Entecavir Sandoz tablets 1mg, no. 30

Entecavir Sandoz tablets 1mg, no. 30; 'Chronic hepatitis B in adults with compensated liver damage and the presence of viral replication, increased levels of serum transaminase activity (ALT or ACT) and histological signs of liver inflammation and / or fibrosis; c decompensated liver damage.

It is taken internally. The dose is 500-1000 mcg 1 time / day. The frequency of admission depends on the degree of impaired renal function, indications in the history of therapy with nuleoside drugs, liver condition.

Pink film-coated tablets, round. biconvex with 'SZ' engraved on one side, '109' engraved on the other.

1 tab. entecavir monohydrate * 1.065 mg

which corresponds to the content of entecavir 1 mg

Excipients: lactose monohydrate ** - 240.935 mg, microcrystalline cellulose - 138 mg, crospovidone - 16 mg, magnesium stearate - 4 mg.

Children and adolescents up to 18 years old;

hypersensitivity to entecavir.

pharmachologic effect

Antiviral agent, a guanosine nucleoside analogue with potent and selective activity against hepatitis B virus (HBV) polymerase.

Entecavir is phosphorylated to form 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, and there is no significant accumulation of the drug after the initial 'plateau' level. By competing with the natural substrate, deoxyguanosine triphosphate, entecavir triphosphate inhibits all 3 functional activities of viral polymerase: 1) priming of HBV polymerase, 2) reverse transcription of a negative strand from pregenomic mRNA, and 3) synthesis of a positive HBV DNA strand. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases?,? And? with Ki 18-40 ?M. In addition, at high concentrations of entecavir triphosphate and entecavir, no side effects were observed in relation to? polymerase and DNA synthesis in the mitochondria of HepG2 cells.

Pharmacokinetics

In healthy people, the absorption of entecavir is fast, the Cmax in the blood plasma is determined after 0.5-1.5 hours. With repeated administration of entecavir at a dose of 0.1 to 1 mg, there is a dose-proportional increase in Cmax and AUC. The equilibrium state is achieved after 6-10 days of oral administration 1 time / day, while the plasma concentration increases by about 2 times. Cmax and Cmin in plasma in the equilibrium state were 4.2 and 0.3 ng / ml, respectively, when the drug was taken at a dose of 500 ?g, 8.2 and 0.5 ng / ml, respectively, when taken at a dose of 1 mg. When entecavir was taken orally at a dose of 500 mcg, both with food with a high fat content and with a low diet, there was a minimal delay in absorption (1-1.5 hours when taken with food and 0.75 hours when taken on an empty stomach), a decrease in Cmax by 44-46% and a decrease in AUC by 18-20%.

Vd of entecavir exceeded the total volume of water in the body, which indicates a good penetration of the drug into the tissues. The binding of entecavir to human plasma proteins in vitro is about 13%.

Entecavir is not a substrate, inhibitor or inducer of isoenzymes of the P450 system. After administration of labeled 14C-entecavir to humans and rats, no oxidized or acetylated metabolites were detected, while phase II metabolites (glucuronides and sulfates) were detected in small amounts.

After reaching Cmax, the concentration of entecavir in plasma decreased biexponentially, with T1 / 2 being 128-149 hours. When taken 1 time / day, the concentration (cumulation) of the drug increased by 2 times, that is, the effective T1 / 2 was approximately 24 hours.

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

Side effect

From the digestive system : rarely - diarrhea, dyspepsia, nausea, vomiting; possibly - an increase in the activity of transaminases.

From the side of the central nervous system: often - headache, fatigue; rarely - insomnia, dizziness, drowsiness.

From the immune system: possibly - anaphylactoid reaction.

On the part of the skin and subcutaneous tissue: possibly - alopecia, rash.

From the side of metabolism: possibly - lactic acidosis (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, in patients with decompensated liver damage, the following additional side effects were noted: often - a decrease in the concentration of bicarbonate in the blood, an increase in the activity of ALT and the concentration of bilirubin by more than 2 times compared with VGN, the concentration of albumin is less than 2.5 g / dl, an increase in the activity of lipase more than 3 times compared with the norm, the platelet concentration is below 50,000 / ?l; rarely renal failure.

Application during pregnancy and lactation

There have been no adequate and well-controlled studies in pregnant women. Use during pregnancy is possible only in cases where the expected benefit of therapy to the mother outweighs the potential risk to the fetus.

There are no data on the elimination of entecavir in breast milk. During the treatment period, breastfeeding is not recommended.

special instructions

When treating with nucleoside analogues, incl. with entecavir, in the form of monotherapy and in combination with antiretroviral drugs, cases of lactic acidosis and severe hepatomegaly with steatosis have been described, 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 appear or if laboratory confirmation of lactic acidosis is obtained, treatment with the drug should be discontinued.

Cases of exacerbation of hepatitis after discontinuation of antiviral therapy have been described, incl. entecavir. Most of these cases resolved without treatment. However, severe exacerbations may develop, incl. fatal. The causal relationship of these exacerbations to treatment withdrawal is unknown. After stopping treatment, it is necessary to periodically monitor liver function. Antiviral therapy can be resumed if necessary.

—ледует учитывать, что при применении энтекавира у пациентов с сочетанной инфекцией ¬»„, не получающим антиретровирусную терапию, возможен риск развити¤ устойчивых штаммов ¬»„. Ёнтекавир не был изучен дл¤ лечени¤ ¬»„ инфекции и не рекомендуетс¤ дл¤ подобного применени¤.

There was a high risk of developing serious side effects from the liver, in particular, in patients with decompensated liver disease of class C according to the Child-Pugh classification. These patients are also more at risk of developing lactic acidosis and specific renal side effects such as hepatorenal syndrome. In this regard, patients should be carefully monitored for clinical signs of lactic acidosis and renal dysfunction, as well as appropriate laboratory tests should be carried out in this group of patients (liver enzyme activity, blood lactic acid concentration, serum creatinine concentration).

The presence of hepatitis B virus resistance mutations to lamivudine increases the risk of developing entecavir resistance. Therefore, in lamivudine-resistant patients, frequent viral load monitoring and, if necessary, appropriate testing for resistance mutations is required.

For patients with impaired renal function, a dosage adjustment is recommended.

The safety and efficacy of entecavir in liver transplant patients is unknown. Renal function should be closely monitored before and during treatment with entecavir in patients undergoing liver transplantation and receiving immunosuppressants that may affect renal function, such as cyclosporine and tacrolimus.

Drug interactions

Since entecavir is excreted mainly by the kidneys, with the simultaneous administration of entecavir and drugs that cause impaired renal function or compete at the level of tubular secretion, an increase in the serum concentration of entecavir or these drugs is possible.

The interaction of entecavir with other drugs that are excreted by the kidneys or affect renal function has not been studied. With the simultaneous use of entecavir with such drugs, the patient's condition should be carefully monitored.