Baraclude

Nucleoside and Nucleotide Analog Antivirals for Hepatitis B

For storage information, see specific product information within the How Supplied section.
Hazardous Drugs Classification
NIOSH 2016 List: Group 2
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.

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 or less should receive the oral solution.

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

hepatic encephalopathy / Delayed / 10.0-10.0
hepatitis B exacerbation / Delayed / 6.0-6.0
renal failure (unspecified) / Delayed / 0-1.0
anaphylactoid reactions / Rapid / Incidence not known
lactic acidosis / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known

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

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

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 (2% of HBeAg-positive and 8% of HBeAg-negative patients) experienced hepatitis B exacerbations; the median time to exacerbation was 23 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.

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.

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).

Baraclude

Rx

Nucleoside analog
Used for chronic hepatitis B virus infection in nucleoside-naive and lamivudine resistant-patients, and patients with decompensated hepatic disease
In HBV/HIV coinfected patients, entecavir cannot be considered an active component of a HAART regimen

0.5 mg PO once daily. The optimal duration of therapy is not known.

0.5 mg PO once daily. The optimal duration of therapy is not known.

0.5 mg PO once daily. The optimal duration of therapy is not known.

0.5 mg PO once daily. The optimal duration of therapy is not known.

0.5 mg PO once daily. The optimal duration of therapy is not known.

0.5 mg PO once daily. The optimal duration of therapy is not known.

0.45 mg PO once daily. The optimal duration of therapy is not known.

0.4 mg PO once daily. The optimal duration of therapy is not known.

0.35 mg PO once daily. The optimal duration of therapy is not known.

0.3 mg PO once daily. The optimal duration of therapy is not known.

0.25 mg PO once daily. The optimal duration of therapy is not known.

0.2 mg PO once daily. The optimal duration of therapy is not known.

0.15 mg PO once daily. The optimal duration of therapy is not known.

1 mg PO once daily.The optimal duration of therapy is not known.

1 mg PO once daily. The optimal duration of therapy is not known.

1 mg PO once daily. The optimal duration of therapy is not known.

1 mg PO once daily. The optimal duration of therapy is not known.

1 mg PO once daily. The optimal duration of therapy is not known.

1 mg PO once daily. The optimal duration of therapy is not known.

0.9 mg PO once daily. The optimal duration of therapy is not known.

0.8 mg PO once daily. The optimal duration of therapy is not known.

0.7 mg PO once daily. The optimal duration of therapy is not known.

0.6 mg PO once daily. The optimal duration of therapy is not known.

0.5 mg PO once daily. The optimal duration of therapy is not known.

0.4 mg PO once daily. The optimal duration of therapy is not known.

0.3 mg PO once daily. The optimal duration of therapy is not known.

0.5 mg PO once daily in combination with lamivudine- or emtricitabine-containing HAART regimen as an alternative for coinfected persons unable to receive tenofovir. Increase the dose to 1 mg PO once daily in coinfected persons with decompensated liver disease or lamivudine-resistant HBV infection. Entecavir must be used in combination with a fully suppressive antiretroviral treatment regimen that includes either lamivudine or emtricitabine. HIV and HBV resistance may develop in a coinfected person who is not receiving HAART and is taking entecavir.

0.5 mg PO once daily in combination with lamivudine- or emtricitabine-containing HAART regimen as an alternative for coinfected persons unable to receive tenofovir. Increase the dose to 1 mg PO once daily in coinfected persons with decompensated liver disease or lamivudine-resistant HBV infection. Entecavir must be used in combination with a fully suppressive antiretroviral treatment regimen that includes either lamivudine or emtricitabine. HIV and HBV resistance may develop in a coinfected person who is not receiving HAART and is taking entecavir.

1 mg PO once daily. The optimal duration of therapy is not known.

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

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 or greater: No dosage adjustment is needed.
CrCl 30 to 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 to 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 less than 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.

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 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) Closely monitor for entecavir-related adverse reactions if coadministration with cisplatin is necessary. Entecavir is primarily eliminated by the kidneys and cisplatin can cause nephrotoxicity; entecavir concentrations may be increased. The effects of coadministration of entecavir with drugs that are known to affect renal function have not been evaluated.
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.
Colistin: (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; 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.
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; 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.
Ertugliflozin; 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.
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; 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.
Interferons: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
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.
Levoketoconazole: (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.
Lisinopril; 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.
Megestrol: (Minor) Entecavir and megestrol are eliminated by active renal tubular secretion. In theory, coadministration of these drugs may increase the serum concentrations of either drug due to competition for the drug elimination pathway. Coadministration of entecavir with antiviral drugs known to be eliminated by active tubular secretion did not result in significant drug interactions in studies.
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; 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: (Moderate) 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) Monitor patients receiving pancuronium and entecavir closely. Coadministration may increase serum concentrations of either drug due to competition for elimination via active tubular secretion.
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.
Pioglitazone; 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.
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.
Quinapril; 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.
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.
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.
Triamterene; Hydrochlorothiazide, HCTZ: (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.

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

1 mg/day PO.

1 mg/day PO.

16 years and older: 1 mg/day PO.
13 to 15 years and more than 30 kg: 1 mg/day PO.
13 to 15 years and 27 to 30 kg: 0.9 mg/day PO (oral solution).
13 to 15 years and 24 to 26 kg: 0.8 mg/day PO (oral solution).

2 to 12 years and more than 30 kg: 1 mg/day PO.
2 to 12 years and 27 to 30 kg: 0.9 mg/day PO (oral solution).
2 to 12 years and 24 to 26 kg: 0.8 mg/day PO (oral solution).
2 to 12 years and 21 to 23 kg: 0.7 mg/day PO (oral solution).
2 to 12 years and 18 to 20 kg: 0.6 mg/day PO (oral solution).
2 to 12 years and 15 to 17 kg: 0.5 mg/day PO (oral solution).
2 to 12 years and 12 to 14 kg: 0.4 mg/day PO (oral solution).
2 to 12 years and 10 to 11 kg: 0.3 mg/day PO (oral solution).
younger than 2 years or less than 10 kg: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Entecavir is a deoxyguanosine 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.[31230]
 
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.[46638] The EC50 value of entecavir against a variety of HIV type 1 laboratory strains ranged from 0.026 to more than 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 an HIV-resistant strain may occur. In cell cultures, entecavir selected for an M184I substitution in HIV reverse transcriptase.[31230]
 
Data from cell-based assays show an 8- to 30-fold reduction in entecavir phenotypic susceptibility in strains conferring lamivudine-resistance. Lamivudine-resistance strains harboring amino acid substitutions rtL180M, rtM204V, and rtA181C confer a 16- to 122-fold reduction in entecavir phenotypic susceptibility. A postmarketing analysis of entecavir resistance data from 17 phase 2 and 3 clinical trials identified emergent entecavir resistance-associated substitution rtA181C in 5 out of 1,461 (0.3%) subjects. This substitution was detected only in the presence of lamivudine resistance-associated substitutions rtL180M plus rtM204V.[31230]

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.

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.

Use of entecavir during pregnancy has been evaluated in a limited number of women; however, data reported to the Antiretroviral Pregnancy Registry (APR) are insufficient to adequately assess the risk of birth defects, miscarriages, or adverse maternal or fetal outcomes. Nucleoside reverse transcriptase inhibitors (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. Reproduction studies performed in rats and rabbits have not identified any association between entecavir (at clinically relevant exposures) and adverse developmental effects; however, at exposures 3,100-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 used 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.[27468] 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. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to entecavir; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.[31230]

It is not known if entecavir is excreted in human breast milk, affects milk production, or has an adverse effect on breastfed infants. Antiviral medications whose passage into human breast milk have been evaluated include tenofovir and lamivudine. A consensus among healthcare providers has not been established regarding the treatment of hepatitis B infection and breast-feeding. 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.[31230] [46710] [46680] [46688]