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

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 the cellular DNA polymerases α, β and δ with Ki of 18-40 μM. In addition, at high concentrations of entecavir triphosphate and entecavir, no side effects have been observed with respect to γ polymerase and DNA synthesis in mitochondria of HepG2 cells.

Pharmacokinetics:

In healthy people, absorption of entecavir is rapid, the maximum concentrationin blood plasma is determined after 0.5-1.5 hours. When repeated administration of entecavir in a dose of 0.1 to 1 mg, there is a dose-proportional increase in the maximum concentration and 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 times. The maximum concentration and the minimum plasma concentration in the equilibrium state were 4.2 and 0.3 ng / ml, respectively, when taking the drug at a dose of 500 μg, and 8.2 and 0.5 ng / ml, respectively, with 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, there was a minimal delay in absorption (1-1.5 h when taken with food and 0.75 h when taken on an empty stomach), a decrease in the maximum concentrationby 44-46% and AUC decrease by 18-20%.

The equilibrium volume 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%.

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

After reaching the maximumthe concentration of entecavir in plasma decreased bi-exponentially, while the half-lifewas 128-149 hours. When taking 1 time per day, there was an increase in concentration (cumulation) of the drug in 2 times, that is, an effective half-lifewas approximately 24 hours.

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. The renal clearance is dose independent and ranges from 360 to 471 ml / min, indicating glomerular filtration and tubular secretion of entecavir.

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; with decompensated liver damage.

ICD-10

I.B15-B19.B18.1 Chronic viral hepatitis B without delta-agent

I.B15-B19.B18.0 Chronic viral hepatitis B with delta-agent

Contraindications:

Hypersensitivity to entecavir or any other component of the drug; children under 18 years of age, pregnancy, breast-feeding; liver failure.

Carefully:

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

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.

Pregnancy and lactation:

Recommendations for FDA - Category C. Adequate and well-controlled studies in pregnant women have not been conducted. Application 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. During treatment, breastfeeding is not recommended.

Dosing and Administration:

Is taken internally.The dose is 500-1000 mcg once a day. The frequency of admission depends on the degree of impaired renal function, indications in the history of therapy with nerozidic drugs, liver conditions.

Side effects:

From the side digestive system: rarely - diarrhea, dyspepsia, nausea, vomiting; possibly - increased activity of transaminases.

From the side CNS: often - headache, fatigue; rarely - insomnia, dizziness, drowsiness.

From the side immune system: possibly anaphylactoid reaction.

From the side skin and subcutaneous tissue: possibly - alopecia, rash.

From the side metabolism: possibly 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, in patients with decompensated liver disease, the following side effects were noted additionally: often a decrease in bicarbonate concentration in the blood, an increase in ALT activity and a bilirubin concentration of more than 2-fold compared with the upper limit of normal, an albumin concentration of less than 2.5 g / dl ,the increase in lipase activity is more than 3 times higher than normal, the concentration of platelets is below 50,000 / μL; rarely - kidney failure.

Overdose:

Feeling of anxiety, dizziness, headache, drowsiness, lethargy, convulsions, nausea, vomiting and other manifestations of 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 is excreted mainly by the kidneys, while concomitant administration of entecavir and drugs that cause impaired renal function or competing at the level of tubular secretion, it is possible to increase the concentration in the serum of entecavir or these drugs.

The interaction of entecavir with other drugs that are excreted by the kidneys or affect the function of the kidneys has not been studied. If you simultaneously use entecavir with such drugs, you should carefully monitor the patient's condition.

Special instructions:

In the treatment of nucleoside analogues, including entecavir in the form of monotherapy and in combination with antiretroviral drugs, cases of lactic acidosis and severe hepatomegaly with steatosis, sometimes leading to the death of the patient, are described.

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, 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.

It should be borne in mind that with the use of entecavir in patients with co-infected HIV infection not receiving antiretroviral therapy, the risk of developing resistant strains of HIV is possible. Entecavir It has not been studied for the treatment of HIV infection and is not recommended for such use.

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).

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 in resistance.

Instructions

Entecavir (Entecavirum)