Prescription Drug Information: Entecavir

ENTECAVIR- entecavir tablet, film coated
Marlex Pharmaceuticals Inc

WARNING: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS COINFECTED

WITH HIV AND HBV, AND LACTIC ACIDOSIS AND HEPATOMEGALY

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including Entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for atleast several months in patients who dis continue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1) ] .

Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if entecaviris used to treat chronic hepatitis B virus (HBV) infection in patients with HIV infection that is not being treated. Therapy with entecaviris not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART) [see Warnings and Precautions (5.2) ] .

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 [see Warnings and Precautions (5.3) ] .

1 INDICATIONS AND USAGE

Entecavir tablets are indicated for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

The following points should be considered when initiating therapy with Entecavir tablets:

  • In adult patients, this indication is based on clinical trial data in nucleoside-inhibitor-treatment-naïve and lamivudine-resistant subjects with HBeAg-positive and HBeAg-negative HBV infection and compensated liver disease and a more limited number of subjects with decompensated liver disease [see Clinical Studies (14.1)].

Pediatric use information is approved for Bristol-Myers Squibb Company’s Baraclude (entecavir) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that information.

2 DOSAGE AND ADMINISTRATION

2.1 Timing of Administration

Entecavir tablets should be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).

2.2 Recommended Dosage in Adults

Compensated Liver Disease

The recommended dose of Entecavir tablets for chronic hepatitis B virus infection in nucleosideinhibitor- treatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily.

The recommended dose of Entecavir tablets in adults and adolescents (at least 16 years of age) with a history of hepatitis B viremia while receiving lamivudine or known lamivudine or telbivudine resistance substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily.

Decompensated Liver Disease

The recommended dose of Entecavir tablets for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily.

2.3 Recommended Dos age in Pediatric Patients

Pediatric use information is approved for Bristol-Myers Squibb Company’s Baraclude (entecavir) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that information.

2.4 Renal Impairment

In adult subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased [see Clinical Pharmacology (12.3)]. Dosage adjustment is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), as shown in Table 2. The once-daily dosing regimens are preferred.

Table 2: Recommended Dos age of Entecavir Tablets in Adult Patients with Renal Impairment
Creatinine Clearance (mL/min) Usual Dose (0.5 mg) Lamivudine- Refractory or Decompensated Liver Disease (1 mg)
50 or greater 0.5 mg once daily 1 mg once daily
30 to less that 50 0.5 mg every 48 hours 0.5 mg once dailyOR1 mg every 48 hours
10 to less than 30 0.5 mg every 72 hours 1 mg every 72 hours
Less than 10Hempdialysis*ORCAPD 0.5 mg every 7 days 1 mg every 7 days

* If administered on a hemodialysis day, administer Entecavir tablets after the hemodialysis session.

Pediatric use information is approved for Bristol-Myers Squibb Company’s Baraclude (entecavir) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that information.

2.5 Hepatic Impairment

No dosage adjustment is necessary for patients with hepatic impairment.

2.6 Duration of Therapy

The optimal duration of treatment with Entecavir tablets for patients with chronic hepatitis B virus infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.

3 DOSAGE FORMS AND STRENGTHS

  • Entecavir tablets 0.5 mg are white to off-white, oval, film-coated, biconvex bevel edged, unscored tablets, debossed with “AN” on one side and “446” on the other side.
  • Entecavir tablets 1 mg are pink, oval, film-coated, biconvex bevel edged, unscored tablets, debossed with “AN” on one side and “449” on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Severe Acute Exacerbations of Hepatitis B

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued antihepatitis B therapy, including Entecavir [see Adverse Reactions (6.1)]. Hepatic function should be monitored closely with both 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.

5.2 Patients Co-infected with HIV and HBV

Entecavir has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment. 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 infection in patients with HIV infection that is not being treated [see Microbiology (12.4)]. Therefore, therapy with Entecavir is not recommended for HIV/HBV co-infected patients who are not also receiving HAART. Before initiating Entecavir therapy, HIV antibody testing should be offered to all patients. Entecavir has not been studied as a treatment for HIV infection and is not recommended for this use.

5.3 Lactic Acidos is and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors, including entecavir, alone or in combination with antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside inhibitor exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogue inhibitors to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.

Lactic acidosis with entecavir use has been reported, often in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk for lactic acidosis. Treatment with entecavir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

6 ADVERSE REACTIONS

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

6.1 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 Entecavir 0.5 mg/day (n=679), Entecavir 1 mg/day (n=183), or lamivudine (n=858) for up to 2 years. Median duration of therapy was 69 weeks for Entecavir-treated subjects and 63 weeks for lamivudine-treated subjects in Studies AI463022 and AI463027 and 73 weeks for Entecavir-treated subjects and 51 weeks for lamivudine-treated subjects in Studies AI463026 and AI463014. The safety profiles of Entecavir 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 Entecavir-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 Entecavir-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 Entecavir was compared with lamivudine are presented in Table 3.

Table 3: Clinical Adverse Reactions a of Moderate-Severe Intens ity (Grades 2 to 4) Reported in Four Entecavir Clinical Trials Through 2 Years
Nucleos ide-Inhibitor-Naïve b Lamivudine-Refractory c
Body System /Adverse Reaction Entecavir 0.5 mg N=679 Lamivudine 100 mg N=668 Entecavir 1 mg N=183 Lamivudine 100 mg N=190
Any Grade 2 to 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%

a Includes events of possible, probable, certain, or unknown relationship to treatment regimen.

b Studies AI463022 and AI463027.

c Includes Study AI463026 and the Entecavir 1 mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of Entecavir (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.

Laboratory Abnormalities

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

Table 4: Selected Treatment-Emergent a Laboratory Abnormalities Reported in Four Entecavir Clinical Trials Through 2 Years
Nucleoside-Inhibitor-Naïve b Lamivudine-Refractory c
Test Entecavir 0.5 mg N=679 Lamivudine 100 mg N=668 Entecavir 1 mg N=183 Lamivudine 100 mg N=190
Any Grade 3 to 4 laboratory abnormalityd ALT >10 x ULN and >2 x baselineALT >5 x ULNAlbumin <2.5 g/dLTotal bilirubin >2.5 x ULNLipase >2.1 x ULNCreatinine >3 x ULNConfirmed creatinine increase >0.5 mg/dLHyperglycemia, fasting >250 mg/dLGlycosuriae Hematuriaf Platelets <50,000/mm³ 35%2%11%<1%2%7%01%2%4%9%<1% 36%4%16%<1%2%6%01%1%3%10%<1% 37%2%12%03%7%02%3%4%9%<1% 45%11%24%2%2%7%01%1%6%6%<1%

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 x ULN and >2 x baseline.

b Studies AI463022 and AI463027.

c Includes Study AI463026 and the Entecavir 1 mg and lamivudine treatment arms of Study AI463014, a

Phase 2 multinational, randomized, double-blind study of three doses of Entecavir (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.

Among Entecavir-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 log /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 entecavir is discontinued without regard to treatment response, the rate of post-treatment flares could be higher [see also 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 x ULN and >2 x Referencea
Entecavir Lamivudine
Nucleoside-inhibitor-naïve HBeAg-positive HBeAg-negativeLamivudine-refractory 4/174 (2%)24/320 (8%)6/52 (12%) 13/147 (9%)30/270 (11%)0/16

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 Entecavir-treated subjects and 10 weeks for lamivudine-treated subjects.

Decompensated Liver Disease

Study AI463048 was a randomized, open-label study of Entecavir 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 Entecavir, the most common treatmentemergent 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 2 that were observed through Week 48 include blood bicarbonate decreased (2%) and renal failure (<1%).

Eighteen of 102 (18%) subjects treated with Entecavir and 18/89 (20%) subjects treated with adefovir dipivoxil died during the first 48 weeks of therapy. The majority of deaths (11 in the Entecavir 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 Entecavir 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 x baseline and >10 x ULN) through Week 48. Eleven of 102 (11%) subjects treated with entecavir 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 Entecavir 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)].

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