Baraclude^® (Tablets) Instructions for Use

Marketing Authorization Holder

Bristol-Myers Squibb Company (USA)

Manufactured By

Patheon Inc. (Canada)

Labeled By

CATALENT ANAGNI, S.R.L. (Italy)

Quality Control Release

BRISTOL-MYERS SQUIBB PHARMACEUTICAL OPERATIONS, External Manufacturing (Ireland)

Contact Information

BRISTOL-MYERS SQUIBB (USA)

ATC Code

J05AF10 (Entecavir)

Active Substance

Entecavir (Rec.INN registered by WHO)

Dosage Forms

	Baraclude®	Film-coated tablets, 0.5 mg: 30 pcs.
		Film-coated tablets, 1 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, triangular, marked “BMS” on one side and “1611” on the other side.

Excipients: lactose monohydrate, microcrystalline cellulose Avicel^® PH102, crospovidone, povidone K30, magnesium stearate.

Film coating composition Opadry white (YS-1-18027-A): titanium dioxide, hypromellose 3 cP, hypromellose 6 cP, macrogol 400, polysorbate 80.

10 pcs. – blisters (3) – cardboard packs.

Film-coated tablets pink, triangular, marked “BMS” on one side and “1612” on the other side.

Excipients: lactose monohydrate, microcrystalline cellulose Avicel^® PH102, crospovidone, povidone K-30/K-29/K-32, magnesium stearate

Film coating composition Opadry pink (03B14899): titanium dioxide, hypromellose 6 cP, macrogol 400, iron oxide red dye (E172, CFR21).

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; nucleoside and nucleotide reverse transcriptase inhibitors

Pharmacological Action

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

Entecavir is phosphorylated to form the 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 observed after the initial “plateau” level.

By competing with the natural substrate, deoxyguanosine triphosphate, entecavir triphosphate 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 triphosphate is a weak inhibitor of cellular DNA polymerases α, β, and δ with Ki 18-40 µM.

Furthermore, at high concentrations of entecavir triphosphate and entecavir, no side effects on γ polymerase and DNA synthesis in the mitochondria of HepG2 cells were observed.

Pharmacokinetics

Absorption

In healthy individuals, the absorption of entecavir is rapid, with C_max in plasma reached within 0.5-1.5 hours.

With repeated administration of entecavir in doses ranging from 0.1 to 1 mg, a dose-proportional increase in C_max and AUC was observed.

Steady state is achieved after 6-10 days of oral administration once daily, with plasma concentrations increasing approximately 2-fold.

Steady-state plasma C_max and C_min were 4.2 and 0.3 ng/ml, respectively, when taking the drug at a dose of 500 mcg, and 8.2 and 0.5 ng/ml, respectively, when taking a dose of 1 mg.

When entecavir was administered orally at a dose of 500 mcg, both with a high-fat meal and a low-fat meal, minimal absorption delay was observed (1-1.5 hours when taken with food and 0.75 hours when taken on an empty stomach), with a decrease in C_max by 44-46% and a decrease in AUC by 18-20%.

Distribution

The V_d of entecavir exceeded the total body water volume, indicating good penetration of the drug into tissues.

The binding of entecavir to human plasma proteins in vitro is approximately 13%.

Metabolism

Entecavir is not a substrate, inhibitor, or inducer of the P450 enzyme system isoforms.

After administration of labeled ¹⁴C-entecavir to humans and rats, no oxidized or acetylated metabolites were detected, and Phase II metabolites (glucuronides and sulfates) were detected in small amounts.

Excretion

After reaching C_max, the plasma concentration of entecavir decreased in a bi-exponential manner, with a T_1/2 of 128-149 hours.

When taken once daily, the drug concentration increased (accumulated) by 2-fold, meaning the effective T_1/2 was approximately 24 hours.

Entecavir is primarily excreted by the kidneys, with 62-73% of the dose excreted unchanged in the urine at steady state.

Renal 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 disease and the presence of viral replication, elevated serum transaminase (ALT or AST) activity, and histological evidence of liver inflammation and/or fibrosis;
• Decompensated liver disease.

ICD codes

Dosage Regimen

The drug should be taken orally on an empty stomach (i.e., at least 2 hours after a meal and no later than 2 hours before the next meal).

The recommended dose of Baraclude^® for patients with compensated liver disease is 500 mcg once daily.

In the presence of lamivudine resistance (i.e., a history of hepatitis B viremia persisting during lamivudine therapy, or confirmed lamivudine resistance), it is recommended to prescribe Entecavir at a dose of 1 mg once daily.

For patients with decompensated liver disease, the drug is prescribed at a dose of 1 mg once daily.

In patients with renal impairment, the clearance of entecavir decreases with decreasing CrCl. For CrCl <50 ml/min, including patients on hemodialysis and continuous ambulatory peritoneal dialysis, dose adjustment of Baraclude^® is recommended as indicated in the table.

*the drug should be taken after a hemodialysis session.

In patients with hepatic impairment, no dose adjustment of entecavir is required.

In elderly patients, no dose adjustment is required.

Adverse Reactions

Digestive system: uncommon (≥1/1000, <1/100) – diarrhea, dyspepsia, nausea, vomiting.

Central nervous system: common (≥1/100, <1/10) – headache, fatigue; uncommon (≥1/1000, <1/100) – insomnia, dizziness, somnolence.

Post-marketing data (frequency cannot be determined)

Immune system anaphylactoid reaction

Skin and subcutaneous tissue: alopecia, rash.

Liver increased transaminase activity.

Metabolism lactic acidosis (general fatigue, nausea, vomiting, abdominal pain, sudden weight loss, shortness of breath, rapid breathing, muscle weakness), especially in patients with decompensated liver disease.

In addition, the following side effects were additionally noted in patients with decompensated liver disease: common – decreased blood bicarbonate concentration, increased ALT activity and bilirubin concentration more than 2 times the ULN, albumin concentration less than 2.5 g/dL, increased lipase activity more than 3 times the normal level, platelet count below 50,000/mm³; uncommon – renal failure.

Contraindications

• Age under 18 years;
• Rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption;
• Hypersensitivity to the components of the drug.

Use in Pregnancy and Lactation

Adequate and well-controlled studies in pregnant women have not been conducted. The use of Baraclude^® during pregnancy is possible only in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

Data on the excretion of entecavir in breast milk are not available. Breastfeeding is not recommended while using the drug.

Use in Hepatic Impairment

In patients with hepatic impairment, no dose adjustment of entecavir is required.

Use in Renal Impairment

In patients with renal impairment, the clearance of entecavir decreases with decreasing CrCl. For CrCl <50 ml/min, including patients on hemodialysis and continuous ambulatory peritoneal dialysis, dose adjustment of Baraclude^® is recommended.

Pediatric Use

Contraindicated: age under 18 years.

Geriatric Use

In elderly patients, no dose adjustment is required.

Special Precautions

Cases of lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported with the use of nucleoside analogues, including entecavir, both as monotherapy and in combination with antiretroviral drugs.

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 include female sex, obesity, long-term use of nucleoside analogues, hepatomegaly. If these symptoms occur or laboratory confirmation of lactic acidosis is obtained, treatment with the drug should be discontinued.

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

Patients with concomitant hepatitis B/HIV infection

It should be considered that when prescribing entecavir to patients with HIV co-infection who are not receiving antiretroviral therapy, there is a risk of developing resistant HIV strains.

Entecavir has not been studied for the treatment of HIV infection and is not recommended for such use.

Patients with concomitant hepatitis B/hepatitis C/hepatitis D infection

There are no data on the efficacy of entecavir in patients with concomitant hepatitis B/hepatitis C/hepatitis D infections.

Patients with decompensated liver disease

A high risk of developing serious liver-related adverse events has been noted, particularly in patients with decompensated liver disease classified as Child-Pugh class C.

These patients are also more susceptible to the risk of developing lactic acidosis and specific renal adverse events such as hepatorenal syndrome.

Therefore, close monitoring of patients for clinical signs of lactic acidosis and renal impairment should be carried out, 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 hepatitis B virus resistance mutations to lamivudine increases the risk of developing resistance to entecavir.

Therefore, in lamivudine-resistant patients, frequent monitoring of viral load is required and, if necessary, appropriate testing for resistance mutations should be performed.

Patients with renal impairment

Dosage regimen adjustment is recommended for patients with renal impairment.

Patients who have undergone liver transplantation.

The safety and efficacy 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 hepatitis B transmission and, therefore, appropriate precautions must be taken.

Overdose

There is limited data on cases of drug overdose in patients. In healthy volunteers who received the drug in doses up to 20 mg/day for up to 14 days or in single doses up to 40 mg, there were no unexpected adverse reactions.

Treatment in case of overdose requires careful medical monitoring of the patient’s condition. If necessary, standard supportive therapy is provided.

Drug Interactions

Since Entecavir is primarily excreted by the kidneys, concomitant administration of entecavir and drugs that impair renal function or compete at the level of tubular secretion may increase the serum concentration of entecavir or these drugs.

No clinically significant drug interaction was identified when entecavir was co-administered with lamivudine, adefovir, or tenofovir.

The interaction of entecavir with other drugs that are excreted by the kidneys or affect renal function has not been studied.

When entecavir is co-administered with such drugs, the patient requires careful medical monitoring.

Storage Conditions

The drug should be stored out of the reach of children, at a temperature from 15°C (59°F) to 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.