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

Core: lactose monohydrate - 54.47 mg / 108.94 mg; cellulose microcrystalline - 90 mg / 180 mg; giproloza low-substituted - 40 mg / 80 mg; Povidone K30 - 5 mg / 10 mg; crospovidone - 8 mg / 16 mg; silicon dioxide colloidal - 1 mg / 2 mg; magnesium stearate - 1 mg / 2 mg.

Film Sheath: hypromellose E5 - 4.2 mg / 8.4 mg; macrogol 6000 - 0.54 mg / 1.08 mg; titanium dioxide - 1.2 mg / 2.4 mg; polysorbate 80 - 0.06 mg / 0.12 mg.

Description:

For a dosage of 0.5 mg: tablets, coated with a white film shell, biconvex, round, on the transverse section of the tablet the core is white.

For a dosage of 1.0 mg: tablets, coated with a white film shell, biconvex, capsular form, in the transverse section of the tablet the nucleus is white.

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 (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 and RNA; and (3) the synthesis of the positive HBV DNA strand. Entecavir-TF is a weak inhibitor of cellular DNA polymerases a, b and γ with Ki of 18-40 μM. In addition, at high concentrations of entecavir-TF and entecavir, no side effects have been observed with respect to polymerase y and DNA synthesis in mitochondria of HepG2 cells.

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 (C_mOh) 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 (FROM_max) and the minimum (C_max) plasma concentrations 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, respectively, with 1 mg. When ingesting 0.5 mg of entecavir with a high-fat diet 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 in C_mOh by 44-46% and the 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, while T_1/2 was 128-149 hours. At reception once a day there was an increase in concentration (cumulation) of a preparation in 2 times, that is effective T_1/2 was approximately 24 hours. Entecavir is mainly excreted by the kidneys, and 62-73% of the dose is determined unchanged in the urine in the equilibrium state. 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, enhancing the activity level of serum transaminases (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's age till 18 years;

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

Carefully:

There is no information.

Pregnancy and lactation:

Pregnancy

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

Breast-feeding

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

Dosing and Administration:

Therapy should be started by a physician experienced in the treatment of chronic hepatitis B. The drug 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 lamivudine patients and patients with decompensated liver damage
≥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 correction of the dose of entecavir is not required.

In elderly patients correction of the dose 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 (the 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.

Separate Adverse Reactions

Exacerbations of hepatitis during treatment

In clinical studies in patients who have not previously received nucleoside analogues, exacerbation of hepatitis (increased ALT activity by more than 10 times compared with the upper limit of the norm and more than 2 times compared with baseline) was observed in 2% of patients who received entecavir, compared with 4% of patients who received lamivudine. In lamivudine-resistant patients, an increase in ALT activity by more than 10-fold compared with the upper limit of the norm and more than 2-fold compared with the baseline was detected in 2% of patients who received entecavir, compared with 11% of patients who received lamivudine. Among patients who received therapy with entecavir, who had an increase in ALT activity, the median time before the onset of symptoms was 4-5 weeks. As a rule, the resolution of symptoms is noted while continuing treatment. In most cases, increased ALT activity was associated with a decrease in viral load in 2 log10 / ml and more, which preceded or coincided with an increase in ALT activity. During treatment, periodic monitoring of liver function is recommended.

Exacerbations of hepatitis after discontinuation of treatment

There are reports of cases of exacerbation of hepatitis in patients who stopped taking drugs for the treatment of hepatitis B, including after discontinuation of entecavir. In studies in patients who had not previously received nucleoside analogs, 6% of patients taking entecavir, and in 10% of patients who took lamivudine, increased ALT activity (more than 10-fold compared with the upper limit of the norm and more than 2-fold compared with baseline) during follow-up after treatment. Among patients who had not previously received nucleoside analogues, after discontinuation of entecavir therapy, the median time to increase in ALT was 23-24 weeks, with 86% (24/28) being HBeAg-negative patients. In studies involving a limited number of lamivudine-resistant patients in 11% of patients receiving entecavir therapy and not taking lamivudine, there was an increase in ALT activity in the follow-up period.

In clinical studies, therapy with entecavir was discontinued if patients reached a pre-determined response. If therapy is discontinued without taking into account the response to treatment, the likelihood of changes in ALT activity may be higher.

Special patient groups

Patients with decompensated liver disease

The entecavir safety profile in patients with decompensated liver disease was evaluated in an open, comparative, randomized clinical trial in which patients received entecavir in a dose of 1 mg per day (n = 102) or adefovir dipivoxyl at a dose of 10 mg per day (n = 89).In this study, the cumulative death rate was 23% (23/102). The cause of death, as a rule, was liver disease. The cumulative incidence of hepatocellular carcinoma was 12% (12/102). Serious side effects, usually from the side of the liver, were detected with a cumulative frequency of 69%. In patients with a high score on Child-Pugh scale, the risk of serious side effects was higher.

Deviations in laboratory tests

Up to 48 weeks after initiation of therapy with entecavir in patients with decompensated liver disease, no patient showed an increase in ALT activity by more than 10-fold compared with the upper limit of the norm and more than 2-fold compared with baseline. In 1% of patients, the ALT activity increased more than 2 times in comparison with the baseline level, while the bilirubin level increased more than 2 times compared with the upper limit of the norm and more than 2 times compared with the baseline level. A decrease in albumin level <2.5 g / dl occurred in 30% of patients, an increase in the level of lipase more than 3 times compared with the baseline level in 10% of patients, a decrease in the number of platelets <50 000 / mm³ - in 20% of patients.

Patients with co-infection with hepatitis B / HIV infection

The safety profile of entecavir in a limited number of patients co-infected with hepatitis B / HIV receiving highly active antiretroviral therapy with lamivudine was similar to the safety profile in monoinfected HBV patients.

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:

Lactic acidosis / severe hepatomegaly with steatosis

In the treatment with nucleoside analogs, cases of lactic acidosis and severe hepatomegaly with steatosis have been described, sometimes leading to the death of the patient. Because the entecavir is a nucleoside analogue, one can not exclude the risk of developing this complication when it is used.

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. In severe cases, sometimes fatal, the development of lactic acidosis was associated with pancreatitis, hepatic insufficiency / steatosis of the liver, kidney failure and hyperlactatemia. Risk factors are female sex, obesity, long-term use of nucleoside analogs, hepatomegaly.

Treatment with nucleoside analogues should be discontinued in case of symptomatic hyperlactatemia and metabolic acidosis / lactic acidosis, progressive hepatomegaly, or a rapid increase in the level of aminotransferases.

Care should be taken when using nucleoside analogues to treat any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver damage and steatosis of the liver (including the use of certain drugs and alcohol use). The treatment of such patients requires careful clinical and laboratory monitoring.

In order to distinguish the increase in aminotransferase activity as evidence of the effectiveness of treatment against an increase potentially associated with lactic acidosis, the physician should ascertain that changes in ALT activity are associated with improvements in other laboratory markers of chronic hepatitis B.

Exacerbations of hepatitis

Spontaneous exacerbations of chronic hepatitis B are quite common and are characterized by a transient increase in serum ALT activity. After the initiation of antiviral therapy in some patients, an increase in ALT activity may be possible with a decrease in the level of HBV DNA in the blood serum. In most cases, exacerbation of hepatitis developed during the first 4-5 weeks of therapy with entecavir.In patients with compensated liver disease, this increase in ALT activity is usually not accompanied by an increase in serum bilirubin concentration or liver failure. In patients with progressive liver disease or cirrhosis, the risk of decompensating liver function is increased. In the treatment of such patients, careful clinical and laboratory monitoring should be carried out.

There have also been reports of cases of exacerbation of hepatitis in patients who stopped taking drugs for the treatment of hepatitis B. Aggravations after withdrawal of treatment are usually associated with an increase in the level of HBV DNA, in most cases do not lead to decompensation of liver function and stop spontaneously. However, severe exacerbations, including fatalities, have been reported.

Among patients who had not previously received nucleoside analogues, who were assigned entecavir, the exacerbation developed on average during the first 23-24 weeks after drug withdrawal, in most cases - in HBeAg-negative patients (see section "Side effect"). Periodically, liver function should be monitored for at least 6 months after discontinuation of hepatitis therapy.If necessary, the resumption of drugs for the treatment of hepatitis B may be justified.

Patients with co-infection with hepatitis B / HIV infection

It should be noted that when administering entecavir to patients with a co-infected HIV infection that does not receive highly active antiretroviral therapy (HAART), the risk of developing resistant strains of HIV is possible. Therefore, do not apply entecavir in patients with co-infection with hepatitis B / HIV infection not receiving HAART. Entecavir It has not been studied as a tool for treating 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

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 kidney side effects as hepatorenal syndrome.In this regard, 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 the blood, serum creatinine concentration) .

Lamivudine-resistant patients

Lamivudine-resistant patients are at a higher risk of subsequent development of entecavir resistance than patients without resistance to lamivudine. The probability of development of genotypic resistance to entecavir after 1, 2, 3, 4 and 5 years of treatment in studies of lamivudine-resistant patients was 6%, 15%, 36%, 47% and 51% respectively. In this regard, lamivudine-resistant patients require frequent monitoring of the viral load and an appropriate examination for the detection of resistance. In patients with suboptimal virologic response, after 24 weeks of treatment with entecavir, the possibility of changing the regimen of therapy should be considered. Starting therapy for patients with documented HBV resistance to lamivudine,it is preferable to administer entecavir in combination with another antiviral drug (without cross-resistance to lamivudine or entecavir) with entecavir monotherapy.

The presence of HBV resistance to lamivudine is associated with an increased risk of developing resistance to entecavir, regardless of the degree of impaired hepatic function. In patients with decompensated liver disease, a virologic breakthrough may be associated with serious clinical complications of liver disease. Thus, in lamivudine-resistant patients with decompensated liver disease, the use of entecavir in combination with another antiviral drug that does not have cross-resistance with lamivudine or entecavir is more preferred than monotherapy with entecavir.

Patients with impaired renal function

For patients with impaired renal function, correction of the dosing regimen is recommended (see section "Dosage and Administration"). The suggested recommendations are based on the extrapolation of limited data, the safety and efficacy of these regimens has not been clinically evaluated.Therefore, patients with impaired renal function should carefully monitor the virologic response.

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 54.47 mg (tablets 0.5 mg) or 108.94 mg (tablets 1.0 mg) of lactose monohydrate. In this regard, patients with a rare hereditary intolerance to lactose, a deficiency of lactase or glucose-galactose malabsorption, is contraindicated in taking the drug.

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

During the treatment period, it is necessary to refrain from driving and practicing potentially dangerous activities,requiring increased concentration and speed of psychomotor reactions, since the drug may cause dizziness and other side effects that may affect these abilities.

Form release / dosage:

Tablets, film-coated, 0.5 and 1.0 mg.

Packaging:

Primary packaging of medicinal product

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 30, 60 tablets in a can of polymer with a lid pulled with the control of the first opening. Free space is filled with cotton wool.

Secondary packaging of medicinal product

By 3, 6 contour mesh packages together with instructions for use in a pack of cardboard.

On 1 bank together with the instruction on application in a pack from a cardboard.

The packets are placed in a group package.

Storage conditions:

In the original packaging of the manufacturer, 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 expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003643

Date of registration:20.05.2016

Expiration Date:20.05.2021

The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Information update date: & nbsp13.07.2016

Illustrated instructions

Instructions

Elgraveur (Elgraveur)