Entecavir - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 69.97 mg, microcrystalline cellulose 24.50 mg, crospovidone type B 2.00 mg, povidone K-30 2.50 mg, magnesium stearate 0.50 mg;

shell: film coating 3.00 mg, which includes: polyvinyl alcohol (40.00%), titanium dioxide (E 171) (25.00%), macrogol (20.20%), talc (14.80%).

Entecavir 1.0 mg

1 tablet, film-coated, contains:

active substance: entecavir monohydrate in terms of entecavir 1.00 mg;

Excipients: lactose monohydrate 139.94 mg, microcrystalline cellulose 49.00 mg, crospovidone type B 4.00 mg, povidone K-30 5.00 mg, magnesium stearate 1.00 mg;

shell: film coating 6.00 mg, which includes: polyvinyl alcohol (40.00%), titanium dioxide (E 171) (24.24%), macrogol (20.20%), talc (14.80%), (E 172) (0.37%), iron dye oxide red (E 172) (0.36%), ferric oxide black oxide (E 172) (0.03%).

Description:

0.5 mg: round, biconvex tablets, covered with a film shell of white or almost white color. The cross-section of the tablet is white or almost white.

1.0 mg: round, biconcave tablets, covered with a film shell of pink color. The cross-section of the tablet is white or almost white.

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

J.05.A.F.10 Entecavir

Pharmacodynamics:

Mechanism of action

Entecavir is an analogue of guanosine nucleoside with pronounced and selective activity against HBV polymerase. Entecavir phosphorylated with the formation of active triphosphate (TF), which has an intracellular half-life (T_1/2) 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 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-TF is a weak inhibitor of cellular DNA polymerases α-, β- δ- with a Ki inhibition constant of 18-40 μM. In addition, at high concentrations of entecavir-TF and entecavir, no side effects were observed with respect to γpolymerase and DNA synthesis in the mitochondria of HepG2 cells.

Antiviral activity

Antiviral activity of entecavir relative to DNA synthesis HBV was evaluated on HepG2 cells transfected with wild type HBV. EU₅₀ (EU₅₀ - the concentration of the drug necessary to suppress 50% of the viruses) was 0.004 μM. Median EU₅₀entecavir relative to the lamivudine-resistant strains of HBV (rtL180M and rtM204V) was 0.026 μM (in the range of 0.010 to 0.059 μM).

An analysis of the antiviral activity of entecavir on the panel of laboratory and clinical isolates of HIV-1 revealed the EU range₅₀ from 0.026 to> 10 μM.

In studies on cell cultures of combinations of entecavir with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zidovudine, didanosine) and a nucleotide reverse transcriptase inhibitor (tenofovir) antagonistic effect on the antiviral activity of the drug to HBV was not revealed.In the study of antiviral activity of entecavir in relation to HIV with the same six NRTIs, an antagonistic effect was also not detected.

Resistance

In comparison with the wild type HBV, in lamivudine-resistant strains with a mutation rtM204V and rtL180M in reverse transcriptase, sensitivity to entecavir is reduced by 8 times. Mutations rtT 184, rtS202 and rtM250, responsible for resistance to entecavir, do not significantly affect the sensitivity to entecavir in the absence of mutations that cause resistance to lamivudine.

Pharmacokinetics:

Absorption

In healthy people entecavir quickly absorbed, and the maximum concentration (C_mOh) 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, there is a dose-proportional increase in C_mOh and the area under the "concentration-time" curve (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. FROM_mOh and the minimum concentration (C_min) in the plasma in the equilibrium state were 4.2 and 0.3 ng / ml, respectively, when taking 0.5 mg; and 8.2 and 0.5 ng / ml - with the intake of 1 mg. When ingesting 0.5 mg of entecavir as a food with a high fat content,both low and low a delayed absorption (1-1.5 h - with food intake and 0.75 h - with fasting), a decrease in C_mOh by 44-46% and the decrease AUC on the 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 the enzymes of the CYP450 system. After administration of the labeled ¹⁴C-entecavir, oxidized or acetylated metabolites were not detected, and phase II metabolites (glucuronides and sulfates) were determined in small amounts.

After reaching the maximum level, the concentration of entecavir in the plasma decreased bi-exponentially, while the period of zero-elimination (T_1/2) was 128-149 hours. When taking 1 time a day, the concentration of the drug increased twofold (cumulation), that is, an effective T_1/2 was approximately 24 hours.

Entekavir 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,which indicates the 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 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);

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

Pregnancy and lactation:

Pregnancy

Adequate and well-controlled studies in pregnant women have not been conducted. In animal studies, entecavir showed the presence of a toxic effect on reproductive function when used in high doses. Entecavir may be taken during pregnancy, if the potential use of the application exceeds the potential risk to the fetus.

Lactation period

There are no data on the penetration of entecavir into the female milk. In animal studies, excretion of entecavir into breast milk was noted. Breastfeeding with the use of the drug is not recommended, including to prevent the risk of postnatal transmission of HBV.

Fertility

Women with preserved reproductive potential are recommended to use effective methods of contraception during the administration of entecavir.

Studies in animals have not shown the effect of entecavir on fertility.

Dosing and Administration:

Enteravir should be taken orally on an empty stomach (i.e., at least 2 hours after meals and no later than 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 uncompensated liver damage 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 / mn)	Patients who have not previously received nucleoside preparations	Resistant to lamivudine patients and patients with decompensated liver damage
≥ 50	0.5 mg once daily	1.0 mg once daily
30 - <50	0.5 mg every 48 hours	1.0 mg every 48 hours
10 - <30	0.5 mg every 72 hours	1.0 mg every 72 hours
<10
Hemodialysis * or long-term outpatient peritoneal dialysis	0.5 mg every 5-7 days	1.0 mg every 5-7 days

* Entecavir should be taken after a hemodialysis session.

In patients with hepatic insufficiency correction of the dose of entecavir is not required.

In elderly patients correction of the dose of entecavir is not required.

Side effects:

The adverse events presented below are listed according to anatomophysiological classification and frequency of occurrence.Within each group, the frequency of occurrence of unwanted reactions is given in order of decreasing severity. Undesirable reactions according to frequency of occurrence are defined as: Often (≥ 1/10), often (from ≥ 1/100 to <1/10), infrequently (from ≥ 1/1000 to <1/100), rarely (from ≥ 1/10000 to <1/1000).

From the digestive system:

Often: vomiting, diarrhea, nausea, indigestion.

From the central nervous system:

Often: headache, dizziness, drowsiness.

Mental disorders:

Often: insomnia.

From the side of the liver:

Often: increased activity of transaminases.

General disorders and disorders at the site of administration:

Often: weakness.

From the skin and subcutaneous tissue:

Infrequent: rash, alopecia.

From the immune system:

Rarely: anaphylactoid reaction.

From the side of metabolism:

Lactoacidosis has been reported (general fatigue, nausea, vomiting, abdominal pain, sudden weight loss, shortness of breath, rapid breathing, muscle weakness), often associated with uncompensated liver damage, other serious illnesses, or the concomitant medication (see p.section "Special instructions").

In addition, patients with decompensated liver disease also had the following side effects:

Often: a decrease in the concentration of bicarbonate in the blood, an increase in ALT activity and a bilirubin concentration more than 2 times higher than the upper limit of the norm, an albumin concentration of less than 2.5 g / dL, an increase in lipase activity of more than 3 times as compared with the norm, a platelet count lower 50000 / mm³;

Rarely: renal insufficiency.

With an increase in the duration of administration of entecavir to 96 weeks, no changes in the safety profile were noted.

Overdose:

There are isolated reports of cases of overdose of entecavir in patients. In a study in healthy volunteers who received up to 20 mg of the drug per day for 14 days or single doses up to 40 mg, no unexpected side effects were reported.

In the event of an overdose, the patient should undergo thorough medical supervision and, if necessary, standard maintenance therapy.

Interaction:

Because the entecavir is excreted mainly by the kidneys,while concurrent administration of entecavir and drugs that reduce renal function or compete at the level of tubular secretion, it is possible to increase the concentration in the serum 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:

Lactic acidosis and severe hepatomegaly with steatosis

In the treatment of nucleoside analogues in the form of monotherapy and in combination with antiretroviral drugs, cases of lactic acidosis associated with severe hepatomegaly and steatosis, sometimes leading to the death of the patient, are described. As entecavir is an analogue of nucleosides, the risk of developing these complications is not ruled out.

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.Severe cases of lactic acidosis can be accompanied by pancreatitis, hepatic insufficiency / steatosis of the liver, kidney failure and high serum lactate levels.

Risk factors are female sex, obesity, long-term use of nucleoside analogs, hepatomegaly.

Treatment with entecavir should be discontinued with a rapid increase in the level of aminotransferases, with progressive hepatomegaly or with the symptoms of metabolic or lactic acidosis described above.

When differential diagnosis of an increase in the level of aminotransferases due to response to therapy and an increase in the level potentially associated with lactic acidosis, doctors need to make sure that the increase in ALT is accompanied by an improvement in other laboratory indicators of the activity of chronic viral hepatitis B.

Care should be taken when prescribing the drug to patients with hepatomegaly, hepatitis and other known risk factors for liver disease. Careful monitoring of the condition of such patients is necessary.

Exacerbation of hepatitis

The cases of exacerbation of hepatitis after the abolition of antiviral therapy, incl. entecavir.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.

In patients with compensated liver disease, an increase in ALT activity is possible.

Patients with decompensated liver disease have a high risk of developing exacerbation of hepatitis.

It is necessary to monitor liver function at recurrent intervals for at least 6 months after discontinuation of therapy. If necessary, antiviral therapy can be resumed (see section "Use in special patient groups").

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 such 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 disease

A high risk of developing serious side effectsside of the liver, regardless of the presence of a cause-and-effect relationship with therapy, in patients with decompensated liver damage, in particular Child-Pugh class C.

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.In patients with suboptimal virologic response, after 24 weeks of therapy with entecavir, treatment may change.

At the beginning of therapy of patients with established resistance to lamivudine, the use of entecavir in combination with another antiviral drug that is not cross-resistant is preferred.

Patients with impaired renal function

For patients with impaired renal function, correction of the dosing regimen is recommended (see section "Use in special patient groups"). During therapy, monitoring of the virologic response is necessary.

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.

Lactose

Each tablet contains 69.97 mg (0.5 mg tablet) or 139.94 mg (1.0 mg tablet) of lactose monohydrate. In this regard, patients with a rare hereditary intolerance to galactose, a deficiency of lactase or glucose-galactose malabsorption, the drug is contraindicated.

Effect on the ability to drive transp. cf. and fur:

Studies on the effect of entecavir on the ability to drive and move vehicles have not been carried out.

Form release / dosage:

Tablets, film-coated, 0.5 mg and 1.0 mg.

Packaging:

For 10 tablets in a contour mesh box made of aluminum foil and PVC film.

By 3 contour mesh packages together with instructions for use in a pack of cardboard.

Storage conditions:

In the original packaging, protected from light, at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004053

Date of registration:29.12.2016

Expiration Date:29.12.2021

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

PHARMSTANDART-TOMSKHIMFARM, OJSC Russia

Representation: & nbspBIOCAD CJSC BIOCAD CJSC Russia

Information update date: & nbsp27.01.2017

Illustrated instructions

Instructions

Entecavir (Entekavir)