Drugs List

Therapeutic Indications

Uses

Hepatitis B - chronic active

Treatment of chronic hepatitis B virus (HBV) infection in adults with compensated hepatic disease and evidence of active viral replication, persistently elevated alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.

Treatment of chronic hepatitis B virus infection in adults with decompensated liver disease.

Treatment of chronic HBV infection in nucleoside naive paediatric patients from 2 to less than 18 years of age with compensated liver disease who have evidence of active viral replication and persistently elevated serum ALT levels, or histological evidence of moderate to severe inflammation and/or fibrosis.

Clinical trials with entecavir included nucleoside naive patients with HBeAg positive and HBeAg negative hepatitis B infection, and patients with lamivudine-refractory hepatitis B.

Contraindications

Children under 2 years
Breastfeeding

Precautions and Warnings

Females of childbearing potential
Predisposition to hepatic disorder
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic cirrhosis
Hepatitis C
Hepatomegaly
Hereditary fructose intolerance
Lactose intolerance
Liver transplant
Positive HIV status
Pregnancy
Renal impairment - creatinine clearance below 50ml/minute

Reduce dose in patients with creatinine clearance below 50ml/min
Treatment does not prevent risk of transmission of Hepatitis B
Advise ability to drive/operate machinery may be affected by side effects
Treatment should be started by a doctor experienced in hepatitis management
Oral liquid contains hydroxybenzoate: caution in hypersensitivity
Oral solution with maltitol unsuitable in hereditary fructose intolerance
Some formulations contain lactose
Monitor all parameters for at least 6 months post treatment cessation
Monitor hepatic function regularly
Monitor viral markers frequently
Discontinue if raised LFTs/hepatomegaly/lactic acidosis occur
Disease flare may occur at beginning of treatment
Discontinue if hepatic function deteriorates
Female: Ensure adequate contraception during treatment

Patients should be advised that therapy does not reduce the risk of transmission and appropriate precautions must be taken.

Virological response should be closely monitored in patients with renal impairment.

Spontaneous exacerbations of chronic hepatitis B may occur and are characterised by transient increases in serum ALT.
After antiviral therapy is started, serum ALT levels may rise in some patients as HBV DNA levels fall. Exacerbations usually occurred 4 to 5 weeks after the start of entecavir therapy.
In patients with compensated hepatic disease, the increases in ALT are not generally accompanied by an increase in serum bilirubin or hepatic decompensation.

Acute exacerbations of hepatitis B have also been reported when therapy for the condition is discontinued. Some cases have been severe or fatal. These exacerbations are usually associated with increasing HBV DNA.
In entecavir-treated nucleoside naive patients, post-treatment exacerbations generally occurred after 23 to 24 weeks and the majority were reported in HBeAg negative patients.

A higher risk of serious hepatic adverse events has been observed in patients with decompensated liver disease, in particular in those with Child-Pugh class C disease. These patients may also be at higher risk of lactic acidosis and for specific renal adverse events such as hepatorenal syndrome. Clinical and laboratory parameters should be closely monitored in this patient group.

Potentially fatal lactic acidosis, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues. Severe cases of lactic acidosis have also been associated with pancreatitis, hepatic failure, renal failure and high levels of serum lactate. As a nucleoside analogue, it is also possible for entecavir to cause these effects.

Benign digestive symptoms including nausea, vomiting and abdominal pain may indicate the development of lactic acidosis.

Physicians should ensure that changes in ALT are associated with improvements in other markers of chronic hepatitis B in order to differentiate between increases due to a response to therapy and those due to lactic acidosis development.

Resistance may occur during therapy. Mutations in the HBV polymerase that encode lamivudine-resistance substitutions may lead to the subsequent emergence of secondary substitutions, including those associated with entecavir-associated resistance. Patients with lamivudine-resistant HBV are at higher risk of developing entecavir resistance than patients without lamivudine resistance.
Virological response should be closely monitored in lamivudine-refractory patients and appropriate resistance testing should be performed. In patients with suboptimal virological response after 24 weeks of treatment with entecavir a modification of treatment should be considered.

Lamivudine-resistant HBV is associated with an increased risk of subsequent entecavir resistance regardless of the degree of liver disease. In patients with decompensated liver disease, virologic breakthrough may be associated with serious complications of the underlying liver disease. Therefore, a combination use of entecavir plus a second antiviral agent (which does not share cross-resistance with either lamivudine or entecavir) should be considered in preference to entecavir monotherapy in patients with both decompensated liver disease and lamivudine-resistant HBV.

There is limited data on the safety and efficacy of entecavir in liver transplant recipients.

Renal function should be carefully evaluated before and during entecavir therapy in liver transplant recipients receiving ciclosporin or tacrolimus.

Entecavir has not been evaluated in patients with hepatitis B and HIV who are not receiving effective HIV therapy. Emergence of HIV resistance has been observed when entecavir was used to treat chronic hepatitis B in patients with HIV who are not receiving highly active antiretroviral treatment (HAART). Entecavir should not be used in patients with hepatitis B and HIV who are not receiving HAART.

Entecavir should be used in paediatric patients only if the potential benefit justifies the potential risk to the child (e.g. resistance). Since some paediatric patients may require long-term or even lifetime management of chronic active hepatitis B, consideration should be given to the impact of entecavir on future treatment options.

Pregnancy and Lactation

Pregnancy

Use entecavir with caution in pregnancy.

There are no adequate data from the use of entecavir during human pregnancy. Animal studies have shown reproductive toxicity at high doses.
It is not known if entecavir crosses the human placenta. The molecular weight (about 277), minimal metabolism, and long elimination half-life suggest that the drug will cross to the embryo and foetus.

There are no data on whether entecavir affects the transmission of hepatitis B from the mother to the neonate. Appropriate interventions should be used to prevent neonatal acquisition of hepatitis B.

Toxicology studies in animals have shown no evidence of impaired fertility.

Briggs (2011) concludes that entecavir should not be withheld because of pregnancy if a woman requires therapy and gives informed consent.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Entecavir is contraindicated in breastfeeding.

It is not known if entecavir is excreted in human breast milk. The molecular weight (about 277), minimal metabolism, and long elimination half-life (128 to 149 hours) suggest that the drug will be excreted into breast milk. Animal studies have demonstrated the excretion of entecavir in breast milk.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Alopecia
Anaphylactoid reaction
Decrease in blood bicarbonate
Decreased serum albumin
Diarrhoea
Dizziness
Dyspepsia
Elevated amylase levels
Elevated serum lipase
Exacerbation of hepatitis
Fatigue
Headache
Increase of liver transaminases
Insomnia
Lactic acidosis
Nausea
Rash
Reduced platelet count
Serum bilirubin increased
Somnolence
Vomiting

Presentation

Oral formulations of entecavir

Drugs List

Therapeutic Indications

Uses

Hepatitis B - chronic active

Treatment of chronic hepatitis B virus (HBV) infection in adults with compensated hepatic disease and evidence of active viral replication, persistently elevated alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.

Treatment of chronic hepatitis B virus infection in adults with decompensated liver disease.

Treatment of chronic HBV infection in nucleoside naive paediatric patients from 2 to less than 18 years of age with compensated liver disease who have evidence of active viral replication and persistently elevated serum ALT levels, or histological evidence of moderate to severe inflammation and/or fibrosis.

Clinical trials with entecavir included nucleoside naive patients with HBeAg positive and HBeAg negative hepatitis B infection, and patients with lamivudine-refractory hepatitis B.

Dosage

Adults

Elderly

Children

Patients with Renal Impairment

Additional Dosage Information

Contraindications

Children under 2 years
Breastfeeding

Precautions and Warnings

Females of childbearing potential
Predisposition to hepatic disorder
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic cirrhosis
Hepatitis C
Hepatomegaly
Hereditary fructose intolerance
Lactose intolerance
Liver transplant
Positive HIV status
Pregnancy
Renal impairment - creatinine clearance below 50ml/minute

Reduce dose in patients with creatinine clearance below 50ml/min
Treatment does not prevent risk of transmission of Hepatitis B
Advise ability to drive/operate machinery may be affected by side effects
Treatment should be started by a doctor experienced in hepatitis management
Oral liquid contains hydroxybenzoate: caution in hypersensitivity
Oral solution with maltitol unsuitable in hereditary fructose intolerance
Some formulations contain lactose
Monitor all parameters for at least 6 months post treatment cessation
Monitor hepatic function regularly
Monitor viral markers frequently
Discontinue if raised LFTs/hepatomegaly/lactic acidosis occur
Disease flare may occur at beginning of treatment
Discontinue if hepatic function deteriorates
Female: Ensure adequate contraception during treatment

Patients should be advised that therapy does not reduce the risk of transmission and appropriate precautions must be taken.

Virological response should be closely monitored in patients with renal impairment.

Spontaneous exacerbations of chronic hepatitis B may occur and are characterised by transient increases in serum ALT.
After antiviral therapy is started, serum ALT levels may rise in some patients as HBV DNA levels fall. Exacerbations usually occurred 4 to 5 weeks after the start of entecavir therapy.
In patients with compensated hepatic disease, the increases in ALT are not generally accompanied by an increase in serum bilirubin or hepatic decompensation.

Acute exacerbations of hepatitis B have also been reported when therapy for the condition is discontinued. Some cases have been severe or fatal. These exacerbations are usually associated with increasing HBV DNA.
In entecavir-treated nucleoside naive patients, post-treatment exacerbations generally occurred after 23 to 24 weeks and the majority were reported in HBeAg negative patients.

A higher risk of serious hepatic adverse events has been observed in patients with decompensated liver disease, in particular in those with Child-Pugh class C disease. These patients may also be at higher risk of lactic acidosis and for specific renal adverse events such as hepatorenal syndrome. Clinical and laboratory parameters should be closely monitored in this patient group.

Potentially fatal lactic acidosis, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues. Severe cases of lactic acidosis have also been associated with pancreatitis, hepatic failure, renal failure and high levels of serum lactate. As a nucleoside analogue, it is also possible for entecavir to cause these effects.

Benign digestive symptoms including nausea, vomiting and abdominal pain may indicate the development of lactic acidosis.

Physicians should ensure that changes in ALT are associated with improvements in other markers of chronic hepatitis B in order to differentiate between increases due to a response to therapy and those due to lactic acidosis development.

Resistance may occur during therapy. Mutations in the HBV polymerase that encode lamivudine-resistance substitutions may lead to the subsequent emergence of secondary substitutions, including those associated with entecavir-associated resistance. Patients with lamivudine-resistant HBV are at higher risk of developing entecavir resistance than patients without lamivudine resistance.
Virological response should be closely monitored in lamivudine-refractory patients and appropriate resistance testing should be performed. In patients with suboptimal virological response after 24 weeks of treatment with entecavir a modification of treatment should be considered.

Lamivudine-resistant HBV is associated with an increased risk of subsequent entecavir resistance regardless of the degree of liver disease. In patients with decompensated liver disease, virologic breakthrough may be associated with serious complications of the underlying liver disease. Therefore, a combination use of entecavir plus a second antiviral agent (which does not share cross-resistance with either lamivudine or entecavir) should be considered in preference to entecavir monotherapy in patients with both decompensated liver disease and lamivudine-resistant HBV.

There is limited data on the safety and efficacy of entecavir in liver transplant recipients.

Renal function should be carefully evaluated before and during entecavir therapy in liver transplant recipients receiving ciclosporin or tacrolimus.

Entecavir has not been evaluated in patients with hepatitis B and HIV who are not receiving effective HIV therapy. Emergence of HIV resistance has been observed when entecavir was used to treat chronic hepatitis B in patients with HIV who are not receiving highly active antiretroviral treatment (HAART). Entecavir should not be used in patients with hepatitis B and HIV who are not receiving HAART.

Entecavir should be used in paediatric patients only if the potential benefit justifies the potential risk to the child (e.g. resistance). Since some paediatric patients may require long-term or even lifetime management of chronic active hepatitis B, consideration should be given to the impact of entecavir on future treatment options.

Pregnancy and Lactation

Pregnancy

Use entecavir with caution in pregnancy.

There are no adequate data from the use of entecavir during human pregnancy. Animal studies have shown reproductive toxicity at high doses.
It is not known if entecavir crosses the human placenta. The molecular weight (about 277), minimal metabolism, and long elimination half-life suggest that the drug will cross to the embryo and foetus.

There are no data on whether entecavir affects the transmission of hepatitis B from the mother to the neonate. Appropriate interventions should be used to prevent neonatal acquisition of hepatitis B.

Toxicology studies in animals have shown no evidence of impaired fertility.

Briggs (2011) concludes that entecavir should not be withheld because of pregnancy if a woman requires therapy and gives informed consent.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Entecavir is contraindicated in breastfeeding.

It is not known if entecavir is excreted in human breast milk. The molecular weight (about 277), minimal metabolism, and long elimination half-life (128 to 149 hours) suggest that the drug will be excreted into breast milk. Animal studies have demonstrated the excretion of entecavir in breast milk.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Alopecia
Anaphylactoid reaction
Decrease in blood bicarbonate
Decreased serum albumin
Diarrhoea
Dizziness
Dyspepsia
Elevated amylase levels
Elevated serum lipase
Exacerbation of hepatitis
Fatigue
Headache
Increase of liver transaminases
Insomnia
Lactic acidosis
Nausea
Rash
Reduced platelet count
Serum bilirubin increased
Somnolence
Vomiting

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: September 2014

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Joint Formulary Committee. British National Formulary(online) London: BMJ Group and Pharmaceutical Press Accessed on 10 September 2014.

Summary of Product Characteristics: Baraclude 0.5mg and 1.0mg film coated tablets and Baraclude 0.05mg/ml oral solution. Bristol-Myers Squibb Pharmaceuticals Ltd. Revised August 2014.

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Entecavir Last revised: 1 August 2014
Last accessed: 10 September 2014