ABACAVIR SULFATE, LAMIVUDINE AND ZIDOVUDINE
Clinical safety rating: safe
Abacavir sulfate, lamivudine, and zidovudine is a fixed-dose combination antiretroviral agent used for the treatment of HIV-1 infection. It combines a carbocyclic nucleoside analogue (abacavir) with two nucleoside reverse transcriptase inhibitors (lamivudine and zidovudine) to inhibit viral replication.
Abacavir is a carbocyclic synthetic nucleoside analog guanosine analogue that is phosphorylated to carbovir triphosphate, which inhibits HIV-1 reverse transcriptase by competing with natural substrate dGTP and causing chain termination. Lamivudine is a dideoxy-nucleoside cytidine analogue that is phosphorylated to lamivudine triphosphate, which inhibits HIV-1 reverse transcriptase via incorporation into viral DNA and chain termination. Zidovudine is a thymidine analogue that is phosphorylated to zidovudine triphosphate, which inhibits HIV-1 reverse transcriptase by competing with dTTP and causing chain termination. All three drugs are nucleoside reverse transcriptase inhibitors (NRTIs).
| Metabolism | Abacavir is primarily metabolized by alcohol dehydrogenase and glucuronidation; minor contribution from CYP450. Lamivudine is minimally metabolized (5-10%) via hepatic metabolism, primarily to trans-sulfoxide metabolite, not extensively metabolized by CYP450. Zidovudine is primarily metabolized via glucuronidation (to 5'-glucuronide) by UGT2B7; also undergoes phosphorylation intracellularly. |
| Excretion | Renal excretion of unchanged drug and metabolites: abacavir (83% as metabolites, 1% unchanged), lamivudine (70% unchanged), zidovudine (72-74% as metabolites, 14-18% unchanged). Biliary/fecal elimination is minor (<10% for each component). |
| Half-life | Abacavir: 1.5 h; lamivudine: 5-7 h; zidovudine: 0.5-3 h. Terminal half-lives: abacavir ~1.5 h, lamivudine ~13-19 h intracellularly (active triphosphate), zidovudine ~1 h (plasma) but intracellular triphosphate ~3-4 h. Clinical context: Twice-daily dosing due to prolonged intracellular half-life of active metabolites. |
| Protein binding | Abacavir: ~50% (albumin); lamivudine: <36% (albumin); zidovudine: 34-38% (albumin). |
| Volume of Distribution | Abacavir: 0.86 L/kg; lamivudine: 1.3 L/kg; zidovudine: 1.6 L/kg. Clinical meaning: Indicates extensive tissue distribution and penetration into cells, including CNS and genital tract. |
| Bioavailability | Oral: Abacavir 83%, lamivudine 86-88%, zidovudine 60-70% (with high first-pass metabolism). |
| Onset of Action | Oral: Antiviral effect begins within 1-2 hours post-dose; maximal inhibition occurs within 1-2 weeks of continuous therapy. |
| Duration of Action | Oral: Dosing interval 12 h; effect persists as long as intracellular triphosphate levels remain above inhibitory concentrations. Clinical note: Adherence critical for sustained viral suppression; missed doses can lead to viral rebound. |
| Molecular Weight | Abacavir sulfate: 670.74 Da (as hemisulfate); Lamivudine: 229.26 Da; Zidovudine: 267.24 Da |
One tablet (abacavir 600 mg/lamivudine 300 mg/zidovudine 300 mg) twice daily or as a single tablet once daily (abacavir 600 mg/lamivudine 300 mg/zidovudine 300 mg) depending on formulation.
| Dosage form | TABLET |
| Renal impairment | Contraindicated in CrCl <50 mL/min; no dose adjustment possible due to fixed combination. For CrCl 30-49 mL/min, separate components recommended with dose adjustment. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh C). For mild-moderate impairment, use with caution; abacavir is not recommended due to risk of increased exposure. |
| Pediatric use | Approved for children ≥3 months and weight ≥6 kg; dosing based on weight and age using tablets or oral solution of separate components. |
| Geriatric use | Cautious use; monitor renal function and hematologic parameters due to age-related decline in renal function and increased risk of anemia or neutropenia. |
| 1st trimester | Data are limited but available evidence shows no increase in major birth defects in first trimester. However, zidovudine is known to cross the placenta and has been associated with mitochondrial dysfunction in some infants. Use only if benefit outweighs risk. |
| 2nd trimester | Use during second trimester is generally considered acceptable when indicated, as the benefits of preventing HIV transmission outweigh potential risks. Monitoring for anemia and neutropenia is recommended. |
| 3rd trimester | Recommended for prevention of mother-to-child transmission (PMTCT) as part of combination therapy. Zidovudine intravenous infusion recommended during labor. Increased risk of hematologic toxicity in neonates (anemia, neutropenia); monitor complete blood count. |
Clinical note
Use during pregnancy only if clearly needed; sufficient data in humans (zidovudine and lamivudine are well-studied) show no increased risk of major birth defects; abacavir has minimal data but is considered acceptable if HLA-B*5701 negative. The combination is a recommended option in certain guideline-based regimens for pregnant women.
| FDA category | Human |
■ FDA Black Box Warning
Abacavir: Hypersensitivity reactions (fatal in some cases); HLA-B*5701 allele screening required prior to initiation; discontinue if hypersensitivity suspected and never restart. Zidovudine: Hematologic toxicity (neutropenia, anemia), especially in advanced HIV disease; prolonged use associated with myopathy. Lamivudine: limited to black box warning for abacavir and zidovudine as per labeling; no separate boxed warning.
| Common Effects | Nausea, Headache, Fatigue, Diarrhea, Insomnia, Cough, Rash |
| Serious Effects | Lactic acidosis with hepatomegaly and steatosis; abacavir hypersensitivity reaction (fever, rash, GI symptoms, respiratory symptoms); severe anemia, neutropenia, and thrombocytopenia (zidovudine); pancreatitis (especially in children); hepatic toxicity; myocardial infarction risk (abacavir). |
Hypersensitivity to abacavir, lamivudine, or zidovudineHepatic impairment (Child-Pugh class B or C) for abacavirNeutropenia (absolute neutrophil count < 750 cells/mm^3) or severe anemia (hemoglobin < 7.5 g/dL or < 4.5 mmol/L) due to zidovudineConcurrent use with other zidovudine-containing products or stavudineLow body weight (< 40 kg) due to fixed-dose combination not appropriateRenal impairment (creatinine clearance < 50 mL/min) due to lamivudine and zidovudine dose adjustment neededGenetic presence of HLA-B*5701 allele (abacavir hypersensitivity)
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| Placental transfer | All components cross the placenta. Zidovudine demonstrates extensive placental transfer with cord blood levels similar to maternal levels. Lamivudine and abacavir also cross but to a lesser extent. |
| Breastfeeding | Breastfeeding is not recommended in women with HIV in developed countries due to risk of HIV transmission. In resource-limited settings where breastfeeding is essential, abacavir, lamivudine, and zidovudine are excreted into breast milk at low levels; potential for adverse effects in nursing infant including hematologic toxicity. Weigh benefits of breastfeeding against risks. |
| Lactation Rating | L5 (Contraindicated) in HIV-positive mothers in settings where safe alternatives exist; otherwise consider L3 (Moderately Safe) if breastfeeding is unavoidable. |
| Teratogenic Risk | Abacavir sulfate, lamivudine, and zidovudine are classified as FDA Pregnancy Category C. Zidovudine crosses the placenta and has been associated with an increased risk of congenital anomalies when used in early pregnancy, though the absolute risk is low. Lamivudine and abacavir do not show significant teratogenicity in animal studies. In human data, zidovudine use in the first trimester may be associated with a slight increase in birth defects (e.g., neural tube defects). Second and third trimester exposure: no clear increase in major malformations, but mitochondrial toxicity has been reported in infants exposed in utero. Overall, the benefit of preventing vertical HIV transmission outweighs the potential teratogenic risk. |
| Fetal Monitoring | Monitor maternal complete blood count (CBC) with differential every month during pregnancy, as zidovudine can cause anemia and neutropenia. Hepatic function tests (AST, ALT) and serum lactate levels should be assessed due to risk of lactic acidosis/hepatic steatosis. HIV viral load and CD4 count should be monitored every 1-3 months. Fetal ultrasound for anomalies in the first trimester if exposure occurred. Newborn monitoring: CBC at birth and 4-6 weeks of age; HIV PCR testing at birth, 4-6 weeks, and 4-6 months. Long-term follow-up for mitochondrial dysfunction if in utero exposure. |
| Fertility Effects | No significant adverse effects on female or male fertility have been reported. In animal studies, abacavir, lamivudine, and zidovudine showed no impairment of fertility at doses up to 2-3 times human exposure. For males, no specific effects on sperm quality or quantity are documented. HIV infection itself may impair fertility, but antiretroviral therapy generally improves overall health and fertility potential. |
| Precautions | Hypersensitivity reactions (with abacavir; screened by HLA-B*5701); hematologic toxicity (zidovudine: severe anemia, neutropenia, especially with advanced HIV); lactic acidosis and severe hepatomegaly with steatosis (NRTI class effect); pancreatitis (especially with lamivudine in pediatric HIV); immune reconstitution syndrome; fat redistribution (lipodystrophy); myocardial infarction risk (abacavir association debated); bone marrow suppression (zidovudine); monitor CBC, liver function, and lactate. |
| Food/Dietary | No significant food interactions. Take with or without food. Avoid alcohol. |
| Clinical Pearls | Monitor for hypersensitivity reaction, especially in HLA-B*5701-positive patients; discontinue immediately if suspected. Check for anemia, neutropenia, and hepatotoxicity with zidovudine component. Dose adjustment needed for renal impairment (CrCl <50 mL/min). |
| Patient Advice | Take exactly as prescribed; do not skip doses to prevent resistance. · Report any signs of allergic reaction (rash, fever, malaise) immediately. · Avoid alcohol; it may worsen liver side effects. · Inform all healthcare providers about this medication. · This drug does not cure HIV but reduces viral load. · May cause nausea, headache, or fatigue; take with food if tolerated. |