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ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Pronunciation

(en TE ka veer)

Generic Available (U.S.)

No

Brand Names: U.S.

• Baraclude®

Brand Names: Canada

• Baraclude®

Pharmacologic Category

• Antiretroviral Agent, Reverse Transcriptase Inhibitor (Nucleoside)

Pharmacologic Category Synonyms

• NRTI
• Nucleoside Reverse Transcriptase Inhibitor
• Retroviral Therapy, Reverse Transcriptase Inhibitor (Nucleoside)
• Reverse Transcriptase Inhibitor, Nucleoside
• RTI, Nucleoside

Use: Labeled Indications

Treatment of chronic hepatitis B infection, with compensated or decompensated liver disease, in adults with evidence of active viral replication and either evidence of persistent transaminase elevations or histologically-active disease

Pregnancy Risk Factor

C

Pregnancy Considerations

Teratogenic effects have been observed in animal studies. There are no adequate and well-controlled studies in pregnant women. Use only if benefit outweighs risk. Pregnant women taking entecavir should enroll in the pregnancy registry by calling 1-800-258-4263.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Warnings/Precautions

Boxed warnings:

• Chronic hepatitis B: See “Disease-related concerns” below.

• Human immunodeficiency virus (HIV): See “Disease-related concerns” below.

• Lactic acidosis/hepatomegaly: See “Concerns related to adverse effects” below.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects:

• Lactic acidosis/hepatomegaly: [U.S Boxed Warning]: Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with nucleoside analogues; use with caution in patients with risk factors for liver disease (risk may be increased with female gender, decompensated liver disease, obesity, or prolonged nucleoside exposure) and suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (transaminase elevation may/may not accompany hepatomegaly and steatosis).

Disease-related concerns:

• Chronic hepatitis B: [U.S Boxed Warning]: Severe, acute exacerbation of hepatitis B may occur upon discontinuation of antihepatitis B therapy, including entecavir. Monitor liver function for at least several months after stopping treatment; reinitiation of antihepatitis B therapy may be required.

• HIV: [U.S. Boxed Warning]: May cause the development of HIV resistance in chronic hepatitis B patients with unrecognized or untreated HIV infection. Determine HIV status prior to initiating treatment with entecavir. Not recommended for HIV/HBV coinfected patients unless also receiving highly active antiretroviral therapy (HAART). The manufacturer's labeling states that entecavir does not exhibit any clinically-relevant activity against human immunodeficiency virus (HIV type 1). However, a small number of case reports have indicated declines in virus levels during entecavir therapy. HIV resistance to a common HIV drug has been reported in an HIV/HBV-infected patient receiving entecavir as monotherapy for HBV.

• Hepatic impairment: Dose adjustment not required. Limited data supporting treatment of chronic hepatitis B in patients with decompensated liver disease; observe for increased adverse reactions, including hepatorenal dysfunction.

• Renal impairment: Use with caution in patients with renal impairment or patients receiving concomitant therapy which may reduce renal function; dose adjustment recommended for Cl_cr <50 mL/minute.

Special populations:

• Liver transplant recipients: Safety and efficacy have not been established in liver transplant patients; monitor renal function before and during treatment in liver transplant patients receiving concurrent therapy of cyclosporine or tacrolimus; entecavir dosage may need to be adjusted.

Other warnings/precautions:

• Resistance: Cross-resistance may develop in patients failing previous therapy with lamivudine.

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (16% with decompensated liver disease)

Central nervous system: Pyrexia (14% with decompensated liver disease)

Hepatic: Ascites (15% with decompensated liver disease), ALT increased (>5 x ULN: 11% to 12%; post-treatment flare [lamivudine refractory]: >10 x ULN and >2 x baseline: 12%)

1% to 10%:

Central nervous system: Headache (2% to 4%), fatigue (1% to 3%), dizziness

Endocrine & metabolic: Hyperglycemia (2% to 3%), blood bicarbonate decreased (2% with decompensated liver disease)

Gastrointestinal: Lipase increased (7%), amylase increased (2% to 3%), diarrhea (≤1%), dyspepsia (≤1%), nausea

Hepatic: Hepatic encephalopathy (10% with decompensated liver disease), bilirubin increased (2% to 3%), ALT increased (>10 x ULN and >2 x baseline: 2%; post-treatment flare [nucleoside-naive]: >10 x ULN and >2 x baseline: 2% to 8%)

Renal: Hematuria (9%), glycosuria (4%), creatinine increased (1% to 2%)

Respiratory: Upper respiratory tract infection (10% with decompensated liver disease)

<1%, postmarketing, and/or case reports (limited to important or life-threatening): Alopecia, anaphylactoid reaction, hepatomegaly, hypoalbuminemia, insomnia, lactic acidosis, rash, renal failure, somnolence, thrombocytopenia, vomiting

Metabolism/Transport Effects

None known.

Drug Interactions

Ganciclovir-Valganciclovir: May enhance the adverse/toxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Hematologic toxicity is of specific concern. Risk D: Consider therapy modification

Ribavirin: May enhance the hepatotoxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Lactic acidosis may occur. Risk D: Consider therapy modification

Ethanol/Nutrition/Herb Interactions

Food: Food delays absorption and reduces AUC by 18% to 20%. Management: Administer on an empty stomach 2 hours before or after a meal.

Storage

Store at controlled room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect oral solution from light.

Mechanism of Action

Entecavir is intracellularly phosphorylated to guanosine triphosphate which competes with natural substrates to effectively inhibit hepatitis B viral polymerase; enzyme inhibition blocks reverse transcriptase activity thereby reducing viral DNA synthesis.

Pharmacodynamics/Kinetics

Absorption: Delayed with food; C_max decreased 44% to 46%, AUC decreased 18% to 20%

Distribution: Extensive (V_d in excess of body water)

Protein binding: ~13%

Metabolism: Minor hepatic glucuronide/sulfate conjugation

Half-life elimination: Terminal: ~5-6 days; accumulation: ~24 hours

Time to peak, plasma: 0.5-1.5 hours

Excretion: Urine (60% to 73% as unchanged drug)

Dosage

Oral: Adolescents ≥16 years and Adults:

Nucleoside treatment naive: 0.5 mg once daily

Lamivudine-refractory or -resistant viremia (or known lamivudine- or telbivudine-resistance mutations): 1 mg once daily

Decompensated liver disease: 1 mg once daily

HIV/HBV coinfection (unlabeled use):

Nucleoside treatment naive: 0.5 mg once daily

Lamivudine refractory or resistant: 1 mg once daily

Note: Only recommended in patients who cannot take tenofovir; must be used in addition to a fully suppressive antiretroviral therapy regimen (DHHS, 2011).

Treatment duration (AASLD Practice Guidelines, 2009):

Hepatitis Be antigen (HBeAg) positive chronic hepatitis: Treat ≥1 year until HBeAg seroconversion and undetectable serum HBV DNA; continue therapy for ≥6 months after HBeAg seroconversion

HBeAg negative chronic hepatitis: Treat >1 year until hepatitis B surface antigen (HBsAg) clearance

Decompensated liver disease: Lifelong treatment is recommended

Note: Patients not achieving a primary response (<2 log decrease in serum HBV DNA) after at least 6 months of therapy should either receive additional treatment or be switched to an alternative therapy.

Dosage adjustment in renal impairment: Daily-dosage regimen preferred:

Cl_cr 30-49 mL/minute: Administer 50% of usual dose daily or administer the normal dose every 48 hours

Cl_cr 10-29 mL/minute: Administer 30% of usual dose daily or administer the normal dose every 72 hours

Cl_cr <10 mL/minute (including hemodialysis and CAPD): Administer 10% of usual dose daily or administer the normal dose every 7 days; administer after hemodialysis

Dosage adjustment in hepatic impairment: No adjustment necessary.

Administration: Oral

Administer on an empty stomach (2 hours before or after a meal). Do not dilute or mix oral solution with water or other beverages; use calibrated oral dosing syringe. Oral solution and tablet are bioequivalent on a mg-to-mg basis.

Monitoring Parameters

HIV status (prior to initiation of therapy); liver function tests, renal function; in HBV/HIV-coinfected patients, monitor HIV viral load and CD4 count; HBeAg, HBV DNA; in patients with lamivudine-refractory or -resistant viremia (or known lamivudine- or telbivudine-resistance mutations) entecavir resistance can develop rapidly. Monitor HBV DNA every 3 months (DHHS, 2011)

Dietary Considerations

Take on an empty stomach (2 hours before or after a meal).

Patient Education

This medication is not a cure for hepatitis B and has not been found to reduce transmission. Take on an empty stomach. If using oral solution, carefully measure dose with the spoon provided; do not dilute or mix with liquids or food. May cause headache, tiredness, dizziness, nausea, vomiting, indigestion, or diarrhea (consult prescriber if severe or unremitting). Report persistent lethargy or unusual fatigue, easy bruising, yellowing of eyes, pale stool or dark urine, palpitations, or severe nausea or vomiting.

Geriatric Considerations

See dosing for renal impairment.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Infectious Diseases Comment

Entecavir does not exhibit any activity against human immunodeficiency virus (HIV type 1) in vitro. The manufacturer's labeling states that entecavir does not exhibit any clinically-relevant activity against human immunodeficiency virus (HIV type 1). However, a small number of case reports have indicated declines in virus levels during entecavir therapy, as well as emerging resistance to a common HIV treatment drug. Coadministration of entecavir with other HIV NRTI agents in vitro did not show any antagonistic activity (against the NRTIs), so it is expected that entecavir would not reduce HIV antiretroviral efficacy in vivo. However, studies of entecavir in HIV/hepatitis B coinfected patients not receiving concurrent HIV therapy have not been conducted, so the long-term effects on efficacy are unknown at this time. Must be used in addition to a fully suppressive antiretroviral therapy regimen.

Mental Health: Effects on Mental Status

May cause sedation

Mental Health: Effects on Psychiatric Treatment

None reported

Nursing: Physical Assessment/Monitoring

Determine HIV status prior to beginning therapy. Use caution in presence of impaired renal function. Assess results of renal function tests on a regular basis during therapy (especially when administered concurrently with other drugs that are renally eliminated or are known to affect renal function). Monitor liver function for several months after stopping therapy (acute exacerbation of hepatitis B may occur upon discontinuation).

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, oral:

Baraclude®: 0.05 mg/mL (210 mL) [orange flavor]

Tablet, oral:

Baraclude®: 0.5 mg, 1 mg

Pricing: U.S. (www.drugstore.com)

Tablets (Baraclude)

0.5 mg (30): $937.00

1 mg (30): $920.98

References

DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents, “Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, Department of Health and Human Services,” October 14, 2011; 1-167. Available at http://www.aidsinfo.nih.gov

Lok AS and McMahon BJ, “AASLD Practice Guidelines, Chronic Hepatitis B: Update 2009,” Hepatology, 2009. Available at http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Chronic_Hep_B_Update_2009%208_24_2009.pdf

International Brand Names

• Baraclude (AR, AT, AU, BE, BG, CH, CL, CN, CO, CR, CZ, DE, DK, DO, EE, ES, FI, FR, GB, GR, GT, HK, HN, ID, IE, IL, IT, KP, MT, MY, NI, NL, NO, NZ, PA, PE, PH, PK, PT, RU, SE, SG, SK, SV, TH, TR, TW, UY)

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Last full review/revision March 2012

Content last modified March 2012