Entecavir

• Baraclude^®

Taking this medicine will not prevent you from passing hepatitis B to other people. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HBV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Other drugs may interact with entecavir, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Entecavir is a prescription medicine used to treat chronic (long term) hepatitis B virus (swelling of the liver caused by a virus) in adults and children 2 years of age and older who have active liver damage. 

Entecavir belongs to a group of drugs called nucleoside analogs. It works by decreasing the amount of virus in the body.

• Take entecavir exactly as your healthcare provider tells you to.
• Your healthcare provider will tell you how much entecavir to take.
• Your healthcare provider will tell you when and how often to take entecavir.
• Take entecavir on an empty stomach, at least 2 hours after a meal and at least 2 hours before the next meal.
• If you are taking entecavir oral solution, carefully measure your dose with the spoon provided, as follows:
  • Hold the spoon in a vertical (upright) position and fill it gradually to the mark corresponding to the prescribed dose. Holding the spoon with the volume marks facing you, check that it has been filled to the proper mark.
  • Swallow the medicine directly from the measuring spoon.
  • After each use, rinse the spoon with water and allow it to air dry.
  • If you lose the spoon, call your pharmacist or healthcare provider for instructions.

• Do not change your dose or stop taking entecavir without talking to your healthcare provider.
• If you forget to take entecavir, take it as soon as you remember and then take your next dose at its regular time. If it is almost time for your next dose, skip the missed dose. Do not take two doses at the same time. Call your healthcare provider or pharmacist if you are not sure what to do.
• When your supply of entecavir starts to run low, call your healthcare provider or pharmacy for a refill. Do not run out of entecavir.

You should not take entecavir if you have HIV (human immunodeficiency virus) that is not being treated.

Symptoms of hepatitis B can come back or get worse after you stop taking entecavir. You will need frequent blood tests to check your liver function during treatment and for several months after you stop using this medicine.

This medicine may cause a serious condition called lactic acidosis. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.

You should not take entecavir if you are allergic to it, or if you also have HIV (human immunodeficiency virus) that is not being treated.

You may need to be tested for HIV before you start taking entecavir. Taking medicine to treat chronic hepatitis B can cause HIV infection to become resistant to certain HIV and AIDS medications.

To make sure entecavir is safe for you, tell your doctor if you have:

• HIV or AIDS (or if you have been exposed to HIV);

• kidney disease;

• liver disease;

• if you also take lamivudine (Epivir, Epzicom, Trizivir) or telbivudine (Tyzeka); or

• if you have had a liver transplant.

Tell your doctor about all medicines you have used to treat hepatitis B in the past.

Some people taking entecavir develop a serious condition called lactic acidosis. This may be more likely if you have liver or kidney disease, congestive heart failure, a heart attack or stroke, a severe infection, if you are 65 or older, if you are dehydrated, or if you drink a lot of alcohol. Talk with your doctor about your risk.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of entecavir on the baby.

It is not known whether entecavir passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Other drugs may interact with entecavir, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Contraindications

• None known.1

Warnings/Precautions

Warnings

Clinical and laboratory evidence of severe acute exacerbations of hepatitis may occur following discontinuance of HBV therapy, including entecavir.1 Exacerbations of hepatitis or ALT flare (e.g. ALT elevations ≥10 times ULN and ≥2 times baseline) reported in 2, 8, or 12% of nucleoside-naive HBeAg-positive patients, nucleoside-naive HBeAg-negative patients, or lamivudine-refractory patients, respectively, following discontinuance of entecavir.1 The median time to exacerbations of hepatitis was 23 weeks.1

Exacerbations of hepatitis also reported during entecavir treatment, but generally resolved with continued therapy.1

Closely monitor hepatic function clinically and with laboratory studies at repeated intervals for at least several months after entecavir discontinued.1 If appropriate, resumption of anti-HBV therapy may be warranted.1

Use of entecavir for treatment of chronic HBV infection in patients with unrecognized or untreated HIV infection may result in emergence of HIV isolates resistant to NRTIs.1 23 30 31 32 33 HIV testing should be offered to all patients prior to entecavir therapy.1

Entecavir has some activity against HIV and has suppressed HIV-1 RNA levels in at least 3 patients coinfected with HBV and HIV who were receiving entecavir for treatment of HBV infection but were not receiving antiretroviral therapy.23 30 HIV-1 resistance (M184V mutation) was reported in at least 1 of these patients following 6 months of entecavir therapy; this mutation was not present at baseline.23 30

Has not been systematically evaluated in HIV-infected patients with HBV who were not receiving concomitant antiretroviral therapy.23

Because of possible risk of emergence of NRTI-resistant HIV, entecavir should not be used for treatment of HBV in HIV-infected patients who are not receiving antiretroviral therapy.1 29 31 33

Has not been systematically evaluated for treatment of HIV infection and such use is not recommended.1

Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported in patients receiving nucleoside analogs alone or in conjunction with antiretrovirals.1 Most reported cases have involved women; obesity and long-term therapy with nucleoside reverse transcriptase inhibitors (NRTIs) also may be risk factors.1

Nucleoside analogs should be used with particular caution in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have been reported in patients with no known risk factors.1

Discontinue entecavir in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).1

General Precautions

Safety and efficacy in liver transplant recipients not evaluated.1 If entecavir considered necessary in liver transplant recipients who have received or are receiving an immunosuppressive agent that may affect renal function (e.g., cyclosporine, tacrolimus), monitor renal function prior to and during entecavir treatment.1 (See Interactions.)

Specific Populations

Category C.1

Pregnancy registry at 800-258-4263.1 Data not available regarding effect of entecavir therapy on transmission of HBV to the infant; infants born to HBV-infected women should receive HBV vaccine according to the recommended childhood immunization schedule to prevent neonatal acquisition of HBV.1 8 9

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug, taking into account the importance of the drug to the women.1

Safety and efficacy not established in children <16 years of age.1

Experience in those ≥65 years of age insufficient to determine whether they respond differently than younger adults.1

Use with caution.1 Because of age-related decreases in renal function, select dosage based on degree of renal impairment; monitor renal function in such patients.1 (See Renal Impairment under Dosage and Administration.)

Dosage adjustment recommended in patients with Clcr <50 mL/minute, including those undergoing hemodialysis or CAPD.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Headache, fatigue, dizziness, nausea.1 10 Elevated ALT concentrations, hyperbilirubinemia, elevated lipase concentrations, hematuria, glycosuria, hyperglycemia, elevated creatinine concentrations.1 10

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Entecavir in pregnant women. Because animal reproduction studies are not always predictive of human response, Entecavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to Entecavir, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Animal Data

Animal reproduction studies with Entecavir in rats and rabbits revealed no evidence of teratogenicity. Developmental toxicity studies were performed in rats and rabbits. There were no signs of embryofetal or maternal toxicity when pregnant animals received oral Entecavir at approximately 28 (rat) and 212 (rabbit) times the human exposure achieved at the highest recommended human dose of 1 mg/day. In rats, maternal toxicity, embryofetal toxicity (resorptions), lower fetal body weights, tail and vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs were observed at exposures 3100 times those in humans. In rabbits, embryofetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at exposures 883 times those in humans. In a peri-postnatal study, no adverse effects on offspring occurred when rats received oral Entecavir at exposures greater than 94 times those in humans.

Labor and Delivery

There are no studies in pregnant women and no data on the effect of Entecavir on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.

Nursing Mothers

It is not known whether Entecavir is excreted into human milk; however, Entecavir is excreted into the milk of rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Entecavir, a decision should be made to discontinue nursing or to discontinue Entecavir taking into consideration the importance of continued hepatitis B therapy to the mother and the known benefits of breastfeeding.

Pediatric Use

Entecavir was evaluated in two clinical trials of pediatric subjects 2 years of age and older with HBeAg-positive chronic HBV infection and compensated liver disease. The exposure of Entecavir in nucleoside-inhibitor-treatment-naïve and lamivudine-experienced pediatric subjects 2 years of age and older with HBeAg-positive chronic HBV infection and compensated liver disease receiving 0.015 mg/kg (up to 0.5 mg once daily) or 0.03 mg/kg (up to 1 mg once daily), respectively, was evaluated in Study AI463028. Safety and efficacy of the selected dose in treatment-naïve pediatric subjects were confirmed in Study AI463189, a randomized, placebo-controlled treatment trial [see Indications and Usage (1), Dosage and Administration (2.3), Adverse Reactions (6.2), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

There are limited data available on the use of Entecavir in lamivudine-experienced pediatric patients; Entecavir should be used in these patients only if the potential benefit justifies the potential risk to the child. Since some pediatric patients may require long-term or even lifetime management of chronic active hepatitis B, consideration should be given to the impact of Entecavir on future treatment options [see Microbiology (12.4)].

The efficacy and safety of Entecavir have not been established in patients less than 2 years of age. Use of Entecavir in this age group has not been evaluated because treatment of HBV in this age group is rarely required.

Geriatric Use

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. 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 elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.4)].

Racial/Ethnic Groups

There are no significant racial differences in Entecavir pharmacokinetics. The safety and efficacy of Entecavir 0.5 mg once daily were assessed in a single-arm, open-label trial of HBeAg-positive or -negative, nucleoside-inhibitor-naïve, Black/African American (n = 40) and Hispanic (n = 6) subjects with chronic HBV infection. In this trial, 76% of subjects were male, the mean age was 42 years, 57% were HBeAg-positive, the mean baseline HBV DNA was 7.0 log10 IU/mL, and the mean baseline ALT was 162 U/L. At Week 48 of treatment, 32 of 46 (70%) subjects had HBV DNA < 50 IU/mL (approximately 300 copies/mL), 31 of 46 (67%) subjects had ALT normalization (≤ 1 × ULN), and 12 of 26 (46%) HBeAg-positive subjects had HBe seroconversion. Safety data were similar to those observed in the larger controlled clinical trials.

Because of low enrollment, safety and efficacy have not been established in the US Hispanic population.

Renal Impairment

Dosage adjustment of Entecavir is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or CAPD [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Liver Transplant Recipients

The safety and efficacy of Entecavir were assessed in a single-arm, open-label trial in 65 subjects who received a liver transplant for complications of chronic HBV infection. Eligible subjects who had HBV DNA less than 172 IU/mL (approximately 1000 copies/mL) at the time of transplant were treated with Entecavir 1 mg once daily in addition to usual post-transplantation management, including hepatitis B immune globulin. The trial population was 82% male, 39% Caucasian, and 37% Asian, with a mean age of 49 years; 89% of subjects had HBeAg-negative disease at the time of transplant.

Four of the 65 subjects received 4 weeks or less of Entecavir (2 deaths, 1 retransplantation, and 1 protocol violation) and were not considered evaluable. Of the 61 subjects who received more than 4 weeks of Entecavir, 60 received hepatitis B immune globulin post-transplant.

Fifty-three subjects (82% of all 65 subjects treated) completed the trial and had HBV DNA measurements at or after 72 weeks treatment post-transplant. All 53 subjects had HBV DNA < 50 IU/mL (approximately 300 copies/mL). Eight evaluable subjects did not have HBV DNA data available at 72 weeks, including 3 subjects who died prior to study completion. No subjects had HBV DNA values ≥ 50 IU/mL while receiving Entecavir (plus hepatitis B immune globulin). All 61 evaluable subjects lost HBsAg post-transplant; 2 of these subjects experienced recurrence of measurable HBsAg without recurrence of HBV viremia. This trial was not designed to determine whether addition of Entecavir to hepatitis B immune globulin decreased the proportion of subjects with measurable HBV DNA post-transplant compared to hepatitis B immune globulin alone.

If Entecavir treatment is determined to be necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus, renal function must be carefully monitored both before and during treatment with Entecavir [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

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.

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.

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 antihepatitis B therapy may be warranted.

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 antiretroviral therapy.

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.

• 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 lactic acidosis (fast breathing, tachycardia, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), or signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice) (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.

More frequently reported side effects include: glycosuria, hematuria, increased serum aspartate aminotransferase, and increased serum lipase. See below for a comprehensive list of adverse effects.

Applies to entecavir: oral solution, oral tablet

General

The most common side effects reported in patients with chronic hepatitis B virus (HBV) infection and compensated liver disease during clinical trials have included headache, fatigue, dizziness, and nausea. One percent of patients discontinued therapy due to side effects or laboratory abnormalities (compared to 4% of lamivudine-treated patients).

The most common side effects reported in patients with chronic HBV infection and evidence of hepatic decompensation (n=102) through Week 48 of a study have included peripheral edema, ascites, pyrexia, hepatic encephalopathy, and upper respiratory infection. The cumulative death rate was 23% with entecavir during the first 48 weeks of therapy (compared to 33% with adefovir). The majority of deaths were due to liver-related causes such as hepatic failure, hepatic encephalopathy, hepatorenal syndrome, and upper gastrointestinal hemorrhage. Through Week 48, up to 7% of patients discontinued this drug due to a side effect.[Ref]

Hepatic

Very common (10% or more): Elevated ALT (up to 12%), posttreatment exacerbation of hepatitis/ALT flare (up to 12%), deaths due to liver-related causes (e.g., hepatic failure, hepatic encephalopathy, hepatorenal syndrome, upper gastrointestinal hemorrhage; 11%), hepatic encephalopathy (10%)
Common (1% to 10%): On-treatment exacerbation of hepatitis/ALT flares
Frequency not reported: Elevated AST, lactic acidosis and severe hepatomegaly with steatosis (including fatal cases), severe acute exacerbations of hepatitis B (after discontinuation of therapy)
Postmarketing reports: Increased transaminases[Ref]

Elevated ALT (greater than 10 times ULN and greater than 2 times baseline: up to 2%; greater than 5 times ULN: up to 12%; greater than 3 times baseline: up to 5%; greater than 2 times baseline [with total bilirubin greater than 2 times ULN and greater than 2 times baseline]: up to 1%) and total bilirubin (greater than 2.5 times ULN; up to 3%) have been reported.

Posttreatment exacerbations of hepatitis or ALT flare, as defined by ALT greater than 10 times ULN and greater than 2 times baseline, have been reported in patients who discontinued therapy at or after 52 weeks after achieving a defined treatment response (nucleoside-naive HBeAg-positive: 2%; nucleoside-naive HBeAg-negative: 8%; lamivudine-refractory: 12%). The median time to exacerbation was 23 to 24 weeks. The rate may be higher in patients who discontinue this drug without regard to treatment response.

Hepatic encephalopathy and deaths due to liver-related causes (such as hepatic failure, hepatic encephalopathy, hepatorenal syndrome, and upper gastrointestinal hemorrhage) were reported in patients with hepatic decompensation.[Ref]

Hematologic

Decreased albumin (less than 2.5 g/dL) and platelets (less than 50,000/mm3) were reported in 30% and 20% of patients with hepatic decompensation, respectively.[Ref]

Very common (10% or more): Decreased albumin (up to 30%), decreased platelets (up to 20%)[Ref]

Gastrointestinal

Very common (10% or more): Elevated lipase (up to 18%)
Common (1% to 10%): Diarrhea, dyspepsia, nausea, vomiting, elevated amylase
Frequency not reported: Abdominal pain (unspecified), upper abdominal pain, upper gastrointestinal hemorrhage[Ref]

Elevated lipase (greater than 3 times baseline: up to 18%; at least 2.1 times upper limit of normal [ULN]: 7%) and amylase (greater than 3 times baseline: 2%) have been reported.[Ref]

Other

Very common (10% or more): Peripheral edema (16%), ascites (15%), pyrexia/fever (14%)
Common (1% to 10%): Fatigue
Frequency not reported: Accidental injury, influenza[Ref]

Peripheral edema, ascites, and pyrexia were reported in patients with hepatic decompensation.[Ref]

Oncologic

Very common (10% or more): Hepatocellular carcinoma (up to 12%)
Frequency not reported: Malignant neoplasms[Ref]

Hepatocellular carcinoma was reported in patients with hepatic decompensation.

Malignant neoplasms, occurring at a rate of 8.4 per 1000 patient-years, have been reported.[Ref]

Renal

Confirmed creatinine increase of at least 0.5 mg/dL was reported in up to 2% of patients with compensated liver disease. Confirmed increase in serum creatinine of 0.5 mg/dL (11%) and renal failure were reported in patients with hepatic decompensation.[Ref]

Very common (10% or more): Increased serum creatinine (up to 11%)
Uncommon (0.1% to 1%): Renal failure[Ref]

Respiratory

Very common (10% or more): Upper respiratory infection (10%)
Frequency not reported: Cough, nasopharyngitis, rhinitis[Ref]

Upper respiratory infection was reported in patients with hepatic decompensation.[Ref]

Metabolic

Common (1% to 10%): Elevated fasting hyperglycemia, decreased blood bicarbonate
Frequency not reported: Elevated alkaline phosphatase
Postmarketing reports: Lactic acidosis[Ref]

Elevated fasting hyperglycemia (greater than 250 mg/dL) was reported in up to 3% of patients.

Decreased blood bicarbonate was reported in patients with hepatic decompensation.

Lactic acidosis was often associated with hepatic decompensation, other serious medical conditions, or drug exposures.[Ref]

Genitourinary

Common (1% to 10%): Hematuria, glycosuria
Frequency not reported: Dysuria[Ref]

Grade 3 to 4 hematuria (9%) and glycosuria (4%) were reported.[Ref]

Nervous system

Common (1% to 10%): Headache, dizziness, somnolence[Ref]

Psychiatric

Common (1% to 10%): Insomnia[Ref]

Hypersensitivity

Postmarketing reports: Anaphylactoid reaction[Ref]

Dermatologic

Frequency not reported: Erythema, photosensitivity with lethargy
Postmarketing reports: Rash, alopecia[Ref]

Musculoskeletal

Frequency not reported: Arthralgia, myalgia, back pain[Ref]

Some side effects of entecavir may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Compensated Liver Disease:
-Nucleoside-inhibitor-therapy-naive: 0.5 mg orally once a day
-History of hepatitis B viremia while using lamivudine or known lamivudine or telbivudine resistance substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L: 1 mg orally once a day

Decompensated Liver Disease: 1 mg orally once a day

Use: For the treatment of chronic HBV infection in patients with evidence of active viral replication and either persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease

US BOXED WARNINGS:
-SEVERE ACUTE EXACERBATIONS OF HEPATITIS B: Severe acute exacerbations of hepatitis B reported in patients who have discontinued antihepatitis B therapy. Patients who discontinue this drug should have close monitoring of hepatic function with clinical and laboratory follow-up for at least several months. If appropriate, resumption of antihepatitis B therapy may be necessary.
-PATIENTS COINFECTED WITH HIV AND HBV: This drug is not recommended for HIV/HBV-coinfected patients not also receiving HAART. There is a risk of developing resistance to HIV nucleoside reverse transcriptase inhibitors if this drug is used for chronic HBV in coinfected patients not receiving adequate treatment for their HIV infection.
-LACTIC ACIDOSIS AND HEPATOMEGALY: Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) reported with use of nucleoside analog inhibitors, alone or in combination with antiretrovirals.

Safety and efficacy have not been established in patients younger than 2 years.

Consult WARNINGS section for additional precautions.