Drugs List

Therapeutic Indications

Uses

Hepatitis B - chronic active

Treatment of chronic hepatitis B in patients with compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and fibrosis.

Treatment of chronic hepatitis B in patients with decompensated liver disease in combination with a second agent without cross-resistance to adefovir.

Contraindications

Children under 18 years
Breastfeeding
Galactosaemia
Renal impairment - creatinine clearance below 10ml/minute

Precautions and Warnings

Patients over 65 years
Predisposition to hepatic disorder
Predisposition to hepatic steatosis
End stage renal disease
Glucose-galactose malabsorption syndrome
Haemodialysis
Hepatic cirrhosis
Hepatomegaly
Lactose intolerance
Positive HIV status
Pregnancy
Renal impairment - creatinine clearance below 50ml/minute

Reduce dose in patients with creatinine clearance below 50ml/min
Therapy cessation not recommended in decompensated liver disease/cirrhosis
Treatment does not prevent risk of transmission of Hepatitis B
Treatment should be started by a doctor experienced in hepatitis management
Contains lactose
Monitor renal function prior to initiating treatment
Monitor for development of lactic acidosis
Monitor for presence of hepatitis B markers
Monitor patient for some months after discontinuing treatment
Monitor renal function every 4 weeks during first year, then every 3 months
Monitor renal function in patients with renal impairment
On discontinuation, may cause recurrence of hepatitis B
Discontinue if raised LFTs/hepatomegaly/lactic acidosis occur
Female: Barrier or non-hormonal contraception advised during treatment

Patients should be monitored every six months for biochemical, virological and serological markers of hepatitis B.

Adefovir resistance can cause viral load rebound resulting in exacerbation of hepatitis B and, where hepatic impairment is evident, this can lead to hepatic decompensation and a potential fatal outcome. The virological response should be closely monitored in patients receiving adefovir and HBV DNA should be monitored every 3 months. Resistance testing should be performed if viral rebound occurs. The modification of therapy is recommended if resistance occurs.

Renal function
During adefovir therapy, renal impairment may occur. Long-term treatment may increase the risk of renal impairment. The risk of this effect is low in patients with adequate renal function, but is of special importance in patients at risk of, or having underlying renal dysfunction and in patients receiving concurrent drugs that may affect renal function.

Renal function, including creatinine clearance and serum phosphate, should be monitored every four weeks during the first year and then every three months thereafter. These investigations should be completed more frequently in patients with renal impairment or patients receiving concurrent nephrotoxic drugs.

Patients who develop renal impairment and have advanced hepatic disease or cirrhosis may require dose adjustments or switching to alternative therapy for hepatitis B. The cessation of therapy for hepatitis B is not recommended in these patients.

Hepatic function
Transient increases in serum alanine aminotransferase (ALT) may be due to relatively common spontaneous exacerbations in chronic hepatitis B. After initiating antiviral therapy, serum ALT may increase in some patients as serum HBV DNA levels decline. These increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation in patients with compensated liver disease.
Closely monitor patients with advanced hepatic disease or cirrhosis who may be at a higher risk for potentially fatal hepatic decompensation following exacerbation of the disease. In these patients cessation of therapy is not recommended.

Exacerbations of hepatitis have occurred after discontinuation of adefovir (generally within 12 weeks) so continue to monitor patients for several months after cessation of treatment with adefovir. These exacerbations occurred in the absence of HBeAg seroconversion and presented as serum ALT elevations and increases in serum HBV DNA.
In patients with compensated hepatic function treated with 10mg of adefovir, elevations in serum ALT were not accompanied by clinical and laboratory changes associated with hepatic decompensation.

Lactic acidosis and severe hepatomegaly with steatosis
Lactic acidosis (in the absence of hypoxaemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues. As adefovir is structurally related to nucleoside analogues, this risk cannot be excluded. Discontinue treatment with adefovir dipivoxil if rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown cause occur.
Benign digestive symptoms, such as nausea, vomiting and abdominal pain, might be indicative of lactic acidosis development. Severe cases, sometimes fatal, were associated with pancreatitis, hepatic failure, hepatic steatosis, renal failure and higher levels of serum lactate.
Caution should be exercised when prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and monitor these patients closely.

Ensure that changes in ALT are associated with improvements in other laboratory markers of chronic hepatitis B in order to differentiate between elevations in transaminases due to response to treatment and increases potentially related to lactic acidosis.

Co-infection with HIV
There is limited data on the safety and efficacy of adefovir in patients with hepatitis B co-infected with HIV. There is no evidence that daily dosing with adefovir results in emergence of adefovir-associated resistance mutations in the HIV reverse transcriptase, but there is a potential risk of selection of HIV strains resistant to adefovir with possible cross resistance to other antiviral medication.

As far as possible, treatment with adefovir in an HIV co-infected patient should be reserved for patients whose HIV RNA is controlled. Adefovir has not been shown to be effective against HIV replication.

Pregnancy and Lactation

Pregnancy

Use adefovir with caution in pregnancy.

Briggs suggests due to the lack of human data an assessment of the embryo-foetal risk cannot be made. If indicated, treatment with adefovir should not be withheld because of pregnancy. The manufacturer suggests adefovir should only be used in pregnancy if the potential benefits outweigh the possible risks.

At the time of writing, there are limited adequate data on the use of adefovir during human pregnancy. As the potential risks to the developing foetus are unknown, it is recommended that women of child bearing potential take adequate contraceptive precautions.

Animal studies with intravenous adefovir have shown reproductive toxicity. Oral studies did not indicate teratogenic or foetotoxic effects.

At the time of writing, there are no data on the effects of adefovir on transmission of HBV from mother to infant. The standard recommended procedures for immunisation of infants should be followed to prevent neonatal acquisition of HBV.

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

Adefovir is contraindicated in breastfeeding.

Briggs suggests if adefovir is used in breastfeeding there is a potential risk of serious toxicity in the breastfed infant. The manufacturer suggests, as the risk to the breastfed infant cannot be excluded it is recommended that mothers do not breastfeed.

The molecular weight (about 501) of the pro-drug, adefovir dipivoxil, the relative lack of protein binding and moderately long terminal elimination half-life suggest adefovir will be excreted into 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

Abdominal pain
Asthenia
Diarrhoea
Dyspepsia
Flatulence
Headache
Hypophosphataemia
Increase in ALT level
Myopathy
Nausea
Osteomalacia
Pancreatitis
Pruritus
Rash
Reduction in carnitine
Renal failure
Renal impairment
Serum creatinine increased
Vomiting

Presentation

Oral formulations containing adefovir as adefovir dipivoxil

Drugs List

Therapeutic Indications

Uses

Hepatitis B - chronic active

Treatment of chronic hepatitis B in patients with compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and fibrosis.

Treatment of chronic hepatitis B in patients with decompensated liver disease in combination with a second agent without cross-resistance to adefovir.

Dosage

Adults

Elderly

Patients with Renal Impairment

Additional Dosage Information

Contraindications

Children under 18 years
Breastfeeding
Galactosaemia
Renal impairment - creatinine clearance below 10ml/minute

Precautions and Warnings

Patients over 65 years
Predisposition to hepatic disorder
Predisposition to hepatic steatosis
End stage renal disease
Glucose-galactose malabsorption syndrome
Haemodialysis
Hepatic cirrhosis
Hepatomegaly
Lactose intolerance
Positive HIV status
Pregnancy
Renal impairment - creatinine clearance below 50ml/minute

Reduce dose in patients with creatinine clearance below 50ml/min
Therapy cessation not recommended in decompensated liver disease/cirrhosis
Treatment does not prevent risk of transmission of Hepatitis B
Treatment should be started by a doctor experienced in hepatitis management
Contains lactose
Monitor renal function prior to initiating treatment
Monitor for development of lactic acidosis
Monitor for presence of hepatitis B markers
Monitor patient for some months after discontinuing treatment
Monitor renal function every 4 weeks during first year, then every 3 months
Monitor renal function in patients with renal impairment
On discontinuation, may cause recurrence of hepatitis B
Discontinue if raised LFTs/hepatomegaly/lactic acidosis occur
Female: Barrier or non-hormonal contraception advised during treatment

Patients should be monitored every six months for biochemical, virological and serological markers of hepatitis B.

Adefovir resistance can cause viral load rebound resulting in exacerbation of hepatitis B and, where hepatic impairment is evident, this can lead to hepatic decompensation and a potential fatal outcome. The virological response should be closely monitored in patients receiving adefovir and HBV DNA should be monitored every 3 months. Resistance testing should be performed if viral rebound occurs. The modification of therapy is recommended if resistance occurs.

Renal function
During adefovir therapy, renal impairment may occur. Long-term treatment may increase the risk of renal impairment. The risk of this effect is low in patients with adequate renal function, but is of special importance in patients at risk of, or having underlying renal dysfunction and in patients receiving concurrent drugs that may affect renal function.

Renal function, including creatinine clearance and serum phosphate, should be monitored every four weeks during the first year and then every three months thereafter. These investigations should be completed more frequently in patients with renal impairment or patients receiving concurrent nephrotoxic drugs.

Patients who develop renal impairment and have advanced hepatic disease or cirrhosis may require dose adjustments or switching to alternative therapy for hepatitis B. The cessation of therapy for hepatitis B is not recommended in these patients.

Hepatic function
Transient increases in serum alanine aminotransferase (ALT) may be due to relatively common spontaneous exacerbations in chronic hepatitis B. After initiating antiviral therapy, serum ALT may increase in some patients as serum HBV DNA levels decline. These increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation in patients with compensated liver disease.
Closely monitor patients with advanced hepatic disease or cirrhosis who may be at a higher risk for potentially fatal hepatic decompensation following exacerbation of the disease. In these patients cessation of therapy is not recommended.

Exacerbations of hepatitis have occurred after discontinuation of adefovir (generally within 12 weeks) so continue to monitor patients for several months after cessation of treatment with adefovir. These exacerbations occurred in the absence of HBeAg seroconversion and presented as serum ALT elevations and increases in serum HBV DNA.
In patients with compensated hepatic function treated with 10mg of adefovir, elevations in serum ALT were not accompanied by clinical and laboratory changes associated with hepatic decompensation.

Lactic acidosis and severe hepatomegaly with steatosis
Lactic acidosis (in the absence of hypoxaemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues. As adefovir is structurally related to nucleoside analogues, this risk cannot be excluded. Discontinue treatment with adefovir dipivoxil if rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown cause occur.
Benign digestive symptoms, such as nausea, vomiting and abdominal pain, might be indicative of lactic acidosis development. Severe cases, sometimes fatal, were associated with pancreatitis, hepatic failure, hepatic steatosis, renal failure and higher levels of serum lactate.
Caution should be exercised when prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and monitor these patients closely.

Ensure that changes in ALT are associated with improvements in other laboratory markers of chronic hepatitis B in order to differentiate between elevations in transaminases due to response to treatment and increases potentially related to lactic acidosis.

Co-infection with HIV
There is limited data on the safety and efficacy of adefovir in patients with hepatitis B co-infected with HIV. There is no evidence that daily dosing with adefovir results in emergence of adefovir-associated resistance mutations in the HIV reverse transcriptase, but there is a potential risk of selection of HIV strains resistant to adefovir with possible cross resistance to other antiviral medication.

As far as possible, treatment with adefovir in an HIV co-infected patient should be reserved for patients whose HIV RNA is controlled. Adefovir has not been shown to be effective against HIV replication.

Pregnancy and Lactation

Pregnancy

Use adefovir with caution in pregnancy.

Briggs suggests due to the lack of human data an assessment of the embryo-foetal risk cannot be made. If indicated, treatment with adefovir should not be withheld because of pregnancy. The manufacturer suggests adefovir should only be used in pregnancy if the potential benefits outweigh the possible risks.

At the time of writing, there are limited adequate data on the use of adefovir during human pregnancy. As the potential risks to the developing foetus are unknown, it is recommended that women of child bearing potential take adequate contraceptive precautions.

Animal studies with intravenous adefovir have shown reproductive toxicity. Oral studies did not indicate teratogenic or foetotoxic effects.

At the time of writing, there are no data on the effects of adefovir on transmission of HBV from mother to infant. The standard recommended procedures for immunisation of infants should be followed to prevent neonatal acquisition of HBV.

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

Adefovir is contraindicated in breastfeeding.

Briggs suggests if adefovir is used in breastfeeding there is a potential risk of serious toxicity in the breastfed infant. The manufacturer suggests, as the risk to the breastfed infant cannot be excluded it is recommended that mothers do not breastfeed.

The molecular weight (about 501) of the pro-drug, adefovir dipivoxil, the relative lack of protein binding and moderately long terminal elimination half-life suggest adefovir will be excreted into 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

Abdominal pain
Asthenia
Diarrhoea
Dyspepsia
Flatulence
Headache
Hypophosphataemia
Increase in ALT level
Myopathy
Nausea
Osteomalacia
Pancreatitis
Pruritus
Rash
Reduction in carnitine
Renal failure
Renal impairment
Serum creatinine increased
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: July 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 https://www.medicinescomplete.com [Accessed on [date]].

Summary of Product Characteristics: Hepsera 10 mg tablets. Gilead Sciences Ltd. Revised March 2014.