Drugs List

Therapeutic Indications

Uses

HIV infection-combined with other antiretrovirals

Treatment of Human Immunodeficiency Virus (HIV) infection in combination with other antiretrovirals in adults and children weighing over 14 kg.

Contraindications

Children weighing less than 14kg
Haemoglobin concentration below 7.5g / dL
Neutrophil count below 0.75 x 10 to the power of 9 / L
Breastfeeding
Porphyria

Precautions and Warnings

Elderly
Haemoglobin concentration below 9g/dl
Neutrophil count below 1.0 x 10 to the power of 9 / L
Predisposition to hepatic disorder
Predisposition to hepatic steatosis
Weight between 14kg and 30kg
Abnormal liver function test
Hepatic impairment
Hepatic steatosis
Hepatitis
Hepatitis C treated with alpha interferon and ribavirin
Hepatomegaly
Pregnancy
Renal impairment
Vitamin B12 deficiency

Switch to more suitable alternative if lipoatrophy occurs
Treatment does not prevent risk of transmission of HIV
Treatment should be initiated by doctor experienced in HIV management
Autoimmune disorders can occur many months after initiation of treatment
Avoid sorbitol or other polyalcohols, may reduce lamivudine efficacy
Blood lipid and glucose levels may increase requiring treatment
Monitor for development of lactic acidosis
Monitor for signs of osteonecrosis
Monitor haematological parameters regularly throughout treatment
Monitor patients at risk of hepatic disease
On discontinuation, may cause recurrence of hepatitis B
Advise patient to seek medical advice if joint aches or pain occur
Advise patient to seek medical advice if movement becomes difficult
Autoimmune diseases may occur during treatment
Discontinue if raised LFTs/hepatomegaly/lactic acidosis occur
Inflammatory symptoms should be evaluated and treated appropriately
Neonate exposed in utero: Risk of mitochondrial dysfunction
Risk of developing opportunistic infections
Discontinue if hepatic function deteriorates in pts with hepatic impairment
Discontinue if pancreatitis occurs
Discontinue if symptomatic hyperlactataemia occurs
Discontinue or interrupt dose if anaemia, neutropenia or leucopenia occur

Haematological reactions are to be expected with zidovudine treatment and generally occur after 4 to 6 weeks of therapy. Reactions include anaemia, neutropenia and leucopenia (usually secondary to neutropenia), and are more likely to occur in patients receiving higher zidovudine doses (1200 to 1500 mg/day) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease. Careful monitoring of haematological parameters is recommended. In patients with advanced symptomatic HIV infection, blood tests should be performed at least every 2 weeks for the first 3 months of treatment and at least once a month after that.

Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of nucleoside analogues. This generally occurs after a few or several months of treatment.
Caution should be exercised and close monitoring is advisable when administering nucleoside analogues to at risk patients (particularly obese women) with hepatomegaly, hepatic enzyme abnormalities, hepatitis, or any known risk factors for hepatic disease and hepatic steatosis.

Patients with chronic hepatitis B or C who are treated with combination antiretroviral therapy have an increased risk of developing severe and potentially fatal hepatic adverse effects, and therefore should be closely monitored during treatment. The product literature relating to concurrent treatments for hepatitis B or C should be consulted. If hepatic disease worsens in these patients, interruption or discontinuation of therapy should be considered.

Patients with pre-existing hepatic impairment, including chronic active hepatitis, have an increased risk of developing hepatic function abnormalities during therapy. These patients should be closely monitored and treatment should be interrupted or discontinued if hepatic disease worsens in these patients.

If lamivudine with zidovudine is discontinued in patients co-infected with the hepatitis B virus, liver function tests and markers of HBV replication should be monitored for 4 months, as lamivudine withdrawal may result in acute exacerbation of hepatitis.

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. Reports have predominatly concerned treatments containing zidovudine. 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.

Zidovudine containing regimens have been associated with loss of subcutaneous fat, which, in turn, has been linked to mitochondrial toxicity. Fat loss in the face, limbs and buttocks is most evident and may not be reversible when switching to a regimen without zidovudine. Assess patient for lipoatrophy regularly and switch to an alternative, zidovudine-free, therapy if lipoatrophy is suspected.

Blood lipid and glucose levels may increase during antiretroviral therapy. This may be linked to disease control and lifestyle. Refer to established HIV treatment guidelines for monitoring and manage lipid and glucose level disorders as appropriate.

When combination antiretroviral therapy is initiated in HIV-infected patients with severe immune deficiency, an inflammatory reaction to asymptomatic or residual opportunist pathogens may arise. This can lead to the aggravation of symptoms or other serious clinical conditions such as cytomegalovirus retinitis, mycobacterial infections or pneumocystis carinii pneumonia. These reactions are usually observed within the first few weeks or months after treatment initiation. Any inflammatory symptoms should be evaluated and treated appropriately.

Pregnancy and Lactation

Pregnancy

Use zidovudine with lamivudine with caution in pregnancy.

When considering the treatment of a HIV infected women during pregnancy, the present and future health of the mother, the prevention of maternal to foetal transmission and the limitations from the drug toxicity to the HIV-exposed foetus should be considered. The optimal antiretroviral therapy regimen for each patient depends on their HIV RNA levels, previous disease history and obstetric history. Lamivudine and zidovudine cross the placenta and foetal levels have been found to be similar to, or higher than, the maternal levels. The use of zidovudine in pregnant women over 14 weeks of gestation, with subsequent treatment of their newborn infants, has been shown to reduce the rate of maternal-foetal transmission of HIV significantly. Pregnant women should be advised that transmission may still occur in some cases despite therapy.

Lamivudine and zidovudine are not teratogenic in animals except at very high doses (zidovudine), and the experience in humans shows no pattern of birth defects Briggs (2011). Zidovudine is known to cause neonatal anaemia. Mitochondrial dysfunction in neonates following in utero zidovudine exposure has also been reported. It is unknown whether there are any long term consequences of in utero and infant exposure to zidovudine. 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.

Animal studies on rats showed that lamivudine and zidovudine are toxic to rodent embryos, by preventing blastocyst development, if given before implantation occurs. Briggs (2011) reports that there is some experience that lamivudine and zidovudine may affect human trophoblast cell growth and function in a dose related manner. Therefore, lamivudine and zidovudine should only be used in pregnancy prior to the second trimester if the potential benefit to the mother outweighs the risk to the foetus.

The efficacy of zidovudine to reduce the maternal foetal transmission in women with previously prolonged treatment with zidovudine or other antiretroviral agents or women infected with HIV strains with reduced sensitivity to zidovudine is unknown.

Based on the animal carcinogenicity/mutagenicity findings a carcinogenic risk to humans cannot be excluded. The relevance of these findings to both infected and uninfected infants exposed to lamivudine and zidovudine is unknown. Pregnant women should be made aware of these findings when considering lamivudine and zidovudine treatment.

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

Zidovudine and Lamivudine are contraindicated while breastfeeding.

Lamivudine and zidovudine are excreted into breast milk. HIV can be transmitted from mother to child through breast milk. Therefore it is recommended that HIV-infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

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 cramps
Abdominal pain
Alopecia
Anaemia
Angioedema
Anorexia
Anxiety
Aplastic anaemia
Arthralgia
Asthenia
Autoimmune disorders
Autoimmune hepatitis
Bone marrow hypoplasia
Cardiomyopathy
Chest pain
Chills
Convulsions
Cough
Depression
Diarrhoea
Dizziness
Dyspepsia
Dyspnoea
Elevated amylase levels
Fatigue
Fever
Flatulence
Graves' disease
Gynaecomastia
Headache
Hepatic disorders
Hepatic steatosis
Hepatitis
Hypercholesterolaemia
Hyperglycaemia
Hyperlactataemia
Hyperlipaemia
Hypersensitivity reactions
Hypertonia
Hypertriglyceridaemia
Immune Reactivation/Reconstitution Syndrome
Increase in serum ALT/AST
Influenza-like syndrome
Insomnia
Insulin resistance
Lactic acidosis
Leucopenia
Lipoatrophy
Loss of mental acuity
Malaise
Metabolic disorders
Muscle disorders
Myalgia
Myopathy
Nasal symptoms
Nausea
Neutropenia
Osteonecrosis
Pain - generalised
Pancreatitis
Pancytopenia
Paraesthesia
Peripheral neuropathy
Pigmentation of nails, skin and oral mucosa
Pruritus
Rash
Red cell aplasia
Respiratory tract infection
Rhabdomyolysis
Serum bilirubin increased
Severe hepatomegaly
Somnolence
Sweating
Taste disturbances
Thrombocytopenia
Urinary frequency
Urticaria
Vomiting

Presentation

Tablets containing zidovudine and lamivudine.

Drugs List

Therapeutic Indications

Uses

HIV infection-combined with other antiretrovirals

Treatment of Human Immunodeficiency Virus (HIV) infection in combination with other antiretrovirals in adults and children weighing over 14 kg.

Dosage

When discontinuation of one of the active substances or a dose reduction is required, individual preparations of lamivudine and zidovudine should be considered.

Adults

Elderly

Children

Patients with Renal Impairment

Patients with Hepatic Impairment

Additional Dosage Information

Contraindications

Children weighing less than 14kg
Haemoglobin concentration below 7.5g / dL
Neutrophil count below 0.75 x 10 to the power of 9 / L
Breastfeeding
Porphyria

Precautions and Warnings

Elderly
Haemoglobin concentration below 9g/dl
Neutrophil count below 1.0 x 10 to the power of 9 / L
Predisposition to hepatic disorder
Predisposition to hepatic steatosis
Weight between 14kg and 30kg
Abnormal liver function test
Hepatic impairment
Hepatic steatosis
Hepatitis
Hepatitis C treated with alpha interferon and ribavirin
Hepatomegaly
Pregnancy
Renal impairment
Vitamin B12 deficiency

Switch to more suitable alternative if lipoatrophy occurs
Treatment does not prevent risk of transmission of HIV
Treatment should be initiated by doctor experienced in HIV management
Autoimmune disorders can occur many months after initiation of treatment
Avoid sorbitol or other polyalcohols, may reduce lamivudine efficacy
Blood lipid and glucose levels may increase requiring treatment
Monitor for development of lactic acidosis
Monitor for signs of osteonecrosis
Monitor haematological parameters regularly throughout treatment
Monitor patients at risk of hepatic disease
On discontinuation, may cause recurrence of hepatitis B
Advise patient to seek medical advice if joint aches or pain occur
Advise patient to seek medical advice if movement becomes difficult
Autoimmune diseases may occur during treatment
Discontinue if raised LFTs/hepatomegaly/lactic acidosis occur
Inflammatory symptoms should be evaluated and treated appropriately
Neonate exposed in utero: Risk of mitochondrial dysfunction
Risk of developing opportunistic infections
Discontinue if hepatic function deteriorates in pts with hepatic impairment
Discontinue if pancreatitis occurs
Discontinue if symptomatic hyperlactataemia occurs
Discontinue or interrupt dose if anaemia, neutropenia or leucopenia occur

Haematological reactions are to be expected with zidovudine treatment and generally occur after 4 to 6 weeks of therapy. Reactions include anaemia, neutropenia and leucopenia (usually secondary to neutropenia), and are more likely to occur in patients receiving higher zidovudine doses (1200 to 1500 mg/day) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease. Careful monitoring of haematological parameters is recommended. In patients with advanced symptomatic HIV infection, blood tests should be performed at least every 2 weeks for the first 3 months of treatment and at least once a month after that.

Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of nucleoside analogues. This generally occurs after a few or several months of treatment.
Caution should be exercised and close monitoring is advisable when administering nucleoside analogues to at risk patients (particularly obese women) with hepatomegaly, hepatic enzyme abnormalities, hepatitis, or any known risk factors for hepatic disease and hepatic steatosis.

Patients with chronic hepatitis B or C who are treated with combination antiretroviral therapy have an increased risk of developing severe and potentially fatal hepatic adverse effects, and therefore should be closely monitored during treatment. The product literature relating to concurrent treatments for hepatitis B or C should be consulted. If hepatic disease worsens in these patients, interruption or discontinuation of therapy should be considered.

Patients with pre-existing hepatic impairment, including chronic active hepatitis, have an increased risk of developing hepatic function abnormalities during therapy. These patients should be closely monitored and treatment should be interrupted or discontinued if hepatic disease worsens in these patients.

If lamivudine with zidovudine is discontinued in patients co-infected with the hepatitis B virus, liver function tests and markers of HBV replication should be monitored for 4 months, as lamivudine withdrawal may result in acute exacerbation of hepatitis.

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. Reports have predominatly concerned treatments containing zidovudine. 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.

Zidovudine containing regimens have been associated with loss of subcutaneous fat, which, in turn, has been linked to mitochondrial toxicity. Fat loss in the face, limbs and buttocks is most evident and may not be reversible when switching to a regimen without zidovudine. Assess patient for lipoatrophy regularly and switch to an alternative, zidovudine-free, therapy if lipoatrophy is suspected.

Blood lipid and glucose levels may increase during antiretroviral therapy. This may be linked to disease control and lifestyle. Refer to established HIV treatment guidelines for monitoring and manage lipid and glucose level disorders as appropriate.

When combination antiretroviral therapy is initiated in HIV-infected patients with severe immune deficiency, an inflammatory reaction to asymptomatic or residual opportunist pathogens may arise. This can lead to the aggravation of symptoms or other serious clinical conditions such as cytomegalovirus retinitis, mycobacterial infections or pneumocystis carinii pneumonia. These reactions are usually observed within the first few weeks or months after treatment initiation. Any inflammatory symptoms should be evaluated and treated appropriately.

Pregnancy and Lactation

Pregnancy

Use zidovudine with lamivudine with caution in pregnancy.

When considering the treatment of a HIV infected women during pregnancy, the present and future health of the mother, the prevention of maternal to foetal transmission and the limitations from the drug toxicity to the HIV-exposed foetus should be considered. The optimal antiretroviral therapy regimen for each patient depends on their HIV RNA levels, previous disease history and obstetric history. Lamivudine and zidovudine cross the placenta and foetal levels have been found to be similar to, or higher than, the maternal levels. The use of zidovudine in pregnant women over 14 weeks of gestation, with subsequent treatment of their newborn infants, has been shown to reduce the rate of maternal-foetal transmission of HIV significantly. Pregnant women should be advised that transmission may still occur in some cases despite therapy.

Lamivudine and zidovudine are not teratogenic in animals except at very high doses (zidovudine), and the experience in humans shows no pattern of birth defects Briggs (2011). Zidovudine is known to cause neonatal anaemia. Mitochondrial dysfunction in neonates following in utero zidovudine exposure has also been reported. It is unknown whether there are any long term consequences of in utero and infant exposure to zidovudine. 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.

Animal studies on rats showed that lamivudine and zidovudine are toxic to rodent embryos, by preventing blastocyst development, if given before implantation occurs. Briggs (2011) reports that there is some experience that lamivudine and zidovudine may affect human trophoblast cell growth and function in a dose related manner. Therefore, lamivudine and zidovudine should only be used in pregnancy prior to the second trimester if the potential benefit to the mother outweighs the risk to the foetus.

The efficacy of zidovudine to reduce the maternal foetal transmission in women with previously prolonged treatment with zidovudine or other antiretroviral agents or women infected with HIV strains with reduced sensitivity to zidovudine is unknown.

Based on the animal carcinogenicity/mutagenicity findings a carcinogenic risk to humans cannot be excluded. The relevance of these findings to both infected and uninfected infants exposed to lamivudine and zidovudine is unknown. Pregnant women should be made aware of these findings when considering lamivudine and zidovudine treatment.

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

Zidovudine and Lamivudine are contraindicated while breastfeeding.

Lamivudine and zidovudine are excreted into breast milk. HIV can be transmitted from mother to child through breast milk. Therefore it is recommended that HIV-infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

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 cramps
Abdominal pain
Alopecia
Anaemia
Angioedema
Anorexia
Anxiety
Aplastic anaemia
Arthralgia
Asthenia
Autoimmune disorders
Autoimmune hepatitis
Bone marrow hypoplasia
Cardiomyopathy
Chest pain
Chills
Convulsions
Cough
Depression
Diarrhoea
Dizziness
Dyspepsia
Dyspnoea
Elevated amylase levels
Fatigue
Fever
Flatulence
Graves' disease
Gynaecomastia
Headache
Hepatic disorders
Hepatic steatosis
Hepatitis
Hypercholesterolaemia
Hyperglycaemia
Hyperlactataemia
Hyperlipaemia
Hypersensitivity reactions
Hypertonia
Hypertriglyceridaemia
Immune Reactivation/Reconstitution Syndrome
Increase in serum ALT/AST
Influenza-like syndrome
Insomnia
Insulin resistance
Lactic acidosis
Leucopenia
Lipoatrophy
Loss of mental acuity
Malaise
Metabolic disorders
Muscle disorders
Myalgia
Myopathy
Nasal symptoms
Nausea
Neutropenia
Osteonecrosis
Pain - generalised
Pancreatitis
Pancytopenia
Paraesthesia
Peripheral neuropathy
Pigmentation of nails, skin and oral mucosa
Pruritus
Rash
Red cell aplasia
Respiratory tract infection
Rhabdomyolysis
Serum bilirubin increased
Severe hepatomegaly
Somnolence
Sweating
Taste disturbances
Thrombocytopenia
Urinary frequency
Urticaria
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: August 2014

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.

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press https://www.medicinescomplete.com Accessed on August 6, 2014.

Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.

Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.

Paediatric Formulary Committee. BNF for Children (online) London: BMJ Group, Pharmaceutical Press, and RCPCH Publications https://www.medicinescomplete.com Accessed on August 6, 2014.

Summary of Product Characteristics: Combivir Film Coated Tablets. ViiV Healthcare UK Ltd. Revised January 2019.

The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.

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: February 4, 2014
Last accessed: August 6, 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
Zidovudine Last revised: February 4, 2014
Last accessed: August 6, 2014

The Norwegian Porphyria Centre (NAPOS).
Available at: https://www.drugs-porphyria.com/languages/UnitedKingdom/s1.php?l=gbr
Last revised:
Last accessed: August 6, 2014