Release form, composition and packing Baraclude
Tablets, film-coated white or nearly white, triangular, with the marking "Bms" on one side and "1611" on the other side. 1 tab. entecavir 500 mcg. Excipients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, magnesium stearate, Opadry white colorant (titanium dioxide, hypromellose 6cP, hypromellose 3cP, macrogol 400, polysorbate 80).
Tablets, film-coated pink, triangular, with the marking "Bms" on one side and "1612" on the other side. 1 tab. entecavir 1 mg. Excipients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, magnesium stearate, Opadry pink dye (6sR hypromellose, titanium dioxide, macrogol 400, iron oxide red dye).
Clinico-pharmacological group: antiviral drugs.
Pharmacological action
Antiviral drug, is a nucleoside guanosine analogue with a strong and selective activity against hepatitis B virus polymerase B (HBV). Entecavir is phosphorylated to form the active triphosphate (TP), which has an intracellular half-life of 15 hours the intracellular concentration of HF is directly related to the extracellular level of entecavir, not noted a significant accumulation of the drug after the initial level of the plateau.
By competition with the natural substrate, deoksiguanozina-FF-FF entecavir inhibits all three functional activity of the viral polymerase: (1) HBV polymerase priming, (2) reverse transcription of the negative threads from pregenomnoy mRNA and (3) synthesis of HBV DNA positive thread. Entecavir-TP is a weak inhibitor of cellular DNA polymerases α, β and δ with Ki 18-40 uM. In addition, high concentrations of entecavir-TP and entecavir are not marked adverse effects on the polymerase γ and DNA synthesis in the mitochondria of cells HepG2.
Pharmacokinetics
Suction
In healthy people, absorption of entecavir fast, Cmax in blood plasma determined by 0.5-1.5 h. The re-admission of entecavir at a dose of 0.1 to 1 mg dose is proportional to the observed increase in Cmax and AUC. The equilibrium state is achieved after 6-10 days intake 1 time per day, while the plasma concentration increases by a factor of 2. Cmax and Cmin in plasma at steady state were 4.2 and 0.3 ng / ml, respectively, while taking the drug at a dose of 500 micrograms, 8.2 and 0.5 ng / ml, respectively, when receiving a dose of 1 mg.
When comparing the bioavailability in healthy humans tablets and oral solution, it turned out to be equivalent, ie These two formulations are interchangeable.
If ingestion of entecavir at a dose of 500 mcg as a food high in fat and low-observed minimum delay absorption (1-1.5 hours at the reception with food and 0.75 hours at the reception on an empty stomach), decreased Cmax by 44-46% and decrease AUC by 18-20%.
Distribution
Vd entecavir exceeded total body water, indicating good penetration of the drug in the tissue. Binding of entecavir to human plasma proteins in vitro is about 13%.
Metabolism
Entecavir is not a substrate, inhibitor or inducer of isozymes of P450. After the introduction of 14C-labeled entecavir man and rats have not been determined oxidized or acetylated metabolites, and metabolites of phase II (glucuronide and sulfate) were found in small quantities.
Breeding
After reaching Cmax plasma concentrations of entecavir decreased biexponential, with T1 / 2 was 128-149 h. When you receive a time / day there was an increase of concentration (accumulation) of the drug in 2 times, that is effective T1 / 2 was approximately 24 hours entecavir primarily excreted by the kidneys, and in equilibrium unchanged in the urine is determined by the 62-73% of the dose.
Renal clearance is not dose dependent and ranges from 360 to 471 ml / min, indicating glomerular filtration and tubular secretion of the drug.
Statement
chronic hepatitis B in adults with evidence of viral replication and increase the activity level of serum transaminases (ALT or ACT) or the presence of histological signs of inflammation in the liver.
Dosing regimen
The drug is taken orally on an empty stomach (ie, not less than 2 hours after meals and at least 2 hours before the next meal). Recommended dose is 500 mcg Baraklyud 1 time per day.
If there is resistance to lamivudine (ie, when specifying a history of viremia with HBV, continuing on therapy with lamivudine, or in the case confirmed that resistance to lamivudine) are encouraged to nominate entecavir 1 mg 1 time per day.
In patients with renal failure the clearance of entecavir decreases with KK. In patients with hepatic impairment dose adjustment of entecavir is not required.
Side effect
From the digestive system: rare (> 1 / 1000, <1 / 100) - diarrhea, indigestion, nausea, and vomiting.
CNS: frequent (> 1 / 100, <1> 1 / 1000, <1 / 100) - insomnia, dizziness, drowsiness.
Contraindications
age 18;
hypersensitivity to entecavir or any component of the drug.
Pregnancy and lactation
Adequate and well controlled clinical studies on the safety of the drug during pregnancy has not been carried out.
Application Baraklyuda during pregnancy only in cases where the expected benefits of therapy to the mother justifies the potential risk to the fetus. Data on the penetration of entecavir in human milk is not.
Using the drug breastfeeding is not recommended.
Use in hepatic dysfunction
In patients with hepatic impairment dose adjustment of entecavir is not required.
Use in renal impairment
In patients with renal failure the clearance of entecavir decreases with KK. With CC <50 ml / min, including patients in hemodialysis and long-term ambulatory peritoneal dialysis, recommended dosage adjustment Baraklyuda.
Cautions
In the treatment of nucleoside analogues, alone and in combination with antiretroviral drugs are described cases of lactic acidosis and severe hepatomegaly with steatosis, leading sometimes to death of the patient. There are cases of acute hepatitis B after discontinuation of antiviral therapy, including entecavir. Most of these exacerbations were held without treatment. However, there may develop severe exacerbations, including fatal.
The causal relationship between these exacerbations with the abolition of therapy has not been established. After discontinuation of treatment should be periodically monitor liver function.
If necessary, antiviral therapy may be resumed. Safety and efficacy of entecavir in patients who underwent liver transplantation, are unknown.
Should carefully monitor renal function before and during treatment with entecavir in patients who underwent liver transplantation and receiving immunosuppressive drugs, which may affect renal function, such as cyclosporine and tacrolimus.
Overdose
Entecavir overdose cases are not registered.
Treatment: with an overdose requires careful medical supervision of a medical condition and if necessary, standard supportive therapy.
Drug Interactions
Since entecavir is excreted mainly by the kidneys, while the introduction of entecavir and drugs that cause impaired renal function or compete at the level of tubular secretion may increase serum concentrations of entecavir and these drugs.
When concomitant administration of entecavir with lamivudine, adefovir or tenofovir is not revealed clinically significant drug interactions. Interaction of entecavir with other drugs that affect the kidneys or kidney function, has not been studied. When concomitant administration of entecavir with such drugs the patient requires careful medical supervision.
Conditions and terms of
The drug should be stored in a place inaccessible to children at a temperature not exceeding 25 ° C. Shelf life - 2 years.
Tablets, film-coated white or nearly white, triangular, with the marking "Bms" on one side and "1611" on the other side. 1 tab. entecavir 500 mcg. Excipients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, magnesium stearate, Opadry white colorant (titanium dioxide, hypromellose 6cP, hypromellose 3cP, macrogol 400, polysorbate 80).
Tablets, film-coated pink, triangular, with the marking "Bms" on one side and "1612" on the other side. 1 tab. entecavir 1 mg. Excipients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, magnesium stearate, Opadry pink dye (6sR hypromellose, titanium dioxide, macrogol 400, iron oxide red dye).
Clinico-pharmacological group: antiviral drugs.
Pharmacological action
Antiviral drug, is a nucleoside guanosine analogue with a strong and selective activity against hepatitis B virus polymerase B (HBV). Entecavir is phosphorylated to form the active triphosphate (TP), which has an intracellular half-life of 15 hours the intracellular concentration of HF is directly related to the extracellular level of entecavir, not noted a significant accumulation of the drug after the initial level of the plateau.
By competition with the natural substrate, deoksiguanozina-FF-FF entecavir inhibits all three functional activity of the viral polymerase: (1) HBV polymerase priming, (2) reverse transcription of the negative threads from pregenomnoy mRNA and (3) synthesis of HBV DNA positive thread. Entecavir-TP is a weak inhibitor of cellular DNA polymerases α, β and δ with Ki 18-40 uM. In addition, high concentrations of entecavir-TP and entecavir are not marked adverse effects on the polymerase γ and DNA synthesis in the mitochondria of cells HepG2.
Pharmacokinetics
Suction
In healthy people, absorption of entecavir fast, Cmax in blood plasma determined by 0.5-1.5 h. The re-admission of entecavir at a dose of 0.1 to 1 mg dose is proportional to the observed increase in Cmax and AUC. The equilibrium state is achieved after 6-10 days intake 1 time per day, while the plasma concentration increases by a factor of 2. Cmax and Cmin in plasma at steady state were 4.2 and 0.3 ng / ml, respectively, while taking the drug at a dose of 500 micrograms, 8.2 and 0.5 ng / ml, respectively, when receiving a dose of 1 mg.
When comparing the bioavailability in healthy humans tablets and oral solution, it turned out to be equivalent, ie These two formulations are interchangeable.
If ingestion of entecavir at a dose of 500 mcg as a food high in fat and low-observed minimum delay absorption (1-1.5 hours at the reception with food and 0.75 hours at the reception on an empty stomach), decreased Cmax by 44-46% and decrease AUC by 18-20%.
Distribution
Vd entecavir exceeded total body water, indicating good penetration of the drug in the tissue. Binding of entecavir to human plasma proteins in vitro is about 13%.
Metabolism
Entecavir is not a substrate, inhibitor or inducer of isozymes of P450. After the introduction of 14C-labeled entecavir man and rats have not been determined oxidized or acetylated metabolites, and metabolites of phase II (glucuronide and sulfate) were found in small quantities.
Breeding
After reaching Cmax plasma concentrations of entecavir decreased biexponential, with T1 / 2 was 128-149 h. When you receive a time / day there was an increase of concentration (accumulation) of the drug in 2 times, that is effective T1 / 2 was approximately 24 hours entecavir primarily excreted by the kidneys, and in equilibrium unchanged in the urine is determined by the 62-73% of the dose.
Renal clearance is not dose dependent and ranges from 360 to 471 ml / min, indicating glomerular filtration and tubular secretion of the drug.
Statement
chronic hepatitis B in adults with evidence of viral replication and increase the activity level of serum transaminases (ALT or ACT) or the presence of histological signs of inflammation in the liver.
Dosing regimen
The drug is taken orally on an empty stomach (ie, not less than 2 hours after meals and at least 2 hours before the next meal). Recommended dose is 500 mcg Baraklyud 1 time per day.
If there is resistance to lamivudine (ie, when specifying a history of viremia with HBV, continuing on therapy with lamivudine, or in the case confirmed that resistance to lamivudine) are encouraged to nominate entecavir 1 mg 1 time per day.
In patients with renal failure the clearance of entecavir decreases with KK. In patients with hepatic impairment dose adjustment of entecavir is not required.
Side effect
From the digestive system: rare (> 1 / 1000, <1 / 100) - diarrhea, indigestion, nausea, and vomiting.
CNS: frequent (> 1 / 100, <1> 1 / 1000, <1 / 100) - insomnia, dizziness, drowsiness.
Contraindications
age 18;
hypersensitivity to entecavir or any component of the drug.
Pregnancy and lactation
Adequate and well controlled clinical studies on the safety of the drug during pregnancy has not been carried out.
Application Baraklyuda during pregnancy only in cases where the expected benefits of therapy to the mother justifies the potential risk to the fetus. Data on the penetration of entecavir in human milk is not.
Using the drug breastfeeding is not recommended.
Use in hepatic dysfunction
In patients with hepatic impairment dose adjustment of entecavir is not required.
Use in renal impairment
In patients with renal failure the clearance of entecavir decreases with KK. With CC <50 ml / min, including patients in hemodialysis and long-term ambulatory peritoneal dialysis, recommended dosage adjustment Baraklyuda.
Cautions
In the treatment of nucleoside analogues, alone and in combination with antiretroviral drugs are described cases of lactic acidosis and severe hepatomegaly with steatosis, leading sometimes to death of the patient. There are cases of acute hepatitis B after discontinuation of antiviral therapy, including entecavir. Most of these exacerbations were held without treatment. However, there may develop severe exacerbations, including fatal.
The causal relationship between these exacerbations with the abolition of therapy has not been established. After discontinuation of treatment should be periodically monitor liver function.
If necessary, antiviral therapy may be resumed. Safety and efficacy of entecavir in patients who underwent liver transplantation, are unknown.
Should carefully monitor renal function before and during treatment with entecavir in patients who underwent liver transplantation and receiving immunosuppressive drugs, which may affect renal function, such as cyclosporine and tacrolimus.
Overdose
Entecavir overdose cases are not registered.
Treatment: with an overdose requires careful medical supervision of a medical condition and if necessary, standard supportive therapy.
Drug Interactions
Since entecavir is excreted mainly by the kidneys, while the introduction of entecavir and drugs that cause impaired renal function or compete at the level of tubular secretion may increase serum concentrations of entecavir and these drugs.
When concomitant administration of entecavir with lamivudine, adefovir or tenofovir is not revealed clinically significant drug interactions. Interaction of entecavir with other drugs that affect the kidneys or kidney function, has not been studied. When concomitant administration of entecavir with such drugs the patient requires careful medical supervision.
Conditions and terms of
The drug should be stored in a place inaccessible to children at a temperature not exceeding 25 ° C. Shelf life - 2 years.
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