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entecavir 0.5 mg tablet generic baraclude

In stock Manufacturer CAMBER PHARMACE 31722083330
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Uses

Chronic Hepatitis B Virus Infection

Entecavir is used for the management of chronic hepatitis B virus (HBV) infection in adults and adolescents 16 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. This indication is based on histologic, virologic, biochemical, and serologic responses in nucleoside-naive (had not previously received treatment with nucleoside antivirals) adults and adolescents 16 years of age or older and in adults with lamivudine-resistant HBV with HBeAg-positive or -negative chronic HBV with compensated liver function. Limited information is available from a study in adults with chronic HBV infection who were coinfected with both HBV and human immunodeficiency virus (HIV) infection and previously received lamivudine therapy. The relationship between these treatment responses and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis is not known. Patient management guidelines employed in these clinical studies were determined by a predefined protocol and are not intended as guidance in clinical practice.

Entecavir should not be used for the treatment of HBV infection in HIV-infected patients who are not receiving antiretroviral therapy.(See Individuals Coinfected with HBV and HIV under Cautions: Warning/Precautions.)

Safety and efficacy of entecavir have not been established for treatment of HBV infection in patients with liver transplants.(See Liver Transplant Recipients under Cautions: Warnings/Precautions.)

Safety and efficacy of entecavir have not been established for treatment of HBV infection in patients with decompensated liver disease.

The goal of antiviral therapy in patients with chronic HBV infection is to achieve sustained suppression of HBV replication and remission of liver disease. The long-term goal of therapy is to prevent cirrhosis, hepatic failure, and hepatocellular carcinoma. Currently available therapies for chronic HBV infection (e.g., entecavir, adefovir, lamivudine, telbivudine, tenofovir, interferon alfa, peginterferon alfa) do not eradicate HBV and may have only limited long-term efficacy. Therefore, decisions on the appropriate time to initiate therapy should take into consideration the patient's age, severity of liver disease, likelihood of response, potential for selection of resistant HBV strains, and potential for adverse reactions and complications.

The American Association for the Study of Liver Diseases (AASLD) states that treatment is indicated if both the risk of liver-related morbidity and mortality in the near future (5-10 years) and the likelihood of achieving viral suppression during continuing treatment are high. Treatment also is indicated if both the risk of liver-related morbidity and mortality in the foreseeable future (10-20 years) and the likelihood of achieving sustained viral suppression after a defined course of therapy are high. These experts state that treatment is not indicated if both the risk of liver-related morbidity or mortality in the next 20 years and the likelihood of achieving sustained viral suppression after a defined course of treatment are low. Factors to consider in selecting an antiviral agent for initial therapy include safety and efficacy, risks of drug resistance, pregnancy potential (women), cost, and patient and provider preferences. Entecavir is one of several first-line agents that can be used in the treatment of HBV infection.

Because the treatment of chronic HBV infection is complex and rapidly evolving, it is recommended that treatment be directed by clinicians who are familiar with the disease, and that a specialist be consulted to obtain the most up-to-date information.

HBeAg-positive Patients

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 0.5 mg of entecavir daily had normal serum ALT concentrations (i.e., biochemical response) at week 48 compared with 60% of those receiving lamivudine. 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 0.5 mg daily 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, respectively, who received 0.5 mg of entecavir daily or 100 mg of lamivudine daily. 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 Patients

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 daily. 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 0.5 mg daily compared with a mean decrease of 4.53 log10 copies/mL in those receiving lamivudine 100 mg daily. 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.

Patients 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 active 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.

HIV-infected Individuals

Entecavir has been evaluated for the treatment of chronic HBV infection in a phase III, randomized, double-blind, active-controlled study (AI463038) in HIV-infected patients receiving highly active antiretroviral therapy (HAART) that included lamivudine. These 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.

Patients with HBV who are 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 Individuals Coinfected with HBV and HIV under Cautions: Warning/Precautions.)

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 should not be diluted or mixed with water or any other liquid.

Dosage

Chronic Hepatitis B Virus Infection

For the treatment of chronic hepatitis B virus (HBV) infection in nucleoside-naive (had not previously received treatment with nucleoside antivirals) adults and adolescents 16 years of age and older, the recommended dosage of entecavir is 0.5 mg once daily. Adults and 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 optimum duration of entecavir therapy in patients with chronic HBV infection is not known.

Because severe, sometimes fatal, acute exacerbations of hepatitis have occurred in patients with HBV infection following discontinuance of anti-HBV therapy, hepatic function should be closely monitored at repeated intervals over a period of time (e.g., for at least several months) following discontinuance of entecavir. If appropriate, resumption of anti-HBV therapy may be warranted.(See Exacerbation of Hepatitis under Cautions: Warnings/Precautions.)

Special Populations

Dosage of entecavir should be adjusted in patients 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 1.) According to the manufacturer, the once daily regimens are preferred. Patients undergoing hemodialysis should receive the entecavir dose after the dialysis session.

Table 1. Dosage for Treatment of HBV Infection in Adults and Adolescents 16 Years of Age and Older with Renal Impairment[1 ]
Creatinine Clearance (mL/min) Recommended dosage in nucleoside-naive patients Recommended dosage in lamivudine-refractory patients
30 to less than 50 0.25 mg once daily or 0.5 mg once every 48 hours 0.5 mg once daily or1 mg once every 48 hours
10 to less than 30 0.15 mg once daily or 0.5 mg once every 72 hours 0.3 mg once daily or1 mg once every 72 hours
Less than 10, hemodialysis, or continuous ambulatory peritoneal dialysis (CAPD) 0.05 mg once daily or0.5 mg once every 7 days 0.1 mg once daily or1 mg once every 7 days

Dosage adjustments are not necessary in patients with hepatic impairment.

Cautions

Contraindications

The manufacturer states there are no known contraindications to the use of entecavir.

Warnings/Precautions

Warnings

Exacerbation of Hepatitis

Severe acute exacerbations of hepatitis have occurred 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 monitored during entecavir therapy and should be monitored closely with both clinical and laboratory follow-up at repeated intervals for at least several months after entecavir is discontinued. If appropriate, resumption of anti-HBV therapy may be warranted.

Individuals Coinfected with HBV and HIV

Use of entecavir for treatment of chronic HBV infection in patients with unrecognized or untreated HIV infection may result in emergence of HIV isolates with resistance to nucleoside reverse transcriptase inhibitors (NRTIs). Prior to initiation of entecavir therapy, all patients should be offered HIV testing.

Entecavir has some activity against HIV and there are at least 3 reports of virologic suppression of HIV (i.e., reduction in plasma HIV-1 RNA levels of at least 1 log10 copies/mL) in patients coinfected with HBV and HIV who were receiving entecavir for treatment of HBV infection but were not receiving antiretroviral therapy. HIV-1 resistance testing identified the M184V mutation (confers resistance to abacavir, emtricitabine) in at least 1 of these patients following 6 months of entecavir therapy; this mutation was not present at baseline.

Entecavir has not been systematically evaluated in HIV-infected patients with HBV 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.

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 transaminase elevations).

General Precautions

Liver Transplant Recipients

The safety and efficacy of entecavir in liver transplant recipients have not been evaluated. If use of the drug 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.)

Specific Populations

Pregnancy

Category C.

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

There are no studies in pregnant women and no data regarding the effect of entecavir on vertical transmission of HBV; infants born to HBV-infected women should receive the usually recommended combined regimen of hepatitis B virus vaccine and hepatitis B immune globulin (HBIG).

Lactation

Not known whether entecavir is distributed into milk. Discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy not established in children younger than 16 years of age.

Geriatric Use

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

Entecavir 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 Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects reported in 3% or more of patients 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).

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.

Drugs Affecting or 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 pharmacokinetic interaction observed with adefovir dipivoxil.

Immunosuppressive Agents

Possible pharmacokinetic interaction (increased entecavir serum concentrations because of altered renal function) with cyclosporine or tacrolimus. Monitor renal function prior to and during entecavir treatment in patients (e.g., transplant patients) receiving cyclosporine, tacrolimus, or other immunosuppressive agents that may affect renal function.

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

No pharmacokinetic interaction observed with lamivudine or tenofovir disoproxil fumarate.

In vitro evidence indicates that concurrent use of nucleoside reverse transcriptase inhibitors (NRTIs) and entecavir is unlikely to reduce the antiviral efficacy of entecavir against HBV or the antiretroviral activity of NRTIs (e.g., abacavir, didanosine, lamivudine, stavudine, tenofovir disoproxil fumarate, or zidovudine) against HIV.

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