pharmachologic effect
Antiviral medication.
The active component is an analogue of guanosine nucleoside with pronounced, selective, powerful activity, which manifests itself against HBV polymerase - hepatitis B virus .
Entecavir is capable of phosphorylation to form an active triphosphate, which has an intracellular half-life of 15 hours.
The concentration of entecavir triphosphate inside the cell directly depends on the level of entecavir outside the cell, but no significant accumulation of the active substance is recorded after the initial plateau.
As a result of competition with its own natural substrate, desoquiguanosine triphosphate suppresses the functional activity of the virus polymerase, affecting 3 links at once:
- synthesis of the positive strand of HBV DNA;
- reverse transcription of negative strand pregenomic mRNA;
- HBV polymerase priming.
Entecavir triphosphate is a fairly weak inhibitor of cellular DNA polymerases, and at high concentrations does not have a negative effect on mitochondrial DNA synthesis.
BARACLUD film-coated tablets 1 mg No. 30
Pharmaceutical group: Antiviral drug. Pharmaceutical action: Baraclude is an antiviral drug, an analogue of guanosine nucleoside with powerful and selective activity against hepatitis B virus (HBV) polymerase. Entecavir is phosphorylated to form active triphosphate (TP), which has an intracellular half-life of 15 hours. The intracellular concentration of TP 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-TF, entecavir-TF inhibits all 3 functional activities of the viral polymerase: (1) priming of HBV polymerase, (2) reverse transcription of the negative strand from pregenomic mRNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir-TF is a weak inhibitor of cellular DNA polymerases α, β and δ with a Ki of 18-40 μM. In addition, at high concentrations of entecavir-TP and entecavir, no side effects were observed in relation to γ polymerase and DNA synthesis in the mitochondria of HepG2 cells. Pharmacokinetics: Absorption In healthy people, the absorption of entecavir is rapid, Cmax in the blood 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 Cmax and AUC is noted. An equilibrium state is achieved after 6-10 days of oral administration once a day, while the plasma concentration increases approximately 2 times. Cmax and Cmin in plasma at steady state were 4.2 and 0.3 ng/ml, respectively, when taking the drug at a dose of 500 mcg, 8.2 and 0.5 ng/ml, respectively, when taking the drug at a dose of 1 mg. When entecavir was taken orally at a dose of 500 mcg with both a high-fat and low-fat meal, 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 AUC by 18-20%. The Vd distribution of entecavir exceeded the total volume of water in the body, which indicates good penetration of the drug into tissues. The binding of entecavir to human plasma proteins in vitro is about 13%. Metabolism Entecavir is not a substrate, inhibitor or inducer of P450 isoenzymes. After administration of 14C-labeled entecavir to humans and rats, no oxidized or acetylated metabolites were detected, and phase II metabolites (glucuronides and sulfates) were detected in small quantities. Elimination After reaching Cmax, the plasma concentration of entecavir decreased biexponentially, with T1/2 being 128-149 hours. When taken 1 time/day. there was an increase in the concentration (cumulation) of the drug by 2 times, that is, the effective T1/2 was approximately 24 hours. Entecavir is excreted mainly by the kidneys, and at steady state, 62-73% of the dose is determined unchanged in the urine. Renal clearance is independent of dose and ranges from 360 to 471 ml/min, indicating glomerular filtration and tubular secretion of the drug.
Pharmacodynamics and pharmacokinetics
The active component is absorbed from the digestive tract within a short period of time, and the maximum concentration is recorded after 0.5-1.5 hours.
After repeated use of the antiviral agent at a dose of 0.1-1.0 mg, a proportional increase in AUC and Cmax is recorded. A state of equilibrium is achieved on days 6-10 of therapy when treated according to the treatment regimen (once a day). Fatty foods interfere with the absorption of the active substance, reducing AUC by 20% and Cmax by 45%.
The drug penetrates well into body tissues and binds to plasma proteins by 13%. The active substance is not an inhibitor, substrate or enzyme inducer in the P450 system.
Baraklyuda is characterized by the accumulation of entecavir. The medication is excreted through the renal system by tubular secretion and glomerular filtration .
Side effects
In patients with a decompensated form of damage to the hepatic system, lactic acidosis , which is characterized by:
- nausea;
- general weakness;
- pain in the abdominal cavity, epigastrium;
- rapid breathing;
- muscle weakness;
- sudden weight loss;
- severe shortness of breath.
Other reactions:
- dyspepsia;
- diarrhea syndrome;
- vomit;
- drowsiness;
- nausea;
- sleep disorders, insomnia;
- dizziness;
- skin rashes;
- fast fatiguability;
- anaphylactoid reactions;
- increased liver transaminases.
Additionally, the following negative reactions were recorded in persons suffering from decompensated liver damage:
- renal failure (rare);
- a drop in bicarbonate levels in the blood;
- increased bilirubin ;
- increase in lipase activity by 3 or more times;
- decrease in platelet less than 50 thousand/mm3;
- increased ALT;
- decrease in albumin concentration less than 2.5 g/dl.
Baraclude®
Lactic acidosis and severe hepatomegaly with steatosis When using nucleoside analogs, the occurrence of lactic acidosis (without hypoxemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, has been described. Since entecavir is a nucleoside analogue, this risk cannot be excluded. Treatment with nucleoside analogs should be discontinued if there is a sharp increase in aminotransferase activity, the development of progressive hepatomegaly, or metabolic acidosis/lactic acidosis of unknown etiology. Benign gastrointestinal symptoms such as nausea, vomiting and abdominal pain may indicate the development of lactic acidosis. Severe cases, sometimes fatal, have been associated with pancreatitis, liver failure/steatosis, renal failure and increased serum lactate concentrations. Caution should be exercised when prescribing nucleoside analogs to any patients (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease. Careful monitoring of such patients is necessary. To differentiate between an increase in aminotransferase activity due to response to treatment and an increase likely related to lactic acidosis, the clinician must ensure that changes in ALT are associated with improvements in other laboratory markers of chronic hepatitis B.
Exacerbation of hepatitis Spontaneous exacerbations of chronic hepatitis B are relatively common and are characterized by a transient increase in ALT activity in the blood serum. After initial antiviral therapy, serum ALT may increase while HBV DNA levels decrease in some patients. Among patients treated with entecavir, the median time to an exacerbation during treatment was 4-5 weeks. In patients with compensated liver damage, this increase in ALT activity was generally not accompanied by an increase in bilirubin concentrations or decompensation of liver function. Patients with cirrhosis may be at higher risk of liver decompensation following exacerbation of hepatitis and should therefore be closely monitored during treatment. Exacerbation of hepatitis has also been described in patients who have discontinued hepatitis B therapy. Exacerbations after treatment are usually associated with an increase in HBV DNA, and most resolve spontaneously. However, severe exacerbations, including deaths, have been described. Among entecavir-treated patients who had not previously received nucleoside therapy, the median time to post-treatment exacerbation was 23-24 weeks, and the majority of exacerbations were described in HBeAg-negative patients. Liver function, clinical symptoms, and laboratory values should be monitored at regular intervals for at least 6 months after discontinuation of hepatitis B treatment. Therapy may need to be reinitiated.
Patients with hepatitis B/HIV co-infection Entecavir has not been evaluated in patients with hepatitis B/HIV co-infection who are not receiving concurrent effective treatment for HIV infection. There may be a risk of developing resistant strains of HIV if entecavir is used to treat chronic B virus infection in patients with HIV infection not receiving highly active antiretroviral therapy (HAART). Therefore, entecavir therapy should not be used in patients with HBV/HIV co-infection who are not receiving HAART therapy. Entecavir has not been studied as a drug for the treatment of HIV infection and is not recommended for use for this indication. Entecavir was studied in 68 adult patients with HIV/AIDS co-infection receiving a lamivudine-containing HAART regimen. There are no data on the effectiveness of entecavir in HBeAg-negative patients with HIV co-infection. There is limited data on the use of the drug in patients with HIV co-infection who have a reduced number of CD4 lymphocytes (< 200 cells/mm3).
Patients with hepatitis B/hepatitis C/hepatitis D co-infection There are no data on the effectiveness of entecavir in patients with concomitant hepatitis C and D virus infection.
Patients with decompensated liver disease Patients with decompensated liver disease (regardless of cause), particularly Child-Pugh class C, had a higher incidence of serious hepatic adverse events compared with patients with compensated liver function. In addition, patients with decompensated liver disease may be at higher risk of developing lactic acidosis and certain renal adverse events, such as hepatorenal syndrome. Therefore, clinical and laboratory parameters should be carefully monitored in such patients.
Lamivudine-resistant patients Mutations in HBV polymerase that cause nucleotide substitutions associated with lamivudine resistance can lead to subsequent secondary substitutions, including substitutions associated with entecavir resistance (ETVr). A small proportion of lamivudine-resistant patients had ETVr substitutions at residues rtTl 84, rtS202, or rtM250 at baseline. Patients with lamivudine-resistant HBV are at greater risk of developing subsequent entecavir resistance than patients without lamivudine resistance. The cumulative probability of new genotypic resistance to entecavir at 1, 2, 3, 4 and 5 years in lamivudine resistance studies was 6%, 15%, 36%, 47% and 51%, respectively. The virologic response in lamivudine-resistant patients should be monitored frequently and appropriate resistance testing should be performed. In patients with a suboptimal virological response after 24 weeks of treatment with entecavir, a change in treatment regimen should be considered. When initiating therapy in patients with a documented history of lamivudine resistance, the combination of entecavir and a second antiviral drug (to which there is no cross-resistance with lamivudine or entecavir) should be considered as an option over entecavir monotherapy. Pre-existing lamivudine-resistant HBV is associated with an increased risk of subsequent entecavir resistance, regardless of the severity of liver disease; In patients with decompensated liver disease, virological breakthrough may be associated with serious clinical complications of existing liver disease. Therefore, in patients with decompensated liver disease and lamivudine-resistant HBV, the combination of entecavir and a second antiviral drug (to which there is no cross-resistance with lamivudine or entecavir) should be considered as a superior option to entecavir monotherapy.
Patients with impaired renal function
For patients with impaired renal function, adjustment of the dosage regimen is recommended (see section "Dosage and Administration"). Proposed recommendations for dose adjustment of entecavir are based on extrapolation of limited data, and their effectiveness and safety have not been evaluated clinically. Therefore, careful monitoring of the virological response is necessary during treatment.
Patients who have undergone liver transplantation The safety and effectiveness of entecavir in patients who have undergone liver transplantation are unknown. Renal function should be carefully monitored before and during treatment with entecavir in patients who have undergone liver transplantation and are 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 transmission of hepatitis B and therefore appropriate precautions should be taken. Each tablet of the drug contains 120.5 mg (0.5 mg tablets) or 241 mg (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.
Instructions for use Baraklyud (Method and dosage)
The tablets are taken on an empty stomach, orally (the break between meals and tablets is at least 2 hours).
In case of compensated damage to the hepatic system, 0.5 mg is prescribed once a day. The dosage is doubled to 1.0 mg per day if resistance to lamivudine ( HCV viremia ) is diagnosed.
Persons with decompensated lesions of the hepatic system are prescribed 1.0 mg 1 time per day. In case of renal failure, the dosage is selected taking into account the QC indicator.
special instructions
Therapy with nucleoside analogues (including Baraklud) together with antiretroviral medications (and in monotherapy too) can cause lactic acidosis, severe hepatomegaly, which is accompanied by steatosis.
Possible death. Risk factors include:
- hepatomegaly (increase in liver size);
- long-term therapy with nucleoside analogues;
- overweight;
- female.
With laboratory confirmation of lactic acidosis and registration of the clinical picture of this condition, Baraclude therapy is canceled.
Against the background of antiviral therapy, exacerbation of hepatitis is possible, which does not require special therapy. Severe, fatal complications rarely occur. Upon completion of treatment, monitoring of indicators of the functional state of the hepatic system is mandatory. A repeated course of antiviral therapy is carried out as needed.
Treatment of patients suffering from hepatitis B and HIV infection
When treated with Baraklud, the lack of adequate antiretroviral therapy can lead to the formation of resistant strains of the human immunodeficiency virus . Entecavir is not recommended for HIV therapy, since its effectiveness in this area has not been sufficiently studied.
Treatment of patients with hepatitis B, C, D
There are no reliable data on the effectiveness of Baraklud in the treatment of this group of patients.
Therapy of patients with lesions of the hepatic system in the stage of decompensation
Patients with diseases of the hepatic system class C (Child-Pugh classification) have a high risk of developing severe negative reactions from the liver. hepatorenal syndrome increases significantly , which requires more careful monitoring (assessment of biochemical blood parameters, monitoring the functioning of the renal system).
Treatment of patients resistant to lamivudine
It has been noted that in the presence of mutating resistance to Lamivudine in the HCV virus, resistance to entecavir increases. That is why in resistant patients it is necessary to constantly monitor the viral load and identify resistance mutations through examinations.
Treatment of patients with pathology of the renal system
Correction of the dosage regimen is required.
Treatment of patients after liver transplantation
The effectiveness and safety of Entecavir therapy in this group of citizens is unknown.
After a liver transplant, patients receive immunosuppressants ( Tacrolimus, Cyclosporine ), which can affect the functioning of the renal system.
Treatment with Baraklud does not reduce the risk of HCV transmission, which requires special precautions.
Baraklyud, 30 pcs., 1 mg, film-coated tablets
When treated with nucleoside analogues as 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 gender, obesity, long-term use of nucleoside analogs, and hepatomegaly. If these symptoms appear or 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 with discontinuation of therapy is unknown. After stopping treatment, liver function should be periodically monitored. If necessary, antiviral therapy can be resumed.
Patients with combined hepatitis B/HIV infection.
It should be taken into account that when prescribing entecavir to patients co-infected with HIV who are not receiving antiretroviral therapy, there may be a risk of developing resistant strains of HIV. Entecavir has not been studied for the treatment of HIV infection and is not recommended for such use.
Patients with combined hepatitis B/hepatitis C/hepatitis D infection.
There are no data on the effectiveness of entecavir in patients with combined hepatitis B/hepatitis C/hepatitis D infections.
Patients with decompensated liver damage.
There is a high risk of developing serious side effects from the liver, in particular in patients with decompensated liver disease class C according to the Child-Pugh classification. These patients are also at greater risk of developing lactic acidosis and specific renal side effects such as hepatorenal syndrome. In this regard, patients should be carefully monitored to identify clinical signs of lactic acidosis and renal dysfunction, and appropriate laboratory tests should be performed in this group of patients (liver enzyme activity, lactic acid concentration in the blood, serum creatinine concentration).
Lamivudine-resistant patients.
The presence of resistance mutations in the hepatitis B virus to lamivudine increases the risk of developing resistance to entecavir. In this regard, lamivudine-resistant patients require frequent monitoring of the viral load and, if necessary, appropriate testing to identify resistance mutations.
Patients with impaired renal function.
For patients with impaired renal function, adjustment of the dosage regimen is recommended.
Patients who have undergone liver transplantation. The safety and effectiveness of entecavir in patients undergoing liver transplantation are unknown. Renal function should be carefully monitored before and during treatment with entecavir in patients who have undergone liver transplantation and are 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 transmission of hepatitis B 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.
Analogues of Baraklyuda
Level 4 ATX code matches:
Zeffix
Zidovudine
Lamivudine
Structural analogues have not been developed. Medicines with similar pharmacological effects:
- Alfarekin;
- Pegasis;
- Intron A.
