Baraclude - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life and Storage Other Information

Active ingredients: Entecavir

Baraclude 0.5 mg film-coated tablets

Baraclude package inserts are available for pack sizes:
  • Baraclude 0.5 mg film-coated tablets
  • Baraclude 1 mg film-coated tablets
  • Baraclude 0.05 mg / ml oral solution

Indications Why is Baraclude used? What is it for?

Baraclude tablets is an antiviral medicine used in adults to treat chronic (long-term) hepatitis B virus infection. Baraclude can be used in people whose liver is damaged but still functioning properly (compensated liver disease) and in people whose liver is damaged and does not function properly (decompensated liver disease).

Baraclude tablets are also used to treat chronic (long-term) hepatitis B virus infection in children and adolescents from 2 to 18 years of age. Baraclude can be used in children whose liver is damaged but still functioning properly (compensated liver disease).

Infection with the hepatitis B virus can cause liver damage. Baraclude reduces the amount of virus in the body and improves the condition of the liver.

Contraindications When Baraclude should not be used

Do not take Baraclude if you are allergic (hypersensitive) to entecavir or any of the other ingredients of this medicine (listed in section 6).

Precautions for use What you need to know before you take Baraclude

Talk to your doctor or pharmacist before taking Baraclude

  • if you have had kidney problems, please tell your doctor. This is important as Baraclude is eliminated from the body via the kidneys and may need to be adjusted in the dosage or schedule.
  • do not stop taking Baraclude without your doctor's advice as hepatitis can get worse after stopping treatment. If Baraclude treatment is stopped, your doctor will continue to monitor you and have blood tests performed for several months.
  • discuss with your doctor whether your liver is working properly and, if not, what the effects may be on your treatment with Baraclude.
  • if you are also infected with the HIV virus (human immunodeficiency virus), please tell your doctor. You should not take Baraclude to treat hepatitis B infection unless you are already taking HIV medicines, as the effectiveness of future HIV treatment may be reduced. Baraclude will not check for his HIV infection.
  • Taking Baraclude will not prevent you from infecting other people with the hepatitis B virus (HBV) through sexual intercourse or body fluids (including contamination with blood). For this reason it is important to take precautions to prevent others from becoming infected with the virus. of hepatitis B (HBV). A vaccine is available to protect those who are at risk of contracting hepatitis B virus (HBV) infection.
  • Baraclude belongs to a class of medicines which can cause lactic acidosis (excess lactic acid in the blood) and enlargement of the liver. Symptoms such as nausea, vomiting and stomach pain may indicate the development of lactic acidosis. This rare but serious side effect has occasionally been fatal. Lactic acidosis is more common in women, especially if they are very overweight. Your doctor will check you regularly while you are being treated with Baraclude.
  • if you have previously received treatment for chronic hepatitis B, please tell your doctor.

Children and adolescents

Baraclude should not be given to children under 2 years of age or weighing less than 10 kg.

Interactions Which drugs or foods may change the effect of Baraclude

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Baraclude with food and drink

In most cases, you can take Baraclude with or without food. However, if you have previously been treated with a medicine containing the active substance lamivudine you will need to consider the following. If you have been switched to Baraclude treatment because lamivudine therapy was unsuccessful, you will need to take Baraclude once a day on an empty stomach. If your liver disease is very advanced, your doctor will prescribe you to take Baraclude on an empty stomach. An empty stomach is defined as at least 2 hours after a meal and at least 2 hours before the next meal.

Children and adolescents (2 to 18 years of age) can take Baraclude with or without food.

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

Tell your doctor if you are pregnant or planning to become pregnant. It has not been proven that the use of Baraclude during pregnancy is safe. Unless specifically stated by your doctor, Baraclude should not be used during pregnancy. It is important that women of childbearing potential use an effective method while being treated with Baraclude. of contraception to avoid pregnancy.

You should not breast-feed while on Baraclude therapy. Tell your doctor if you are breastfeeding. It is not known whether entecavir, the active substance in Baraclude, is excreted in human breast milk.

Driving and using machines

Dizziness, fatigue and sleepiness are common side effects which may impair your ability to drive and use machines. For any clarification, consult your doctor.

Baraclude contains lactose

This medicinal product contains lactose. If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Baraclude: Posology

Not all patients need to take the same dose of Baraclude.

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

For adults, the recommended dose is 0.5 mg or 1 mg once daily orally (by mouth).

Your dose will depend on:

  • if you have already received treatment for hepatitis B virus (HBV) infection, and what medicine you have been treated with.
  • if you have kidney problems. Your doctor may prescribe a lower dose or tell you to take it less than once a day.
  • the condition of your liver.

For children and adolescents (2 to 18 years of age), your child's doctor will decide the right dose based on your child's weight.

Baraclude oral solution is recommended for patients weighing 10 kg to 32.5 kg.

Children who weigh at least 32.6 kg can take the oral solution or 0.5 mg tablets.

Each dosage will be administered once daily orally (mouth).

There are no recommendations for Baraclude in children younger than 2 years of age or weighing less than 10 kg.

Your doctor will advise you on the correct dosage. For the medicine to be fully effective and to reduce the development of resistance to therapy, always take the dose recommended by your doctor. Take Baraclude for as long as your doctor tells you. Your doctor will tell you if and when to stop treatment.

Some patients should take Baraclude on an empty stomach (see Baraclude with food and drink in section 2). If your doctor has told you to take Baraclude on an empty stomach, this means at least 2 hours after a meal and at least 2 hours before your next meal.

If you forget to take Baraclude

It is important that you do not miss any doses. If you miss a dose of Baraclude, take it as soon as possible, and then take the next dose at the right time. If it is almost time for your next dose, skip the missed dose. Wait and take your next dose at the right time.

Do not take a double dose to make up for a forgotten dose.

Do not stop taking Baraclude without your doctor's advice

Many people have very severe hepatitis symptoms when they stop taking Baraclude. Tell your doctor immediately if you notice any change in symptoms after stopping treatment.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Baraclude

If you take more Baraclude than you should contact your doctor immediately.

Side Effects What are the side effects of Baraclude

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Patients treated with Baraclude have reported the following side effects:

  • common (at least 1 in 100 patients): headache, insomnia (inability to sleep), fatigue (excessive tiredness), dizziness, somnolence (drowsiness), vomiting, diarrhea, nausea, dyspepsia (indigestion) and high levels of liver enzymes in the blood.
  • uncommon (at least 1 in 1,000 patients): rash (rash), hair loss.
  • rare (at least 1 in 10,000 patients): severe allergic reaction.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the bottle, blister or carton after EXP. The expiry date refers to the last day of the month.

Blister packs: Do not store above 30 ° C. Store in the original carton.

Bottle packs: Do not store above 25 ° C. Keep the bottle tightly closed.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Deadline "> Other information

What Baraclude contains

  • The active ingredient is entecavir. Each film-coated tablet contains 0.5 mg of entecavir.
  • The other excipients are:
    • Tablet core: crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose and povidone.
    • Tablet coating: hypromellose, macrogol 400, titanium dioxide (E171) and polysorbate 80 (E433).

Description of what Baraclude looks like and contents of the pack

The film-coated tablets (tablets) are white to off-white and triangular in shape. They are marked with "BMS" on one side and "1611" on the other.

Baraclude 0.5 mg film-coated tablets are available in cartons containing 30 x 1 or 90 x 1 film-coated tablet (in perforated unit dose blisters) and in bottles containing 30 film-coated tablets.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Baraclude can be found in the "Summary of Features" tab. 01.0 NAME OF THE MEDICINAL PRODUCT - 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION - 03.0 PHARMACEUTICAL FORM - 04.0 CLINICAL PARTICULARS - 04.1 Therapeutic indications - 04.2 Posology and method of administration - 04.3 Contraindications - 04.4 Special warnings and appropriate precautions for use - 04.5 Interactions with other medicinal products and other forms of interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION - 10.0 DATE OF REVISION OF THE TEXT - 11.0 FOR RADIO DRUGS, FULL DATA ON INTERNAL RADIATION DOSIMETRY -

01.0 NAME OF THE MEDICINAL PRODUCT -

BARACLUDE 0.5 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Each tablet contains 0.5 mg of entecavir (as monohydrate).

Excipients with known effects: each tablet contains 120.5 mg of lactose

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Film-coated tablet (tablet).

White to off-white triangular shaped tablet marked with "BMS" on one side and "1611" on the other.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Baraclude is indicated for the treatment of chronic hepatitis B virus (HBV) infection (see section 5.1) in adults with:

§ compensated liver disease and evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and / or fibrosis.

§ decompensated liver disease (see section 4.4)

For both compensated and decompensated liver disease, this indication is based on clinical data in previously untreated patients with nucleoside infection with HBeAg positive and HBeAg negative hepatitis B virus. For lamivudine-refractory hepatitis B patients see the sections 4.2, 4.4 and 5.1.

Baraclude is also indicated for the treatment of chronic hepatitis B virus (HBV) infection in nucleoside-naïve pediatric patients 2 to 18 years of age with compensated liver disease who have evidence of active viral replication and Persistently elevated serum alanine aminotransferase (ALT) levels or moderate to severe histological evidence of active inflammation and / or fibrosis. Regarding the decision to initiate treatment in pediatric patients, see sections 4.2, 4.4 and 5.1

04.2 Posology and method of administration -

Treatment should be initiated by a physician experienced in the treatment of chronic hepatitis B virus infection.

Dosage

Compensated liver disease

Patients never treated with nucleosides: The recommended dose for adults is 0.5 mg once a day, with or without food.

Patients refractory to lamivudine (i.e. with evidence of viraemia during lamivudine treatment or with the presence of mutations conferring resistance to lamivudine [LVDr]) (see sections 4.4 and 5.1): the recommended dose in adults is 1 mg once daily to be taken at empty stomach (more than 2 hours before and more than 2 hours after a meal) (see section 5.2). In the presence of LVDr mutations, the combined use of entecavir plus a second antiviral agent (which does not show cross-resistance with lamivudine or entecavir) should be preferred over entecavir monotherapy (see section 4.4).

Decompensated liver disease

The recommended dose for adult patients with decompensated liver disease is 1 mg once daily taken on an empty stomach (more than 2 hours before and more than 2 hours after a meal) (see section 5.2). For lamivudine-refractory hepatitis B patients, see sections 4.4 and 5.1

Duration of therapy

The optimal duration of treatment is unknown. Treatment can be stopped:

§ in HBeAg positive adult patients, treatment should be continued at least up to 12 months after achieving HBe seroconversion (loss of HBeAg and negativization of HBV DNA with appearance of anti HBe in 2 consecutive serum measurements repeated at at least 3 - 6 months later) or until HBs seroconversion or in case of loss of efficacy (see section 4.4.).

§ In HBeAg negative adult patients, treatment should be continued at least until HBs seroconversion or if there is evidence of loss of efficacy. In prolonged treatments for more than 2 years, adjustment is recommended to confirm that continuation of the chosen therapy remains suitable for the patient.

In patients with decompensated liver disease or cirrhosis, discontinuation of treatment is not recommended.

Pediatric population

The decision to treat pediatric patients should be based on careful consideration of the patient's individual needs and referring to current pediatric treatment guidelines including the value of histological background information. With continued therapy, the benefits of long-term virological suppression must be weighed considering the risk of prolonged treatment, including the emergence of visrus resistance of hepatitis B.

Serum alanine aminotransferase (ALT) levels should be persistently elevated, for at least 6 months prior to treatment, in pediatric patients with compensated liver disease due to chronic hepatitis B with HBeAg positive and for at least 12 months in patients with HBeAg negative infection. . Pediatric patients weighing at least 32.6 kg should be given a daily dose of one 0.5 mg or 10 ml (0.5 mg) tablet of oral solution, with or without food. used for patients with a body weight of less than 32.6 kg.

Duration of therapy in pediatric patients

The optimal duration of treatment is unknown. In accordance with current pediatric guidelines, treatment can be stopped:

§ in HBeAg positive pediatric patients, treatment should be continued for at least 12 months after the disappearance of HBV DNA and HBeAg seroconversion (loss of HBeAg and appearance of anti HBe in 2 consecutive serum measurements repeated at at least 3 - 6 months later) or until HBs seroconversion or in case of loss of efficacy. Serum alanine aminotransferase (ALT) and HBV DNA levels should be monitored regularly after discontinuation of treatment (see section 4.4).

§ In HBeAg negative pediatric patients, treatment should be continued at least until HBsAg seroconversion or if there is evidence of loss of efficacy.

Pharmacokinetics in pediatric patients with renal or hepatic impairment have not been studied.

Senior citizens: No dose adjustment is required based on age. The dose should be adjusted according to the patient's renal function (see dosing recommendations in renal insufficiency and section 5.2)

Gender and race: No gender or race adjustments are required.

Kidney failure: Entecavir clearance decreases with decreasing creatinine clearance (see section 5.2) Dosage adjustment is recommended in patients with creatinine clearance hemodialysis or on continuous ambulatory peritoneal dialysis (CAPD). When using Baraclude oral solution a reduction of the daily dose is recommended, as described in the table. Alternatively, if the oral solution is not available, the dosage can be adjusted by increasing the interval between doses, also described in the table. The proposed dose modifications are based on extrapolation of limited data and their safety and efficacy have not been clinically evaluated. Therefore, virological response should be carefully monitored.

Creatinine clearance (ml / min) Dosage * of Baraclude Patients never treated with nucleosides Patients refractory to lamivudine or with decompensated liver disease ≥ 50 0.5 mg once a day 1 mg once a day 30 - 49 0.25 mg once daily * or 0.5 mg every 48 hours 0.5 mg once a day 10 - 29 0.15 mg once daily * or 0.5 mg every 72 hours 0.3 mg once daily * or 0.5 mg every 48 hours 0.05 mg once daily * 0.1 mg once daily * or 0.5 mg every 72 hours 0.5 mg every 5-7 days

* for dosages

** on hemodialysis days, administer entecavir after hemodialysis.

Hepatic insufficiency: No dosage adjustment is required in patients with hepatic insufficiency.

Method of administration

Baraclude must be taken orally.

04.3 Contraindications -

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

04.4 Special warnings and appropriate precautions for use -

Kidney failure: Dosage adjustment is recommended in patients with renal insufficiency (see section 4.2). Proposed dose modifications are based on extrapolation of limited data and the related safety and efficacy have not been clinically evaluated. Therefore, the virological response must be carefully monitored.

Exacerbation of hepatitisExacerbations characterized by transient elevations in serum ALT are relatively common in chronic hepatitis B. After the initiation of antiviral therapy, serum ALT may increase in some patients as well as decrease in HBV DNA levels (see section 4.8). Among entecavir-treated patients, flare-ups during treatment had a median of onset of 4 to 5 weeks. In patients with compensated liver disease, these elevations in serum ALT are generally not accompanied by increased serum bilirubin concentrations or hepatic decompensation. Patients with advanced liver disease or cirrhosis may be at higher risk of hepatic decompensation following an exacerbation of hepatitis, and therefore will need to be closely monitored during therapy.

Acute exacerbation of hepatitis has also been reported in patients who had discontinued therapy for hepatitis B (see section 4.2). Post-treatment exacerbations are usually associated with elevated HBV DNA, and most of them are however, severe exacerbations, including deaths, were observed.

Among entecavir-treated patients who never received nucleosides, post-treatment exacerbations had a median of onset of 23 - 24 weeks and most occurred in HBeAG negative patients (see section 4.8). Liver function should be monitored at repeated intervals with clinical and laboratory tests at least every 6 months after discontinuation of hepatitis B therapy. If appropriate, hepatitis B therapy can be resumed.

Patients with decompensated liver disease: A "high rate of serious hepatic adverse events (regardless of causation) was observed in patients with decompensated liver disease, particularly those with Child-Turcotte-Pugh disease (CTP) class C, compared to the percentages found in patients with compensated liver function. In addition, patients with decompensated liver disease may have a higher risk of lactic acidosis and specific renal adverse events such as hepatorenal syndrome. Therefore, clinical and laboratory parameters should be closely monitored in this patient population. (see also sections 4.8 and 5.1).

Lactic acidosis and severe hepatomegaly with steatosis: lactic acidosis (in the absence of hypoxemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, has been reported with the use of nucleoside analogues. Since entecavir is a nucleoside analogue, this risk cannot be excluded. Treatment with nucleoside analogues should be discontinued in the event of elevated aminotransferase levels, progressive hepatomegaly or metabolic / lactic acidosis of unknown aetiology. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, may indicate the development of lactic acidosis. Serious cases, sometimes with fatal outcome, have been associated with pancreatitis, liver failure / fatty liver disease, renal failure and elevated serum lactic acid levels. Care should be taken when administering nucleoside analogues to patients (especially obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease These patients should be followed closely mind.

To differentiate elevations in aminotransferases due to treatment response from those potentially related to lactic acidosis, physicians should ensure that changes in ALT are associated with increases in other laboratory markers of chronic hepatitis B.

Resistance and special precaution for patients refractory to lamivudine: Mutations in HBV polymerase that decode lamivudine resistance substitutions may lead to the subsequent occurrence of secondary substitutions, including those associated with entecavir resistance (ETVr). In a small percentage of lamivudine-refractory patients, ETVr mutations to rtT184, rtS202, or rtM & SUP2; 50, were present at baseline. Patients with lamivudine-resistant HBV are at higher risk of developing subsequent entecavir resistance compared to patients non-lamivudine resistant. The cumulative probability of emergence of entecavir-resistant genotypes after 1, 2, 3, 4 and 5 years of treatment in lamivudine-refractory patient studies was 6%, 15%, 36%, 47% and 51%, respectively. Virological response should be monitored frequently in the refractory population. lamivudine and appropriate resistance testing should be performed In patients with a suboptimal virologic response after 24 sets During treatment with entecavir, treatment adjustment should be considered (see sections 4.5 and 5.1). When initiating therapy in patients with a documented history of lamivudine-resistant HBV, the combined use of entecavir plus a second antiviral agent (which does not show cross-resistance with lamivudine or entecavir) should be preferred over entecavir monotherapy. HBV-lamivudine resistant is associated with an increased risk of subsequent resistance to entecavir regardless of the degree of liver disease; virologic breakthrough may be associated with severe clinical complications of the underlying liver disease in patients with decompensated liver disease. with decompensated liver disease and lamivudine-resistant HBV, the combined use of entecavir plus a second antiviral agent (which does not show cross-resistance with lamivudine or entecavir) should be preferred over entecavir monotherapy.

Pediatric population: A lower virological response rate (HBV DNA

Liver transplantation: Renal function should be carefully evaluated before and during entecavir therapy in liver transplant recipients receiving cyclosporine or tacrolimus (see section 5.2).

Co-infection with hepatitis C or D: There are no data on the efficacy of entecavir in patients co-infected with hepatitis C or D viruses.

Human immunodeficiency virus (HIV) / HBV co-infected patients not receiving concomitant antiretroviral therapy: entecavir has not been evaluated in HIV / HBV co-infected patients not receiving concomitant effective HIV treatment. Onset of HIV resistance has been observed when entecavir was used to treat chronic hepatitis B infection. in HIV infected patients not receiving highly active antiretroviral therapy (HAART) (see section 5.1). Therefore, entecavir therapy should not be used for HIV / HBV co-infected patients who are not being treated with HAART. Entecavir has not been studied for the treatment of HIV infection and is not recommended for this use.

HIV / HBV co-infected patients receiving concomitant antiretroviral therapy: entecavir was studied in 68 HIV / HBV co-infected adults receiving lamivudine-containing HAART (see section 5.1). No data are available on the efficacy of entecavir in HIV-infected HBeAg negative patients. There are limited data on HIV co-infected patients with low CD4 cell counts (cells / mm³).

General: Patients should be advised that entecavir therapy has not been shown to reduce the risk of HBV transmission and therefore adequate precautions should continue to be taken.

Lactose: Each 0.5 mg daily dose of this medicinal product contains 120.5 mg of lactose.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Baraclude oral solution, which does not contain lactose, is available for these individuals.

04.5 Interactions with other medicinal products and other forms of interaction -

Since entecavir is eliminated primarily via the kidneys (see section 5.2), co-administration with medicinal products that reduce renal function or compete with active tubular secretion may increase the serum concentrations of both medicinal products. Apart from lamivudine, adefovir dipivoxil and tenofovir disoproxil fumarate, the effects of co-administration of entecavir with medicinal products that are eliminated via the kidney or affect renal function have not been evaluated. Patients should be closely monitored for undesirable effects that may arise during co-administration of entecavir with such medicinal products.

No pharmacokinetic interactions were observed between entecavir and lamivudine, adefovir or tenofovir.

Entecavir is not a substrate, inducer or inhibitor of cytochrome P450 (CYP450) enzymes (see section 5.2). Drug interactions carried by CYP450 are therefore unlikely to occur with entecavir.

Pediatric population

Interaction studies have only been performed in adults.

04.6 Pregnancy and breastfeeding -

Women of childbearing potential: As the potential risks to fetal development are unknown, women of childbearing potential should use effective contraception.

Pregnancy: There are no adequate studies regarding the use of entecavir in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3).

The potential risk for humans is unknown. Baraclude should not be used during pregnancy unless clearly necessary. There are no data on the effects of entecavir on HBV transmission from mother to neonate. Therefore, appropriate action should be taken to prevent neonatal acquisition of HBV.

Feeding time: it is not known whether entecavir is excreted in human milk. Available toxicological data in animals have shown excretion of entecavir in breast milk (for details see section 5.3). A risk to children cannot be excluded. Breastfeeding should be discontinued during Baraclude therapy.

Fertility: Toxicology studies in animals administered entecavir have shown no evidence of loss of fertility (see section 5.3).

04.7 Effects on ability to drive and use machines -

No studies on the ability to drive and use machines have been performed. Dizziness, fatigue and somnolence are common side effects that may impair the ability to drive and use machines.

04.8 Undesirable effects -

to. Summary of the safety profile

In clinical studies in patients with compensated liver disease, the most common adverse reactions of any severity, with at least one possible relationship to entecavir, were: headache (9%), fatigue (6%), dizziness (4%) and nausea ( 3%). Exacerbation of hepatitis has been reported during and after discontinuation of entecavir therapy (see section 4.4 c. Description of selected adverse reactions).

b. List of adverse reactions

Assessment of adverse reactions is based on postmarketing surveillance experience and on four clinical studies in which 1,720 patients with chronic hepatitis B virus infection and compensated liver disease were treated in a double-blind manner with entecavir (n = 862) or lamivudine. (n = 858) up to 107 weeks (see section 5.1). In these studies, the safety profiles, including changes in laboratory parameters, were similar for entecavir 0.5 mg once daily (679 nucleoside-naïve HBeAg positive or negative patients for a median of 53 weeks), entecavir 1 mg once daily (183 lamivudine-refractory patients treated for a median of 69 weeks) and lamivudine.

Adverse reactions considered at least possibly related to entecavir treatment are listed by system organ class. Frequency is defined as very common (≥ 1/10); common (≥ 1/100 to

Disorders of the immune system: rare: anaphylactoid reaction

Psychiatric disorders: common: insomnia

Nervous system disorders: common: headache, dizziness, somnolence

Gastrointestinal disorders: common: vomiting, diarrhea, nausea, dyspepsia

Hepatobiliary disorders common: elevation of transaminases

Skin and subcutaneous tissue disorders: uncommon: rash, alopecia

General disorders and administration site conditions: common: fatigue

Cases of lactic acidosis, often associated with hepatic decompensation, other serious medical conditions or drug exposure, have been reported (see section 4.4).

Treatment beyond 48 weeks: Continued entecavir treatment for a median duration of 96 weeks showed no new safety signals.

c. Description of selected adverse reactions

Laboratory Test Abnormalities: In clinical trials in nucleoside-naïve patients 5% had ALT elevations> 3-fold of baseline and 2-fold of patients from baseline along with total bilirubin> 2-fold limits higher than normal (Upper Limit of Normal, ULN) and> 2 times the baseline values. Albumin amylase levels> 3 times baseline in 2%, lipase levels> 3 times baseline in 11% and platelets

In clinical studies in lamivudine-refractory patients, 4% had ALT elevations> 3-fold of baseline and a 2-fold percentage of baseline along with total bilirubin> 2-fold upper limit of normal and> 2 times compared to baseline values. Amylase levels> 3 times baseline occurred in 2% of patients, lipase levels> 3 times baseline in 18% and platelets

On-treatment flare-ups: In studies of nucleoside-naïve patients, ALT elevations> 10 times ULN and> 2 times baseline occurred during treatment in 2% of entecavir-treated patients versus 4. % of patients treated with lamivudine. In studies of lamivudine-refractory patients, ALT elevations> 10 times ULN and> 2 times baseline occurred during treatment in 2% of entecavir-treated patients versus 11% of patients treated with lamivudine. Among entecavir-treated patients, ALT elevations during treatment had a mean time to elevation of 4 to 5 weeks, generally resolved on continued treatment and, in the majority of cases, were associated with decreased viral load ≥ 2 log10 / ml which preceded or coincided with the ALT elevation. During treatment, periodic monitoring of liver function is recommended.

Exacerbations after discontinuation of treatment: Acute exacerbations of hepatitis have been reported in patients who discontinued treatment for hepatitis B virus, including entecavir therapy (see section 4.4). nucleosides, 6% of entecavir-treated patients and 10% of lamivudine-treated patients experienced ALT elevations (> 10 times the ULN and> 2 times the reference values ​​[trough values ​​at baseline or measurements at "last dose administered]) during post-treatment follow-up. Among the nucleoside-naïve patients treated with entecavir, ALT elevations had a mean time to elevation of 23 - 24 weeks, and 86% (24/28) of ALT elevations occurred in HBeAg negative patients. studies in lamivudine-refractory patients, only a limited number of patients had follow-up, 11% of entecavir-treated patients and none of lamivudine-treated patients developed ALT elevations during post-treatment follow-up.

In clinical studies, entecavir treatment was stopped if patients achieved a prespecific response. If treatment is stopped regardless of response to therapy, the rate of ALT elevations after treatment may be higher.

d. Pediatric population

The safety of entecavir in pediatric patients 2 to 8 years of age is based on two ongoing clinical trials in chronically infected subjects with HBV; a Phase 2 pharmacokinetic study (study 028) and a Phase 3 study (study 189). These studies involved 173 HBeAg positive subjects who had never been treated with nucleosides before and were treated with entecavir for a mean duration of 60 weeks. Adverse reactions observed in pediatric subjects who were treated with entecavir were consistent with those observed in clinical trials of entecavir in adults (see a Summary of the safety profile and section 5.1).

And. Other special populations

Experience in patients with decompensated liver disease: The safety profile of entecavir in patients with decompensated liver disease was evaluated in a randomized, open-label comparative study in which patients were treated with entecavir 1 mg / day (n = 102) o adefovir dipivoxil 10 mg / day (n = 89) (study 048). Compared to the adverse reactions reported in the section b. List of adverse reactions, an "additional adverse reaction [decrease in blood bicarbonate (2%)] was observed in patients treated with entecavir up to week 48. The cumulative mortality rate over the course of the study was 23% (23/102), and causes of death were generally related to the liver, as expected in this population. The cumulative rate of hepatocellular carcinoma (HCC) over the course of the study was 12% (12/102). Serious adverse events were generally related liver, with a cumulative frequency of 69% over the course of the study Patients with a high CTP score at baseline had an increased risk of developing serious adverse events (see section 4.4).

Abnormal laboratory tests: Among patients with decompensated liver disease treated with entecavir up to week 48, none had ALT elevations> 10 times upper limit of normal (ULN) and> 2 times baseline, el "1% of patients had ALT elevations> 2 times baseline along with total bilirubin> 2 times upper limit of normal (ULN) and> 2 times baseline. Albumin levels 3 times baseline. basal values ​​in 10% and platelets

Experience in HIV co-infected patients: The safety profile of entecavir in a limited number of HIV / HBV co-infected patients undergoing HAART (highly active antiretroviral therapy) treatment was similar to the safety profile of monoinfected patients. with HBV (see section 4.4).

Gender / age: There was no apparent difference in the safety profile of entecavir with respect to gender (≈ 25% women in clinical trials) or age (≈ 5% of patients> 65 years of age).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

04.9 Overdose -

There are limited reports of entecavir overdose in patients. Healthy subjects who received up to 20 mg / day for 14 days and single doses up to 40 mg had no unexpected adverse reactions. In the event of an overdose, the patient should be monitored for signs of toxicity and given appropriate standard supportive treatment.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: antivirals for systemic use, nucleosides and nucleotides reverse transcriptase inhibitors

ATC code: J05AF10

Mechanism of action: entecavir, a nucleoside analogue of guanosine active against HBV polymerase, is efficiently phosphorylated into the active triphosphate (TP) form, which has an intracellular half-life of 15 hours. Competing with the natural substrate deoxyguanosine TP, entecavir-TP functionally it inhibits the 3 activities of viral polymerase: priming of HBV polymerase, reverse transcription of the negative strand of DNA starting from the pregemonic messenger RNA and synthesis of the positive strand of HBV DNA. The Ki of entecavir-TP for HBV DNA polymerase is 0.0012 mcM. Entecavir-TP is a weak inhibitor of cellular DNA polymerase α, β and δ with Ki values ​​of 18 to 40 mcM. Furthermore, high entecavir exposures do not have significant adverse effects on γ polymerases or mitochondrial DNA synthesis on HepG2 cells (Ki> 160 mcM).

Antiviral activity: entecavir inhibited HBV DNA synthesis (50% reduction, EC50) at a concentration of 0.004 μM in human HepG2 cells transinfected with wild-type HBV. The median EC50 value for entecavir versus LVDr HBV (rtL 180M and rtM204V) was 0.026 μM (range 0.010 - 0.059 μM) Recombinant viruses with adefovir-resistant substitutions rtN236T or rtA181V remained fully susceptible to entecavir.

An analysis of entecavir inhibitory activity against a laboratory panel and HIV-1 clinical isolates performed using different cells and methods produced EC50 values ​​ranging from 0.026 to> 10 μM; the lowest EC50 values ​​were observed when in the test Low levels of virus were used. In cell culture, entecavir selected an M184I substitution at micromolar concentrations confirming the inhibitory pressure of entecavir at high concentrations. HIV variants containing the M184V substitution showed loss of susceptibility to entecavir (see section 4.4 ).

In the HBV combination assay in cell culture, abacavir, didanosine, lamivudine, stavudine, tenofovir or zidovudine were not antagonists of the anti-HBV activity of entecavir over a large percentage of concentrations. In the HIV antiviral assay, entecavir at micromolar concentrations was not antagonist to anti-HIV activity in cell culture of these six NRTIs or emtricitabine.

Resistance in cell culture: relative to wild-type HBV, the LVDr viruses containing the substitutions rtM204V and rtL180M within the reverse transcriptase show an 8-fold decrease in susceptibility to entecavir. The incorporation of further amino acid substitutions rtT184, rtS202 and / or rtM250 causes decreased susceptibility to entecavir in cell culture. The substitutions observed in clinical isolates (rtT184A, C, F, G, I, L, M or S; rtS202 C, G or I; and / or rtM250I , L or V) resulted in a further 16- to 741-fold decrease in entecavir susceptibility compared to wild-type virus. The single ETVr (entecavir resistance) substitutions rtT184, rtS202 and rtM250 have only a modest effect on entecavir susceptibility and were not observed in the absence of LVDr substitutions (lamivudine resistance) in more than 1000 patient samples. Resistance is mediated by reduced inhibitory binding to impaired inv ersa of HBV and resistant HBV exhibit reduced replication capacity in cell culture.

Clinical Experience: Demonstration of benefit is based on histological, virological, biochemical and serological responses after 48 weeks of treatment in active controlled clinical trials of 1,633 adults with chronic hepatitis B infection, evidence of viral replication and compensated liver disease. The safety and efficacy of entecavir were also evaluated in a controlled clinical study in 191 HBV infected patients with decompensated liver disease and in a clinical study in 68 HBV and HIV co-infected patients.

In studies in patients with compensated liver disease, histological improvement defined as ≥ 2-point reduction in Knodell necro-inflammatory index from baseline without worsening in Knodell fibrosis score. Responses for patients with baseline one Knodell fibrosis scores of 4 (cirrhosis) were comparable with all responses on all efficacy measures (all patients had compensated liver disease). High baseline Knodell histological activity index (HAI) scores (> 10) were associated with greater histological improvement in nucleoside-naïve patients. Baseline ALT levels ≥ 2 times the baseline in nucleoside-naïve HBeAg positive patients upper limit of normal and baseline HBV DNA ≤ 9.0 log 10 copies / mL were both associated with high rates of virologic response (week 48 HBV DNA

Experience in nucleoside-naïve patients with compensated liver disease: The results of 48-week randomized, double-blind, trials comparing entecavir (ETV) and lamivudine (LVD) in HBeAg positive and HBeAg negative patients are shown in the table below:

Never treated with nucleosides HBeAg Positive (study 022) HBeAg Negative (study 027) ETV 0.5 mg once daily LVD 100 mg once daily ETV 0.5 mg once daily LVD 100 mg once daily n 314a 314a 296a 287a Histological improvement b 72%* 62% 70%* 61% Improvement of the Ishak score for fibrosis 39% 35% 36% 38% Worsening of Ishak's score for fibrosis 8% 10% 12% 15% n 354 355 325 313 Viral load reduction (log copies / ml) c -6,86* -5,39 -5,04* -4,53 HBV DNA undetectable (PCR) c 67%* 36% 90%* 72% ALT normalization (≤ 1 times ULN) 68%* 60% 78%* 71% Seroconversion of HBeAg 21% 18%

* p-value vs lamivudine

patients with evaluable histology at baseline (baseline Knodell Necroinflammatory Score ≥ 2)

b primary goal

cRoche Cobas Amplicor PCR Assay (LLOQ = 300 copies / mL)

Experience in patients refractory to lamivudine with compensated liver disease: In a double-blind, randomized study of lamivudine-refractory HBeAg positive patients, with 85% of patients with LVDr mutations at baseline, patients taking lamivudine at study entry were switched to entecavir 1 mg once daily, with no washout or overlap period (n = 141), or continued with lamivudine 100 mg once daily (n = 145). The results at 48 weeks are shown in the table below.

Lamivudine refractories HBeAg positive (study 026) ETV 1.0 mg once daily LVD 100 mg once daily n 124a 116a Histological improvement b 55%* 28% Improvement of the Ishak score for fibrosis 34%* 16% Worsening of Ishak's score for fibrosis 11% 26% n 141 145 Viral load reduction (log copies / ml) c -5,11* -0,48 Untraceable HBV DNA ( 19%* 1% normalization of ALT (≤ 1 times ULN) 61%* 15% Seroconversion of HBeAg 8% 3%

* p-value vs lamivudine

patients with evaluable histology at baseline (baseline Knodell Necroinflammatory Score ≥ 2)

b primary goal

cRoche Cobas Amplicor PCR Assay (LLOQ = 300 copies / mL)

Results beyond 48 weeks of treatment:

Treatment was discontinued when prespecific response criteria were met at 48 weeks or during the second year of therapy. The response criteria were the virological suppression of HBV (HBV DNA

Patients never treated with nucleosides:

HBeAg positive (study 022): treatment with entecavir for up to 96 weeks (n = 354) resulted in a cumulative response rate of 80% for HBV DNA

At the end of dosing, among patients who continued treatment beyond 52 weeks (median of 96 weeks), 81% of the 243 entecavir-treated patients and 39% of the 164 lamivudine-treated patients had HBV DNA.

HBeAg negative (study 027): Treatment with entecavir up to 96 weeks (n = 325) resulted in a cumulative response rate of 94% for HBV DNA

For the 26 entecavir-treated and 28 lamivudine-treated patients who continued treatment beyond 52 weeks (median of 96 weeks), 96% of entecavir-treated patients and 64% of lamivudine-treated patients at the end of dosing they had HBV DNA

For patients who responded to the protocol, the response criterion was maintained for up to 24 weeks of follow-up after treatment in 75% (83/111) of those who responded to entecavir treatment towards 73. % (68/93) of those who responded to lamivudine treatment in study 022 and 46% (131/286) of those who responded to entecavir versus 31% (79/253) of those who responded to lamivudine treatment in study 027. Within 48 weeks of follow-up after the end of treatment, a substantial number of HBeAg negative patients lost response.

Liver biopsy results: 57 patients from pivotal studies conducted in nucleoside-naïve patients 022 (HBeAg positive) and 027 (HBeAg negative), enrolled in a study of rollover long-term, they were evaluated on long-term hepatic histological outcomes. In the pivotal studies, entecavir dosing was 0.5 mg per day (mean exposure 85 weeks) and in the pivotal study rollover of 1 mg per day (mean exposure 177 weeks) and initially 51 patients in the study rollover they also received lamivudine (median duration of 29 weeks). Of these patients, 55/57 (96%) had histological improvement as defined above (see above) and 50/57 (88%) had decreased Ishak fibrosis score ≥ 1 point. Among patients with Ishak fibrosis score ≥ 2 at baseline, 25/43 (58%) showed a decrease of ≥ 2 points. All patients (10/10) with baseline fibrosis or advanced cirrhosis (Ishak fibrosis score of 4, 5, or 6) had a decrease of ≥ 1 point (median decrease from baseline was 1, 5 points). At the time of long-term biopsy, all patients had HBV DNA

Refractories to lamivudine:

HBeAg positive (study 026): Treatment with entecavir for up to 96 weeks (n = 141) resulted in a 30% cumulative rate of response for HBV DNA serum HBeAg conversion.

For the 77 patients who continued entecavir treatment beyond 52 weeks (median of 96 weeks), 40% of patients experienced HBV DNA

Age / gender:

There was no apparent difference in efficacy for entecavir with regard to differences in gender (≈ 25% women in clinical trials) or age (≈ 5% of patients> 65 years).

Special populations

Patients with decompensated liver disease: In study 048, 191 patients with HBeAg positive or negative chronic HBV infection and with evidence of hepatic decompensation, defined as a CTP score of 7 or greater, received entecavir 1 mg once daily or adefovir dipivoxil 10 mg once daily. day. Patients had never received HBV treatment or had already been pretreated (excluding pretreatment with entecavir, adefovir dipivoxil or tenofovir disoproxil fumarate). At baseline, patients had a mean CTP score of 8.59 and 26% of patients were CTP class C. The mean Model for End Stage Liver Disease (MELD) score at baseline was 16.23. The mean serum HBV DNA concentration by PCR was 7.83 log 10 copies / mL and the mean serum ALT concentration was 100 U / L; 54% of patients were HBeAg positive, and 35% of patients had LVDr substitutions at the Entecavir was superior to adefovir dipivoxil in the primary efficacy endpoint evaluating mean changes from baseline in serum HBV DNA concentration by PCR at week 24. Results from selected study endpoints at weeks 24 and 48 are shown in table.

Week 24 Week 48 ETV 1 mg once daily Adefovir Dipivoxil 10 mg once daily ETV 1 mg once daily Adefovir Dipivoxil 10 mg once daily n 100 91 100 91 HBV DNAa Percentage of patients with undetectable viraemia ( 49%* 16% 57%* 20% Mean changes from baseline (log copies / mL) c -4,48* -3,40 -4,66 -3,90 Stable or improved CTP scoreb, d 66% 71% 61% 67% MELD score Mean changes from baseline c, e -2,0 -0,9 -2,6 -1,7 Loss of HBsAg b 1% 0 5% 0 Dif normalization: ALT (≤1 X ULN) b 46/78 (59%)* 28/71 (39%) 49/78 (63%)* 33/71 (46%) Albumin (≥1 X LLN) b 20/82 (24%) 14/69 (20%) 32/82 (39%) 20/69 (29%) Bilirubin (≤1 X ULN) b 12/75 (16%) 10/65 (15%) 15/75 (20%) 18/65 (28%) Prothrombin time (≤1 X ULN) b 9/95 (9%) 6/82 (7%) 8/95 (8%) 7/82 (9%)

a Roche COBAS Amplicor PCR Assay (LLOQ = 300 copies / mL).

bNC = F (patient who did not complete = failure), means that the treatment was stopped before the analysis week, including reasons such as death, lack of efficacy, adverse events, lack of adherence / loss to follow-up, considered as failures (e.g. HBV DNA ≥ 300 copies / mL)

cNC = M (patients not completed = missing)

d Defined as a reduction or no change from baseline in the CTP score

eMean MELD score at baseline was 17.1 for ETV and 15.3 for adefovir dipivoxil.

f The denominator is the number of patients with abnormal values ​​at baseline.

* p

ULN = upper limit of the norm, LLN = lower limit of the norm.

The time to onset of HCC or death (whichever occurred first) was comparable in the two treatment groups; cumulative mortality rates over the course of the study were 23% (23/102) and 33% (29/89) for entecavir and adefovir dipivoxil treated patients, respectively, and the cumulative HCC rates over the course of the study were 12% (12/102) and 20% (18/89) for entecavir and adefovir dipivoxil, respectively.

For patients with baseline LVDr replacements, the percentage of patients with HBV DNA

HIV / HBV co-infected patients concurrently treated with HAART: Study 038 included 67 HBeAg positive and 1 HBeAg negative patients co-infected with HIV. Patients exhibited stable, controlled HIV (HIV RNA placebo (n = 17) for 24 weeks followed by an additional 24 weeks where all patients were given entecavir. At 24 weeks, the reduction in HBV viral load was significantly greater. with entecavir (-3.65 vs an increase of 0.11 log10 copies / ml). For patients originally assigned to entecavir treatment, the reduction in HBV DNA at 48 weeks was -4.20 log10 copies / ml, the ALT normalization appeared in 37% of patients with baseline ALT abnormalities and none achieved HBeAg seroconversion.

HIV / HBV co-infected patients not concomitant with HAART therapy: entecavir has not been evaluated in HIV / HBV co-infected patients not receiving concomitant effective HIV treatment. Reductions in HIV RNA have been reported in HIV / HBV co-infected patients receiving entecavir monotherapy without HAART . In some cases, selection of the HIV variant M184V has been observed which may have implications for the selection of HAART regimens the patient may take in the future. Therefore, entecavir should not be used in this type of population due to the potential for development of resistance to HIV (see section 4.4).

Liver transplantation: The safety and efficacy of entecavir 1 mg once daily were evaluated in a single-arm study in 65 patients who received liver transplantation for complications of chronic HBV infection and showed Caucasian and 37% Asian HBV DNA, with age mean 49 years: 89% of patients were HBeAg-negative at the time of transplant. Of the 61 patients evaluable for efficacy (they received entecavir for at least 1 month), 60 also received hepatitis B immunoglobulin (HBIg) as part of the post-transplant prophylaxis regimen. Of these 60 patients, 49 received HBIg therapy for more than 6 months. At week 72 post-transplant, none of the 55 cases observed showed reactivation of viral replication [defined as HBV DNA ≥ 50 IU / ml (approximately 300 copies / ml)], and no virological reactivation of HBV was reported in the remaining 6 excluded patients. All 61 patients showed post-transplant HBsAg loss, and 2 of these became HBsAg positive while maintaining undetectable levels of HBV DNA (

Pediatric population: Study 189 is an ongoing study based on the efficacy and safety of entecavir, involving 180 children and adolescents, 2 to 18 years of age, previously untreated with nucleosides and suffering from chronic hepatitis B with HBeAg positive, compensated liver disease, and elevated ALT levels. Subjects were randomized (2: 1) to receive blinded entecavir treatment from 0.015 mg / kg to 0.5 mg / day (N = 120) or placebo. (N = 60). Randomisation was stratified by age group (2 to 6 years;> 6 to 12 years; and> 12 to

24% (20/82) of subjects in the entecavir group and 2% (1/41) of subjects in the placebo group met the main endpoint. At 48 weeks, 46% (38 / 82) of subjects receiving entecavir and 2% (1/41) of subjects receiving placebo achieved HBV DNA values

In the 2 pediatric studies (study 028 and 189), 110 patients who had received entecavir for up to 48 weeks were monitored for resistance. Genotypic evaluations were performed on all patients who had virologic breakthrough, or HBV DNA ≥ 50 IU / mL at 48 weeks or who had discontinued therapy early. No amino acid substitution associated with entecavir resistance was identified.

Clinical Resistance: Patients initially treated in clinical trials with entecavir 0.5 mg (nucleoside-naïve) or 1.0 mg (lamivudine-refractory) and with a 24-week HBV DNA measurement by PCR during therapy or thereafter, they were monitored for resistance. In clinical studies up to 240 weeks, in nucleoside naïve patients, genotypic evidence of ETVr substitutions in rtT184, rtS202 or rtM250 was identified in 3 of the patients receiving entecavir , 2 of which also had virologic breakthrough (see table). These substitutions were observed only in the presence of LVDr substitutions (rtM204V and rtL180M).

Emergence of genotypic resistance to entecavir for 5 years in studies of nucleoside-naïve patients Year 1 Year 2 Year 3a Year 4a Year 5a Patients treated and monitored for resistance b 663 278 149 121 108 Patients / year with: - emergence of genotypic resistance to ETVc 1 1 1 0 0 - ETVcgenotypic with virological breakthrough 1 0 1 0 0 Cumulative probability of: - emergence of genotypic resistance to ETVc 0,2% 0,5% 1,2% 1,2% 1,2% - ETVcgenotypic with virological breakthrough 0,2% 0,2% 0,8% 0,8% 0,8%

a The results reflect the use of a 1mg dose of entecavir for 147 of 149 patients at year 3, for all patients at year 4 and 5 and combined entecavir-lamivudine therapy (followed by long-term therapy with entecavir) for a median of 20 weeks for 130 of 149 patients in year 3 and for 1 week for 1 of 121 patients in year 4 in the rollover study.

b Includes patients with at least one on-treatment HBV DNA measurement by PCR at 24 weeks or up to 58 weeks (Year 1), after 58 weeks up to 102 weeks (Year 2), after 102 weeks up to 156 weeks ( Year 3), after 156 weeks to 204 weeks (Year 4) or after 204 weeks to 252 weeks (Year 5).

cPatients who have also had LVDr replacements.

increase ≥ 1 log10 above the nadir in HBV DNA by PCR, confirmed with subsequent measurements or at the end of the windowed time point.

ETVr substitutions (in addition to LVDr rtM204V / I ± rtL180M substitutions) were observed at baseline in isolates from 10/187 (5%) lamivudine-refractory patients treated with entecavir and monitored for resistance, indicating that previous lamivudine treatment can select these resistance substitutions and that they may exist at a low frequency prior to entecavir treatment. During 240 weeks, 3 of 10 patients experienced virologic rebound (≥ 1 log10 increase above nadir). The onset of resistance to entecavir in lamivudine-refractory patient studies during 240 weeks is summarized in the table below.

Emergence of genotypic resistance to entecavir during 5 years in studies of patients refractory to lamivudine Year 1 Year 2 Year 3a Year 4a Year 5a Patients treated and monitored for resistance b 187 146 80 52 33 Patients / year with: - emergence of genotypic resistance to ETVc 11 12 16 6 2 - genotypic resistance to ETVc with virological breakthrough d 2e 14e 13e 9e 1e Cumulative probability of: - emergence of genotypic resistance to ETVc 6,2% 15% 36,3 46,6 51,45% - genotypic resistance to ETVc with virological breakthrough d 1.1% e 10.7% e 27% e 41.3% e 43.6% e

a Results reflect use of entecavir-lamivudine combination therapy (followed by long-term entecavir therapy) for a median of 13 weeks for 48 of 80 patients in the 3-year study, a median of 38 weeks for 10 of 52 patients in the 4-year and 16-week study for 1 of 33 patients in the 5-year rollover study.

b Includes patients with at least one on-treatment HBV DNA measurement by PCR at or after 24 weeks to 58 weeks (Year 1), after 58 weeks to 102 weeks (Year 2), after 102 weeks to 156 weeks ( Year 3), after 156 weeks to 204 weeks (Year 4) or after 204 weeks to 256 weeks (Year 5).

cPatients who have also had LVDr replacements.

increase ≥ 1 log10 above the nadir in HBV DNA by PCR, confirmed with subsequent measurements or at the end of the windowed time point.

eEmergence of resistance to ETV every year; virological rebound / year.

Among lamivudine-refractory patients with HBV DNA

05.2 "Pharmacokinetic properties -

Absorption: entecavir is rapidly absorbed with peak plasma concentrations between 0.5 and 1.5 hours. Absolute bioavailability has not been determined. Based on urinary excretion of unchanged drug, bioavailability is estimated to be at least 70%. Following multiple dosing of 0.1 to 1 mg, there is a proportionate increase in Cmax and AUC values. Steady state is achieved between 6 and 10 days after once daily dosing with ≈ 2 times the accumulation time. Steady-state Cmax and Cmin are 4.2 and 0.3 ng / mL for the 0.5 mg dose and 8.2 and 0.5 ng / mL for the 1 mg dose, respectively. The tablet and oral solution were equivalent in healthy subjects; therefore, both pharmaceutical forms can be interchanged.

Administration of 0.5 mg entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in minimal delay in absorption (1 - 1.5 hours on a full stomach vs 0.75 hours on an empty stomach), a decrease in Cmax of 44 - 46% and a decrease in AUC of 18 - 20%. Lowering Cmax and AUC with food is not considered to be of clinical relevance in nucleoside-naïve patients but may affect efficacy in lamivudine-refractory patients (see section 4.2).

Distribution: Estimated volume of distribution for entecavir is in excess of total body water. Plasma binding to human serum proteins in vitro è ≈ 13%.

Biotransformation: entecavir is not a substrate, inhibitor or inducer of the CPYP450 enzyme system. Following administration of 14C-entecavir, no oxidative or acetylated metabolites and minor amounts of phase II metabolites, glucuronide and its sulfate conjugates were observed.

Elimination: entecavir is eliminated predominantly by the kidney with urinary recovery of unchanged drug at steady-state of approximately 75% of the dose. Renal clearance is dose independent and ranges from 360 to 471 mL / min suggesting that entecavir undergoes both glomerular filtration and distinct tubular secretion. After reaching peak levels, entecavir plasma concentration decreased bi-exponentially with a terminal elimination half-life of ≥ 128 - 149 hours. The observed accumulation index of the drug is ≈ 2 times with single daily dosing, suggesting an effective accumulation half-life of approximately 24 hours.

Liver diseases: Pharmacokinetic parameters in patients with moderate to severe liver disease are similar to those in patients with normal liver function.

Kidney failure: Entecavir clearance decreases with decreasing creatinine clearance. In a 4-hour hemodialysis session ≈ 13% of the dose was removed and 0.3% was removed by CAPD. The pharmacokinetic data of entecavir following a single 1 mg dose (in patients without chronic hepatitis B infection) are shown in the table below:

Baseline Creatinine Clearance (mL / min) Intact> 80 Mild> 50; ≤ 80 Moderate 30-50 Severe 20- Severe treated with hemodialysis Severe treated with CAPD (n = 6) (n = 6) (n = 6) (n = 6) (n = 6) (n = 4) Cmax (ng / ml) (CV%) 8,1 10,4 10,5 15,3 15,4 16,6 AUC (0-T) (ng h / ml) 27,9 51,5 69,5 145,7 233,9 221,8 (CV) CLR (ml / min) 383,2 197,9 135,6 40,3 NA NA (SD) CLT / F (ml / min) 588,1 309,2 226,3 100,6 50,6 35,7 (SD)

Liver transplantation: Entecavir exposure in HBV infected patients who underwent hepatic transplantation receiving a stable dose of cyclosporin A or tacrolimus (n = 9) was ≥ 2 times the exposure in healthy subjects with normal renal function. Impaired renal function contributed to the increase in entecavir exposure in these patients (see section 4.4).

Sex: AUC was 14% higher in women than in men, due to differences in renal function and weight. After adjustments in differences in creatinine clearance and body weight there were no differences in exposure between males. and females.

Senior citizens: The effect on age in entecavir pharmacokinetics was evaluated by comparing elderly subjects with an age range of 65 to 83 years (mean age in females 69 years, in males 74) with young subjects in the age range of 20 and 40 years (mean age in females 29 years, in males 25). The AUC was 29% higher in elderly than in young subjects, mainly due to differences in renal function and weight. After adjustments for differences in creatinine clearance and body weight, elderly subjects showed a higher AUC. high by 12.5% ​​of young subjects. Population pharmacokinetic analysis including patients aged 16 to 75 years did not demonstrate that age significantly affects entecavir pharmacokinetics.

Race: The population pharmacokinetic analysis did not demonstrate that race significantly affects entecavir pharmacokinetics. However, conclusions can only be drawn for the Caucasian and Asian groups as there were too few subjects from other categories.

Pediatric population: The pharmacokinetic steady-state phases of entecavir were evaluated (study 028) in HBeAg positive pediatric subjects, 2 to 18 years of age, with compensated liver disease of which 24 were never treated with nucleosides and 19 were previously treated with lamivudine. Entecavir exposure among nucleoside-naïve subjects receiving an entecavir daily dose of 0.015 mg / kg up to a maximum of 0.5 mg was similar to the exposure achieved in adults receiving a daily dose of 0.5. mg. The Cmax, AUC (0-24), and Cmin in these subjects were 6.31 ng / mL, 18.33 ng h / mL, and 0.28 ng / mL, respectively.

Entecavir exposure in subjects previously treated with lamivudine and receiving an entecavir daily dose of 0.030 mg / kg up to a maximum dose of 1.0 mg was similar to the exposure achieved in adults receiving a 1.0 mg daily dose. The Cmax, AUC (0-24), and Cmin in these subjects were 14.48 ng / mL, 38.58 ng h / mL, and 0.47 ng / mL, respectively.

05.3 Preclinical safety data -

In repeated dose toxicology studies in dogs, "reversible perivascular inflammation of the central nervous system was observed. However, this inflammation was not detected at doses 9 and 10 times higher than those in humans (when administering doses of 0.5 and 1 mg) This effect did not occur in repeat dose studies in other species, including monkeys treated with entecavir daily for 1 year at doses ≥ 100 times the doses administered in humans.

In reproductive toxicology studies where animals were given entecavir for 4 weeks, no loss of fertility was observed in male or female rats at high doses. Changes to the testes (seminiferous tubular degeneration) have been observed in repeated dose toxicology studies in rodents and dogs at doses ≥ 26 times the doses administered in humans. Changes in the testes were not observed in a 1-year monkey study. In pregnant rats and rabbits administered entecavir, no actual level of embryotoxicity or maternal toxicity corresponded to doses ≥ 21 times the doses administered in humans. At high doses, the following effects were observed in rats: maternal toxicity, embryo-fetal toxicity (resorption), reductions in fetal body weight, malformations of the

tail and vertebrae, reduced ossification (of the vertebrae, sternebras, and phalanges), and extra lumbar vertebrae. At high doses, the following effects were observed in rabbits: embryo-fetal toxicity (resorption), reduced ossification (of the hyoid bone), an increase in cases of the 13th rib. In a peri-post natal study in rats this was not No adverse events were observed in the offspring. In a separate study in which entecavir was administered at a dose of 10 mg / kg to pregnant and lactating female rats, both fetal exposure to entecavir and secretion of entecavir in milk were observed. . In juvenile rats treated with entecavir from the fourth to the eightieth day postnatally, a moderately reduced response to acoustic stimuli was observed during the recovery period (110-114 postnatal days) but not during the administration period at AUC values ​​≥ 92 times higher than those in humans at a dose of 0.5 mg or an equivalent pediatric dose. Given the margin of exposure, this finding is considered to be of unlikely clinical relevance.

Genotoxicity was not observed with either the Ames microbial mutagenicity test, the mammalian cell gene mutation test, or the Syrian hamster embryonic cell transformation test. Both a micronucleus study and a DNA repair study in rats were negative. Entecavir was clastogenic in human lymphocyte cultures at concentrations substantially higher than those achieved in the clinical setting.

In the two-year carcinogenicity studies: in male mice, an increase in cases of lung tumors, at doses ≥ 4 and ≥ 2 times the doses in humans, at doses of 0.5 mg and 1 mg, respectively. The development of the tumor was preceded by proliferation of pneumocytes in the lung, which was however not observed in rats, dogs or monkeys, suggesting that the key event in the development of lung cancer in mice is probably species-specific. The following effects were observed with administration for long periods of time: an increase in cases of other types of tumors including brain glioma in male and female rats, liver cancer in male mice, benign vascular tumors in female mice and adenomas and carcinomas of the liver in female rats. However, no precise effect on levels can be established. The predictivity of such observations in humans is unknown.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Tablet core:

crospovidone

lactose monohydrate

magnesium stearate

microcrystalline cellulose

povidone

Tablet coating:

titanium dioxide

hypromellose

macrogol 400

Polysorbate 80 (E433)

06.2 Incompatibility "-

Not relevant.

06.3 Period of validity "-

2 years

06.4 Special precautions for storage -

Blister:

Do not store above 30 ° C. Store in the original box.

Bottles:

Do not store above 25 ° C. Keep the bottle tightly closed.

06.5 Nature of the immediate packaging and contents of the package -

Each box contains:

§ 30 x 1 film-coated tablet; 3 blisters of 10 x 1 film-coated tablet, each Alu / Alu perforated unit dose blister, or:

§ 90 x 1 film-coated tablet; 9 blisters of 10 x 1 film-coated tablet, each Alu / Alu perforated unit dose blister

High density polyethylene (HDPE) bottle with polypropylene child resistant closure, containing 30 film-coated tablets. Each box contains one bottle.

Not all pack sizes and container types may be marketed.

06.6 Instructions for use and handling -

Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

BRISTOL-MYERS SQUIBB PHARMA EEIG

Uxbridge Business Park

Sanderson Road

Uxbridge UB8 1DH

UK

08.0 MARKETING AUTHORIZATION NUMBER -

Blister: EU / 1/06/343/003

037221076

EU / 1/06/343/006

Bottle: EU / 1/06/343/001

037221052

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

Date of first authorization: 26 June 2006

Date of last renewal: June 26, 2011

10.0 DATE OF REVISION OF THE TEXT -

D.CCE August 2014

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -

none:  bone-health oils-and-fats nutrition