ERTIVIX

Entecavir is an oral antiviral drug used in the treatment of hepatitis B infection.

It is marketed under the trade name Baraclude (BMS).

Entecavir is a guanine analogue that inhibits all three steps in the viral replication process, and the manufacturer claims that it is more efficacious than previous agents used to treat hepatitis B (lamivudine and adefovir).

It was approved by the

U.S. Food and Drug Administration (FDA) in March 2005.

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.

Entecavir is a guanosine nucleoside analogue with selective activity against hepatitis B virus (HBV).

It is designed to selectively inhibit the Hepatitis B virus, blocking all three steps in the replication process.

Entecavir is more efficient than an older Hepatitis B drug, lamivudine.

Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours.

In healthy subjects, the bioavailability of the tablet is 100% relative to the oral solution.

Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system.

Entecavir is efficiently phosphorylated to the active triphosphate form.

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 phosphorylated metabolite has a half-life of 15 hours.

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• 101.8 mL/min renal cl=197.9 +/.

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• 31.6 mL/min renal cl=40.3 +/.

• 10.1 mL/min apparent oral cl=588.1 +/.

• 153.7 mL/min apparent oral cl=309.2 +/.

• 62.6 mL/min apparent oral cl=226.3 +/.

• 60.1 mL/min apparent oral cl=100.6 +/.

• 29.1 mL/min apparent oral cl=50.6 +/.

• 16.5 mL/min apparent oral cl=35.7 +/.

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Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase in or unexpected adverse events.

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Nucleoside-inhibitor-treatment-naïve with compensated liver disease (greater than or equal to 16 years old): 0.5 mg once daily.

Nucleoside-inhibitor-treatment-naïve and lamivudine-experienced pediatric patients at least 2 years of age and weighing at least 10 kg: dosing is based on weight.

Lamivudine-refractory or known lamivudine or telbivudine resistance substitutions (greater than or equal to 16 years old): 1 mg once daily.

Decompensated liver disease (adults): 1 mg once daily.

Renal impairment

Dosage adjustment is recommended if creatinine clearance is less than 50 mL/min. Entecavir tablets should be administered on an empty stomach. 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 nucleoside-inhibitor-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.

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 Dosage in Pediatric Patients Table 1 describes the recommended dose of entecavir tablets for pediatric patients 2 years of age or older and weighing at least 10 kg. The oral solution should be used for patients with body weight up to 30 kg. Table 1: Dosing Schedule for Pediatric Patients Recommended Once-Daily Dose of Oral Solution (mL) Body Weight (kg) Treatment-Naïve Patients a Lamivudine-Experienced Patients b to 11 3 6 greater than to 14 4 8 greater than to 17 5 10 greater than to 20 6 12 greater than to 23 7 14 greater than to 26 8 16 greater than to 30 9 18 greater than 30 10 20 a Children with body weight greater than 30 kg should receive 10 mL (0.5 mg) of oral solution or one 0.5 mg tablet once daily. b Children with body weight greater than 30 kg should receive 20 mL (1 mg) of oral solution or one 1 mg tablet once daily. 2.4 Renal Impairment In adult subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased.

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 Dosage 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 to less than 50 0.5 mg every 48 hours 0.5 mg once daily OR 1 mg every 48 hours to less than 30 0.5 mg every 72 hours 1 mg every 72 hours Less than 10 Hemodialysis or CAPD 0.5 mg every 7 days 1 mg every 7 days If administered on a hemodialysis day, administer entecavir tablets after the hemodialysis session.

Although there are insufficient data to recommend a specific dose adjustment of entecavir tablets in pediatric patients with renal impairment, a reduction in the dose or an increase in the dosing interval similar to adjustments for adults should be considered. 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.

Entecavir tablets, USP 0.5 mg, are supplied as white to off-white, oval, film-coated, biconvex bevel edged, unscored tablet, debossed with “AN” on one side and “446” on the other side.

They are available as follows

Bottles of 30: NDC 65162-446-03 Bottles of 90: NDC 65162-446-09 Entecavir tablets, USP 1 mg, are supplied as pink, oval, film-coated, biconvex bevel edged, unscored tablet, debossed with “AN” on one side and “449” on the other side.

Bottles of 30: NDC 65162-449-03 Storage Entecavir tablets, USP should be stored in a tightly closed container at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) .

Protect from light.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to entecavir during pregnancy.

Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects, miscarriage or adverse maternal or fetal outcomes.

Entecavir use during pregnancy has been evaluated in a limited number of individuals reported to the APR and the number of exposures to entecavir is insufficient to make a risk assessment compared to a reference population.

The estimated background rate for major birth defects is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).

The rate of miscarriage is not reported in the APR.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15% to 20%.

In animal reproduction studies, no adverse developmental effects were observed with entecavir at clinically relevant exposures.

No developmental toxicities were observed at systemic exposures (AUC) approximately 25 (rats) and 200 (rabbits) times the exposure at the maximum recommended human dose (MRHD) of 1 mg/day.

Entecavir was administered orally to pregnant rats (at 2, 20, and 200 mg per kg per day) and rabbits (at 1, 4, and 16 mg per kg per day) during organogenesis (on gestation Days 6 through 15 [rat] and 6 through 18 [rabbit]).

In rats, embryofetal toxicity including post-implantation loss, resorptions, tail and vertebral malformations, skeletal variations including reduced ossification (vertebrate, sternebrae, and phalanges) and extra lumbar vertebrae and ribs, and lower fetal body weights were observed at systemic exposures (AUC) 3,100 times those in humans at the MRHD.

Maternal toxicity was also observed at this dose level.

In rabbits, embryofetal toxicity including post implantation loss, resorptions and skeletal variations, including reduced ossification (hyoid) and increased incidence of 13 th rib, were observed at systemic exposures (AUC) 883 times those in humans at the MRHD.

There were no signs of embryofetal toxicity when pregnant animals received oral entecavir at 28 (rat) and 212 (rabbit) times the human exposure (AUC) at the MRHD.

In a pre/postnatal development study, entecavir was administered orally to pregnant rats at 0.3, 3, and 30 mg per kg per day from gestation day to lactation/post-partum day 20.

No adverse effects on the offspring occurred at up to the highest dose evaluated, resulting in exposures (AUC) greater than 94 times those in humans at the MRHD.

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.

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.

The efficacy and safety of entecavir have not been established in patients less than 2 years of age.

Use of entecavir in this has not been evaluated because treatment of HBV in this is rarely required.

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.