Zidovudine/ Lamivudine

Registered South African indications:

• HIV infection

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Abnormally low neutrophil counts (<0.75 x 10⁹/l)
• Abnormally low haemoglobin levels (<7.5 g/dl or 4.65 mmol/l)

Cautions

• Moderate to severe renal impairment
• Hepatic impairment
• Elderly
• Transmission of HIV
• Poor bone marrow reserve
• Hepatomegaly
• Hepatitis 
• Risk factors for hepatic disease and hepatic steatosis
• Co-infected with hepatitis C and treated with alpha interferon and ribavirin 
• Mitochondrial dysfunction
• Longer duration of antiretroviral treatment 
• Metabolic disturbances
• Immune Reactivation Syndrome
• Concomitant antiviral therapy for hepatitis B or C
• Co-infected with hepatitis B virus 
• Co-infected with hepatitis C virus
• Advanced HIV-disease 
• Long-term exposure to combination antiretroviral therapy 

Forms avail. in SA and covered in this monograph: tab

HIV infection

Zidovudine/ Lamivudine
300/150 (mg)

• Oral (tab): 1 tab, 12hrly

HIV post exposure prophylaxis

Zidovudine/ Lamivudine
300/150 (mg)

• Oral (tab): 1 tab, 12hrly; Treatment duration: 28 days

Use in combination with other antiretrovirals

Paed. forms avail. in SA and covered in this monograph: tab

HIV infection

Zidovudine/ Lamivudine
300/150 (mg)

Less than 25kg

• Not established for use

Greater than 25kg

• See adult dosage

Use in combination with other antiretrovirals

Consult HIV/infectious disease specialists prior to any decisions related to ARV regimen termination/switch

Pregnancy

• Safe
• As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data, as well as the clinical experience in pregnant women, should be taken into account. In the present case, the use in pregnant women of zidovudine, with subsequent treatment of the newborn infants, has been shown to reduce the rate of maternal-foetal transmission of HIV. A large amount of data on pregnant women taking lamivudine or zidovudine indicate no malformative toxicity (more than 3000 outcomes from first-trimester exposure each, of which over 2000 outcomes involved exposure to both lamivudine and zidovudine). The malformative risk is unlikely in humans based on the mentioned large amount of data
• The active ingredients of lamivudine/ zidovudine may inhibit cellular DNA replication and zidovudine has been shown to be a transplacental carcinogen in one animal study. The clinical relevance of these findings is unknown
• For patients co-infected with hepatitis who are being treated with lamivudine-containing medicinal products and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine
• Mitochondrial dysfunction: nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues

Breastfeeding

• Compatible
• Both lamivudine and zidovudine are excreted in breast milk at similar concentrations to those found in serum
• Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (< 4% of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age.  After administration of a single dose of 200 mg zidovudine to HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum. Breastfeeding mothers may breastfeed their infants
• The South African HIV guidelines strongly recommend exclusive breastfeeding for the first 6 months, after which the nutritional needs of the child will require the introduction of complementary foods, while breastfeeding continues. Mothers failing second or third line regimens should not breastfeed, provided the mother fulfils the AFASS (affordable, feasible, acceptable, sustainable and safe) criteria

Renal Impairment

• CrCl ≥50 ml/min: No dose adjustment recommended
• CrCl <50ml/min: Caution; dose adjustment recommended
  Not recommended; Consider switching to dose adjustable single-agent formulations

Hepatic Impairment

• Caution: dose adjustment recommended
  Not recommended; Consider switching to dose adjustable single-agent formulations

Elderly

• Caution; no dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Insomnia
• Peripheral neuropathy 
• Paresthesia
• Fatigue
• Malaise

Respiratory Disorders

• Cough
• Nasal symptoms

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain 
• Cramps
• Diarrhoea
• Pancreatitis
• Increased serum amylase

Hepatobiliary Disorders

• Transient rises in liver enzymes 
• Hepatitis

Musculoskeletal Disorders

• Arthralgia
• Muscle disorders
• Rhabdomyolysis

Skin and Subcutaneous Tissue Disorders

• Rash
• Alopecia
• Angioedema

Immune, Blood and Lymphatic System Disorders

• Neutropenia 
• Anaemia
• Thrombocytopenia
• Pure red cell aplasia

Others

• Fever

• Stavudine
• Lamivudine 
• Emtricitabine
• UGT enzyme inducers
• UGT enzymes inhibitors
• Organic cation transporter inhibitors
• Nephrotoxic agents
• Atovaquone 
• Lamivudine
• Trimethoprim
• Sulfamethoxazole
• Phenytoin

• Full blood count

Specific cases may require

• Hepatic function
• Renal function

Zidovudine
Zidovudine, a structural analog of thymidine, is a prodrug which is phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate. Zidovudine-TP inhibits HIV-1 reverse transcriptase via DNA chain termination, after incorporation of the nucleotide analogue.  

Lamivudine
Lamivudine is a nucleoside analogue which has activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). It is metabolised intracellularly to the active moiety, lamivudine 5'-triphosphate. Its main mode of action is as a chain terminator of viral reverse transcription. The triphosphate has selective inhibitory activity against HIV-1 and HIV-2 replication and is also active against zidovudine-resistant clinical isolates of HIV. 

COMBINATION PREPARATIONS

Zidovudine/ Lamivudine

Tablet 300mg/150mg

• Adco Lamivudine and Zidovudine (Adcock)
• Aspen Lamzid (Pharmacare)
• Cipla Duovir (Cipla)
• Combivir (GSK) originator
• Combozil 150/300 (Hetero)
• Divuwin (Zentiva)
• Lodiz (Novagen)
• Macleods Lamivudine 150 mg / Zidovudine 300 mg
• Retrovir/3TC starter pack (GSK) originator
• Sonke Lamivudine+Zidovudine (Ranbaxy) originator
• Zovilam (Mylan)