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Entecavir

Pronunciation

(en TE ka veer)

Dosage Forms

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

Slideshow: The ABC's of Hepatitis: Get to Know This Viral Disease

Solution, Oral:

Baraclude: 0.05 mg/mL (210 mL) [contains methylparaben, propylparaben; orange flavor]

Tablet, Oral:

Baraclude: 0.5 mg, 1 mg

Generic: 0.5 mg, 1 mg

Brand Names: U.S.

  • Baraclude

Pharmacologic Category

  • Antihepadnaviral, Reverse Transcriptase Inhibitor, Nucleoside (Anti-HBV)

Pharmacology

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.

Absorption

Delayed with food; Cmax decreased 44% to 46%, AUC decreased 18% to 20%

Distribution

Extensive (Vd in excess of body water)

Metabolism

Minor hepatic glucuronide/sulfate conjugation

Excretion

Urine (60% to 73% as unchanged drug)

Time to Peak

0.5-1.5 hours

Half-Life Elimination

Terminal: ~5-6 days; accumulation: ~24 hours

Protein Binding

~13%

Special Populations: Renal Function Impairment

Apparent oral clearance of entecavir decreased as CrCl decreased. Cmax and AUC increased. Hemodialysis removed about 13% of the entecavir dose over 4 hours; continuous ambulatory peritoneal dialysis (CAPD) removed about 0.3% of the dose during 7 days.

Special Populations: Elderly

AUC was 29.3% greater in elderly subjects, most likely because of differences in renal function. Base dose adjustment of entecavir on renal function of patient, not on age.

Use: Labeled Indications

U.S. labeling: Treatment of chronic hepatitis B virus (HBV) infection in adults and pediatric patients 2 years and older with evidence of active viral replication and either evidence of persistent transaminase elevations or histologically-active disease. Note: In adults, indication is based on data in patients with compensated and decompensated liver disease; in children, indication is based on data in patients with compensated liver disease.

Canadian labeling: Treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease and evidence of active viral replication and either evidence of persistent transaminase elevations or histologically-active disease.

Use: Unlabeled

HBV reinfection prophylaxis, post liver transplant; HIV/HBV coinfection

Contraindications

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

Canadian labeling: Hypersensitivity to entecavir or any component of the formulation

Dosage

Hepatitis B virus (HBV) infection, treatment: Oral:

U.S. labeling:

Children ≥2 years and Adolescents: Note: Oral solution should be used for patients weighing ≤30 kg.

Treatment-naive:

10 to 11 kg: 0.15 mg once daily (oral solution)

>11 to 14 kg: 0.2 mg once daily (oral solution)

>14 to 17 kg: 0.25 mg once daily (oral solution)

>17 to 20 kg: 0.3 mg once daily (oral solution)

>20 to 23 kg: 0.35 mg once daily (oral solution)

>23 to 26 kg: 0.4 mg once daily (oral solution)

>26 to 30 kg: 0.45 mg once daily (oral solution)

>30 kg: 0.5 mg once daily (oral solution or tablet)

Lamivudine-experienced:

10 to 11 kg: 0.3 mg once daily (oral solution)

>11 to 14 kg: 0.4 mg once daily (oral solution)

>14 to 17 kg: 0.5 mg once daily (oral solution)

>17 to 20 kg: 0.6 mg once daily (oral solution)

>20 to 23 kg: 0.7 mg once daily (oral solution)

>23 to 26 kg: 0.8 mg once daily (oral solution)

>26 to 30 kg: 0.9 mg once daily (oral solution)

>30 kg: 1 mg once daily (oral solution or tablet)

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

Canadian labeling: Adolescents ≥16 years and Adults:

Nucleoside treatment-naive: 0.5 mg once daily

Lamivudine-refractory or known lamivudine-resistance mutations: 1 mg once daily

HBV reinfection prophylaxis, post liver transplant (with or without HBIG) (off-label use): Adults: Oral: 0.5 mg once daily (Fung, 2011) or 1 mg once daily (Perrillo, 2012)

HIV/HBV coinfection (off-label use): Adults: Oral:

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, 2013).

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:

Children >2 years and Adolescents: Insufficient data to recommend a specific dose adjustment in pediatric patients with renal impairment; consider a reduction in the dose or an increase in the dosing interval similar to adjustments for adults.

Adults (Canadian labeling: Adolescents ≥16 years and Adults): Daily-dosage regimen preferred:

CrCl ≥50 mL/minute: No dosage adjustment necessary.

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

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

CrCl <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:

Children >2 years and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Adults (Canadian labeling: Adolescents ≥16 years and Adults): No dosage adjustment necessary.

Administration

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.

Hazardous agent - use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Dietary Considerations

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

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. After opening, oral solution can be used up to expiration date on the bottle.

Drug Interactions

Ganciclovir-Valganciclovir: May enhance the adverse/toxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Hematologic toxicity with zidovudine is of particular concern. Ganciclovir-Valganciclovir may increase the serum concentration of Reverse Transcriptase Inhibitors (Nucleoside). Management: Monitor patients receiving any of these combination closely for toxicity of the reverse transcriptase inhibitor. Avoid zidovudine. Intravitreal implants would not be affected. Consider therapy modification

Ribavirin (Oral Inhalation): May enhance the hepatotoxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Monitor therapy

Ribavirin (Systemic): May enhance the hepatotoxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Monitor therapy

Adverse Reactions

Adverse reactions are generally similar in adult and pediatric patients.

>10%:

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

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

Renal: Increased serum creatinine (11% with decompensated liver disease; 1% to 2% with compensated liver disease)

Miscellaneous: Fever (14% with decompensated liver disease)

1% to 10%:

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

Dermatologic: Skin rash

Endocrine & metabolic: Glycosuria (4%), hyperglycemia (2% to 3%), decreased serum bicarbonate (2% with decompensated liver disease)

Gastrointestinal: Increased serum lipase (7%), increased serum amylase (2% to 3%), abdominal pain (children and adolescents >1%), diarrhea (children and adolescents >1%; adults ≤1%), unpleasant taste (children and adolescents >1%), vomiting (children and adolescents >1%; adults <1%), dyspepsia (≤1%), nausea

Genitourinary: Hematuria (9%)

Hematologic & oncologic: Hepatic carcinoma (6% with decompensated liver disease)

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

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

<1% (Limited to important or life-threatening): Alopecia, anaphylactoid reaction, hepatomegaly, insomnia, lactic acidosis, macular edema (Muqit, 2011), renal failure, thrombocytopenia

ALERT: U.S. Boxed Warning

Severe acute exacerbations of hepatitis B:

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti–hepatitis B therapy, including entecavir. Closely monitor hepatic function with clinical and laboratory follow-up for at least several months in patients who discontinue anti–hepatitis B therapy. If appropriate, initiation of anti–hepatitis B therapy may be warranted.

HIV and chronic hepatitis B virus coinfection:

Limited clinical experience suggests there is a potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors if entecavir is used to treat chronic hepatitis B virus (HBV) infection in patients with HIV infection not being treated. Therapy with entecavir is not recommended for HIV/HBV coinfected patients who are not also receiving highly active antiretroviral therapy.

Lactic acidosis and hepatomegaly:

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors alone or in combination with antiretrovirals.

Warnings/Precautions

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 analogue inhibitors; 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 inhibitor 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 CrCl <50 mL/minute.

Special populations:

• Children: There are limited data available on the use of entecavir in lamivudine-experienced pediatric patients; use in these patients only if the potential benefit justifies the potential risk to the child.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

Other warnings/precautions:

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

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, 2013)

Pregnancy Risk Factor

C

Pregnancy Considerations

Teratogenic effects have been observed in animal studies. Information related to use in pregnancy is limited; use only if other options are inappropriate (DHHS [OI], 2013). Pregnant women taking entecavir should enroll in the pregnancy registry by calling 1-800-258-4263.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, dizziness, nausea, or loss of strength and energy. Have patient report immediately to prescriber signs of too much lactic acid in the blood (lactic acidosis; fast breathing, fast heartbeat, abnormal heartbeat, vomiting, drowsiness, shortness of breath, feeling very tired or weak, severe dizziness, feeling cold, or muscle pain or cramps) or signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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