 mg (10 mL) of entecavir oral solution containing 0.05 mg/mL once daily or one 0.5-mg tablet of entecavir once daily.

Lamivudine-experienced pediatric patients weighing more than 30 kg may receive 1 mg (20 mL) of entecavir oral solution containing 0.05 mg/mL once daily or one 1-mg tablet of entecavir once daily.

For the treatment of chronic HBV infection in nucleoside-naive (have not previously received treatment with nucleoside antivirals) adolescents 16 years of age and older, the recommended dosage of entecavir is 0.5 mg once daily. Adolescents 16 years of age and older with a history of HBV viremia while receiving lamivudine or with HBV known to have lamivudine- or telbivudine-associated resistance mutations (rtM204I/V +/- rtL180M, rtL80I/V, or rtV173L) should receive entecavir in a dosage of 1 mg once daily.

The optimal duration of entecavir therapy in patients with chronic HBV infection is not known.

Special Populations

Hepatic Impairment

Dosage adjustments are not necessary in patients with hepatic impairment.

Renal Impairment

Dosage of entecavir should be adjusted in adults with preexisting renal impairment (i.e., baseline creatinine clearances less than 50 mL/minute), including patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). (See Table 2.) The manufacturer states that the once-daily regimens are preferred.

Table 2. Dosage of Entecavir for Treatment of HBV Infection in Adults with Renal Impairment[1 ][35 ]
Creatinine Clearance (mL/min) Nucleoside-naive Individuals Lamivudine-refractory HBV or Decompensated Liver Disease
30 to <50 0.25 mg once dailyor 0.5 mg once every 48 hours 0.5 mg once daily or 1 mg once every 48 hours
10 to <30 0.15 mg once dailyor 0.5 mg once every 72 hours 0.3 mg once dailyor 1 mg once every 72 hours
<10, undergoing hemodialysis or CAPD 0.05 mg once dailyor 0.5 mg once every 7 days 0.1 mg once dailyor 1 mg once every 7 days

For doses less than 0.5 mg, entecavir oral solution should be used.

When a dose is indicated on a hemodialysis day, the dose should be given after the hemodialysis session.

Although data are insufficient to recommend specific dosage adjustments in pediatric patients 2 years of age or older with renal impairment, the manufacturer states that dose reductions or increases in dosing interval similar to those recommended for adults with renal impairment should be considered.

Geriatric Patients

Dosage of entecavir for geriatric patients should be selected with caution because of possible age-related decreases in renal function and patients should be monitored closely. (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Cautions

Contraindications

The manufacturers state there are no known contraindications to use of entecavir.

Warnings/Precautions

Warnings

Exacerbations of Hepatitis

Severe acute exacerbations of hepatitis have been reported following discontinuance of hepatitis B virus (HBV) therapy, including entecavir therapy.

In studies that evaluated safety of entecavir, exacerbations of hepatitis or ALT flare was defined as ALT elevations greater than 10 times the upper limit of normal (ULN) and greater than 2 times baseline serum concentrations. In clinical studies (AI463022, AI463027, AI463026), ALT flare occurred in 2, 8, or 12% of nucleoside-naive HBeAg-positive, nucleoside-naive HBeAg-negative, or lamivudine-refractory patients, respectively, following discontinuance of entecavir. The median time to exacerbations of hepatitis was 23 weeks. Rates of post-treatment ALT flare may be higher if entecavir therapy is discontinued without regard to previous response to therapy.

Exacerbations of hepatitis also have been reported during entecavir treatment of HBV, but generally resolved with continued therapy. In clinical studies, exacerbations of hepatitis (e.g., ALT elevations greater than 10 times the ULN and greater than 2 times baseline serum concentrations) occurring during therapy generally were associated with a reduction in viral load of at least of 2 log10 copies/mL that preceded or coincided with the ALT elevations.

Hepatic function should be closely monitored with both clinical and laboratory follow-up for at least several months after entecavir is discontinued. If appropriate, resumption of anti-HBV therapy may be warranted.

HBV-infected Individuals Coinfected with HIV

Use of entecavir for treatment of chronic HBV infection in patients with unrecognized or untreated human immunodeficiency virus (HIV) infection may result in emergence of HIV isolates with resistance to HIV nucleoside reverse transcriptase inhibitors (NRTIs).

Prior to initiation of entecavir therapy, all patients should be offered HIV testing.

Entecavir has not been systematically evaluated in HBV-infected patients coinfected with HIV who were not receiving concomitant antiretroviral therapy.

Because of the possible risk of emergence of NRTI-resistant HIV, entecavir should not be used for the treatment of HBV in HIV-infected patients who are not receiving antiretroviral therapy.

Entecavir has not been systematically evaluated for the treatment of HIV infection and such use is not recommended.

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including some fatalities, have been reported in patients receiving nucleoside analogs alone or in conjunction with antiretrovirals. Most reported cases have involved women; obesity and long-term therapy with nucleoside reverse transcriptase inhibitors also may be risk factors.

Lactic acidosis in patients receiving entecavir often is reported in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk of lactic acidosis.

Nucleoside analogs should be used with particular caution in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have been reported in patients with no known risk factors.

Entecavir therapy should be discontinued in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked aminotransferase elevations).

Liver Transplant Recipients

Limited data are available regarding safety and efficacy of entecavir in liver transplant recipients. In an open-label, post-liver transplant trial, the frequency and nature of adverse events were consistent with those expected in patients who have received a liver transplant and the known safety profile of entecavir.

If entecavir is necessary in liver transplant recipients who have received or are receiving an immunosuppressive agent that may affect renal function (e.g., cyclosporine, tacrolimus), renal function should be carefully monitored prior to and during entecavir treatment.(See Drug Interactions: Immunosuppressive Agents.)

Specific Populations

Pregnancy

Category C.

To monitor maternal-fetal outcomes of pregnant women exposed to entecavir, clinicians are encouraged to contact the pregnancy registry at 800-258-4263 to enroll such women.

There are no adequate, well-controlled studies of entecavir in pregnant women. The drug should be used during pregnancy only if potential benefits justify potential risks to the fetus.

There was no evidence of teratogenicity in rats or rabbits at entecavir exposures approximately 28 or 212 times, respectively, human exposures achieved at the highest recommended human dose of 1 mg daily.

The American Association for the Study of Liver Diseases (AASLD) and other experts state that recommendations regarding antiviral therapy for the management of HBV infection in pregnant women generally are the same as those for other adults. AASLD also suggests that hepatitis B surface antigen (HBsAg)-positive pregnant women with HBV DNA levels exceeding 200,000 IU/mL receive antiviral therapy since this may reduce the risk of perinatal transmission of HBV; however, preferred antiviral agents, exact viral load threshold, and optimal gestational week during the third trimester to initiate such therapy have not been clearly identified.

Data are not available regarding the effect of entecavir therapy during pregnancy on transmission of HBV to the infant. Routine screening for HBV infection is recommended for all pregnant women. For prevention of perinatal transmission of HBV, the US Public Health Service Advisory Committee on Immunization Practices (ACIP), American Academy of Pediatrics (AAP), and other experts state that infants born to HBsAg-positive women should receive their first dose of hepatitis B vaccine and a dose of hepatitis B immune globulin (HBIG) within 12 hours of birth.

Lactation

Entecavir is distributed into milk in rats; it is not known whether the drug is distributed into human milk.

A decision should be made to discontinue nursing or entecavir, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy of entecavir have not been established in children younger than 2 years of age.

The manufacturer states that only limited data are available on use of entecavir in lamivudine-experienced pediatric patients and the drug should be used in such patients only if potential benefits justify potential risks to the child. Since some pediatric patients may require long-term or lifetime management of chronic active HBV infection, consideration should be given to the impact of entecavir use on future treatment options.

Geriatric Use

Experience in those 65 years of age and older is insufficient to determine whether they respond differently than younger adults.

Entecavir should be used with caution in geriatric patients. The drug is substantially excreted by the kidneys, and the risk of entecavir-induced toxicity may be increased in patients with impaired renal function. Because geriatric patients may have decreased renal function, select dosage based on degree of renal impairment; it also may be useful to monitor renal function in such patients.(See Dosage and Administration: Special Populations.)

Renal Impairment

Dosage adjustments are recommended for patients with creatinine clearance less than 50 mL/minute, including patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).(See Renal Impairment under Dosage and Administration: Special Populations.)

Hispanic Patients

The manufacturers state that safety and efficacy of entecavir have not been established in the US Hispanic population because of low enrollment of such patients in clinical trials.

Race

There are no substantial race-related differences in entecavir pharmacokinetics.

Common Adverse Effects

Adverse effects reported in 3% or more of patients with compensated liver disease who received entecavir in clinical trials include headache, fatigue, dizziness, and nausea. Diarrhea, dyspepsia, vomiting, somnolence, and insomnia also have been reported. The most common laboratory abnormalities reported in clinical trials of entecavir are ALT elevations (greater than 5 times the ULN), hematuria, lipase elevations (at least 2.1 times the ULN), glycosuria, hyperbilirubinemia (greater than 2 times the ULN), ALT elevations (greater than 10 times the ULN and greater than 2 times baseline serum concentrations), fasting hyperglycemia (greater than 250 mg/dL), and creatinine increases (at least 0.5 mg/dL).

Adverse effects reported in 10% or more of patients with decompensated liver disease who received entecavir in clinical trials include peripheral edema, ascites, pyrexia, hepatic encephalopathy, and upper respiratory infection.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Entecavir is not a substrate for and does not inhibit or induce cytochrome P-450 (CYP) isoenzymes. Entecavir does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, or 2E1. Entecavir does not induce CYP isoenzymes 1A2, 2C9, 2C19, 3A4, 3A5, or 2B6. Pharmacokinetic interactions with drugs metabolized by CYP isoenzymes are unlikely.

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

Potential pharmacokinetic interactions with drugs that reduce renal function or that may compete with entecavir for active renal tubular secretion; increased serum concentrations of entecavir or the concomitantly used drug may occur. Although the effect of concomitant use of such drugs with entecavir has not been specifically studied, patients receiving entecavir in conjunction with other drugs that may affect renal function or are excreted renally should be monitored closely for adverse effects.

Adefovir Dipivoxil

No clinically important pharmacokinetic interactions with adefovir dipivoxil.

Antiretroviral Agents

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

No pharmacokinetic interactions between entecavir and lamivudine or tenofovir disoproxil fumarate (tenofovir DF).

In vitro evidence indicates that concurrent use of human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitors (NRTIs) and entecavir is unlikely to reduce the antiretroviral activity of the HIV NRTIs (abacavir, didanosine, lamivudine, stavudine, tenofovir, zidovudine) against HIV.

In vitro, concurrent use of HIV NRTIs (abacavir, didanosine, lamivudine, stavudine, tenofovir, zidovudine) does not reduce or antagonize the antiviral activity of entecavir against HBV.

Immunosuppressive Agents

Possible pharmacokinetic interactions with cyclosporine or tacrolimus (increased entecavir serum concentrations because of altered renal function).

In a small pilot study, entecavir exposures in HBV-infected liver transplant recipients receiving a stable dose of cyclosporine or tacrolimus were approximately twofold higher than those observed in healthy individuals 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 or tacrolimus was not formally evaluated.

Renal function should be monitored prior to and during entecavir treatment in patients (e.g., transplant patients) receiving cyclosporine, tacrolimus, or other immunosuppressive agents that may affect renal function.

Pharmacokinetics

Absorption

Bioavailability

Entecavir is well absorbed following oral administration.

Peak plasma concentrations are attained within 0.5-1.5 hours after a dose. Steady-state concentrations are achieved after 6-10 days of once-daily administration with approximately 2-fold accumulation.

Commercially available entecavir tablets and oral solution are bioequivalent.

Food

Food delays absorption, decreases peak plasma concentrations, and decreases the area under the plasma concentration-time curve (AUC) of entecavir.

Distribution

Extent

Entecavir is extensively distributed into tissues.

Entecavir is distributed into milk in rats; it is not known whether the drug is distributed into human milk.

Plasma Protein Binding

Entecavir is approximately 13% bound to serum proteins in vitro.

Elimination

Metabolism

Following oral administration, entecavir undergoes phosphorylation by cellular enzymes to form the active metabolite, entecavir triphosphate.

Entecavir is partially metabolized to glucuronide and sulfate conjugates.

Elimination Route

Entecavir is excreted principally in urine by both glomerular filtration and tubular secretion. Approximately 62-73% of an oral dose is eliminated unchanged in urine.

Hemodialysis removes approximately 13% of a dose in 4 hours; CAPD removes approximately 0.3% of a dose over 7 days.

Half-life

The terminal elimination half-life of entecavir is approximately 128-149 hours.

Special Populations

Adults with moderate or severe hepatic impairment (without hepatitis B virus [HBV] infection): Pharmacokinetics of entecavir are similar to those reported in adults without hepatic impairment.

Adults with impaired renal function (without HBV infection): Entecavir plasma concentrations and AUC are increased and clearance of the drug is decreased compared with adults without renal impairment..

Geriatric adults: AUC of entecavir is increased compared with younger adults, possibly as the result of age-related changes in renal function.

Pediatric patients 2 years to less than 18 years of age with compensated liver disease: Entecavir exposures in those who are nucleoside inhibitor-naive receiving the oral solution in a dosage of 0.015 mg/kg (up to 0.5 mg) once daily are similar to exposures observed in adults receiving a 0.5-mg tablet once daily. Exposures in those who are lamivudine-experienced receiving the oral solution in a dosage of 0.03 mg/kg (up to 1 mg) once daily are similar to exposures observed in adults receiving a 1-mg tablet once daily.

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