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    Nucleoside and Nucleotide Reverse Transcriptase Inhibitors/NRTIs for Hepatitis

    BOXED WARNING

    Hepatitis B exacerbation

    Patients may experience elevations in hepatic enzymes during entecavir treatment, thus the manufacturer recommends periodic monitoring of hepatic function during therapy. In addition, severe, acute hepatitis B exacerbation (defined as ALT elevations 10 times the upper limit of normal and 2 times baseline) has been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. During phase 3 clinical trials, a subset of patients were allowed to discontinue treatment at 52 weeks if they achieved a protocol-defined response to therapy. Six percent of nucleoside naive patients (1% of HBeAg-positive and 8% of HBeAg-negative patients) experienced hepatitis B exacerbations; the median time to exacerbation was 23—24 weeks after therapy discontinuation. Hepatic function should be monitored closely for at least several months after patients discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

    Hepatitis B and HIV coinfection, human immunodeficiency virus (HIV) infection

    Entecavir has not been studied, and is not recommended, for the treatment of human immunodeficiency virus (HIV) infection; however the drug does possess weak activity against HIV type 1. Patients with hepatitis B and HIV coinfection should not receive entecavir unless they are receiving a fully suppressive antiretroviral (ARV) treatment regimen for HIV; entecavir should not be considered part of the ARV regimen. Limited clinical data indicate that in patients coinfected with HIV and HBV who are not receiving adequate treatment for HIV, use of entecavir to treat HBV may induce human immunodeficiency virus (HIV) infection resistance. A man coinfected with HIV and HBV who received entecavir had selection of an HIV variant containing the M184V resistance substitution. At the time of entecavir initiation for HBV, he was not receiving highly active antiretroviral therapy (HAART) for HIV, though he was clinically stable in regard to his HIV infection. Within 2 months of entecavir initiation, the HBV DNA decreased by approximately 5.5 log10 IU/ml, and the HIV RNA decreased to approximately 2,000 copies/mL which was below baseline concentrations. While no HIV resistance was detected before entecavir receipt, the M184V substitution was detected 6 months after the initiation of entecavir therapy. HIV resistance may develop in a coinfected patient who is not receiving HAART and is taking entecavir. In contrast, among 68 patients taking lamivudine-containing HAART for HIV with stable HIV viral loads and CD4 counts, no differences in the HIV RNA concentrations or CD4 counts were noted for patients who received either entecavir or placebo for 24 weeks for concurrent HBV infection. Before initiating entecavir, HIV antibody testing should be offered to all patients in order to ensure appropriate treatment. HIV treatment guidelines recommend use of entecavir in combination with a fully suppressive ARV regimen, as an alternative treatment option for coinfected patients who are unable to take tenofovir. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still requires treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    Females, hepatic disease, hepatotoxicity or lactic acidosis, obesity

    Hepatotoxicity or lactic acidosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in females; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Patients with decompensated hepatic disease may be at higher risk for developing lactic acidosis. Treatment with entecavir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

    DEA CLASS

    Rx

    DESCRIPTION

    Nucleoside analog
    Used for chronic hepatitis B virus infection in nucleoside-naive and lamivudine resistant-patients
    Risk of lactic acidosis and hepatomegaly (like other nucleoside analogs)

    COMMON BRAND NAMES

    Baraclude

    HOW SUPPLIED

    Baraclude Oral Sol: 0.05mg, 1mL
    Baraclude/Entecavir Oral Tab: 0.5mg, 1mg

    DOSAGE & INDICATIONS

    For the treatment of chronic hepatitis B infection in patients with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (AST or ALT) or histologically active disease.
    For the treatment of chronic hepatitis B in nucleoside-treatment-naive patients with compensated liver disease.
    Oral dosage (tablets)
    Adults, Adolescents, and Children weighing more than 30 kg

    0.5 mg PO once daily on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Oral dosage (solution)
    Adults

    0.5 mg PO once daily on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children and Adolescents 2 years and older weighing more than 30 kg

    0.5 mg (10 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 27 to 30 kg

    0.45 mg (9 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 24 to 26 kg

    0.4 mg (8 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 21 to 23 kg

    0.35 mg (7 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 18 to 20 kg

    0.3 mg (6 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 15 to 17 kg

    0.25 mg (5 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 12 to 14 kg

    0.2 mg (4 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 10 to 11 kg

    0.15 mg (3 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    For treatment of chronic hepatitis B in patients with compensated liver disease and a history of hepatitis B viremia while receiving lamivudine or with known lamivudine or telbivudine resistance mutations (rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L).
    Oral dosage (tablets)
    Adults, Adolescents, and Children weighing more than 30 kg

    1 mg PO once daily on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Oral dosage (solution)
    Adults

    1 mg PO once daily on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children and Adolescents 2 years and older weighing more than 30 kg

    1 mg (20 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 27 to 30 kg

    0.9 mg (18 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 24 to 26 kg

    0.8 mg (16 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 21 to 23 kg

    0.7 mg (14 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 18 to 20 kg

    0.6 mg (12 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 15 to 17 kg

    0.5 mg (10 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 12 to 14 kg

    0.4 mg (8 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    Children 2 years and older weighing 10 to 11 kg

    0.3 mg (6 mL) PO once daily. Doses should be given on an empty stomach (2 hours before or after a meal). The optimal duration of therapy is not known.

    For the treatment of chronic hepatitis B in patients coinfected with HIV†.
    NOTE: Per HIV treatment guidelines, patients who are coinfected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV), and who are unable to receive tenofovir, may use entecavir as an alternative; however, entecavir must be use in combination with a fully suppressive antiretroviral treatment regimen that includes either lamivudine or emtricitabine. HIV and HBV resistance may develop in a coinfected patient who is not receiving HAART and is taking entecavir.
    Oral dosage
    Adults and Adolescents 16 years and older

    1 mg PO once daily on an empty stomach (2 hours before or after a meal) has been studied in combination with a lamivudine-containing highly active antiretroviral treatment (HAART) regimen. Of the 51 coinfected patients who received this treatment regimen, 34% achieved ALT normalization by week 24 (1 time upper limit of normal or less). HIV treatment guidelines recommend entecavir (0.5 mg PO once daily) in combination with lamivudine- or emtricitabine-containing HAART regimen as an alternative for coinfected patients unable to receive tenofovir. In coinfected patients with decompensated liver disease or lamivudine-resistant HBV infection, the guidelines recommend increasing the entecavir dose to 1 mg PO once daily.

    For the treatment of chronic hepatitis B in patients with decompensated liver disease.
    Oral dosage
    Adults

    1 mg PO once daily (2 hours before or after a meal). The optimal duration of therapy is not known.

    MAXIMUM DOSAGE

    Adults

    1 mg/day PO.

    Geriatric

    1 mg/day PO.

    Adolescents

    > 30 kg: 1 mg/day PO.
    > 26—30 kg: 0.9 mg/day PO (oral solution).
    > 23—26 kg: 0.8 mg/day PO (oral solution).
    > 20—23 kg: 0.7 mg/day PO (oral solution).

    Children

    >= 2 years and > 30 kg: 1 mg/day PO.
    >= 2 years and > 26—30 kg: 0.9 mg/day PO (oral solution).
    >= 2 years and > 23—26 kg: 0.8 mg/day PO (oral solution).
    >= 2 years and > 20—23 kg: 0.7 mg/day PO (oral solution).
    >= 2 years and > 17—20 kg: 0.6 mg/day PO (oral solution).
    >= 2 years and > 14—17 kg: 0.5 mg/day PO (oral solution).
    >= 2 years and > 11—14 kg: 0.4 mg/day PO (oral solution).
    >= 2 years and 10—11 kg: 0.3 mg/day PO (oral solution).
    < 2 years or < 10 kg: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Adults
    NOTE: According to the manufacturer, once-daily dosing regimens are preferred in patients with renal impairment. For doses less than 0.5 mg, the oral solution is recommended.
    CrCl >= 50 mL/min: No dosage adjustment is needed.
    CrCl 30—49 mL/min: 0.25 mg PO once daily or 0.5 mg PO every 48 hours for nucleoside-treatment naive patients; 0.5 mg PO once daily  or 1 mg PO every 48 hours for lamivudine-refractory patients.
    CrCl 10—29 mL/min: 0.15 mg PO once daily or 0.5 mg PO every 72 hours for nucleoside-treatment naive patients; 0.3 mg PO once daily or 1 mg PO every 72 hours for lamivudine-refractory patients.
    CrCl < 10 mL/min: 0.05 mg PO once daily or 0.5 mg PO every 7 days for nucleoside-treatment naive patients; 0.1 mg PO once daily or 1 mg PO every 7 days for lamivudine-refractory patients.
     
    Pediatrics
    Although data are lacking for dose recommendations in pediatric patients with renal impairment, the manufacturer recommends that dose adjustments similar to those recommended in adult patients should be considered.
     
    Intermittent hemodialysis
    Nucleoside-treatment naive patients should receive 0.05 mg PO once daily or 0.5 mg PO every 7 days and lamivudine refractory-patients should receive 0.1 mg PO once daily or 1 mg PO every 7 days. On days of dialysis, the dose should be administered after dialysis.
     
    Peritoneal dialysis
    Nucleoside-treatment naive patients should receive 0.05 mg PO once daily or 0.5 mg PO every 7 days and lamivudine refractory-patients should receive 0.1 mg PO once daily or 1 mg PO every 7 days.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Oral Administration

    Administer on an empty stomach (2 hours before or after a meal).
    Tablets and a ready-to-use oral solution (0.05 mg/mL) are available to be administered orally. The two dosage forms can be used interchangeably; however, pediatric patients <= 30 kg should receive the oral solution.

    Oral Liquid Formulations

    Administer using the calibrated oral dosing spoon provided to give an accurate dosage.

    STORAGE

    Baraclude:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in carton

    CONTRAINDICATIONS / PRECAUTIONS

    Hepatitis B exacerbation

    Patients may experience elevations in hepatic enzymes during entecavir treatment, thus the manufacturer recommends periodic monitoring of hepatic function during therapy. In addition, severe, acute hepatitis B exacerbation (defined as ALT elevations 10 times the upper limit of normal and 2 times baseline) has been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. During phase 3 clinical trials, a subset of patients were allowed to discontinue treatment at 52 weeks if they achieved a protocol-defined response to therapy. Six percent of nucleoside naive patients (1% of HBeAg-positive and 8% of HBeAg-negative patients) experienced hepatitis B exacerbations; the median time to exacerbation was 23—24 weeks after therapy discontinuation. Hepatic function should be monitored closely for at least several months after patients discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

    Hepatitis B and HIV coinfection, human immunodeficiency virus (HIV) infection

    Entecavir has not been studied, and is not recommended, for the treatment of human immunodeficiency virus (HIV) infection; however the drug does possess weak activity against HIV type 1. Patients with hepatitis B and HIV coinfection should not receive entecavir unless they are receiving a fully suppressive antiretroviral (ARV) treatment regimen for HIV; entecavir should not be considered part of the ARV regimen. Limited clinical data indicate that in patients coinfected with HIV and HBV who are not receiving adequate treatment for HIV, use of entecavir to treat HBV may induce human immunodeficiency virus (HIV) infection resistance. A man coinfected with HIV and HBV who received entecavir had selection of an HIV variant containing the M184V resistance substitution. At the time of entecavir initiation for HBV, he was not receiving highly active antiretroviral therapy (HAART) for HIV, though he was clinically stable in regard to his HIV infection. Within 2 months of entecavir initiation, the HBV DNA decreased by approximately 5.5 log10 IU/ml, and the HIV RNA decreased to approximately 2,000 copies/mL which was below baseline concentrations. While no HIV resistance was detected before entecavir receipt, the M184V substitution was detected 6 months after the initiation of entecavir therapy. HIV resistance may develop in a coinfected patient who is not receiving HAART and is taking entecavir. In contrast, among 68 patients taking lamivudine-containing HAART for HIV with stable HIV viral loads and CD4 counts, no differences in the HIV RNA concentrations or CD4 counts were noted for patients who received either entecavir or placebo for 24 weeks for concurrent HBV infection. Before initiating entecavir, HIV antibody testing should be offered to all patients in order to ensure appropriate treatment. HIV treatment guidelines recommend use of entecavir in combination with a fully suppressive ARV regimen, as an alternative treatment option for coinfected patients who are unable to take tenofovir. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still requires treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    Organ transplant

    If entecavir treatment is determined to be necessary in an organ transplant recipient who is receiving an immunosuppressant that may affect renal function (i.e., cyclosporine, tacrolimus), renal function should be monitored carefully both before and during treatment with entecavir. The safety and effectiveness of entecavir were evaluated in an open-label study involving 65 patients receiving a liver transplant for complications of chronic hepatitis B virus (HBV) infection. Patients were administered entecavir 1 mg PO daily in addition to usual post-transplant treatment, including hepatitis B immune globulin. Of the 65 enrolled patients, 61 received more than 4 weeks of entecavir therapy. All 61 patients experienced loss of HBsAg post-transplant; however, in 2 patients measurable HBsAg levels reoccurred but without recurrence of HBV viremia. At trial completion (defined as greater than or equal to 72 weeks of treatment post-transplant) 53 patients had HBV DNA levels < 50 international units/ml, no patients had HBV DNA levels > 50 international units/ml, and 8 patients did not have HBV DNA data. Adverse events were determined to be consistent with the known safety profile of entecavir and with the liver transplant population.

    Females, hepatic disease, hepatotoxicity or lactic acidosis, obesity

    Hepatotoxicity or lactic acidosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in females; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Patients with decompensated hepatic disease may be at higher risk for developing lactic acidosis. Treatment with entecavir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

    Dialysis, geriatric, renal failure, renal impairment

    Dosage adjustments are recommended in patients with renal impairment (CrCl < 50 mL/min) or renal failure, including patients on dialysis. Clinical studies of entecavir did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects; however, 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 geriatric patients are more likely to have decreased renal function, the dose of entecavir may need to be modified based on renal function; in addition, it may be useful to monitor renal function during entecavir therapy.

    Children, infants, neonates

    Safety and efficacy of entecavir in neonates, infants, or children < 2 years or < 10 kg have not been established.

    Breast-feeding

    It is not known if entecavir is excreted in human breast milk as studies in nursing mothers have not been conducted. Antiviral medications whose passage into human breast milk have been evaluated include tenofovir and lamivudine. According to the manufacturer, a decision should be made to discontinue nursing or to discontinue use of the drug; however, a consensus among health care providers has not been established. In a survey of 226 physicians, 30.5% would recommend breast-feeding for HBV-infected mothers on antiviral therapy, 44% would not recommend breast-feeding during antiviral therapy, and 25.2% stated they were unsure. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Pregnancy

    Entecavir is classified in FDA pregnancy category C. NRTIs are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in-utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some of the early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester of pregnancy and any new symptoms should be evaluated thoroughly. There are no adequate and well-controlled studies of entecavir in pregnant women. Reproduction studies have been performed in rats and rabbits at orally administered doses of up to 200 mg (16 mg/kg/day) and showed no maternal or embryo toxicity; these dosages were equivalent to 28—212 times the systemic exposures that are achieved at a dosage of 1 mg/day in humans. At exposures of 3100 times those used in humans, maternal toxicity and embryo-fetal toxicities have been observed in rats. Likewise, embryo-fetal toxicities have been observed in rabbits at exposures of 883 times those seen in humans. 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. It is strongly encouraged that health care providers who are treating pregnant women or their newborns report cases of prenatal exposure to the Antiretroviral Pregnancy Registry; telephone 800—258—4263; fax 800—800—1052; the Antiretroviral Pregnancy Registry is also accessible via the Internet. There are no data on the effect of entecavir on transmission of hepatitis B virus from mother to infant during labor and obstetric delivery; therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV including immunizations in accordance with current guidelines.

    ADVERSE REACTIONS

    Severe

    hepatic encephalopathy / Delayed / 10.0-10.0
    renal failure (unspecified) / Delayed / 0-1.0
    anaphylactoid reactions / Rapid / Incidence not known
    lactic acidosis / Delayed / Incidence not known

    Moderate

    peripheral edema / Delayed / 16.0-16.0
    ascites / Delayed / 15.0-15.0
    elevated hepatic enzymes / Delayed / 2.0-12.0
    hematuria / Delayed / 9.0-9.0
    glycosuria / Early / 4.0-4.0
    hyperglycemia / Delayed / 2.0-3.0
    hyperbilirubinemia / Delayed / 2.0-3.0
    hypoalbuminemia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    hepatomegaly / Delayed / Incidence not known
    steatosis / Delayed / Incidence not known

    Mild

    fever / Early / 14.0-14.0
    infection / Delayed / 10.0-10.0
    headache / Early / 2.0-4.0
    fatigue / Early / 1.0-3.0
    dyspepsia / Early / 0-1.0
    vomiting / Early / 0-1.0
    nausea / Early / 0-1.0
    diarrhea / Early / 0-1.0
    drowsiness / Early / 0-1.0
    insomnia / Early / 0-1.0
    abdominal pain / Early / 1.0
    dizziness / Early / 3.0
    rash (unspecified) / Early / 1.0
    alopecia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acyclovir: (Moderate) Because entecavir is primarily eliminated by the kidneys and acyclovir can affect renal function, concurrent administration with acyclovir may increase the serum concentrations of entecavir and adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals (i.e., anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs)) are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Additionally, while both entecavir and adefovir are eliminated by active tubular secretion, per the manufacturer of entecavir, neither the pharmacokinetics of entecavir nor adefovir were altered when given concomitantly.
    Alogliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Amiloride: (Moderate) Both entecavir and amiloride are secreted by active tubular secretion. In theory, coadministration of entecavir with amiloride may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Both entecavir and amiloride are secreted by active tubular secretion. In theory, coadministration of entecavir with amiloride may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Aminoglycosides: (Moderate) Because entecavir is primarily eliminated by the kidneys and aminoglycosides can affect renal function, concurrent administration with aminoglycosides may increase the serum concentrations of entecavir and adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Amlodipine; Benazepril: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Entecavir is primarily eliminated by the kidneys and amphotericin B can affect renal function; concurrent administration may increase the serum concentrations of entecavir and adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Amphotericin B lipid complex (ABLC): (Moderate) Entecavir is primarily eliminated by the kidneys and amphotericin B can affect renal function; concurrent administration may increase the serum concentrations of entecavir and adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Amphotericin B liposomal (LAmB): (Moderate) Entecavir is primarily eliminated by the kidneys and amphotericin B can affect renal function; concurrent administration may increase the serum concentrations of entecavir and adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Amphotericin B: (Moderate) Entecavir is primarily eliminated by the kidneys and amphotericin B can affect renal function; concurrent administration may increase the serum concentrations of entecavir and adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Angiotensin-converting enzyme inhibitors: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Benazepril: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Canagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Capreomycin: (Major) Because entecavir is primarily eliminated by the kidneys and capreomycin could affect renal function, concurrent administration may increase entecavir serum concentrations and the risk of adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when administered with potentially nephrotoxic agents, such as capreomycin.
    Captopril: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Cidofovir: (Moderate) Entecavir may affect renal function and should be used cautiously in combination with other drugs that may also affect renal function, including cidofovir.
    Cimetidine: (Moderate) Both entecavir and cimetidine are secreted by active tubular secretion. In theory, coadministration of entecavir with cimetidine may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Cisplatin: (Moderate) Because entecavir is primarily eliminated by the kidneys and cisplatin can affect renal function, concurrent administration with cisplatin may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Colistimethate, Colistin, Polymyxin E: (Major) The manufacturer of entecavir recommends monitoring for adverse effects when administered with potentially nephrotoxic agents, such as colistimethate sodium. Because entecavir is primarily eliminated by the kidneys and colistimethate sodium can affect renal function, concurrent administration may increase entecavir serum concentrations and the risk of adverse events.
    Cyclosporine: (Moderate) In a small pilot study of entecavir in HBV-infected liver transplant recipients on stable doses of cyclosporine, 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. Monitor renal function.
    Dapagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Dextromethorphan; Quinidine: (Major) Both entecavir and quinidine are secreted by active tubular secretion. In theory, coadministration of entecavir with quinidine may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Digoxin: (Moderate) Both entecavir and digoxin are secreted by active tubular secretion. In theory, coadministration of entecavir with digoxin may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Dofetilide: (Major) In the manufacturers package label for dofetilide, administration of drugs that are excreted via renal tubular secretion should be used very cautiously, if at all, with dofetilide. Entecavir is also excreted via renal tubular excretion.
    Donepezil; Memantine: (Moderate) Entecavir is eliminated by active tubular secretion. In theory, coadministration of entecavir with other drugs that are eliminated by active tubular secretion, such as memantine, may increase the serum concentrations of entecavir or memantine due to competition for the drug elimination pathway.
    Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
    Empagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Enalapril, Enalaprilat: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Enalapril; Felodipine: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Food: (Moderate) The pharmacokinetic parameters of anti-retroviral medications (anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs), anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), anti-retroviral nucleotide reverse transcriptase inhibitors, and anti-retroviral protease inhibitors) metabolized through the CYP isoenzyme system are slightly altered by smoked and oral marijuana. Despite this interaction, marijuana is not expected to adversely affect anti-retroviral efficacy. However, the incidence of marijuana associated adverse effects may change following coadministration with anti-retroviral drugs. Many anti-retrovirals are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with anti-retrovirals, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Foscarnet: (Moderate) Entecavir may affect renal function and should be used cautiously in combination with other drugs that may also affect renal function including foscarnet.
    Fosinopril: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Ganciclovir: (Moderate) Entecavir may affect renal function and should be used cautiously in combination with other drugs that may also affect renal function including ganciclovir.
    Glipizide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Glyburide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Both entecavir and triamterene are secreted by active tubular secretion. In theory, coadministration of entecavir with triamterene may increase the serum concentrations of either drug due to competition for the drug elimination pathway. Monitor for adverse effects when these drugs are coadministered.
    Interferon Alfa-2b; Ribavirin: (Major) The concomitant use of ribavirin and entecavir should be done with caution. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Interferons: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Ketoconazole: (Moderate) Both entecavir and ketoconazole are secreted by active tubular secretion. In theory, coadministration of entecavir with ketoconazole may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Linagliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Lisinopril: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Megestrol: (Minor) Entecavir and megestrol are eliminated by active tubular secretion. In theory, coadministration of these drugs may increase the serum concentrations of either drug due to competition for the drug elimination pathway.
    Memantine: (Moderate) Entecavir is eliminated by active tubular secretion. In theory, coadministration of entecavir with other drugs that are eliminated by active tubular secretion, such as memantine, may increase the serum concentrations of entecavir or memantine due to competition for the drug elimination pathway.
    Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Metformin; Pioglitazone: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Metformin; Repaglinide: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Metformin; Rosiglitazone: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Metformin; Saxagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Metformin; Sitagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Midodrine: (Moderate) Both entecavir and midodrine are secreted by active tubular secretion. In theory, coadministration of entecavir with midodrine may increase the serum concentrations of either drug due to competition for the drug elimination pathway.
    Moexipril: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Morphine: (Moderate) Both entecavir and morphine are secreted by active tubular secretion. In theory, coadministration of entecavir with morphine may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Morphine; Naltrexone: (Moderate) Both entecavir and morphine are secreted by active tubular secretion. In theory, coadministration of entecavir with morphine may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Non-Ionic Contrast Media: (Moderate) Because entecavir is primarily eliminated by the kidneys and radiopaque contrast agents can affect renal function, concurrent administration with radiopaque contrast agents may increase the serum concentrations of entecavir and adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Nonsteroidal antiinflammatory drugs: (Moderate) The manufacturer of entecavir recommends monitoring for adverse effects when coadministered with NSAIDs. Entecavir is primarily eliminated by the kidneys; NSAIDs can affect renal function. Concurrent administration may increase the serum concentrations of entecavir and adverse events.
    Orlistat: (Major) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
    Pamidronate: (Moderate) Because entecavir is primarily eliminated by the kidneys and pamidronate can affect renal function, concurrent administration with pamidronate may increase the serum concentrations of entecavir and adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Pancuronium: (Moderate) Both entecavir and pancuronium are secreted by active tubular secretion. In theory, coadministration of entecavir with pancuronium may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Perindopril: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Perindopril; Amlodipine: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Polymyxins: (Major) The manufacturer of entecavir recommends monitoring for adverse effects when administered with potentially nephrotoxic agents, such as colistimethate sodium. Because entecavir is primarily eliminated by the kidneys and colistimethate sodium can affect renal function, concurrent administration may increase entecavir serum concentrations and the risk of adverse events.
    Procainamide: (Major) Both entecavir and procainamide are secreted by active tubular secretion. In theory, coadministration of entecavir with procainamide may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Prochlorperazine: (Moderate) Both entecavir and prochlorperazine are secreted by active tubular secretion. In theory, coadministration of entecavir with prochlorperazine may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Quinapril: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Quinidine: (Major) Both entecavir and quinidine are secreted by active tubular secretion. In theory, coadministration of entecavir with quinidine may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Quinine: (Major) Both entecavir and quinine are secreted by active tubular secretion. In theory, coadministration of entecavir with quinine may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Ramipril: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Ranitidine: (Moderate) Both entecavir and ranitidine are secreted by active tubular secretion. In theory, coadministration of entecavir with ranitidine may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Ribavirin: (Major) The concomitant use of ribavirin and entecavir should be done with caution. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Both entecavir and trimethoprim are secreted by active tubular secretion. In theory, coadministration of entecavir with trimethoprim may increase the serum concentrations of either drug due to competition for the drug elimination pathway.
    Tacrolimus: (Moderate) In a small pilot study of entecavir in HBV-infected liver transplant recipients on stable doses of tacrolimus, 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. Monitor renal function.
    Trandolapril: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Trandolapril; Verapamil: (Moderate) Because entecavir is primarily eliminated by the kidneys and ACE inhibitors can affect renal function, concurrent administration with ACE inhibitors may increase the serum concentrations of entecavir and adverse events. Monitor for adverse effects when these drugs are coadministered.
    Triamterene: (Minor) Both entecavir and triamterene are secreted by active tubular secretion. In theory, coadministration of entecavir with triamterene may increase the serum concentrations of either drug due to competition for the drug elimination pathway. Monitor for adverse effects when these drugs are coadministered.
    Trimethoprim: (Moderate) Both entecavir and trimethoprim are secreted by active tubular secretion. In theory, coadministration of entecavir with trimethoprim may increase the serum concentrations of either drug due to competition for the drug elimination pathway.
    Trospium: (Moderate) Both entecavir and trospium are secreted by active tubular secretion. In theory, coadministration of entecavir with trospium may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Valacyclovir: (Moderate) Entecavir may affect renal function and should be used cautiously in combination with other drugs that may also affect renal function including valacyclovir.
    Valganciclovir: (Moderate) Entecavir may affect renal function and should be used cautiously in combination with other drugs that may also affect renal function including valganciclovir.
    Vancomycin: (Moderate) Vancomycin and entecavir both undergo renal tubular secretion. Monitor patients closely for adverse events when these drugs are coadministered. Elevated serum concentrations of either drug may occur.
    Zoledronic Acid: (Moderate) Entecavir may affect renal function and should be used cautiously in combination with other drugs that may also affect renal function including zoledronic acid.

    PREGNANCY AND LACTATION

    Pregnancy

    Entecavir is classified in FDA pregnancy category C. NRTIs are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in-utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some of the early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester of pregnancy and any new symptoms should be evaluated thoroughly. There are no adequate and well-controlled studies of entecavir in pregnant women. Reproduction studies have been performed in rats and rabbits at orally administered doses of up to 200 mg (16 mg/kg/day) and showed no maternal or embryo toxicity; these dosages were equivalent to 28—212 times the systemic exposures that are achieved at a dosage of 1 mg/day in humans. At exposures of 3100 times those used in humans, maternal toxicity and embryo-fetal toxicities have been observed in rats. Likewise, embryo-fetal toxicities have been observed in rabbits at exposures of 883 times those seen in humans. 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. It is strongly encouraged that health care providers who are treating pregnant women or their newborns report cases of prenatal exposure to the Antiretroviral Pregnancy Registry; telephone 800—258—4263; fax 800—800—1052; the Antiretroviral Pregnancy Registry is also accessible via the Internet. There are no data on the effect of entecavir on transmission of hepatitis B virus from mother to infant during labor and obstetric delivery; therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV including immunizations in accordance with current guidelines.

    It is not known if entecavir is excreted in human breast milk as studies in nursing mothers have not been conducted. Antiviral medications whose passage into human breast milk have been evaluated include tenofovir and lamivudine. According to the manufacturer, a decision should be made to discontinue nursing or to discontinue use of the drug; however, a consensus among health care providers has not been established. In a survey of 226 physicians, 30.5% would recommend breast-feeding for HBV-infected mothers on antiviral therapy, 44% would not recommend breast-feeding during antiviral therapy, and 25.2% stated they were unsure. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Entecavir is a guanosine nucleoside analog with selective and potent activity against hepatitis B virus (HBV), including lamivudine-resistant HBV. Entecavir is phosphorylated to the active triphosphate form and competes with the natural substrate deoxyguanosine triphosphate thereby suppressing HBV replication; suppression of replication occurs at all 3 activities of HBV polymerase (reverse transcriptase): (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. In addition, entecavir triphosphate is a weak inhibitor of cellular DNA polymerase alpha, beta, and delta and mitochondrial DNA polymerase-gamma.
     
    Entecavir displays weak activity against human immunodeficiency virus (HIV); thus, this drug must not be considered an active component in a fully suppressive HIV treatment regimen. The EC50 value of entecavir against a variety of HIV type 1 laboratory strains ranged from 0.026 to > 10 micromolar in cell culture assays. Three patients coinfected with HBV and HIV not taking highly active antiretroviral therapy (HAART) had a 1-log10 reduction in HIV RNA while taking entecavir; however, selection for a HIV-resistant strain may occur. In cell cultures, entecavir selected for an M184I substitution in HIV reverse transcriptase.

    PHARMACOKINETICS

    Entecavir is administered orally as a tablet or oral solution. It is extensively distributed into tissues and is approximately 13% bound to serum proteins. Peak plasma concentrations decrease in a biexponential manner with a terminal half-life of 128—149 hours; an effective accumulation half-life of 24 hours is suggested as the accumulation index is approximately 2-fold. Entecavir is predominately eliminated by the kidney with 62—73% of the dose recovered as unchanged drug in the urine. Entecavir undergoes both glomerular filtration and net tubular secretion. Entecavir is not a substrate, inhibitor, or inducer of the CYP 450 enzyme system.

    Oral Route

    Entecavir oral solution is 100% bioavailable compared to the tablet; the dosage forms can be used interchangeably. Oral absorption of entecavir is affected by food; food delays absorption, decreases Cmax concentrations by 44—46%, and decreases AUC concentrations by 18—20%. Administer entecavir at least 2 hours before or after a meal. Peak plasma concentrations of entecavir occur 0.5—1 hour after oral administration and Cmax and AUC concentrations increase in proportion to the dose following multiple, daily dosing. Steady state concentrations are achieved after 6—10 days of once daily dosing. In adult patients, Cmax concentrations at steady state are 4.2 ng/mL for a 0.5 mg oral dose and 8.2 ng/mL for a 1 mg oral dose. Corresponding trough concentrations are 0.3 ng/mL and 0.5 ng/mL for the 0.5 mg and 1 mg doses, respectively. After oral administration, no oxidative or acetylated metabolites are observed.