Abacavir-Lamivudine (abacavir sulfate/lamivudine)
Last reviewed · Source: First Databank (FDB) drug data
Overview
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).
Abacavir, 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). 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.
Following conversion to a pharmacologically active metabolite, abacavir inhibits replication of retroviruses, including human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2), by interfering with viral RNA-directed DNA polymerase (reverse transcriptase). The drug, therefore, exerts a virustatic effect against retroviruses by acting as a reverse transcriptase inhibitor.
Like other HIV nucleoside reverse transcriptase inhibitors (NRTIs), including didanosine, emtricitabine, lamivudine, and zidovudine, the antiviral activity of abacavir is dependent upon intracellular conversion of the drug to a 5'-triphosphate metabolite. Carbovir triphosphate (carbocyclic guanosine triphosphate) appears to be the pharmacologically active form of the drug. Substantial differences exist in the rates at which human cells phosphorylate various NRTIs and in the enzymatic pathways involved.
Enzymatic conversion of abacavir to carbovir triphosphate is complex and involves certain steps and enzymes that differ from those involved in the enzymatic conversion of dideoxynucleoside reverse transcriptase inhibitors. Abacavir is phosphorylated by adenosine phosphotransferase to abacavir monophosphate, which is converted to carbovir monophosphate by a cytosolic enzyme. Subsequently, carbovir monophosphate is phosphorylated by cellular kinases to carbovir triphosphate.
Abacavir is not a substrate for enzymes (i.e., thymidine kinase, deoxycytidine kinase, adenosine kinase, mitochondrial deoxyguanosine kinase) known to phosphorylate other nucleoside analogs. Because phosphorylation of abacavir depends on cellular rather than viral enzymes, conversion of the drug to the active triphosphate derivative occurs in both virus-infected and uninfected cells. Carbovir triphosphate is a structural analog of deoxyguanosine-5'-triphosphate (dGTP), the usual substrate for viral RNA-directed DNA polymerase.
Although other mechanisms may be involved in the antiretroviral activity of the drug, carbovir triphosphate appears to compete with deoxyguanosine-5'-triphosphate for viral RNA-directed DNA polymerase and incorporation into viral DNA. Following incorporation of carbovir triphosphate into the viral DNA chain instead of deoxyguanosine-5'-triphosphate, DNA synthesis is prematurely terminated because the absence of the 3'-hydroxy group on the drug prevents further 5' to 3' phosphodiester linkages.
Abacavir is rapidly absorbed following oral administration, with similar AUCs observed following the use of the oral solution or tablets. The geometric mean absolute oral bioavailability of abacavir sulfate tablets is 83%. In HIV-infected adults receiving abacavir in a dosage of 300 mg twice daily (given as abacavir succinate), peak plasma concentration and AUC(0-12 hours) of the drug at steady-state averaged 3 mcg/mL and 6.02 mcg*hour/mL, respectively.
In studies in HIV-infected adults employing oral abacavir dosages of 300-1200 mg daily (given as abacavir succinate), the pharmacokinetics of the drug were independent of the dose. Administration of abacavir tablets either during a fasting or fed state does not significantly impact systemic exposure. In pediatric patients, abacavir exposure is expected to be similar regardless of whether the scored tablet or oral solution is administered.
According to the manufacturer, abacavir tablets and oral solution can be used interchangeably. After single and multi-dose regimens of abacavir oral solution at recommended dosages in pediatric subjects, serum concentrations of abacavir were similar to those in adult patients. In crossover studies of pediatric subjects 3 months to 12 years of age receiving abacavir and lamivudine, the use of abacavir oral solution and tablets given once daily resulted in similar exposure to abacavir given twice daily when the same total daily dosage was administered.
In these studies, the mean peak plasma concentrations of abacavir were approximately 1.6- to 2.3-fold higher when the same total daily abacavir dosage was administered once versus twice daily.
Abacavir is about 50% bound to plasma proteins; binding of abacavir to plasma proteins is independent of drug concentration. Abacavir is distributed into CSF. Following administration of radiolabeled abacavir, total blood- and plasma-drug related radioactivity are identical; these results indicate abacavir readily distributes into erythrocytes.
Following oral administration of a 600-mg dose of radiolabeled abacavir, 82.2% of the dose is excreted in urine and 16% of the dose is excreted in feces. The 5'-carboxylic acid metabolite, 5'-glucuronide metabolite, and unchanged abacavir accounted for 30, 36, and 1.2%, respectively, of recovered radioactivity in urine; unidentified minor metabolites accounted for 15% of recovered radioactivity in urine. Abacavir is metabolized by alcohol dehydrogenase to form the 5'-carboxylic acid and by glucuronyltransferase to form the 5'-glucuronide; these metabolites do not appear to have any antiviral activity.
Any involvement of cytochrome P-450 isoenzymes in the metabolism of abacavir is limited. The plasma elimination half-life of abacavir following a single oral dose (given as abacavir sulfate) is about 1.5 hours. Systemic exposure of abacavir is not affected by gender or race (Black vs white patients).
USES: This product contains 2 drugs: abacavir and lamivudine. 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. Abacavir and lamivudine both belong to a class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs). Abacavir/lamivudine 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: abacavir sulfate/lamivudine
Pronunciation: (a-BAK-a-vir/la-MIV-ue-deen)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Abacavir-Lamivudine
Indications
The following indications are listed for Abacavir-Lamivudine:
- Hiv Infection
Also known as: Human Immunodeficiency Virus Disease, Human Immunodeficiency Virus Infection.
Dosing
Abacavir is commercially available as abacavir sulfate; dosage is expressed in terms of abacavir.
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.
Abacavir sulfate is administered orally once or twice daily without regard to meals. If a dose of abacavir is missed, administer the dose as soon as possible. Do not double the next dose or take more than the prescribed dose.
Abacavir is commercially available as a single entity preparation and in the following fixed-combination tablets for oral use: abacavir and lamivudine (Epzicom(R)); abacavir, lamivudine, and zidovudine (Trizivir(R)); and abacavir, dolutegravir, and lamivudine (Triumeq(R) and Triumeq PD(R)). Since the antiretroviral agents contained in the fixed combination preparations also may be available in single-entity or other fixed-combination preparations, exercise care to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals.
Single-entity abacavir sulfate is commercially available as an oral solution or tablets.
Abacavir oral solution is used in pediatric patients or when a solid oral dosage form is inappropriate.
The scored 300-mg abacavir tablets are used in adults and may be used in children weighing 14 kg or greater who have undergone assessment demonstrating ability to reliably swallow tablets.
Store abacavir tablets and oral solution between 20-25degreesC. The oral solution may also be refrigerated.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
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.
In vitro studies indicate that abacavir has the potential to inhibit cytochrome P-450 (CYP) isoenzyme 1A1, and has limited potential to inhibit CYP3A4. Abacavir does not induce nor inhibit CYP2C9 or CYP2D6. At therapeutic exposures, abacavir is not expected to affect substrates of organic anion transporter polypeptide (OATP)1B1 or OATP1B3, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.
In vitro studies indicate that abacavir is a substrate of BCRP and P-gp; however, the concomitant use of modulators of these transporters is not expected to have clinically relevant effects on abacavir serum concentrations. In vitro studies indicate that abacavir is not a substrate of OATP1B1, OAP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, or multidrug resistance-associated protein (MRP)2, or MRP4; therefore, the concomitant use of agents that modulate these transporters is not expected to affect abacavir serum concentrations.
The following drug interactions are based on studies using abacavir. Additional drug interactions may exist for fixed-dose combinations containing abacavir and lamivudine (Epzicom(R)); abacavir, lamivudine, and zidovudine (Trizivir(R)); and abacavir, dolutegravir, and lamivudine (Triumeq(R) and Triumeq PD(R)). See the full prescribing information for drug interactions of 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
*Previous hypersensitivity to lamivudine.
*Presence of the human leukocyte antigen (HLA)-B*5701 allele.
*Moderate or severe hepatic impairment.
*History of hypersensitivity reaction to abacavir.
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
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.
Adverse effects of at least moderate intensity reported in 10% or more of adult patients receiving abacavir for HIV-1 infection include nausea, headache, fatigue and malaise, nausea and vomiting, and dreams/sleep disorders.
Adverse effects of at least moderate intensity reported in 5% or more of pediatric patients receiving abacavir for HIV-1 infection include fever and/or chills, nausea and vomiting, skin rash, and ear, nose, and throat infections.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
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.
Safety and efficacy of single-entity abacavir tablets or oral solution have been established in infants and children 3 months of age and older. Use of abacavir in children 3 months of age and older is supported by pharmacokinetic trials and evidence from adequate and well-controlled trials in adult and pediatric patients. Safety and efficacy have not been established in neonates and infants less than 3 months of age.
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.
To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including abacavir, the Antiretroviral Pregnancy Registry (APR) was established. Clinicians are encouraged to contact the registry at 800-258-4263 to report cases of prenatal exposure to antiretroviral drugs.
Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Use of the MACDP population as the comparator group has several limitations; the MACDP assesses populations from a limited geographic area and does not include outcomes for births that occurred at <20 weeks' gestation. The rate of miscarriage is not reported in the APR.
Abacavir crosses the placenta and is distributed into cord blood in concentrations similar to maternal serum concentrations. Concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. In animal reproductive studies, abacavir administration during organogenesis resulted in developmental toxicities (i.e., depressed fetal body weight, reduced crown-rump length) and fetal malformations (i.e., fetal anasarca, skeletal malformations) based on abacavir exposure 35 times the usual human exposure (based on AUC). No developmental effects were observed at exposures 3.5-times the usual human exposure (based on AUC).
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.
Abacavir is distributed into human milk. The effects of abacavir on the breastfed infant, or the effects of the drug on milk production 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.
Use with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
The manufacturer makes no specific dosage recommendations for single-entity abacavir in geriatric patients. Select dosage with caution due to age-related decreases in 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.
While clinical experience to date has not revealed age-related differences in response to abacavir, clinical studies evaluating abacavir have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults. Dosage of abacavir for geriatric patients should be selected carefully because of limited experience with the drug in this age group and because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
ICD codes
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Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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