Entecavir

277.283

277.28

1806241-263-5

NNU2O4609D

DTXSID4046446

C76494

White to off white powder

J05AF10|J - Antiinfectives for systemic use

29339900

126

-0.8

Solid

1.81±0.1 g/cm3(Predicted)

249-252°C

661.4±65.0 °C(Predicted)

397.9ºC

1.837

H2O: Slightly soluble (2.4 mg/mL at pH 7.9, 25 °C)

-20°C Freezer

4.6X10-18 mm Hg at 25 deg C (est)

pH = 7.9 in a saturated solution of water at 25 °C

Henry's Law constant = 1.6X10-21 atm-cu m/mole at 25 °C (est)

pKa = 8.00 - (est)

White to off-white powder, mp: >220 °C. Specific optical rotation: +35 deg at 25 °C/D (c = 0.38 in water). Solubility in water: 2.4 mg/mL. pH of saturated solution in water is 7.9 at 25 °C /Entecavir monohydrate/

NONH for all modes of transport

3

24/25

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including entecavir, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Danger|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P263, P264, P270, P281, P301+P312, P308+P313, P314, P330, P405, and P501|Aggregated GHS information provided by 7 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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.

Elevations in serum ALT levels occur in 2% to 10% patients with chronic hepatitis B treated with entecavir. These elevations appear to be due to a transient flare in the underlying chronic hepatitis B and occur both during and after therapy. On treatment, ALT flares typically occur during the first 1 to 2 months of therapy and are mild, asymptomatic and self-limited, accompanying the rapid declines in HBV DNA levels. Withdrawal flares in ALT levels occur in 8% to 12% of patients who receive entecavir therapy of hepatitis B and are subsequently withdrawn from treatment. The withdrawal flares arise within 1 to 3 months of stopping treatment and are usually preceded by marked and sudden rises in HBV DNA levels towards pretreatment values. Withdrawal flares of hepatitis B can be symptomatic and severe, and several instances of acute liver failure have been described in patients withdrawn from therapy after 1 to 3 years of treatment. There have been few reports of withdrawal flares after stopping entecavir, because the majority of patients have continued therapy indefinitely. However, the rate of flares and their severity are likely to be similar after stopping entecavir as after withdrawal of other therapies of hepatitis B.

Potential pharmacokinetic interactions with drugs that reduce renal function or that may compete with entecavir for active renal tubular secretion; increased serum concentrations of entecavir or the concomitantly used drug may occur. Although the effect of concomitant use of such drugs with entecavir has not been specifically studied, patients receiving entecavir in conjunction with other drugs that may affect renal function or are excreted renally should be monitored closely for adverse effects.|In vitro evidence indicates that concurrent use of nucleoside reverse transcriptase inhibitors (NRTIs) and entecavir is unlikely to reduce the antiviral efficacy of entecavir against HBV or the antiretroviral activity of NRTIs (e.g., abacavir, didanosine, lamivudine, stavudine, tenofovir disoproxil fumarate, or zidovudine) against HIV.|Possible pharmacokinetic interaction (increased entecavir serum concentrations because of altered renal function) with cyclosporine or tacrolimus. Monitor renal function prior to and during entecavir treatment in patients (e.g., transplant patients) receiving cyclosporine, tacrolimus, or other immunosuppressive agents that may affect renal function.

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

Entecavir's production and use as an antiviral(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that entecavir is expected to have very high mobility in soil(SRC). The estimated pKa of entecavir is 8.00(3), indicating that this compound will exist partially in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of neutral entecavir from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.6X10-21 atm-cu m/mole(SRC), using a fragment constant estimation method(5). The cation form of entecavir will not volatilize(SRC). Entecavir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.6X10-18 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). Biodegradation data in soil were not available(2013, SRC).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that entecavir is not expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 8.00(3) indicates entecavir will exist partially in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces of the ion form is not expected to be an important fate process(SRC). Volatilization of the neutral form from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 1.6X10-21 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 3(SRC), from an estimated log Kow of -0.50(7) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Entecavir is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4). Biodegradation data in water were not available(SRC,2013).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), entecavir, which has an estimated vapor pressure of 4.6X10-18 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase entecavir may be removed from the air by wet or dry deposition(SRC). Entecavir does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Entecavir is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Entecavir does not contain chromophores that absorb at wavelengths >290 nm(1) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 3 was calculated in fish for entecavir(SRC), using an estimated log Kow of -0.50(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of entecavir can be estimated to be 10(SRC). According to a classification scheme(2), this estimated Koc value suggests that entecavir is expected to have very high mobility in soil. The estimated pKa of entecavir is 8.00(3), indicating that this compound will exist partially in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

An estimated pKa of 8.00(1) indicates entecavir will exist partially in the cation form at pH values of 5 to 9 and, therefore, volatilization from water and moist soil surfaces of the ion form is not expected to be an important fate process(SRC). The Henry's Law constant for entecavir is estimated as 1.6X10-21 atm-cu m/mole(SRC) using a fragment constant estimation method(2). This Henry's Law constant indicates that the neutral form of entecavir is expected to be essentially nonvolatile from water surfaces(3). Entecavir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.6X10-18 mm Hg(SRC), determined from a fragment constant method(4).

While data specific to entecavir were not located(SRC, 2013), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Entecavir is distributed into the milk of rats. It is not known whether entecavir is distributed into human milk.

Occupational exposure to entecavir may occur through inhalation of dust and dermal contact with this compound at workplaces where entecavir is produced or used. Exposure to entecavir among the general population may be limited to those administered the drug baraclude, an antiviral which contains entecavir as its active component. (SRC)

Entecavir is distributed into the milk of rats. It is not known whether entecavir is distributed into human milk.

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.|FDA Label|Baraclude is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with:compensated liver disease and evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis;decompensated liver disease.For both compensated and decompensated liver disease, this indication is based on clinical trial data in nucleoside naive patients with HBeAg positive and HBeAg negative HBV infection. With respect to patients with lamivudine-refractory hepatitis B.|Entecavir Mylan is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with:compensated liver disease and evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.decompensated liver disease.For both compensated and decompensated liver disease, this indication is based on clinical trial data in nucleoside naive patients with HBeAg positive and HBeAg negative HBV infection. With respect to patients with lamivudine-refractory hepatitis B.Entecavir Mylan is also indicated for the treatment of chronic HBV infection in nucleoside naive paediatric patients from 2 to|Entecavir Accord is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with:compensated liver disease and evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.decompensated liver disease.For both compensated and decompensated liver disease, this indication is based on clinical trial data in nucleoside naive patients with HBeAg positive and HBeAg negative HBV infection. With respect to patients with lamivudine-refractory hepatitis B.Entecavir Accord is also indicated for the treatment of chronic HBV infection in nucleoside naive paediatric patients from 2 to|Treatment of chronic hepatitis B

Entecavir is a guanosine nucleoside analogue used in the treatment of chronic hepatitis B virus (HBV) infection. Entecavir therapy can be associated with flares of the underlying hepatitis B during or after therapy, but has not been linked to cases of clinically apparent liver injury.

Antiviral Agents|Entecavir has been evaluated for the treatment of chronic HBV infection in a phase III, randomized, double-blind, active-controlled study (AI463038) in HIV-infected patients receiving highly active antiretroviral therapy (HAART) that included lamivudine. These patients had recurrent HBV viremia (99% were HBeAg-positive), active HBV replication (median baseline serum HBV DNA levels 9.13 log10 copies/mL), and persistent elevations in serum ALT concentrations (mean serum ALT of 71.5 IU/L). Patients continued HAART (including lamivudine 300 mg daily) and were randomized to receive concurrent therapy with entecavir (1 mg daily) or placebo for 24 weeks followed by an additional 24-week open-label period during which all patients received entecavir (1 mg daily). Analysis of limited data at 24 weeks indicated that 6% of patients who received entecavir in conjunction with lamivudine-containing HAART had undetectable levels of serum HBV DNA (defined as less than 300 copies/mL by PCR assay) compared with 0% of those who received placebo and lamivudine-containing HAART. Thirty-four percent of patients receiving the regimen that included entecavir had normal serum ALT concentrations (i.e., biochemical response) at week 24 compared with 8% of those who did not receive entecavir. In addition, the mean decrease in serum HBV DNA levels from baseline was 3.65 log10 copies/mL at week 24 in those receiving the regimen that included entecavir compared with an increase of 0.11 log10 copies/mL in those receiving a lamivudine-containing HAART regimen alone. Median serum HIV-1 RNA levels remained stable at approximately 2 log10/mL during the 24-week blinded study period.|Entecavir has been evaluated for the treatment of lamivudine-refractory chronic HBV infection in a phase III, randomized, double-blind, active-controlled study (AI463026) in adults with active HBV replication (median baseline serum HBV DNA levels 9.36 log10 copies/mL), persistent elevations in serum ALT concentrations (mean serum ALT of 128 IU/L), and histologic evidence of active liver disease (mean Knodell necroinflammatory score of 6.5). 27 Seventy-six percent of patients in the study were male, 37% were Asian, 62% were Caucasian, and 52% had prior treatment with interferon alfa. Patients in the study had previously received lamivudine therapy for a mean duration of 2.7 years and lamivudine-resistant mutations were identified at baseline in 85% of patients. Patients were randomized to switch (without a washout or an overlap period) from lamivudine to entecavir (1 mg daily) or to continue lamivudine (100 mg daily) for 52 weeks. Data analysis at 48 weeks indicated that 55% of patients switched to entecavir had histologic improvement (defined as a reduction of at least 2 points in the Knodell necroinflammatory score with no concurrent worsening of the Knodell fibrosis score) compared with 28% of those who continued to receive lamivudine. Sixty-one percent of patients receiving entecavir had normal serum ALT concentrations (i.e., biochemical response) at week 48 compared with 15% of those receiving lamivudine. In addition, the mean decrease in serum HBV DNA levels from baseline was 5.11 log10 copies/mL at week 48 in those receiving entecavir compared with a decrease of 0.48 log10 copies/mL in those receiving lamivudine. Nineteen percent of patients who received entecavir had undetectable levels of serum HBV DNA (defined as less than 300 copies/mL by PCR assay) at week 48 compared with 1% of those who received lamivudine. Seroconversion to anti-HBe occurred in 8 or 3% of patients who received entecavir or lamivudine, respectively. Approximately 55% of patients treated with entecavir continued treatment for up to 96 weeks; 40% of these patients had undetectable levels of serum HBV DNA, 81% had normal ALT concentrations, and 10% achieved seroconversion.|Efficacy of entecavir for the management of HBeAg-negative, anti-HBe- and HBV-DNA-positive chronic HBV infection was evaluated in a phase III, randomized, double-blind, active-controlled study (AI463027) in nucleoside-naive adults with active HBV replication (median baseline serum HBV DNA levels 7.58 log10 copies/mL by a PCR-based assay), persistent elevations in serum ALT concentrations (mean serum ALT of 142 IU/L), and histologic evidence of active liver disease (mean Knodell necroinflammatory score of 7.8). Seventy-six percent of patients in the study were male, 58% were Caucasian, 39% were Asian, and 13% had prior treatment with interferon alfa. Data analysis at 48 weeks indicated that 70% of patients who received entecavir (0.5 mg daily) had histologic improvement (defined as a reduction of at least 2 points in the Knodell necroinflammatory score with no concurrent worsening of the Knodell fibrosis score) compared with 61% of those who received lamivudine (100 mg daily). Serum ALT concentrations also normalized at week 48 in 78% of patients who received entecavir compared with 71% of those who received lamivudine daily. In addition, the mean decrease in serum HBV DNA levels from baseline was 5.04 log10 copies/mL at week 48 in patients receiving entecavir 0.5 mg daily compared with a mean decrease of 4.53 log10 copies/mL in those receiving lamivudine 100 mg daily. Ninety percent of patients who received entecavir had undetectable levels of serum HBV DNA (defined as less than 300 copies/mL by PCR assay) at week 48 compared with 72% of those who received lamivudine. Eighty-five percent of patients treated with entecavir met the response criteria (determined at 48 weeks based on HBV virologic suppression [less than 0.7 MEq/mL by bDNA assay] and loss of HBeAg) and discontinued entecavir at 52 weeks per protocol; very few of these patients had undetectable levels of serum HBV DNA and 46% of patients maintained normal ALT concentrations during an additional 24 weeks of follow-up.|For more Therapeutic Uses (Complete) data for ENTECAVIR (6 total), please visit the HSDB record page.

The optimal duration of treatment with entecavir in patients with chronic hepatitis B infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.|Severe acute exacerbations of hepatitis have occurred following discontinuance of hepatitis B virus (HBV) therapy, including entecavir therapy. In studies that evaluated safety of entecavir, exacerbations of hepatitis or ALT flare was defined as ALT elevations greater than 10 times the upper limit of normal (ULN) and greater than 2 times baseline serum concentrations. In clinical studies (AI463022, AI463027, AI463026), ALT flare occurred in 2, 8, or 12% of nucleoside-naive HBeAg-positive, nucleoside-naive HBeAg-negative, or lamivudine-refractory patients, respectively, following discontinuance of entecavir. The median time to exacerbations of hepatitis was 23 weeks. Rates of post-treatment ALT flare may be higher if entecavir therapy is discontinued without regard to previous response to therapy.|FDA Pregnancy Category C; RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk.|Not known whether entecavir is distributed into milk. Discontinue nursing or the drug, taking into account the importance of the drug to the woman.|For more Drug Warnings (Complete) data for ENTECAVIR (15 total), please visit the HSDB record page.

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.

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. (See all compounds classified as Antiviral Agents.)

Absorption 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.|renal cl=383.2 +/- 101.8 mL/min [Unimpaired renal function]|The bioavailability of /entecavir/ tablets was /equivalent/ to the oral solution.|Oral administration of 0.5 mg of entecavir given with a standard high fat meal resulted in a delayed in absorption (1 to 1.5 hours fed vs. 0.75 hours fasted), a decrease in Cmax of 44% to 46%, and a decrease in AUC of 18% to 20%.|/The estimated apparent volume of distribution is in excess of total body water/, entecavir is extensively distributed into tissues.|/Binding of entecavir to human serum proteins in vitro is/ low (13%)|For more Absorption, Distribution and Excretion (Complete) data for ENTECAVIR (7 total), please visit the HSDB record page.

Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. Entecavir is efficiently phosphorylated to the active triphosphate form.|Following administration of 14C-entecavir, 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 enzyme system.

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.|Elimination /half-life is/ approximately 128 to 149 hours.|Accumulation /half-life is/ 24 hours

By competing with the natural substrate deoxyguanosine triphosphate, entecavir functionally inhibits all three activities of the HBV polymerase (reverse transcriptase, rt): (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. Upon activation by kinases, the drug can be incorporated into the DNA which has the ultimate effect of inhibiting the HBV polymerase activity.|Entecavir is a nucleoside analogue with activity against HBV polymerase. It is efficiently phosphorylated to the active triphosphate form, which competes with the natural substrate deoxyguanosine triphosphate and inhibits all three activities of the HBV polymerase (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 alpha, beta, and delta and mitochondrial DNA polymerase gamma with Ki values ranging from 18 to > 160 microM.

There is no known specific antidote to entecavir. Treatment is generally symptomatic and supportive.|To enhance elimination, hemodialysis removed approximately 13% of a single 1-mg dose of entecavir.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|For more Antidote and Emergency Treatment (Complete) data for ENTECAVIR (8 total), please visit the HSDB record page.

/CASE REPORTS/ ... A 44-year-old man presented with a 3-month history of myalgia and progressive weakness. He had HBV infection and had received entecavir antiviral treatment for 5 years. Laboratory tests showed that serum creatine kinase levels were significantly elevated. Muscle histopathology showed abundant T lymphocyte infiltration of muscle fibers, and HBV surface antigen and HBV core antigen were not present inmuscle fibers. Entecavir-associated myopathy was subsequently diagnosed. His symptoms eventually resolved, and his serum CK levels decreased rapidly after he stopped receiving entecavir treatments.

Baraclude

0.05 mg/mL (Rx) Baraclude (citric acid, maltitol, methylparaben, orange flavor, sodium citrate) /Oral solution/|0.5 mg /tablet/ (Rx) Baraclude (crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polysorbate 80, povidone, titanium dioxide).|1 mg /tablet/ (Rx) Baraclude (crospovidone, hypromellose, iron oxide red, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone, titanium dioxide).

Human drugs -> Baraclude -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group|Human drugs -> Entecavir Mylan -> EMA Drug Category|Human drugs -> Entecavir Accord -> EMA Drug Category|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients