Drugs List

Therapeutic Indications

Uses

Hepatitis B - chronic active

Lamivudine is indicated for the treatment of chronic hepatitis B in adults with:
Compensated hepatic disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and/or fibrosis. Only consider when use of alternative antiviral with a higher genetic barrier is not appropriate.
Or
Decompensated hepatic disease in combination with second agent.

Contraindications

Children under 2 years

Precautions and Warnings

Children aged 2 to 18 years
Breastfeeding
Liver transplant
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 to be initiated and supervised by a specialist
Autoimmune disorders can occur many months after initiation of treatment
Monitor patient for some months after discontinuing treatment
Monitor viral markers frequently
On discontinuation, may cause recurrence of hepatitis B
Perform liver function tests every 3 months
Neonate exposed in utero: Risk of mitochondrial dysfunction

Other lamivudine formulations are indicated for HIV, see relevant monograph and product details for more information.

Patients should be monitored regularly, including ALT levels monitored every 3 months and HBV DNA and HBeAg levels determined every 6 months.

Data is limited on the use of lamivudine in pre-core mutant (HBeAg negative) patients and those receiving concurrent immunosuppressive agents, including cancer chemotherapy. Therefore, caution is advised.

Exacerbations in chronic hepatitis B are characterised by transient increases in serum ALT and re-emergence of HBV DNA. In patients with compensated liver disease, these increases in serum ALT were not generally accompanied by an increase in serum bilirubin or signs of hepatic decompensation.

Hepatitis B viral subpopulations with reduced susceptibility to lamivudine (YMDD variant HBV) may develop with extended therapy. In some patients the development of YMDD variant HBV can lead to exacerbation of hepatitis. In patients with YMDD variant HBV, a switch to or addition of a second agent without lamivudine cross resistance should be considered.

If lamivudine is discontinued a recurrence of hepatitis may occur in some patients. After discontinuation, patients should be periodically monitored clinically and by assessment of serum liver function tests (ALT and bilirubin levels) for at least four months after discontinuation and as clinically indicated thereafter.

There is a greater risk of active viral replication in transplantation recipients and patients with advanced liver disease. The recurrence of hepatitis after discontinuation or when efficacy of lamivudine is reduced in these patients can lead to severe and even fatal decompensation. These patients should be monitored at least every month during treatment, with tests to determine clinical, virological and serological parameters associated with hepatitis B, renal and hepatic function, and antiviral response. If lamivudine is discontinued, these tests should continue for at least 6 months after treatment cessation. Laboratory parameters to be monitored should include at least, serum ALT, bilirubin, albumin, blood urea nitrogen, creatinine, virological status, HBV antigen/antibody, and serum HBV DNA concentrations. Patients experiencing signs of hepatic impairment during or after treatment should be monitored more frequently.
If recurrent hepatitis occurs, there is insufficient data on the reintroduction of lamivudine therapy.

Treatment regimens containing nucleoside or nucleotide analogues have been reported to cause mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally. Adverse reactions such as haematological (anaemia, neutropenia), metabolic (hyperlactataemia, hyperlipasemia) and neurological (hypertonia, convulsions, abnormal behaviour) have been reported. Consider in children exposed to nucleoside or nucleotide analogues in utero (including HIV-negative infants) and who present with neurological symptoms or severe clinical findings of unknown cause.

Pregnancy and Lactation

Pregnancy

Use lamivudine with caution in pregnancy.

Briggs suggests if indicated, lamivudine should not be withheld because of pregnancy. The manufacturer suggests lamivudine can be used in pregnancy if clinically indicated.

Animal studies in rabbits have shown an increase in early embryonic deaths however this was not seen in rats. No teratogenic effects were observed in rats and rabbits administered up to 130 and 60 times the usual adult dose.

More than 1000 pregnancies exposed to lamivudine did not indicate malformative toxicity. Lamivudine crosses the placenta and foetal levels have been found to be similar to or higher than the maternal levels.
Animal and human data suggest low risk to the developing foetus for structural malformations. Impaired fertility as a result of embryonic cytotoxicity could occur with but this has not been studied in humans.

Mitochondrial dysfunction in neonates following in utero exposure to treatment regimens containing nucleoside and nucleotide analogue has been reported. It is unknown whether there are any long term consequences of in utero and infant exposure to lamivudine. Consider in children exposed to nucleoside or nucleotide analogues in utero (including HIV-negative infants) and who present with neurological symptoms or severe clinical findings of unknown cause.

Patients co-infected with hepatitis who become pregnant and withdraw lamivudine may have a re-occurrence of hepatitis.

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

Use lamivudine with caution in breastfeeding.

The manufacturer suggests breastfeeding may be considered in patients being treated for hepatitis B taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. Where there is maternal transmission of hepatitis B, despite adequate prophylaxis, consider discontinuing breastfeeding to reduce of lamivudine resistant mutants in the infant. Maternal hepatitis B is not a contraindication to breastfeeding if the child is adequately managed for hepatitis B prevention at birth.

Lamivudine is excreted into breast milk. Based on more than 200 mother and child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of treated mothers were low (less than 4% of maternal serum concentrations) and progressively decreased to undetectable levels when infants reached 24 weeks old. The low levels ingested by the infant are likely to result in sub-optimal antiviral effect. At the time of writing there are no evidence that the low concentrations in human milk leads to adverse reactions in the breastfed infant.

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 discomfort
Abdominal pain
Alopecia
Angioedema
Autoimmune hepatitis
Creatine phosphokinase increased
Diarrhoea
Exacerbation of hepatitis
Fatigue
Graves' disease
Headache
Hepatic steatosis
Increase in ALT level
Lactic acidosis
Malaise
Muscle disorders
Muscular cramps
Myalgia
Nasal symptoms
Nausea
Pancreatitis
Peripheral neuropathy
Pruritus
Rash
Respiratory tract infection
Rhabdomyolysis
Severe hepatomegaly
Throat discomfort
Thrombocytopenia
Vomiting

Presentation

Tablets containing 100 mg of lamivudine.

Drugs List

Therapeutic Indications

Uses

Hepatitis B - chronic active

Lamivudine is indicated for the treatment of chronic hepatitis B in adults with:
Compensated hepatic disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and/or fibrosis. Only consider when use of alternative antiviral with a higher genetic barrier is not appropriate.
Or
Decompensated hepatic disease in combination with second agent.

Dosage

Therapy should be initiated by a physician experienced in the treatment of chronic hepatitis B.

Adults

Children

Patients with Renal Impairment

Additional Dosage Information

Contraindications

Children under 2 years

Precautions and Warnings

Children aged 2 to 18 years
Breastfeeding
Liver transplant
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 to be initiated and supervised by a specialist
Autoimmune disorders can occur many months after initiation of treatment
Monitor patient for some months after discontinuing treatment
Monitor viral markers frequently
On discontinuation, may cause recurrence of hepatitis B
Perform liver function tests every 3 months
Neonate exposed in utero: Risk of mitochondrial dysfunction

Other lamivudine formulations are indicated for HIV, see relevant monograph and product details for more information.

Patients should be monitored regularly, including ALT levels monitored every 3 months and HBV DNA and HBeAg levels determined every 6 months.

Data is limited on the use of lamivudine in pre-core mutant (HBeAg negative) patients and those receiving concurrent immunosuppressive agents, including cancer chemotherapy. Therefore, caution is advised.

Exacerbations in chronic hepatitis B are characterised by transient increases in serum ALT and re-emergence of HBV DNA. In patients with compensated liver disease, these increases in serum ALT were not generally accompanied by an increase in serum bilirubin or signs of hepatic decompensation.

Hepatitis B viral subpopulations with reduced susceptibility to lamivudine (YMDD variant HBV) may develop with extended therapy. In some patients the development of YMDD variant HBV can lead to exacerbation of hepatitis. In patients with YMDD variant HBV, a switch to or addition of a second agent without lamivudine cross resistance should be considered.

If lamivudine is discontinued a recurrence of hepatitis may occur in some patients. After discontinuation, patients should be periodically monitored clinically and by assessment of serum liver function tests (ALT and bilirubin levels) for at least four months after discontinuation and as clinically indicated thereafter.

There is a greater risk of active viral replication in transplantation recipients and patients with advanced liver disease. The recurrence of hepatitis after discontinuation or when efficacy of lamivudine is reduced in these patients can lead to severe and even fatal decompensation. These patients should be monitored at least every month during treatment, with tests to determine clinical, virological and serological parameters associated with hepatitis B, renal and hepatic function, and antiviral response. If lamivudine is discontinued, these tests should continue for at least 6 months after treatment cessation. Laboratory parameters to be monitored should include at least, serum ALT, bilirubin, albumin, blood urea nitrogen, creatinine, virological status, HBV antigen/antibody, and serum HBV DNA concentrations. Patients experiencing signs of hepatic impairment during or after treatment should be monitored more frequently.
If recurrent hepatitis occurs, there is insufficient data on the reintroduction of lamivudine therapy.

Treatment regimens containing nucleoside or nucleotide analogues have been reported to cause mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally. Adverse reactions such as haematological (anaemia, neutropenia), metabolic (hyperlactataemia, hyperlipasemia) and neurological (hypertonia, convulsions, abnormal behaviour) have been reported. Consider in children exposed to nucleoside or nucleotide analogues in utero (including HIV-negative infants) and who present with neurological symptoms or severe clinical findings of unknown cause.

Pregnancy and Lactation

Pregnancy

Use lamivudine with caution in pregnancy.

Briggs suggests if indicated, lamivudine should not be withheld because of pregnancy. The manufacturer suggests lamivudine can be used in pregnancy if clinically indicated.

Animal studies in rabbits have shown an increase in early embryonic deaths however this was not seen in rats. No teratogenic effects were observed in rats and rabbits administered up to 130 and 60 times the usual adult dose.

More than 1000 pregnancies exposed to lamivudine did not indicate malformative toxicity. Lamivudine crosses the placenta and foetal levels have been found to be similar to or higher than the maternal levels.
Animal and human data suggest low risk to the developing foetus for structural malformations. Impaired fertility as a result of embryonic cytotoxicity could occur with but this has not been studied in humans.

Mitochondrial dysfunction in neonates following in utero exposure to treatment regimens containing nucleoside and nucleotide analogue has been reported. It is unknown whether there are any long term consequences of in utero and infant exposure to lamivudine. Consider in children exposed to nucleoside or nucleotide analogues in utero (including HIV-negative infants) and who present with neurological symptoms or severe clinical findings of unknown cause.

Patients co-infected with hepatitis who become pregnant and withdraw lamivudine may have a re-occurrence of hepatitis.

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

Use lamivudine with caution in breastfeeding.

The manufacturer suggests breastfeeding may be considered in patients being treated for hepatitis B taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. Where there is maternal transmission of hepatitis B, despite adequate prophylaxis, consider discontinuing breastfeeding to reduce of lamivudine resistant mutants in the infant. Maternal hepatitis B is not a contraindication to breastfeeding if the child is adequately managed for hepatitis B prevention at birth.

Lamivudine is excreted into breast milk. Based on more than 200 mother and child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of treated mothers were low (less than 4% of maternal serum concentrations) and progressively decreased to undetectable levels when infants reached 24 weeks old. The low levels ingested by the infant are likely to result in sub-optimal antiviral effect. At the time of writing there are no evidence that the low concentrations in human milk leads to adverse reactions in the breastfed infant.

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 discomfort
Abdominal pain
Alopecia
Angioedema
Autoimmune hepatitis
Creatine phosphokinase increased
Diarrhoea
Exacerbation of hepatitis
Fatigue
Graves' disease
Headache
Hepatic steatosis
Increase in ALT level
Lactic acidosis
Malaise
Muscle disorders
Muscular cramps
Myalgia
Nasal symptoms
Nausea
Pancreatitis
Peripheral neuropathy
Pruritus
Rash
Respiratory tract infection
Rhabdomyolysis
Severe hepatomegaly
Throat discomfort
Thrombocytopenia
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: February 2016

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

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.

Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.

Summary of Product Characteristics: Zeffix 100 mg film-coated tablets. GlaxoSmithKline UK. Revised November 2018.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 12 September 2017

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
Lamivudine Last revised: 10 March, 2015.
Last accessed: 18 February, 2016.