Baraclude

Name: Baraclude

What special dietary instructions should I follow?

Unless your doctor tells you otherwise, continue your normal diet.

In case of emergency/overdose

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Adverse Effects

1-10%

Fatigue (1-3%)

Headache (2-4%)

Dizziness

Nausea

<1%

Diarrhea

Dyspepsia

Vomiting

Somnolence

Insomnia

Postmarketing Reports

Lactic acidosis

Increased transaminases

Pharmacology

Mechanism of Action

Selective HBV DNA polymerase inhibitor; inhibition blocks reverse transcriptase activity, which in turn reduces viral DNA synthesis

Pharmacokinetics

Half-Life, Elimination: 5-6 days

Peak Plasma Time: 0.5-1.5 hr

Peak Plasma Concentration: 0.5 mg dose: 4.2 ng/mL; 1 mg dose: 8.2 ng/mL

Distribution: Extensively in tissues

Protein Bound: 13%

Metabolism: Not a substrate, inducer or inhibitor of the Cytochrome P450 system

Excretion: Primarily urine

Side Effects of Baraclude

Baraclude may cause serious side effects. See “Drug Precautions”.

The most common side effects of Baraclude include:

  • headache
  • tiredness
  • dizziness
  • nausea

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Baraclude. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Baraclude Precautions

Your hepatitis B virus infection may get worse if you stop taking Baraclude. This usually happens within 6 months after stopping Baraclude.

  • Take Baraclude exactly as prescribed.
  • Do not run out of Baraclude.
  • Do not stop Baraclude without talking to your healthcare provider.
  • Your healthcare provider should monitor your health and do regular blood tests to check your liver if you stop taking Baraclude.

If you have or get HIV that is not being treated with medicines while taking Baraclude, the HIV virus may develop resistance to certain HIV medicines and become harder to treat. You should get an HIV test before you start taking Baraclude and anytime after that when there is a chance you were exposed to HIV.

Baraclude can cause serious side effects including lactic acidosis and serious liver problems.

Lactic acidosis (buildup of acid in the blood). Some people who have taken Baraclude or medicines like Baraclude (a nucleoside analogue) have developed a serious condition called lactic acidosis. Lactic acidosis is a serious medical emergency that can cause death. Lactic acidosis must be treated in the hospital. Reports of lactic acidosis with Baraclude generally involved patients who were seriously ill due to their liver disease or other medical condition.

Call your healthcare provider right away if you get any of the following signs or symptoms of lactic acidosis:

  • You feel very weak or tired.
  • You have unusual (not normal) muscle pain.
  • You have trouble breathing.
  • You have stomach pain with nausea and vomiting.
  • You feel cold, especially in your arms and legs.
  • You feel dizzy or light-headed.
  • You have a fast or irregular heartbeat.

Serious liver problems. Some people who have taken medicines like Baraclude have developed serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Hepatomegaly with steatosis is a serious medical emergency that can cause death.

Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:

  • Your skin or the white part of your eyes turns yellow (jaundice).
  • Your urine turns dark.
  • Your bowel movements (stools) turn light in color.
  • You don’t feel like eating food for several days or longer.
  • You feel sick to your stomach (nausea).
  • You have lower stomach pain.

You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight, or have been taking nucleoside analogue medicines, like Baraclude, for a long time.

Interactions for Baraclude

Entecavir is not a substrate for CYP isoenzymes.1 It does not inhibit or induce CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 3A4, or 2B6 and does not inhibit 3A5 or induce 2E1.1

Pharmacokinetic interactions with drugs metabolized by CYP isoenzymes unlikely.1

Drugs Affecting or Eliminated by Renal Excretion

Concomitant use with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of entecavir and/or the other drug.1 Monitor closely for adverse effects if used concomitantly with drugs excreted renally or with drugs known to affect renal function.1

Specific Drugs

Drug

Interaction

Comments

Adefovir

No evidence of pharmacokinetic interaction1

Immunosuppressive agents (cyclosporine, tacrolimus)

Possible increased entecavir concentrations due to altered renal function1

Monitor renal function prior to and during entecavir treatment in patients receiving immunosuppressive agents that may affect renal function1

Nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, zidovudine)

No in vitro evidence of reduced antiviral efficacy of entecavir against HBV or reduced antiretroviral activity of NRTIs 1

Lamivudine: No evidence of pharmacokinetic interaction1

Tenofovir

No evidence of pharmacokinetic interaction 1

No in vitro evidence of reduced antiviral efficacy of entecavir against HBV or reduced antiretroviral activity of tenofovir 1

Baraclude Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.1

Peak plasma concentrations attained within 0.5–1.5 hours after a dose.1 Steady-state concentrations achieved after 6–10 days of once-daily administration with approximately 2-fold accumulation.1

Commercially available tablets and oral solution are bioequivalent.1

Food

Food delays absorption, decreases peak plasma concentrations, and decreases AUC.1

Distribution

Extent

Extensively distributed into tissues.1

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Approximately 13% in vitro.1

Elimination

Metabolism

Undergoes phosphorylation by cellular enzymes to form active metabolite, entecavir triphosphate.1 3 4 5 6

Partially metabolized to glucuronide and sulfate conjugates.1

Elimination Route

Excreted principally in urine by both glomerular filtration and tubular secretion.1 5 Approximately 62–73% of an oral dose eliminated unchanged in urine.1

Hemodialysis removes approximately 13% of a dose in 4 hours;1 CAPD removes approximately 0.3% of a dose over 7 days.1

Half-life

Biphasic; terminal half-life approximately 128–149 hours.1

Special Populations

Impaired hepatic function: Pharmacokinetics not affected.1

Impaired renal function: Decreased clearance and increased plasma concentrations and AUC.1

Geriatric adults: Increased AUC compared with younger adults, possibly as the result of age-related changes in renal function.1

Advice to Patients

  • Importance of providing a copy of the manufacturer’s patient information.1

  • Importance of taking entecavir exactly as prescribed and not discontinuing or interrupting therapy unless instructed by a clinician; importance of regular medical follow-up.1

  • Advise patients that deterioration of liver disease has occurred when entecavir therapy is discontinued and that any change in treatment should be discussed with the clinician.1

  • Importance of taking entecavir once daily on an empty stomach (at least 2 hours before or 2 hours after meals), preferably at the same time each day.1

  • Importance of protecting oral solution from light.1 When using the oral solution, importance of using the calibrated dosing spoon provided, holding the spoon in a vertical position and filling it gradually to the mark corresponding to the prescribed dose, and rinsing it well after each use.1

  • Importance of liver function test monitoring and immediate reporting of potential exacerbations of hepatitis following discontinuance of entecavir therapy.1

  • Importance of immediately reporting to clinicians any signs or symptoms of lactic acidosis (e.g., weakness/fatigue, unusual muscle pain, trouble breathing, stomach pain with nausea and vomiting, feeling cold especially in arms and legs, dizziness or feeling light-headed, fast or irregular heart beat) or hepatotoxicity (e.g., jaundice, dark urine, bowel movements light in color, anorexia, nausea, stomach pain) or any other new symptoms.1

  • Importance of HBV therapy compliance.1 Entecavir is not a cure for HBV infection.1 HBV transmission via sexual contact, sharing needles, or blood contamination is not prevented by entecavir therapy.1

  • Patients should be advised of available measures to prevent spread of HBV infection to close contacts.1

  • Importance of testing for HIV prior to initiation of entecavir therapy.1 Advise patients that if they have HIV infection and are not receiving effective HIV treatment, entecavir may increase the risk of HIV resistance.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, and any concomitant illnesses (e.g., renal disease).1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Commonly used brand name(s)

In the U.S.

  • Baraclude

Available Dosage Forms:

  • Solution
  • Tablet

Therapeutic Class: Antiviral

Chemical Class: Guanosine Nucleoside Analog

Contraindications

None.

Adverse reactions

The following adverse reactions are discussed in other sections of the labeling:

• Exacerbations of hepatitis after discontinuation of treatment [see Boxed Warning, Warnings and Precautions (5.1)]. • Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.3)].

    Clinical Trial Experience in Adults

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Compensated Liver Disease

Assessment of adverse reactions is based on four studies (AI463014, AI463022, AI463026, and AI463027) in which 1720 subjects with chronic hepatitis B virus infection and compensated liver disease received double-blind treatment with Baraclude 0.5 mg/day (n=679), Baraclude 1 mg/day (n=183), or lamivudine (n=858) for up to 2 years. Median duration of therapy was 69 weeks for Baraclude-treated subjects and 63 weeks for lamivudine-treated subjects in Studies AI463022 and AI463027 and 73 weeks for Baraclude-treated subjects and 51 weeks for lamivudine-treated subjects in Studies AI463026 and AI463014. The safety profiles of Baraclude and lamivudine were comparable in these studies.

The most common adverse reactions of any severity (≥3%) with at least a possible relation to study drug for Baraclude-treated subjects were headache, fatigue, dizziness, and nausea. The most common adverse reactions among lamivudine-treated subjects were headache, fatigue, and dizziness. One percent of Baraclude-treated subjects in these four studies compared with 4% of lamivudine-treated subjects discontinued for adverse events or abnormal laboratory test results.

Clinical adverse reactions of moderate-severe intensity and considered at least possibly related to treatment occurring during therapy in four clinical studies in which Baraclude was compared with lamivudine are presented in Table 3.

Table 3:   Clinical Adverse Reactionsa of Moderate-Severe Intensity (Grades 2–4) Reported in Four Entecavir Clinical Trials Through 2 Years
Nucleoside-Inhibitor-Naïveb Lamivudine-Refractoryc
Body System/
   Adverse Reaction
Baraclude
0.5 mg
n=679
Lamivudine
100 mg
n=668
Baraclude
1 mg
n=183
Lamivudine
100 mg
n=190
a   Includes events of possible, probable, certain, or unknown relationship to treatment regimen.
b   Studies AI463022 and AI463027.
c   Includes Study AI463026 and the Baraclude 1 mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of Baraclude (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in subjects who experienced recurrent viremia on lamivudine therapy.

Any Grade 2–4 adverse reactiona

15%

18%

22%

23%

Gastrointestinal

     Diarrhea

<1%

0

1%

0

     Dyspepsia

<1%

<1%

1%

0

     Nausea

<1%

<1%

<1%

2%

     Vomiting

<1%

<1%

<1%

0

General

     Fatigue

1%

1%

3%

3%

Nervous System

     Headache

2%

2%

4%

1%

     Dizziness

<1%

<1%

0

1%

     Somnolence

<1%

<1%

0

0

Psychiatric

     Insomnia

<1%

<1%

0

<1%

Laboratory Abnormalities

Frequencies of selected treatment-emergent laboratory abnormalities reported during therapy in four clinical trials of Baraclude compared with lamivudine are listed in Table 4.

Table 4:   Selected Treatment-Emergenta Laboratory Abnormalities Reported in Four Entecavir Clinical Trials Through 2 Years
  Nucleoside-Inhibitor-Naïveb Lamivudine-Refractoryc
Test Baraclude
0.5 mg
n=679
Lamivudine
100 mg
n=668
Baraclude
1 mg
n=183
Lamivudine
100 mg
n=190
a   On-treatment value worsened from baseline to Grade 3 or Grade 4 for all parameters except albumin (any on-treatment value <2.5 g/dL), confirmed creatinine increase ≥0.5 mg/dL, and ALT >10 × ULN and >2 × baseline.
b   Studies AI463022 and AI463027.
c   Includes Study AI463026 and the Baraclude 1 mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of Baraclude (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in subjects who experienced recurrent viremia on lamivudine therapy.
d   Includes hematology, routine chemistries, renal and liver function tests, pancreatic enzymes, and urinalysis.
e   Grade 3 = 3+, large, ≥500 mg/dL; Grade 4 = 4+, marked, severe.
f   Grade 3 = 3+, large; Grade 4 = ≥4+, marked, severe, many.
ULN=upper limit of normal.

Any Grade 3–4 laboratory abnormalityd

35%

36%

37%

45%

ALT >10 × ULN and >2 × baseline

2%

4%

2%

11%

ALT >5 × ULN

11%

16%

12%

24%

Albumin <2.5 g/dL

<1%

<1%

0

2%

Total bilirubin >2.5 × ULN

2%

2%

3%

2%

Lipase ≥2.1 × ULN

7%

6%

7%

7%

Creatinine >3 × ULN

0

0

0

0

Confirmed creatinine increase ≥0.5 mg/dL

1%

1%

2%

1%

Hyperglycemia, fasting >250 mg/dL

2%

1%

3%

1%

Glycosuriae

4%

3%

4%

6%

Hematuriaf

9%

10%

9%

6%

Platelets <50,000/mm3

<1%

<1%

<1%

<1%

Among Baraclude-treated subjects in these studies, on-treatment ALT elevations greater than 10 times the upper limit of normal (ULN) and greater than 2 times baseline generally resolved with continued treatment. A majority of these exacerbations were associated with a ≥2 log10/mL reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.

Exacerbations of Hepatitis after Discontinuation of Treatment

An exacerbation of hepatitis or ALT flare was defined as ALT greater than 10 times ULN and greater than 2 times the subject’s reference level (minimum of the baseline or last measurement at end of dosing). For all subjects who discontinued treatment (regardless of reason), Table 5 presents the proportion of subjects in each study who experienced post-treatment ALT flares. In these studies, a subset of subjects was allowed to discontinue treatment at or after 52 weeks if they achieved a protocol-defined response to therapy. If Baraclude is discontinued without regard to treatment response, the rate of post-treatment flares could be higher. [See Warnings and Precautions (5.1).]

Table 5:   Exacerbations of Hepatitis During Off-Treatment Follow-up, Subjects in Studies AI463022, AI463027, and AI463026
Subjects with ALT Elevations >10 × ULN and >2 × Referencea
Baraclude Lamivudine
a   Reference is the minimum of the baseline or last measurement at end of dosing. Median time to off-treatment exacerbation was 23 weeks for Baraclude-treated subjects and 10 weeks for lamivudine-treated subjects.

Nucleoside-inhibitor-naïve

 

 

   HBeAg-positive

4/174 (2%)

13/147 (9%)

   HBeAg-negative

24/302 (8%)

30/270 (11%)

Lamivudine-refractory

6/52 (12%)

0/16

Decompensated Liver Disease

Study AI463048 was a randomized, open-label study of Baraclude 1 mg once daily versus adefovir dipivoxil 10 mg once daily given for up to 48 weeks in adult subjects with chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher [see Clinical Studies (14.1)]. Among the 102 subjects receiving Baraclude, the most common treatment-emergent adverse events of any severity, regardless of causality, occurring through Week 48 were peripheral edema (16%), ascites (15%), pyrexia (14%), hepatic encephalopathy (10%), and upper respiratory infection (10%). Clinical adverse reactions not listed in Table 3 that were observed through Week 48 include blood bicarbonate decreased (2%) and renal failure (<1%).

Eighteen of 102 (18%) subjects treated with Baraclude and 18/89 (20%) subjects treated with adefovir dipivoxil died during the first 48 weeks of therapy. The majority of deaths (11 in the Baraclude group and 16 in the adefovir dipivoxil group) were due to liver-related causes such as hepatic failure, hepatic encephalopathy, hepatorenal syndrome, and upper gastrointestinal hemorrhage. The rate of hepatocellular carcinoma (HCC) through Week 48 was 6% (6/102) for subjects treated with Baraclude and 8% (7/89) for subjects treated with adefovir dipivoxil. Five percent of subjects in either treatment arm discontinued therapy due to an adverse event through Week 48.

No subject in either treatment arm experienced an on-treatment hepatic flare (ALT >2 × baseline and >10 × ULN) through Week 48. Eleven of 102 (11%) subjects treated with Baraclude and 11/89 (13%) subjects treated with adefovir dipivoxil had a confirmed increase in serum creatinine of 0.5 mg/dL through Week 48.

HIV/HBV Co-infected

The safety profile of Baraclude 1 mg (n=51) in HIV/HBV co-infected subjects enrolled in Study AI463038 was similar to that of placebo (n=17) through 24 weeks of blinded treatment and similar to that seen in non-HIV infected subjects [see Warnings and Precautions (5.2)].

Liver Transplant Recipients

Among 65 subjects receiving Baraclude in an open-label, post-liver transplant trial [see Use in Specific Populations (8.8)], the frequency and nature of adverse events were consistent with those expected in patients who have received a liver transplant and the known safety profile of Baraclude.

   Clinical Trial Experience in Pediatric Subjects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Baraclude in pediatric subjects 2 to less than 18 years of age is based on two ongoing clinical trials in subjects with chronic HBV infection (one Phase 2 pharmacokinetic trial [AI463028] and one Phase 3 trial [AI463189]). These trials provide experience in 168 HBeAg-positive subjects treated with Baraclude for a median duration of 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with Baraclude were consistent with those observed in clinical trials of Baraclude in adults. Adverse drug reactions reported in greater than 1% of pediatric subjects included abdominal pain, rash events, poor palatability (“product taste abnormal”), nausea, diarrhea, and vomiting.

   Postmarketing Experience

The following adverse reactions have been reported during postmarketing use of Baraclude. Because these reactions were reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to Baraclude exposure.

Immune system disorders:   Anaphylactoid reaction.

Metabolism and nutrition disorders:   Lactic acidosis.

Hepatobiliary disorders:  Increased transaminases.

Skin and subcutaneous tissue disorders:  Alopecia, rash.

Description

Baraclude® is the tradename for entecavir, a guanosine nucleoside analogue with selective activity against HBV. The chemical name for entecavir is 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate. Its molecular formula is C12H15N5O3∙H2O, which corresponds to a molecular weight of 295.3. Entecavir has the following structural formula:

Entecavir is a white to off-white powder. It is slightly soluble in water (2.4 mg/mL), and the pH of the saturated solution in water is 7.9 at 25° C ± 0.5° C.

Baraclude film-coated tablets are available for oral administration in strengths of 0.5 mg and 1 mg of entecavir. Baraclude 0.5 mg and 1 mg film-coated tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400, polysorbate 80 (0.5 mg tablet only), and iron oxide red (1 mg tablet only). Baraclude Oral Solution is available for oral administration as a ready-to-use solution containing 0.05 mg of entecavir per milliliter. Baraclude Oral Solution contains the following inactive ingredients: maltitol, sodium citrate, citric acid, methylparaben, propylparaben, and orange flavor.

Clinical pharmacology

    Mechanism of Action

Entecavir is an antiviral drug [see Microbiology (12.4)].

    Pharmacokinetics

The single- and multiple-dose pharmacokinetics of entecavir were evaluated in healthy subjects and subjects with chronic hepatitis B virus infection.

Absorption

Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours. Following multiple daily doses ranging from 0.1 to 1 mg, Cmax and area under the concentration-time curve (AUC) at steady state increased in proportion to dose. Steady state was achieved after 6 to 10 days of once-daily administration with approximately 2-fold accumulation. For a 0.5 mg oral dose, Cmax at steady state was 4.2 ng/mL and trough plasma concentration (Ctrough) was 0.3 ng/mL. For a 1 mg oral dose, Cmax was 8.2 ng/mL and Ctrough was 0.5 ng/mL.

In healthy subjects, the bioavailability of the tablet was 100% relative to the oral solution. The oral solution and tablet may be used interchangeably.

Effects of food on oral absorption: Oral administration of 0.5 mg of entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in a delay in absorption (1.0–1.5 hours fed vs. 0.75 hours fasted), a decrease in Cmax of 44%–46%, and a decrease in AUC of 18%–20% [see Dosage and Administration (2)].

Distribution

Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that entecavir is extensively distributed into tissues.

Binding of entecavir to human serum proteins in vitro was approximately 13%.

Metabolism and Elimination

Following administration of 14C-entecavir in humans and rats, no oxidative or acetylated metabolites were observed. Minor amounts of phase II metabolites (glucuronide and sulfate conjugates) were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. See Drug Interactions, below.

After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128–149 hours. The observed drug accumulation index is approximately 2-fold with once-daily dosing, suggesting an effective accumulation half-life of approximately 24 hours.

Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent of dose and ranges from 360 to 471 mL/min suggesting that entecavir undergoes both glomerular filtration and net tubular secretion [see Drug Interactions (7)].

Special Populations

Gender: There are no significant gender differences in entecavir pharmacokinetics.

Race: There are no significant racial differences in entecavir pharmacokinetics.

Elderly: The effect of age on the pharmacokinetics of entecavir was evaluated following administration of a single 1 mg oral dose in healthy young and elderly volunteers. Entecavir AUC was 29.3% greater in elderly subjects compared to young subjects. The disparity in exposure between elderly and young subjects was most likely attributable to differences in renal function. Dosage adjustment of Baraclude should be based on the renal function of the patient, rather than age [see Dosage and Administration (2.4)].

Pediatrics: The steady-state pharmacokinetics of entecavir were evaluated in nucleoside-inhibitor-naïve and lamivudine-experienced HBeAg-positive pediatric subjects 2 to less than 18 years of age with compensated liver disease. Results are shown in Table 6. Entecavir exposure among nucleoside-inhibitor-naïve subjects was similar to the exposure achieved in adults receiving once-daily doses of 0.5 mg. Entecavir exposure among lamivudine-experienced subjects was similar to the exposure achieved in adults receiving once-daily doses of 1 mg.

Table 6:   Pharmacokinetic Parameters in Pediatric Subjects
Nucleoside-Inhibitor-Naïvea Lamivudine-Experiencedb
n=24 n=19

Cmax (ng/mL)
(CV%)

6.31
(30)

14.48
(31)

AUC(0–24) (ng•h/mL)
(CV%)

18.33
(27)

38.58
(26)

Cmin (ng/mL)
(CV%)

0.28
(22)

0.47
(23)

  a Subjects received once-daily doses of 0.015 mg/kg up to a maximum of 0.5 mg.   b Subjects received once-daily doses of 0.030 mg/kg up to a maximum of 1 mg.

Renal impairment: The pharmacokinetics of entecavir following a single 1 mg dose were studied in subjects (without chronic hepatitis B virus infection) with selected degrees of renal impairment, including subjects whose renal impairment was managed by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Results are shown in Table 7 [see Dosage and Administration (2.4)].

Table 7:    Pharmacokinetic Parameters in Subjects with Selected Degrees of Renal Function
Renal Function Group
Baseline Creatinine Clearance (mL/min)
Unimpaired
>80

n=6
Mild
>50–≤80

n=6
Moderate
30–50

n=6
Severe
<30

n=6
Severe
Managed with
Hemodialysisa
n=6
Severe
Managed
with CAPD
n=4
a   Dosed immediately following hemodialysis.
CLR = renal clearance; CLT/F = apparent oral clearance.

Cmax (ng/mL)
(CV%)

8.1
(30.7)

10.4
(37.2)

10.5
(22.7)

15.3
(33.8)

15.4
(56.4)

16.6
(29.7)

AUC(0–T) (ng•h/mL)
(CV)

27.9
(25.6)

51.5
(22.8)

69.5
(22.7)

145.7
(31.5)

233.9
(28.4)

221.8
(11.6)

CLR (mL/min)
(SD)

383.2
(101.8)

197.9
(78.1)

135.6
(31.6)

40.3
(10.1)

NA

NA

CLT/F (mL/min)
(SD)

588.1
(153.7)

309.2
(62.6)

226.3
(60.1)

100.6
(29.1)

50.6
(16.5)

35.7
(19.6)

Following a single 1 mg dose of entecavir administered 2 hours before the hemodialysis session, hemodialysis removed approximately 13% of the entecavir dose over 4 hours. CAPD removed approximately 0.3% of the dose over 7 days [see Dosage and Administration (2.4)].

Hepatic impairment: The pharmacokinetics of entecavir following a single 1 mg dose were studied in adult subjects (without chronic hepatitis B virus infection) with moderate or severe hepatic impairment (Child-Turcotte-Pugh Class B or C). The pharmacokinetics of entecavir were similar between hepatically impaired and healthy control subjects; therefore, no dosage adjustment of Baraclude is recommended for patients with hepatic impairment. The pharmacokinetics of entecavir have not been studied in pediatric subjects with hepatic impairment.

Post-liver transplant: Limited data are available on the safety and efficacy of Baraclude in liver transplant recipients. In a small pilot study of entecavir use in HBV-infected liver transplant recipients on a stable dose of cyclosporine A (n=5) or tacrolimus (n=4), 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 subjects. The potential for pharmacokinetic interactions between entecavir and cyclosporine A or tacrolimus was not formally evaluated [see Use in Specific Populations (8.8)].

Drug Interactions

The metabolism of entecavir was evaluated in in vitro and in vivo studies. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. At concentrations up to approximately 10,000-fold higher than those obtained in humans, entecavir inhibited none of the major human CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1. At concentrations up to approximately 340-fold higher than those observed in humans, entecavir did not induce the human CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. The pharmacokinetics of entecavir are unlikely to be affected by coadministration with agents that are either metabolized by, inhibit, or induce the CYP450 system. Likewise, the pharmacokinetics of known CYP substrates are unlikely to be affected by coadministration of entecavir.

The steady-state pharmacokinetics of entecavir and coadministered drug were not altered in interaction studies of entecavir with lamivudine, adefovir dipivoxil, and tenofovir disoproxil fumarate [see Drug Interactions (7)].

    Microbiology

Mechanism of Action

Entecavir, a guanosine nucleoside analogue with activity against HBV reverse transcriptase (rt), is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all three activities of the HBV 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. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β, and δ and mitochondrial DNA polymerase γ with Ki values ranging from 18 to >160 μM.

Antiviral Activity

Entecavir inhibited HBV DNA synthesis (50% reduction, EC50) at a concentration of 0.004 μM in human HepG2 cells transfected with wild-type HBV. The median EC50 value for entecavir against lamivudine-resistant HBV (rtL180M, rtM204V) was 0.026 μM (range 0.010–0.059 μM).

The coadministration of HIV nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) with Baraclude is unlikely to reduce the antiviral efficacy of Baraclude against HBV or of any of these agents against HIV. In HBV combination assays in cell culture, abacavir, didanosine, lamivudine, stavudine, tenofovir, or zidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range of concentrations. In HIV antiviral assays, entecavir was not antagonistic to the cell culture anti-HIV activity of these six NRTIs or emtricitabine at concentrations greater than 100 times the Cmax of entecavir using the 1 mg dose.

Antiviral Activity Against HIV

A comprehensive analysis of the inhibitory activity of entecavir against a panel of laboratory and clinical HIV type 1 (HIV-1) isolates using a variety of cells and assay conditions yielded EC50 values ranging from 0.026 to >10 μM; the lower EC50 values were observed when decreased levels of virus were used in the assay. In cell culture, entecavir selected for an M184I substitution in HIV reverse transcriptase at micromolar concentrations, confirming inhibitory pressure at high entecavir concentrations. HIV variants containing the M184V substitution showed loss of susceptibility to entecavir.

Resistance

In Cell Culture

In cell-based assays, 8- to 30-fold reductions in entecavir phenotypic susceptibility were observed for lamivudine-resistant strains. Further reductions (>70-fold) in entecavir phenotypic susceptibility required the presence of amino acid substitutions rtM204I/V with or without rtL180M along with additional substitutions at residues rtT184, rtS202, or rtM250, or a combination of these substitutions with or without an rtI169 substitution in the HBV reverse transcriptase.

Clinical Studies

Nucleoside-inhibitor-naïve subjects: Genotypic evaluations were performed on evaluable samples (>300 copies/mL serum HBV DNA) from 562 subjects who were treated with Baraclude for up to 96 weeks in nucleoside-inhibitor-naïve studies (AI463022, AI463027, and rollover study AI463901). By Week 96, evidence of emerging amino acid substitution rtS202G with rtM204V and rtL180M substitutions was detected in the HBV of 2 subjects (2/562=<1%), and 1 of them experienced virologic rebound (≥1 log10 increase above nadir). In addition, emerging amino acid substitutions at rtM204I/V and rtL180M, rtL80I, or rtV173L, which conferred decreased phenotypic susceptibility to entecavir in the absence of rtT184, rtS202, or rtM250 changes, were detected in the HBV of 3 subjects (3/562=<1%) who experienced virologic rebound. For subjects who continued treatment beyond 48 weeks, 75% (202/269) had HBV DNA <300 copies/mL at end of dosing (up to 96 weeks).

HBeAg-positive (n=243) and -negative (n=39) treatment-naïve subjects who failed to achieve the study-defined complete response by 96 weeks were offered continued entecavir treatment in a rollover study. Complete response for HBeAg-positive was <0.7 MEq/mL (approximately 7 × 105 copies/mL) serum HBV DNA and HBeAg loss and, for HBeAg-negative was <0.7 MEq/mL HBV DNA and ALT normalization. Subjects received 1 mg entecavir once daily for up to an additional 144 weeks. Of these 282 subjects, 141 HBeAg-positive and 8 HBeAg-negative subjects entered the long-term follow-up rollover study and were evaluated for entecavir resistance. Of the 149 subjects entering the rollover study, 88% (131/149), 92% (137/149), and 92% (137/149) attained serum HBV DNA <300 copies/mL by Weeks 144, 192, and 240 (including end of dosing), respectively. No novel entecavir resistance-associated substitutions were identified in a comparison of the genotypes of evaluable isolates with their respective baseline isolates. The cumulative probability of developing rtT184, rtS202, or rtM250 entecavir resistance-associated substitutions (in the presence of rtM204V and rtL180M substitutions) at Weeks 48, 96, 144, 192, and 240 was 0.2%, 0.5%, 1.2%, 1.2%, and 1.2%, respectively.

Lamivudine-refractory subjects: Genotypic evaluations were performed on evaluable samples from 190 subjects treated with Baraclude for up to 96 weeks in studies of lamivudine-refractory HBV (AI463026, AI463014, AI463015, and rollover study AI463901). By Week 96, resistance-associated amino acid substitutions at rtS202, rtT184, or rtM250, with or without rtI169 changes, in the presence of amino acid substitutions rtM204I/V with or without rtL180M, rtL80V, or rtV173L/M emerged in the HBV from 22 subjects (22/190=12%), 16 of whom experienced virologic rebound (≥1 log10 increase above nadir) and 4 of whom were never suppressed <300 copies/mL. The HBV from 4 of these subjects had entecavir resistance substitutions at baseline and acquired further changes on entecavir treatment. In addition to the 22 subjects, 3 subjects experienced virologic rebound with the emergence of rtM204I/V and rtL180M, rtL80V, or rtV173L/M. For isolates from subjects who experienced virologic rebound with the emergence of resistance substitutions (n=19), the median fold-change in entecavir EC50 values from reference was 19-fold at baseline and 106-fold at the time of virologic rebound. For subjects who continued treatment beyond 48 weeks, 40% (31/77) had HBV DNA <300 copies/mL at end of dosing (up to 96 weeks).

Lamivudine-refractory subjects (n=157) who failed to achieve the study-defined complete response by Week 96 were offered continued entecavir treatment. Subjects received 1 mg entecavir once daily for up to an additional 144 weeks. Of these subjects, 80 subjects entered the long-term follow-up study and were evaluated for entecavir resistance. By Weeks 144, 192, and 240 (including end of dosing), 34% (27/80), 35% (28/80), and 36% (29/80), respectively, attained HBV DNA <300 copies/mL. The cumulative probability of developing rtT184, rtS202, or rtM250 entecavir resistance-associated substitutions (in the presence of rtM204I/V with or without rtL180M substitutions) at Weeks 48, 96, 144, 192, and 240 was 6.2%, 15%, 36.3%, 46.6%, and 51.5%, respectively. The HBV of 6 subjects developed rtA181C/G/S/T amino acid substitutions while receiving entecavir, and of these, 4 developed entecavir resistance-associated substitutions at rtT184, rtS202, or rtM250 and 1 had an rtT184S substitution at baseline. Of 7 subjects whose HBV had an rtA181 substitution at baseline, 2 also had substitutions at rtT184, rtS202, or rtM250 at baseline and another 2 developed them while on treatment with entecavir.

Cross-resistance

Cross-resistance has been observed among HBV nucleoside analogue inhibitors. In cell-based assays, entecavir had 8- to 30-fold less inhibition of HBV DNA synthesis for HBV containing lamivudine and telbivudine resistance substitutions rtM204I/V with or without rtL180M than for wild-type HBV. Substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L, which are associated with lamivudine and telbivudine resistance, also confer decreased phenotypic susceptibility to entecavir. The efficacy of entecavir against HBV harboring adefovir resistance-associated substitutions has not been established in clinical trials. HBV isolates from lamivudine-refractory subjects failing entecavir therapy were susceptible in cell culture to adefovir but remained resistant to lamivudine. Recombinant HBV genomes encoding adefovir resistance-associated substitutions at either rtN236T or rtA181V had 0.3- and 1.1-fold shifts in susceptibility to entecavir in cell culture, respectively.

  • Hepatitis B (HBV, Hep B)

Entecavir Pregnancy Warnings

This drug should be used during pregnancy only if clearly needed and the benefit outweighs the risk to the fetus. AU TGA pregnancy category: B3 US FDA pregnancy category: C Comments: Use of effective contraception has been recommended.

Animal studies have failed to reveal evidence of teratogenicity. Maternal and embryofetal toxicity were not seen with oral doses ranging from 28 to 212 times the highest human exposure (1 mg/day); maternal toxicity, embryofetal toxicity, skeletal malformations, and/or decreased fetal weights were observed with exposures ranging from 883 to 3100 times those in humans. There are no controlled data in human pregnancy. To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral therapy, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to prospectively register patients. For additional information: apregistry.com AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

(web3)