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Encerta- film-coated tablets

INSTRUCTIONS FOR MEDICAL USE

ENCERTA

Trade name of the drug: Encerta

Active substance (INN): Entecavir

Dosage form: film-coated tablets.

Contents:

Each film-coated tablet contains:

Active ingredient: entecavir 0.5 mg or 1.0 mg.

Excipients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyvinylpyrrolidone K-30, corn starch, talc;

Contents of the shell: talc, hydroxypropyl methylcellulose, polyethylene glycol 4000 (macrogoal-4000), castor oil, titanium dioxide, tween 80 (polysorbate-80).

Description: Round, biconvex film-coated tablets, white or almost white.

Pharmacotherapeutic group: Antiviral medicine.

ATX code: J05AF10.

Pharmacological properties

Entecavir is a guanosine nucleoside analogue with potent and selective activity against HBV polymerase. Entecavir is phosphorylated to form active triphosphate (TR), which has an intracellular half-life of 15 hours. The intracellular concentration of TP is directly related to the extracellular level of entecavir, with no significant accumulation of the drug after the initial “plateau” level. By competing with its natural substrate, deoxyguanosine-TR, entecavir-TR inhibits all 3 functional activities of viral polymerase: (1) HUV polymerase priming, (2) reverse transcription of negative strand from pregenomic iRNA, and (3) synthesis of positive strand HBV DNA. Entecavira-TR is a weak inhibitor of cellular DNA polymerases a, ft, and 5 with Ki 18- 40 μm. In addition, at high concentrations of entecavir-TP and entecavir, no adverse effects have been noted with respect to polymerase and DNA synthesis in the mitochondria of HepG2 cells.

Pharmacokinetics

Absorption

In healthy subjects, entecavir is rapidly absorbed and the maximum plasma concentration is determined after 0.5-1.5 hours. When entecavir is taken repeatedly at doses of 0.1 to 1 mg, a dose-proportional increase in maximum concentration (Cmax) and area under the concentration-time curve (AUC) is noted. The equilibrium state is reached after 6-10 days of oral administration once daily, with a plasma concentration increase of about 2-fold. The maximum (Cmax) and minimum (Cmin) equilibrium plasma concentrations were 4.2 and 0.3 ng/ml, respectively, when taking 0.5 mg, and 8.2 and 0.5 ng/ml, respectively, when taking 1 mg. When comparing the bioavailability in healthy subjects, the bioavailability of tablets and oral solution was 100%, i.e., the two dosage forms were interchangeable. Minimal delay in absorption (1-1.5 hours with food and 0.75 hours with fasting), a 44-46% decrease in Cmax and 18-20% decrease in AUC were observed when taking entecavir orally with a high-fat or light meal.

Distribution

The estimated volume of distribution of entecavir exceeded total body water, indicating good tissue penetration of the drug. Entecavir is approximately 13% bound to human serum proteins in vitro.

Metabolism and excretion

Entecavir is not a substrate, inhibitor or inducer of CYP450 enzymes. No oxidized or acetylated metabolites were detected after administration of labeled 14C entecavir in humans and rats, and few phase II metabolites (glucuronides and sulfates) were detected.

After reaching maximum levels, the plasma concentration of entecavir decreased bi-exponentially, with a half-life of 128-149 hours. When administered once daily, there was a 2-fold increase in concentration (cumulation) of the drug, i.e. the effective half-life was approximately 24 hours.

Entecavir is excreted primarily by the kidneys, with 62% to 73% of the dose determined in the urine unchanged in the equilibrium state. Renal clearance is independent of dose and ranges from 360 to 471 mL/min, indicating glomerular filtration and tubular secretion of the drug.

Indications for use

Chronic hepatitis B in adults with signs of viral replication and elevated serum transaminase activity (ALT or ACT) or in presence of histological signs of inflammatory process in liver.

Dosage and administration

Entecavir should be taken orally on an empty stomach (i.e. at least 2 hours after a meal and at least 2 hours before the next meal). The recommended dose of entecavir for patients with compensated liver damage is 0.5 mg once daily. In lamivudine-resistant patients (i.e., patients with a history of hepatitis B virus viremia persisting on lamivudine therapy or patients with confirmed lamivudine resistance), it is recommended that 1 mg of entecavir once daily. In patients with decompensated liver damage, it is recommended to prescribe 1.0 mg entecavir once daily.

Patients with renal impairment

The clearance of entecavir decreases with decreased creatinine clearance. A dose adjustment for entecavir is recommended for 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 impairment.

  Creatinine clearance (ml/min)  Patients who have not previously received nucleoside drugsLamivudine-resistant patients and patients with decompensated liver damage
≥ 500,5 mg once a day1,0 mg once a day
30 – ˂ 500,5 mg every 48 hours1,0 мг mg every 48 hours
10 – ˂ 300,5 mg every 72 hours1,0 mg every 72 hours
  ˂ 10 Hemodialysis* or long-term outpatient perinatal dialysis  0,5 mg every 5-7 days  1,0 mg every 5-7 days

*Entecavir should be taken after hemodialysis.

No dose adjustment of entecavir is required in patients with hepatic impairment. No dose adjustment of entecavir is required in elderly patients.

Side effects

Digestive system disorders: rare (> 1/1000, < 1/100): diarrhea, dyspepsia, nausea, vomiting;

Central nervous system: common (> 1/100, < 1/10): headache, fatigue; rare (> 1/1000, < 1/100): insomnia, dizziness, somnolence;

Immune system: anaphylactoid reaction;

Skin and subcutaneous tissue: alopecia, rash;

Liver: increased transaminase activity;

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;

Besides, in patients with decompensated liver damage, the following side effects were additionally observed: frequent – decrease of bicarbonate concentration in blood, increase of ALT and bilirubin concentration more than 2 times in comparison with IGN, albumin concentration less than 2.5 g/dl, increase of lipase activity more than 3 times versus normal, platelet concentration less than 50000/mm3; rare – renal failure.

Contraindications

  • Hypersensitivity to entecavir or any other component of the drug.
  • Childhood age under 18 years.

Drug interactions

Because entecavir is mainly excreted by the kidneys, concomitant administration of entecavir and drugs that reduce renal function or compete at the level of tubular secretion may increase the serum concentration of entecavir or these drugs. No significant drug interactions have been identified when concomitant administration of entecavir with lamivudine, adefovir dipivoxil or tenofovir disoproxil fumarate. Interactions of entecavir with other drugs that are excreted by the kidneys or affect renal function have not been studied. Patients should be monitored closely if entecavir is concomitantly prescribed with such drugs.

Special indications

During treatment with nucleoside analogues as monotherapy and in combination with antiretroviral drugs, cases of lactoacidosis and marked hepatomegaly with steatosis, sometimes leading to patient’s death, have been described.

Symptoms that may indicate the development of lactoacidosis: general fatigue, nausea, vomiting, abdominal pain, sudden weight loss, shortness of breath, rapid breathing, muscle weakness. Risk factors include female sex, obesity, long-term use of nucleoside analogues, hepatomegaly. If the above symptoms appear or the laboratory confirmation of lactoacidosis is obtained, treatment with the drug should be discontinued.

There have been described cases of hepatitis exacerbation after discontinuation of antiviral therapy, including entecavir. Most of these cases have passed without treatment. However, severe exacerbations, including fatal ones, may develop. The causal relationship of these exacerbations to withdrawal of therapy is unknown. Liver function should be monitored periodically after treatment discontinuation. If necessary, antiviral therapy may be resumed.

Patients with hepatitis B/HIV co-infection

Note that when entecavir is administered to HIV co-infected patients who are not receiving antiretroviral therapy, there may be a risk of developing resistant strains of HIV.

Patients with hepatitis B/hepatitis C/hepatitis D co-infection

There are no data on the efficacy of entecavir in patients with hepatitis B/hepatitis C/hepatitis D co-infection.

Patients with decompensated liver damage

There is a high risk of serious adverse liver effects, particularly in patients with decompensated liver disease of grade C according to the Child-Pugh classification. These patients are also at higher risk of lactoacidosis and specific renal side effects such as hepatorenal syndrome. Therefore, patients should be closely monitored for clinical signs of lactoacidosis and renal dysfunction, and appropriate laboratory tests should be performed in this group of patients (liver enzyme activity, blood lactic acid concentration, serum creatinine concentration).

Lamivudine resistant patients

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

Patients with impaired renal function

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

Patients who have undergone liver transplantation

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

General information for patients

Patients should be informed that entecavir therapy does not reduce the risk of hepatitis B transmission and therefore appropriate precautions should be taken. Each tablet of the drug contains 120.5 mg (0.5 mg tablets) or 241 mg (1 mg tablets) of lactose. In this regard, patients with rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption are not recommended to take the drug.

Pregnancy and lactation

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

There are no data on the penetration of entecavir into the female milk. Breast-feeding during the use of the drug is not recommended.

Overdose

Cases of overdose of entecavir have not been registered. In case of overdose the patient should be under close medical supervision and if necessary – standard supportive therapy.

Form of production

Filmed film-coated tablets 0.5 mg and 1.0 mg in shrink-wrapped packages.

Storage conditions

Store in a dry, dark place at a temperature not exceeding 25°C. Keep out of the reach of children!

Shelf life

2 years. Do not use after the expiration date.

Conditions of dispensing from pharmacies

Released by a doctor’s prescription.

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