Baraklad - instructions for use, doses, side effects, contraindications

Active substanceEntecavirEntecavir

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Baraklyud®

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Bristol-Myers Squibb Company Italy

Elgraveur

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FARMASINTEZ, JSC (Irkutsk) Russia

Entecavir

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BIOCAD, CJSC Russia

Entecavir Sandoz®

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Sandoz d. Slovenia

Dosage form: & nbsppills

Composition:

Each film-coated tablet contains active substance: entecavir 0.5 mg or 1.0 mg.

Excipients: lactose monohydrate 120.5 mg or 241.0 mg, cellulose microcrystalline 65.0 mg or 130.0 mg, crospovidone 8.0 mg or 16.0 mg, povidone K 30 5.0 mg or 10.0 mg, magnesium stearate 1.0 mg or 2.0 mg, opedraj white 6.0 mg - tablets 0.5 mg or opadrai pink 12.0 mg - tablets of 1.0 mg.

Ingredients Opadrai white: titanium dioxide (31.25%), hypromellose 3 cp (29.875%), hypromellose 6cP (29.875%), macrogol 400 (8%), polysorbate 80 (1.0%).

Composition of Opadrai Pink: titanium dioxide (31.04%), hypromellose 6 cP (62.5%), Macrogol 400 (6.250%), iron dye oxide red (E172, CFR21)) (0,210%).

Description:

Tablets, film-coated 0.5 mg: triangular tablets coated with a white or almost white shell, engraved "BMS" on one side and "1611" on the other side.

Film-coated tablets 1.0 mg: triangular tablets, coated with a pink color, engraved "BMS" on one side and "1612" on the other side

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

J.05.A.F.10 Entecavir

Pharmacodynamics:

Entecavir is an analogue of guanosine nucleoside with potent and selective activity against HBV polymerase. Entecavir phosphorylated with the formation of active triphosphate (TF), which has an intracellular half-life of 15 hours. The intracellular concentration of TF is directly related to the extracellular level of entecavir, and there is no significant accumulation of the drug after the initial level of the "plateau". By competition with the natural substrate, deoxyguanosine-TF, entecavir-TF inhibits all 3 functional activities of the viral polymerase: (1) priming HBV polymerase, (2) reverse transcription of the negative strand from the pregenomic and RNA, and (3) the synthesis of the positive strand HBV DNA. Entecavir-TF is a weak inhibitor of cellular DNA polymerases a, P and 5 s Ki 18-40 μM. In addition, at high concentrations of entecavir-TF and entecavir, no side effects were observed with respect to polymerase and DNA synthesis in mitochondria of cells HepG2.

Pharmacokinetics:

Absorption.

In healthy people entecavir quickly absorbed, and the maximum concentration in the plasma is determined after 0.5-1.5 hours.With repeated administration of entecavir in a dose of 0.1 to 1 mg, a dose-proportional increase in the maximum concentration (Cmax) and the area under the curve "concentration - time" (AUC). The equilibrium state is achieved after 6-10 days of oral intake once a day, while the concentration in the plasma increases approximately 2-fold. Maximum (C max) and minimum (Cmin) the plasma concentrations in the equilibrium state were 4.2 and 0.3 ng / ml, respectively, with 0.5 mg and 8.2 and 0.5 ng / ml, respectively, with 1 mg. When ingesting 0.5 mg of entecavir with high-fat food or with light food, a minimal delay of absorption (1-1.5 hours with food intake and 0.75 hours with fasting) was noted, a decrease of Cmax by 44-46% and decrease AUC on 18-20%.

Distribution.

The estimated volume of entecavir distribution exceeded the total volume of water in the body, which indicates a good penetration of the drug into the tissue. Entecavir approximately 13% bind to human serum proteins in vitro.

Metabolism and excretion.

Entecavir is not a substrate, inhibitor or inducer of system enzymes CYP450. After administration of labeled 14C-entecavir, oxidized or acetylated metabolites were not detected in humans and rats, and metabolites of phase II (glucuronides and sulfates) were determined in small amounts.After reaching the maximum level, the entecavir concentration in the plasma decreased bi-exponentially, with a half-life of 128-149 hours. At reception once a day there was an increase in concentration (cumulation) of a preparation in 2 times, that is the effective period of half-elimination has made approximately 24 hours.

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

Indications:

Chronic hepatitis AT in adults with:

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

- decompensated liver damage.

Contraindications:

- Hypersensitivity to entecavir or any other component of the drug.

- Children under 18 years of age (efficacy and safety not studied).

- Rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption

Pregnancy and lactation:

Adequate and well-controlled studies in pregnant women have not been conducted. BARAKLYUD® should be taken during pregnancy only if the potential benefit of the application exceeds the potential risk to the fetus.

There are no data on the penetration of entecavir into the female milk. Breastfeeding when using the drug is not recommended.

Dosing and Administration:

Enteravir should be taken orally on an empty stomach (i.e., at least 2 hours after meals and at the latest 2 hours before the next meal).

The recommended dose of entecavir for patients with compensated liver damage is 0.5 mg once a day.

Resistant to lamivudine patients (that is, patients with a history of viremia with hepatitis B virus persisting against lamivudine therapy, or patients with confirmed resistance to lamivudine), it is recommended that 1 mg of entecavir be administered once a day. Patients with decompensated liver disease are recommended to administer 1 mg of entecavir once a day.

Patients with renal insufficiency.

The clearance of entecavir decreases with a decrease in creatinine clearance. It is recommended to correct the dose of entecavir to patients with creatinine clearance <50 ml / min, including those on hemodialysis and long-term outpatient peritoneal dialysis, according to Table 1.

Table 1: Recommended doses of entecavir in patients with renal insufficiency

Creatinine clearance (ml / min)	Patients who have not previously received nucleoside preparations	Resistant to lamivudnnu patients and patients with decompensated lesions of the liver
≥50	0.5 mg once daily	1 mg once daily
30-<50	0.5 mg every 48 hours	1 mg every 48 hours
10-<30	0.5 mg every 72 hours	1 mg every 72 hours
<10 Hemodialysis * or long-term outpatient peritoneal dialysis	0.5 mg every 5-7 days	1 mg every 5-7 days

* Entecavir should be taken after a hemodialysis session.

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

Side effects:

From the digestive system

Rarely (≥ 1/1000, <1/100): diarrhea, indigestion, nausea, vomiting.

From 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 immune system: anaphylactoid reaction

From the skin and subcutaneous tissue: alopecia, rash.

From the side of the liver: increased activity of transaminases.

From the side of metabolism: lactoacidosis (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 also had the following side effects:

Often: a decrease in the concentration of bicarbonate in the blood, increased ALT activity and bilirubin concentration more than 2 times compared with the upper limit of the norm, the albumin concentration is less than 2.5 g / dL, the increase in lipase activity is more than 3 times as compared with the norm, the concentration platelets below 50,000 / mm3; rarely: kidney failure.

Overdose:

There are limited data on overdose cases in patients. In healthy volunteers who received up to 20 mg of the drug per day for up to 14 days or single doses up to 40 mg, there were no unexpected side effects.In the event of an overdose, the patient should undergo thorough medical supervision and, if necessary, standard maintenance therapy.

Interaction:

Because the entecavir excreted mainly by the kidneys, while the introduction of entecavir and drugs that reduce renal function or competing tubular secretion level may increase serum concentrations of entecavir or these drugs. With simultaneous administration of entecavir with lamivudine, adefovir or tenofovir, no significant drug interactions have been identified.

Interactions of entecavir with other drugs, excreted kidneys or affecting kidney function, have not been studied. Patients should be carefully monitored while concomitant administration of entecavir with such drugs.

Special instructions:

In the treatment of nucleoside analogs, including entecavir, as monotherapy and in combination with antiretroviral agents described cases of lactic acidosis and severe hepatomegaly with steatosis, sometimes resulting in death of the patient. Symptoms that may indicate the development of lactic acidosis: general fatigue, nausea, vomiting,pain in the abdomen, 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 appear or if laboratory confirmation of lactic acidosis is obtained, discontinue drug treatment.

The cases of exacerbation of hepatitis after the abolition of antiviral therapy, including entecavir, are described. Most of these cases were without treatment. However, severe exacerbations, including fatal ones, can develop.

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 It 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 efficacy of entecavir in patients with co-hepatitis B / hepatitis C / hepatitis D there are no infections.

Patients with decompensated liver damage.

There was a high risk of developing serious side effects on the part of the liver, in particular in patients with decompensated liver damage of Class C according to the 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. In this regard, close monitoring of patients for the detection of 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 ciclosporin 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.

Each tablet contains 120.5 mg (tablets 0.5 mg) or 241 mg (1 mg tablet) of lactose. In this regard, patients with a rare hereditary lactose intolerance, deficiency of lactase or glucose-galactose malabsorption does not recommend taking the drug.

Form release / dosage:

Tablets, film-coated 0.5 mg and 1.0 mg.

Packaging:

For 10 tablets per blister A1 / A1. For 3 blisters together with instructions for use in a pack of cardboard.

Storage conditions:

Store at a temperature of 15-25 ° C.

Shelf life:

2 years

Do not use the product after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-000035

Date of registration:09.02.2012 / 18.08.2016

Expiration Date:Unlimited

The owner of the registration certificate:Bristol-Myers Squibb CompanyBristol-Myers Squibb Company Italy

Manufacturer: & nbsp

ASTRAZENECA Pharmaceuticals LP USA

Representation: & nbspBRISTOL-Majers SKVIBB, LLCBRISTOL-Majers SKVIBB, LLCRussia

Information update date: & nbsp15.01.2017

Illustrated instructions

Instructions

Baraklyud® (Baraclude®)