Elgravir, 0.5 mg 30 pcs

Pharmacotherapeutic group: Antiviral drug

Pharmacological action

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

Entecavir is phosphorylated to form active triphosphate with an intracellular half-life of 15 h. 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 “plateau” level. By competing with its natural substrate, deoxyguanosine triphosphate, entecavir triphosphate inhibits all 3 functional activities of viral polymerase: 1) HBV polymerase priming, 2) reverse transcription of negative strand from pregenomic iRNA, and 3) synthesis of positive strand HBV DNA. Entecavir triphosphate 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 triphosphate and entecavir, no adverse effects were noted with respect to γ polymerase and DNA synthesis in mitochondria of HepG2 cells.

Pharmacokinetics

In healthy subjects, absorption of entecavir is rapid, C_max in plasma is determined after 0.5-1.5 h. When entecavir is taken repeatedly at a dose of 0.1 to 1 mg, a dose-proportional increase in C_max and AUC is noted. The equilibrium state is reached after 6-10 days of oral administration once daily, with plasma concentrations increasing approximately 2-fold. C_max and C_min in plasma at equilibrium were 4.2 and 0.3 ng/ml, respectively, when the drug was taken at a dose of 500 mcg; 8.2 and 0.5 ng/ml, respectively, when it was taken at a dose of 1 mg. In oral administration of entecavir at a dose of 500 mcg with both high-fat and low-fat foods, minimal delay in absorption (1-1.5 h when taken with food and 0.75 h when taken on an empty stomach), a 44-46% decrease in C_max and an 18-20% decrease in AUC were observed.

The V_d of entecavir exceeded total body water, indicating good tissue penetration of the drug. The in vitro binding of entecavir to human plasma proteins is about 13%.

Entecavir is not a substrate, inhibitor or inducer of P450 isoenzymes. No oxidized or acetylated metabolites were determined after administration of labeled ¹⁴C-entecavir in humans and rats, and few phase II metabolites (glucuronides and sulfates) were determined.

After reaching C_max, the plasma concentration of entecavir decreased biexponentially, with a T_1/2 of 128-149 h. There was a 2-fold increase in drug concentration (cumulation) when taken once daily, meaning that the effective T_1/2 was approximately 24 h.

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

Indications

Chronic hepatitis B in adults with:

Active ingredient

Composition

Each film-coated tablet contains:

The active ingredient:

Entecavir monohydrate – 0.53 mg / 1.06 mg, converted to entecavir – 0.5 mg

Excipients:

The core: lactose monohydrate, 54.47 mg; microcrystalline cellulose, 90mg; low-substituted hyprolose, 40 mg; povidone K30, 5 mg ; crosspovidone, 8 mg/16 mg; colloidal silicon dioxide, 1 mg; magnesium stearate, 1 mg.

Film coating: hypromellose E5 – 4.2 mg; macrogol 6000 – 0.54 mg; titanium dioxide – 1.2 mg; polysorbate 80 – 0.06 mg.

How to take, the dosage

The therapy should be started by a doctor experienced in treating chronic hepatitis B.

The drug should be taken orally on an empty stomach (that is, 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 disease is 0.5 mg once daily.

Lamivudine-resistant patients (that is, patients with a history of hepatitis B virus viremia persisting on lamivudine therapy or patients with confirmed lamivudine resistance) are recommended to receive 1 mg of entecavir once daily.

Patients with decompensated liver damage are recommended to receive 1 mg of entecavir once daily.

Patients with renal impairment.

The clearance of entecavir decreases with decreased creatinine clearance. Dose adjustment of entecavir is recommended for patients with creatinine clearance < 50 ml/min, including those on hemodialysis and long-term ambulatory peritoneal dialysis, according to Table 1.

Table 1

The recommended doses of entecavir in patients with renal impairment

Creatinine clearance (ml/min)

Patients not previously treated with nucleoside drugs

Lamivudine-resistant patients and patients with decompensated liver damage

≥ 50

0.5 mg once daily

1 mg once daily

30 – < 50

0.5 mg every 48 hours

1 mg every 48 hours

<10

0.5 mg every 5-7 days

1 mg every 5-7 days

Hemodialysis* or prolonged ambulatory peritoneal dialysis

* Entecavir should be taken after a hemodialysis session.

In patients with hepatic impairment, no dose adjustment for entecavir is necessary.

In elderly patients, no dose adjustment of entecavir is required.

Interaction

Since 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 serum concentrations of entecavir or these drugs. No significant drug interactions have been reported with lamivudine, adefovir or tenofovir when entecavir is concomitantly administered.

The interactions of entecavir with other drugs that are excreted by the kidneys or that affect renal function have not been studied. Patients should be closely monitored when concomitantly prescribing entecavir with such drugs.

Special Instructions

Lactoacidosis/extreme hepatomegaly with steatosis

In treatment with nucleoside analogues, cases of lactoacidosis and severe hepatomegaly with steatosis have been described, sometimes leading to patient death. Because entecavir is a nucleoside analog, the risk of this complication cannot be excluded with its use.

Symptoms that may indicate the development of lactoacidosis: general fatigue, nausea, vomiting, abdominal pain, sudden weight loss, shortness of breath, rapid breathing, muscle weakness. In severe cases, sometimes fatal, the development of lactoacidosis has been associated with pancreatitis, liver failure/steatosis, renal failure, and hyperlactatemia. Risk factors include female gender, obesity, long-term use of nucleoside analogues, and hepatomegaly.

The treatment with nucleoside analogues should be discontinued if symptomatic hyperlactatemia and metabolic acidosis/lactoacidosis develop, progressive hepatomegaly or rapid increase in aminotransferases. Caution should be exercised when using nucleoside analogues to treat any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver damage and hepatic steatosis (including use of certain medications and alcohol consumption). Careful clinical and laboratory monitoring is required when treating these patients.

In order to distinguish an increase in aminotransferase activity as evidence of treatment efficacy from an increase potentially associated with lactoacidosis, the clinician should make sure that changes in ALT activity are associated with improvements in other laboratory markers of chronic hepatitis B.

Hepatitis exacerbations

Spontaneous exacerbations of chronic hepatitis B are quite common and are characterized by a transient increase in serum ALT activity. After initiation of antiviral therapy in some patients ALT activity may increase with decreasing HBV DNA level in blood serum. In most cases, exacerbation of hepatitis developed during first 4-5 weeks of entecavir therapy. In patients with compensated liver disease, such increase of ALT activity is usually not accompanied by increase of bilirubin concentration in serum or liver failure. Patients with advanced liver disease or cirrhosis have an increased risk of decompensation of liver function. Close clinical and laboratory monitoring should be performed during treatment of such patients.

Cases of hepatitis exacerbations have also been reported in patients who discontinued hepatitis B drugs. Exacerbations after treatment discontinuation are usually associated with an increase in HBV DNA levels, in most cases do not lead to decompensation of liver function and resolve spontaneously. However, severe exacerbations, including fatal ones, have been reported.

In patients who had not previously received nucleoside analogues and were prescribed entecavir, exacerbations developed on average within the first 23-24 weeks after discontinuation of the drug, in most cases in HBeAg-negative patients (see section “Side effects”). Liver function should be periodically monitored for at least 6 months after discontinuation of hepatitis therapy. Resumption of hepatitis B therapy may be warranted if necessary.

Patients with hepatitis B/HIV co-infection

Patients with HIV co-infection who are not receiving highly active antiretroviral therapy (HAART) should consider that there may be a risk of developing resistant strains of HIV when entecavir is prescribed. Therefore, entecavir should not be used in patients with hepatitis B/HIV co-infection who are not receiving HAART. Entecavir has not been studied as a treatment for HIV infection and is not recommended for such use.

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

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

Patients with decompensated liver disease

There is a high risk of serious liver adverse events, 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. In this regard, patients should be closely monitored for clinical signs of lactoacidosis and impaired renal function, and appropriate laboratory tests should be performed in this group of patients (activity of “liver” enzymes, lactic acid concentration in blood, serum creatinine concentration).

Lamivudine-resistant patients

Lamivudine-resistant patients are at higher risk of developing subsequent resistance to entecavir than patients without lamivudine resistance. The likelihood of developing genotypic resistance to entecavir after 1, 2, 3, 4, and 5 years of treatment in the studies in lamivudine-resistant patients was 6%, 15%, 36%, 47%, and 51%, respectively. Therefore, lamivudine-resistant patients require frequent viral load monitoring and appropriate testing for resistance. In patients with a suboptimal virologic response after 24 weeks of entecavir treatment, a change in the therapy regimen should be considered. When starting therapy in patients with documented HBV resistance to lamivudine, entecavir in combination with another antiviral drug (not cross-resistant with either lamivudine or entecavir) should be preferred over entecavir monotherapy.

The presence of HBV resistance to lamivudine is associated with an increased risk of developing resistance to entecavir, regardless of the degree of liver function impairment. In patients with decompensated liver disease, virologic breakthrough may be associated with serious clinical complications of liver disease. Thus, in lamivudine-resistant patients with decompensated liver disease, the use of entecavir in combination with another antiviral drug that is not cross-resistant with either lamivudine or entecavir is preferable to entecavir monotherapy.

Patients with impaired renal function

In patients with impaired renal function, dosing adjustments are recommended (see section “Dosage and administration”). The suggested recommendations are based on extrapolation of limited data; safety and efficacy of these regimens have not been clinically evaluated. Therefore, virologic response should be carefully monitored in patients with impaired renal function.

Patients with liver transplantation

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

General information for patients

Patients should be informed that therapy with entecavir does not reduce the risk of hepatitis B transmission and, therefore, appropriate precautions should be taken. Each tablet of the drug contains 54.47 mg (0.5 mg tablets) or 108.94 mg (1.0 mg tablets) of lactose monohydrate. In this regard, patients with rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption are contraindicated to take the drug.

Influence on driving and operating ability

When using the drug, it is necessary to refrain from driving vehicles and engaging in potentially dangerous activities requiring increased concentration and quick psychomotor reactions, since the drug may cause dizziness and other side effects which may affect the above mentioned abilities.

Contraindications

Side effects

Digestive system disorders

Rarely (≥ 1/1000, < 1/100): diarrhea, dyspepsia, nausea, vomiting.

Central nervous system disorders

Frequently (≥ 1/100, < 1/10): headache, fatigue; rarely (≥ 1/1000, < 1/100): insomnia, dizziness, somnolence.

Postmarketing data (frequency cannot be determined):

Immune system side: anaphylactoid reaction.

Skin and subcutaneous tissue: alopecia, rash.

Liver disorders: increased transaminase activity.

Metabolic disorders: lactoacidosis (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 have been reported in patients with decompensated liver disease:

Frequently: decreased blood bicarbonate concentration, increased ALT activity and bilirubin concentration more than 2 times the upper limit of normal, albumin concentration less than 2.5 g/dL, increased lipase activity more than 3 times the normal, platelet concentration below 50,000/mm3; rarely: renal failure.

Individual adverse reactions

Hepatitis exacerbations during treatment

. In clinical trials in patients who had not previously received nucleoside analogues, hepatitis exacerbations (an increase in ALT activity of more than 10 times the upper limit of normal and more than 2 times the baseline) were noted in 2% of patients receiving entecavir compared to 4% of patients receiving lamivudine. In lamivudine-resistant patients, an increase in ALT activity of more than 10 times the upper limit of normal and more than twice the baseline was found in 2% of patients receiving entecavir compared to 11% of patients receiving lamivudine. The median time to symptom onset was 4-5 weeks among entecavir-treated patients with increased ALT activity. As a rule, resolution of symptoms was noted with continuation of treatment. In most cases, the increase in ALT activity was associated with a decrease in viral load of 2 log10/ml or more, which preceded or coincided with the increase in ALT activity. Periodic monitoring of liver function is recommended during treatment.

Hepatitis exacerbations after discontinuation of treatment

There have been reports of hepatitis exacerbations in patients who discontinued hepatitis B drugs, including after discontinuation of entecavir. In studies in patients who had not previously received nucleoside analogues, 6% of patients taking entecavir and 10% of patients taking lamivudine showed increased ALT activity (more than 10 times the upper limit of normal and more than twice the baseline) during follow-up after treatment. Among patients who had not previously received nucleoside analogues, after discontinuation of entecavir therapy, the median time to ALT increase was 23-24 weeks, with 86% (24/28) of HBeAg-negative patients. In studies involving a limited number of lamivudine-resistant patients, an increase in ALT activity during the follow-up period was noted in 11% of patients treated with entecavir and not taking lamivudine.

In clinical trials, entecavir therapy was discontinued if patients achieved a predetermined response. If therapy is discontinued without regard to response to treatment, the likelihood of changes in ALT activity may be higher.

Special patient groups

Patients with decompensated liver disease

The safety profile of entecavir in patients with decompensated liver disease was evaluated in an open comparative randomized clinical trial in which patients received entecavir at a dose of 1 mg daily (n = 102) or adefovir dipivoxil at a dose of 10 mg daily (n = 89). In this study, the cumulative mortality rate was 23% (23/102). The cause of death was usually liver disease. The cumulative incidence of hepatocellular carcinoma was 12% (12/102). Serious adverse effects, usually of the liver, were detected at a cumulative incidence of 69%. Patients with a high Child-Pugh score had a higher risk of serious side effects.

Laboratory test abnormalities

To 48 weeks after initiation of entecavir therapy in patients with decompensated liver disease, no patient showed an increase in ALT activity of more than 10 times the upper limit of normal and more than 2 times the baseline level. In 1% of patients, there was an increase in ALT activity more than 2-fold compared to baseline with a simultaneous increase in bilirubin levels more than 2-fold compared to the upper limit of normal and more than 2-fold compared to baseline. A decrease in albumin < 2.5 g/dL occurred in 30% of patients, an increase in lipase levels of more than 3 times the baseline level occurred in 10% of patients, and a decrease in platelet count < 50,000/mm3 occurred in 20% of patients.

Hepatitis B/HIV co-infected patients

The safety profile of entecavir in a limited number of hepatitis B/HIV co-infected patients receiving highly active antiretroviral therapy regimens including lamivudine was similar to the safety profile in patients with HBV mono-infection.

Overdose

Pregnancy use

Pregnancy

There have been no adequate and well-controlled studies in pregnant women. Entecavir should be taken during pregnancy only if the potential benefit of use exceeds the potential risk to the fetus.

Breastfeeding

There are no data on the penetration of entecavir into women’s milk. Breastfeeding is not recommended when using the drug.