Lamivudine-Zidovudine (lamivudine/zidovudine)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Zidovudine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI).
Lamivudine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI) that is active against HIV and hepatitis B virus (HBV).
Zidovudine is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI). Following conversion to a pharmacologically active metabolite, zidovudine inhibits replication of HIV by interfering with viral RNA-directed DNA polymerase (reverse transcriptase). Like other HIV NRTIs, the antiviral activity of zidovudine appears to depend on intracellular conversion of the drug to a triphosphate metabolite.
Zidovudine 5'-triphosphate and not unchanged zidovudine appears to be the pharmacologically active form of the drug.
Zidovudine has a limited spectrum of antiviral activity. Following intracellular conversion to a pharmacologically active metabolite, the drug is active in vitro against HIV type 1. The antiretroviral activity of zidovudine has been evaluated in vitro in cell culture systems, including monocytes and human blood lymphocytes.
HIV type 1 strains with reduced susceptibility or resistance to zidovudine have been selected in vitro in cell culture and also have emerged during therapy with the drug. Genotypic analyses of isolates selected in cell culture and recovered from zidovudine-treated patients showed thymidine analog mutations (TAMs) in the HIV-1 reverse transcriptase that include M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N/Q. The degree of zidovudine resistance appears to depend on the number and combination of these mutations.
Cross-resistance has been reported among the HIV NRTIs. TAM substitutions in HIV-1 reverse transcriptase selected by zidovudine can confer cross-resistance to abacavir, didanosine, and tenofovir.
Following IV infusion of zidovudine, dose-independent pharmacokinetics are observed over the dosage range of 1-5 mg/kg. Zidovudine is rapidly absorbed from the GI tract, with peak serum concentrations generally occurring within 0.5-1.5 hours after an oral dose of the drug. In fasting adults, mean oral bioavailability of zidovudine is 64%.
In pediatric patients, mean oral bioavailability is 61% in infants 14 days to 3 months of age and 65% in pediatric patients 3 months to 12 years of age. Bioavailability is greater in neonates 14 days old or younger and is reported to be 89%. Systemic exposure of zidovudine following administration of zidovudine tablets or oral solution is equivalent to that following administration of the capsules.
In children 3 months to 12 years of age, zidovudine appears to have dose-dependent increases in plasma concentrations after administration of an oral solution over the dosage range of 90-240 mg/m2 every 6 hours. Zidovudine is distributed into CSF following oral or IV administration. The drug is less than 38% bound to plasma proteins.
Zidovudine primarily undergoes elimination via hepatic metabolism. Following oral administration of zidovudine, 14% of the total dose is excreted in urine as unchanged zidovudine and 74% as the major metabolite, 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranuronosylthymidine (GZDV). Following IV administration, 18% of the total dose is excreted in the urine as unchanged zidovudine, and 60% as GZDV.
The plasma half-life of zidovudine in adults averages approximately 0.5-3 hours following oral or IV administration. The plasma half-life of zidovudine in neonates and infants averages approximately 3.1 hours in neonates up to 14 days of age, 1.9 hours in infants 14 days to 3 months of age, and 1.5 hours in pediatric patients 3 months to 12 years of age. Zidovudine clearance is decreased and plasma concentrations are increased in patients with hepatic impairment.
Hemodialysis and peritoneal dialysis appear to have a negligible effect on removal of zidovudine, but may enhance elimination of GZDV. Results of a limited single-dose study indicate that sex does not affect the pharmacokinetics of zidovudine.
Lamivudine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI). Following conversion to a pharmacologically active metabolite, lamivudine apparently inhibits replication of human retroviruses by interfering with viral RNA-directed DNA polymerase (reverse transcriptase). Lamivudine, therefore, exerts a virustatic effect against retroviruses by acting as a reverse transcriptase inhibitor.
Like other HIV nucleoside reverse transcriptase agents and other nucleoside antiviral agents, the antiviral activity of lamivudine appears to depend on intracellular conversion of the drug to a 5'-triphosphate metabolite; thus, 2',3'-dideoxy,3'-thiacytidine-5'-triphosphate (3TC-TP) and not unchanged lamivudine appears to be the pharmacologically active form of the drug. 3TC-TP is a structural analog of deoxycytidine triphosphate (dC-TP), the natural substrate for reverse transcriptase (viral RNA-directed DNA polymerase). Although other mechanisms may be involved in the antiretroviral activity of the drug, 3TC-TP appears to compete with naturally occurring dC-TP for incorporation into viral DNA by reverse transcriptase.
Following incorporation of 3TC-TP into the viral DNA chain instead of dC-TP, viral DNA synthesis is terminated prematurely because the absence of a 3'-hydroxy group on the oxathiolane ring prevents further 5' to 3' phosphodiester linkages.
Lamivudine is rapidly absorbed from the GI tract in patients with HIV or hepatitis B virus (HBV) infection. In HIV-infected patients or healthy individuals, peak plasma concentrations are achieved within 0.5-2 hours after a single dose. The absolute bioavailability of lamivudine 150-mg scored tablets and oral solution in adults is similar (86 and 87%, respectively).
In a crossover study in healthy adults evaluating the steady-state pharmacokinetics of lamivudine administered in a once-daily regimen (300-mg tablet once daily) or twice-daily regimen (150-mg tablet twice daily), AUC was similar with both regimens; however, peak plasma concentrations were 66% higher and trough concentrations were 53% lower with the once-daily regimen compared with the twice-daily regimen.
The absolute bioavailability of lamivudine tablets and lamivudine oral solution is lower in children than in adults. In addition, the relative bioavailability of the oral solution is approximately 40% lower than that of the tablets in children, despite no difference between the preparations in adults. It has been suggested that lower lamivudine exposures reported in pediatric patients receiving lamivudine oral solution are likely due to an interaction between lamivudine and concomitant solutions containing sorbitol (e.g., abacavir oral solution).
Data from pharmacokinetic studies evaluating once- and twice-daily lamivudine regimens in HIV-1-infected pediatric patients 3 months through 12 years of age indicate that AUCs attained with once-daily regimens were similar to those attained with twice-daily regimens when comparing the dosage regimens within the same formulation (i.e., either tablets or the oral solution). However, mean peak plasma concentrations were approximately 80-90% higher with once-daily lamivudine regimens compared with twice-daily lamivudine regimens.
Pharmacokinetics of lamivudine in pregnant women are similar to those reported in nonpregnant adults and postpartum women. Food does not appear to affect the AUC of lamivudine. In a small study in HIV-infected patients, peak plasma concentrations of lamivudine were decreased 40% and the rate of absorption was reduced when lamivudine was administered with food, but clinically important decreases in systemic availability of the drug (AUC) were not observed.
Lamivudine is distributed into CSF. In HIV-infected children who received oral lamivudine in a dosage of 8 mg/kg daily, CSF concentrations ranged from 0.04-0.3 mcg/mL and were 5.6-30.9% of concurrent serum concentrations. Lamivudine crosses the placenta and is distributed into cord blood and amniotic fluid.
Lamivudine concentrations in amniotic fluid are typically twofold higher than maternal serum concentrations and have ranged from 1.2-2.5 mcg/mL or 2.1-5.2 mcg/mL when lamivudine dosage in the mother was 150 or 300 mg twice daily, respectively. Lamivudine is distributed into milk. Lamivudine is less than 36% bound to plasma proteins.
Intracellularly, lamivudine is phosphorylated and converted by cellular enzymes to the active 5'-triphosphate metabolite. Lamivudine is not substantially metabolized by cytochrome P-450 (CYP) isoenzymes. Metabolism is a minor route of elimination of lamivudine; the only known metabolite is the trans-sulfoxide metabolite.
The majority of a lamivudine dose is eliminated unchanged in urine by active organic cationic secretion. Within 12 hours after an oral dose, approximately 5% is excreted in urine as the trans-sulfoxide metabolite. In single-dose studies in healthy individuals or patients with HIV or HBV infection, the mean plasma half-life of lamivudine was 5-7 hours.
The plasma half-life in HIV-infected children 4 months to 14 years of age is 2 hours.
The pharmacokinetics of lamivudine are not altered in patients with hepatic impairment. In patients with impaired renal function, peak plasma concentrations, AUC, and plasma half-life of lamivudine are increased. Hemodialysis increases lamivudine clearance; however, the length of time of hemodialysis (4 hours) is insufficient to substantially alter mean lamivudine exposure after a single dose of the drug.
Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. There are no significant or clinically relevant racial or gender differences in lamivudine pharmacokinetics.
USES: This product contains 2 drugs: lamivudine and zidovudine. It is used with other HIV medications to help control HIV infection. It helps to decrease the amount of HIV in your body so your immune system can work better.
This lowers your chance of getting HIV complications (such as new infections, cancer) and improves your quality of life. Both lamivudine and zidovudine belong to a class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs). Lamivudine/zidovudine is not a cure for HIV infection.
To decrease your risk of spreading HIV disease to others, continue to take all HIV medications exactly as prescribed by your doctor. Use an effective barrier method (latex or polyurethane condoms/dental dams) during sexual activity as directed by your doctor. Do not share personal items (such as needles/syringes, toothbrushes, and razors) that may have contacted blood or other body fluids.
Consult your doctor or pharmacist for more details.
Generic name: lamivudine/zidovudine
Pronunciation: (la-MIV-ue-deen/zye-DOE-vue-deen)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Lamivudine-Zidovudine
Indications
The following indications are listed for Lamivudine-Zidovudine:
- Hiv Infection
Also known as: Human Immunodeficiency Virus Disease, Human Immunodeficiency Virus Infection.
Dosing
Dosage interruption of zidovudine may be required in patients that develop significant anemia (hemoglobin levels of less than 7.5 g/dL or a reduction of over 25% from baseline) and/or neutropenia (granulocyte count less than 750 cells/mm3or a reduction of over 50% from baseline) until bone marrow recovery is evident. In patients who develop significant anemia, dosage interruption does not necessarily eliminate the need for blood transfusions.
If marrow recovery occurs following dosage interruption, reinitiation of zidovudine therapy may be appropriate using adjunctive measures (e.g., epoetin alfa), depending on hematologic indices such as serum erythropoetin level and patient tolerance.
Lamivudine is administered orally once or twice daily without regard to meals.
For the treatment of HIV-1 infection, lamivudine is commercially available as an oral solution containing 10 mg/mL or tablets containing 150 or 300 mg of the drug (Epivir(R), generic). The 150-mg scored tablets are the preferred preparation in pediatric patients who weigh 14 kg or more and can swallow tablets. The oral solution should be used in those unable to safely and reliably swallow tablets. Lamivudine is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection.
For the treatment of chronic HBV infection, lamivudine is commercially available as an oral solution containing 5 mg/mL or film-coated tablets containing 100 mg of the drug (Epivir-HBV(R), generic). The 5-mg/mL oral solution should be used in patients requiring a dosage less than 100 mg and in children unable to reliably swallow tablets.
Lamivudine preparations labeled by FDA for treatment of chronic HBV infection should not be used in HIV-infected patients because they contain a lower dosage of the drug than that required for treatment of HIV-1 infection. If such preparations are used for the management of chronic HBV infection in a patient with unrecognized or untreated HIV infection, rapid emergence of HIV resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy for HIV-infected individuals.
Store lamivudine 100-mg, 150-mg, and 300-mg tablets at 25degreesC (excursions permitted between 15-30degreesC). Store lamivudine 5-mg/mL oral solution at 20-25degreesC and store lamivudine 10-mg/mL oral solution at 25degreesC.
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No dosing information is available for this tab.
Drug interactions
The following drug interactions are based on studies using single-entity zidovudine. When a fixed combination containing zidovudine is used, interactions associated with each drug in the fixed combination should be considered.
The following drug interactions are based on studies using lamivudine. Additional drug interactions may exist for fixed-dose combination products containing lamivudine/zidovudine (Combivir(R), generic) , abacavir/lamivudine (Epzicom(R), generic) , abacavir/lamivudine/zidovudine (Trizivir(R), generic) , lamivudine/tenofovir disoproxil fumarate (Cimduo(R)) , doravirine/lamivudine/tenofovir disoproxil fumarate (Delstrigo(R)) , dolutegravir/lamivudine (Dovato(R)) , efavirenz/lamivudine/tenofovir disoproxil fumarate (Symfi(R); Symfi(R) Lo) , and abacavir/dolutegravir/lamivudine (Triumeq(R); Triumeq PD(R)). See the full prescribing information for information on each of these combination products.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*History of potentially life-threatening hypersensitivity reaction (e.g., anaphylaxis, Stevens-Johnson syndrome) to the drug or any ingredient in the formulation.
*
*Previous hypersensitivity to lamivudine.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse reactions occurring in 15% or more of adult patients receiving zidovudine for HIV-1 in clinical trials include headache, malaise, nausea, vomiting, and anorexia. In pediatric patients receiving zidovudine for HIV-1 in clinical trials, fever and cough were the most commonly reported adverse reactions, occurring in 15% or more of patients. In neonates who received zidovudine for the prevention of maternal-fetal transmission of HIV-1, the most common adverse reaction was anemia (incidence of 15% or greater).
Adverse systemic effects reported with IV zidovudine are similar to those reported with oral zidovudine. However, long-term IV zidovudine therapy (i.e., longer than 2-4 weeks) has not been evaluated in adults and may enhance adverse hematologic effects.
In the treatment of HIV infection in adults, the most common reported adverse reactions (incidence >=15%) were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. In the treatment of HIV infection in pediatric patients, the most common reported adverse reactions (incidence >=15%) were fever and cough.
In the treatment of HBV infection, the most common reported adverse reactions (incidence >=10% and reported at a rate greater than placebo) were ear, nose, and throat infections; sore throat; and diarrhea.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Pharmacokinetics of zidovudine in pediatric patients older than 3 months of age are similar to those reported in adults. Zidovudine pharmacokinetics in neonates 2 weeks of age and younger are substantially different from neonates over 2 weeks of age
The safety and efficacy of lamivudine for the treatment of HIV-1 (Epivir(R)) have been established in pediatric patients 3 months of age and older. The scored tablet is the preferred formulation for HIV-1-infected pediatric patients weighing at least 14 kg for whom a solid dosage form is appropriate; in the ARROW trial, pediatric patients who received the oral solution had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently.
The safety and efficacy of lamivudine for the treatment of chronic HBV (Epivir-HBV(R)) in pediatric patients younger than 2 years of age have not been established.
Zidovudine crosses the human placenta and concentrations in neonatal plasma at birth were equivalent to maternal plasma concentrations. In neonates and infants exposed to zidovudine in utero, cases of mild and transient serum lactate elevations, possibly due to mitochondrial dysfunction, have been reported; the clinical significance of these elevations is unknown. There have also been few reports of seizures, developmental delays, and other neurological disorders; however, a causal relationship of zidovudine exposure in utero or during the peri-partum phase with these events has not been established.
To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including zidovudine, the Antiretroviral Pregnancy Registry was established. Clinicians are encouraged to contact the registry at 800-258-4263 or https://www.APRegistry.com to enroll such women.
Data from the Antiretroviral Pregnancy Registry show no difference in the overall risk of birth defects for zidovudine compared with the background rate for birth defects in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Registry data include over 13,000 prospective reports of zidovudine exposures during pregnancy resulting in live births, including over 4000 first trimester exposures to the drug.
Lamivudine crosses the placenta and is distributed into cord blood in concentrations similar to maternal serum concentrations.
To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including lamivudine, the Antiretroviral Pregnancy Registry was established. Clinicians are encouraged to contact the registry at 800-258-4263 or https://www.apregistry.com/ to report cases of prenatal exposure to antiretroviral agents.
Data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for lamivudine compared with the background rate for major birth defects in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Reproduction studies in rats or rabbits using oral lamivudine dosages that resulted in plasma concentrations up to approximately 35 times higher than plasma concentrations attained with the recommended human dosage used for the treatment of HIV infection in adults have not revealed evidence of teratogenicity. Although there was evidence of early embryolethality in rabbits at exposure levels similar to those observed in humans, this effect was not seen in rats at exposure levels up to 35 times higher than those in humans.
Zidovudine is distributed into human milk. The effects of zidovudine on milk production, or on the breast-fed infant are not known.
The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.
Lamivudine is distributed into milk in humans. It is not known whether the drug affects human milk production or affects the breast-fed infant.
The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.
If lamivudine is being used for treatment of chronic HBV infection, the benefits of breast-feeding and the importance of lamivudine to the woman should be considered along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.
The manufacturer provides no specific dosage recommendations in geriatric patients. The manufacturer states that in general, the dosage of zidovudine should be selected with caution in geriatric patients because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
Use with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
While clinical experience to date has not revealed age-related differences in response to zidovudine, clinical studies evaluating zidovudine have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults.
Zidovudine should be used with caution in geriatric patients because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
Clinical trials of lamivudine (Epivir(R) and Epivir-HBV(R)) did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently from younger subjects. Use caution when administering lamivudine to geriatric patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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Last reviewed · Source: First Databank (FDB) drug data
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