Universal reference book for medicines
Product name: BARAKLUDE ® (BARACLUDE ® )

Active substance: entecavir

Type: Antiviral drug

Manufacturer: BRISTOL-MYERS SQUIBB Company (USA)
Composition, form of production and packaging
Tablets covered with a film shell of
white or almost white color, triangular, marked "BMS" on one side and "1611" on the other side.

1 tab.

entecavir 500 μg

Auxiliary substances: lactose monohydrate - 120.5 mg, microcrystalline cellulose - 65 mg, crospovidone - 8 mg, povidone - 5 mg, magnesium stearate - 1 mg, Opadry white dye (titanium dioxide, hypromellose 6cP, hypromellose 3cP, macrogol 400, polysorbate 80) - 6 mg.

10 pieces.
- blisters (3) - packs of cardboard.
The tablets covered with a film cover of pink color, triangular, with marking "BMS" on one side and "1612" on the other side.

1 tab.

entecavir 1 mg

Excipients: lactose monohydrate 241 mg, microcrystalline cellulose 130 mg, crospovidone 16 mg, povidone 10 mg, magnesium stearate 2 mg, Opadry pink dye (hypromellose 6 cp, titanium dioxide, macrogol 400, iron dye oxide red (E172 , CFR21)) - 12 mg.

10 pieces.
- blisters (3) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2013.

PHARMACHOLOGIC EFFECT

The antiviral drug is an analogue of guanosine nucleoside with potent and selective activity against hepatitis B virus polymerase (HBV).
Entecavir is phosphorylated with the formation of active triphosphate, which has an intracellular half-life of 15 hours. The intracellular concentration of entecavir triphosphate is directly related to the extracellular level of entecavir, with no significant accumulation of the drug after the initial level of the "plateau". By competition with the natural substrate, deoxyguanosine triphosphate, entecavir triphosphate inhibits all 3 functional activities of the viral polymerase: 1) priming of the HBV polymerase; 2) reverse transcription of the negative strand from the pregenomic mRNA; and 3) the synthesis of the positive HBV DNA strand. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases?,? and? with Ki of 18-40 μM. In addition, at high concentrations of entecavir triphosphate and entecavir, no side effects were observed with respect to? polymerase and DNA synthesis in mitochondria of HepG2 cells.
PHARMACOKINETICS

Suction

In healthy people, absorption of entecavir is rapid, Cmax in the blood plasma is determined after 0.5-1.5 hours. With repeated administration of entecavir in a dose of 0.1 to 1 mg, there is a dose-proportional increase in C max and AUC.
The equilibrium state is achieved after 6-10 days of oral intake 1 time / day, while the concentration in the plasma increases approximately 2 times. C max and C min in plasma in the equilibrium state were 4.2 and 0.3 ng / ml, respectively, when taking the drug at a dose of 500 μg, 8.2 and 0.5 ng / ml, respectively, when taken in a dose of 1 mg. When administered entecavir in a dose of 500 mcg, both with food with a high fat content and with a low intake, a minimal delay of absorption (1-1.5 h with food intake and 0.75 h with fasting), a decrease in C max by 44-46%, and AUC decrease by 18-20%.
Distribution

V d of entecavir exceeded the total volume of water in the body, which indicates a good penetration of the drug into the tissue.

The binding of entecavir to human plasma proteins in vitro is about 13% .

Metabolism

Entecavir is not a substrate, inhibitor or inducer of P450 isoenzymes.
After administration of labeled 14C-entecavir, oxidized or acetylated metabolites were not detected in human and rats, and phase II metabolites (glucuronides and sulfates) were detected in small amounts.
Excretion

After reaching C max, the concentration of entecavir in the plasma decreased bi-exponentially, with T 1/2 being 128-149 hours. When taking 1 time / day, the concentration (cumulation) of the drug increased by a factor of 2, that is, the effective T 1/2 was approximately 24 h.

Entecavir is excreted mainly by the kidneys, and in an unchanged state in the unchanged form in the urine 62-73% of the dose is determined.
Kidney clearance is dose independent and ranges from 360 to 471 ml / min, indicating glomerular filtration and tubular secretion of the drug.
INDICATIONS

Chronic hepatitis B in adults with:

- compensated liver damage and the presence of viral replication, increased serum transaminase (ALT or ACT) activity levels and histological signs of the inflammatory process in the liver and / or fibrosis;

- Decompensated liver damage.

DOSING MODE

The drug should be taken orally on an empty stomach (ie no less than 2 hours after eating and no later than 2 hours before the next meal).

The recommended dose of Baraklyud ® with compensated liver damage is 500 μg 1 time / day.

In the presence of resistance to lamivudine (i.e., when a history of hepatitis B virus persisting in the history of lamivudine therapy or in the case of confirmed resistance to lamivudine is indicated in the anamnesis for viremia), it is recommended to administer entecavir at a dose of 1 mg 1 time / day.

Patients with decompensated liver lesions the drug is prescribed in a dose of 1 mg 1 time / day.

In patients with renal insufficiency, clearance of entecavir decreases with decreasing CC.
With CC <50 ml / min, incl. patients who are on hemodialysis and long-term outpatient peritoneal dialysis , it is recommended to adjust the dose of Baraklyud ® as indicated in the table.
Creatinine clearance (ml / min) Patients who have not previously received nucleoside preparations Patients resistant to lamivudine, and patients with decompensated liver damage

? 50 500 mcg 1 time / day 1 mg 1 time / day

30 <50 500 mcg every 48 h 1 mg every 48 h

10- <30 500 μg every 72 h 1 mg every 72 h

<10 hemodialysis * or long-term ambulatory peritoneal dialysis 500 μg every 5-7 days 1 mg every 5-7 days

* The drug should be taken after a hemodialysis session.

In patients with hepatic insufficiency, dose adjustment of entecavir is not required.

In elderly patients, dose adjustment is not required.

SIDE EFFECT

From the digestive system : rarely (? 1/1000, <1/100) - diarrhea, dyspepsia, nausea, vomiting.

From the side of the central nervous system: often (? 1/100, <1/10) - headache, fatigue;
rarely (? 1/1000, <1/100) - insomnia, dizziness, drowsiness.
Post-marketing data (frequency can not be determined)

From the side of the immune system: anaphylactoid reaction

From the skin and subcutaneous tissue: alopecia, rash.

From the liver: increased activity of transaminases.

From the metabolism: lactacidosis (general fatigue, nausea, vomiting, abdominal pain, sudden weight loss, shortness of breath, rapid breathing, muscle weakness), especially in patients with decompensated liver damage.

In addition, patients with decompensated liver disease had additionally the following side effects: often a decrease in the concentration of bicarbonate in the blood, an increase in ALT activity and bilirubin concentration more than 2 times compared to HHV, an albumin concentration of less than 2.5 g / dl, an increase in lipase activity more than 3 times as compared with the norm, the concentration of platelets is below 50,000 / mm 3 ;
rarely - kidney failure.
CONTRAINDICATIONS

- age up to 18 years;

- rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption;

- Hypersensitivity to the components of the drug.

PREGNANCY AND LACTATION

Adequate and well-controlled studies in pregnant women have not been conducted.
The use of the drug Baraklud ® in pregnancy is possible only in cases where the expected benefit of therapy for the mother exceeds the potential risk to the fetus.
There are no data on the excretavir excretion with breast milk.
When applying the drug, breastfeeding is not recommended.
APPLICATION FOR FUNCTIONS OF THE LIVER

In patients with renal insufficiency, clearance of entecavir decreases with decreasing CC.
With CC <50 ml / min, incl. patients on hemodialysis and long-term outpatient peritoneal dialysis are advised to adjust the dose of Baraklyud.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

In patients with hepatic insufficiency, dose adjustment of entecavir is not required.

APPLICATION FOR CHILDREN

Contraindicated: age to 18 years.

APPLICATION IN ELDERLY PATIENTS

In elderly patients, dose adjustment is not required.

SPECIAL INSTRUCTIONS

When treating with analogues of nucleosides, incl.
entecavir, in the form of monotherapy and in combination with antiretroviral drugs described cases of lactic acidosis and severe hepatomegaly with steatosis, sometimes leading to the death of the patient.
Symptoms that may indicate the development of lactic acidosis: general fatigue, nausea, vomiting, abdominal pain, sudden weight loss, shortness of breath, rapid breathing, muscle weakness.

Risk factors are female sex, obesity, long-term use of nucleoside analogs, hepatomegaly.
If these symptoms occur or if laboratory confirmation of lactic acidosis is obtained, discontinue drug treatment.
The cases of exacerbation of hepatitis after the abolition of antiviral therapy, incl.
entecavir. Most of these cases were without treatment. However, severe exacerbations may occur, incl. fatal. The causal relationship of these exacerbations with the withdrawal of therapy is unknown. After discontinuation of treatment, it is necessary to periodically monitor liver function. If necessary, antiviral therapy can be resumed.
Patients with concomitant hepatitis B / HIV infection

It should be borne in mind that with the appointment of entecavir, patients with a co-infected HIV infection who do not receive antiretroviral therapy may have a risk of developing resistant strains of HIV.
Entecavir has not been studied for the treatment of HIV infection and is not recommended for this use.
Patients with concomitant hepatitis B / hepatitis C / hepatitis D infection

Data on the effectiveness of entecavir in patients with co-hepatitis B / hepatitis C / hepatitis D infections are not present.

Patients with decompensated liver disease

There was a high risk of serious side effects on the part of the liver, in particular, in patients with decompensated liver damage of Class C according to Child-Pugh classification.
Also, these patients are more at risk of developing lactic acidosis and such specific side effects from the kidney as hepatorenal syndrome. Therefore, close monitoring of patients for clinical signs of lactic acidosis and renal dysfunction should be carried out, and appropriate laboratory tests should be performed in this group of patients (hepatic enzyme activity, lactic acid concentration in blood, serum creatinine concentration).
Lamivudine-resistant patients

The presence of resistance mutations in hepatitis B virus to lamivudine increases the risk of development of resistance to entecavir.
In this regard, lamivudine-resistant patients require frequent monitoring of the viral load and, if necessary, an appropriate examination to identify mutations of resistance.
Patients with impaired renal function

For patients with impaired renal function, correction of the dosing regimen is recommended.

Patients who underwent liver transplantation.

The safety and efficacy of entecavir in patients who underwent liver transplantation are unknown.
Kidney function should be carefully monitored before and during treatment with entecavir in patients who underwent liver transplantation and receiving immunosuppressants that can affect kidney function such as cyclosporin and tacrolimus.
General information for patients

Patients should be informed that therapy with entecavir does not reduce the risk of transmission of hepatitis B and, therefore, appropriate precautions should be taken.

OVERDOSE

There are limited data on overdose cases in patients.
In healthy volunteers who received the drug in doses up to 20 mg / day for up to 14 days or in single doses up to 40 mg, there were no unexpected side reactions.
Treatment: overdose requires careful medical supervision of the patient's condition.
If necessary, standard maintenance therapy is provided.
DRUG INTERACTION

Since entecavir is excreted primarily by the kidneys, concomitant administration of entecavir and drugs causing renal dysfunction or competing at the level of tubular secretion may increase serum concentrations of entecavir or these drugs.

When concomitant administration of entecavir with lamivudine, adefovir or tenofovir, there is no clinically significant drug interaction.

The interaction of entecavir with other drugs that are excreted by the kidneys or affect the function of the kidneys has not been studied.
When concurrent administration of entecavir with such drugs, the patient requires careful medical supervision.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children, at a temperature of 15 ° to 25 ° C.
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