Epivir Information
Epivir (Lamivudine) Indications And Usage
Epivir (Lamivudine) is a nucleoside analogue indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection. Limitation of use: The dosage of this product is for HIV-1 and not for HBV.
Epivir (Lamivudine) Dosage And Administration
The recommended oral dose of Epivir (Lamivudine) Oral Solution in HIV-1-infected pediatric patients 3 months to 16 years of age is 4 mg/kg twice daily (up to a maximum of 150 mg twice a day), administered in combination with other antiretroviral agents.
Epivir (Lamivudine) is also available as a scored tablet for HIV-1-infected pediatric patients who weigh ≥14 kg and for whom a solid dosage form is appropriate. Before prescribing Epivir (Lamivudine) Tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow Epivir (Lamivudine) Tablets, the oral solution formulation should be prescribed. The recommended oral dosage of Epivir (Lamivudine) Tablets for HIV-1-infected pediatric patients is presented in Table 1.
Dosing of Epivir (Lamivudine) is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2 .
No additional dosing of Epivir (Lamivudine) is required after routine (4-hour) hemodialysis or peritoneal dialysis.
Although there are insufficient data to recommend a specific dose adjustment of Epivir (Lamivudine) in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered.
Epivir (Lamivudine) Contraindications
Epivir (Lamivudine) Tablets and Oral Solution are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., anaphylaxis) to any of the components of the products.
Epivir (Lamivudine) Warnings And Precautions
Posttreatment Exacerbations of Hepatitis:
Important Differences Among Lamivudine-Containing Products:
Emergence of Lamivudine-Resistant HBV:
Epivir (Lamivudine) Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adults - Clinical Trials in HIV-1:
The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea and cough.
Selected clinical adverse reactions in ≥5% of patients during therapy with Epivir (Lamivudine) 150 mg twice daily plus RETROVIR 200 mg 3 times daily for up to 24 weeks are listed in Table 3.
Epivir (Lamivudine) 300 mg Once Daily:
Selected laboratory abnormalities observed during therapy are summarized in Table 4.
The frequencies of selected laboratory abnormalities reported in patients receiving Epivir (Lamivudine) 300 mg once daily or Epivir (Lamivudine) 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.
Pediatric Patients – Clinical Trials in HIV-1:
Selected clinical adverse reactions and physical findings with a ≥5% frequency during therapy with Epivir (Lamivudine) 4 mg/kg twice daily plus RETROVIR 160 mg/m 3 times daily in therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are listed in Table 5.
Paresthesias and Peripheral Neuropathies:
Selected laboratory abnormalities experienced by therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are listed in Table 6.
In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported during postmarketing use of Epivir (Lamivudine) . Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine.
Endocrine and Metabolic:
General:
Hemic and Lymphatic:
Hypersensitivity:
Musculoskeletal:
Skin:
Epivir (Lamivudine) Drug Interactions
Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim). No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.
Epivir (Lamivudine) Use In Specific Populations
Pregnancy Category C. There are no adequate and well-controlled studies of Epivir (Lamivudine) in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of teratogenicity. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. Epivir (Lamivudine) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical studies conducted in South Africa. The study assessed pharmacokinetics in: 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. These studies were not designed or powered to provide efficacy information. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, lamivudine amniotic fluid specimens were collected following natural rupture of membranes. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily). It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients.
Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus
Antiretroviral Pregnancy Registry:
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for serious adverse reactions in nursing infants and HIV-1 transmission, mothers should be instructed not to breastfeed if they are receiving lamivudine.
Lamivudine is excreted into human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.
Epivir (Lamivudine) Overdosage
There is no known antidote for Epivir (Lamivudine) . One case of an adult ingesting 6 g of Epivir (Lamivudine) was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. Two cases of pediatric overdose were reported in Study ACTG300. One case involved a single dose of 7 mg/kg of Epivir (Lamivudine) ; the second case involved use of 5 mg/kg of Epivir (Lamivudine) twice daily for 30 days. There were no clinical signs or symptoms noted in either case. Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.
Epivir (Lamivudine) Description
Epivir (Lamivudine) (also known as 3TC) is a brand name for lamivudine, a synthetic nucleoside analogue with activity against HIV-1 and HBV. The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of CHNOS and a molecular weight of 229.3. It has the following structural formula:
Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C.
Epivir (Lamivudine) Tablets are for oral administration. Each scored 150-mg film-coated tablet contains 150 mg of lamivudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.
Each 300-mg film-coated tablet contains 300 mg of lamivudine and the inactive ingredients black iron oxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.
Epivir (Lamivudine) Oral Solution is for oral administration. One milliliter (1 mL) of Epivir (Lamivudine) Oral Solution contains 10 mg of lamivudine (10 mg/mL) in an aqueous solution and the inactive ingredients artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben, propylene glycol, propylparaben, sodium citrate (dihydrate), and sucrose (200 mg).
Epivir (Lamivudine) Clinical Pharmacology
Pharmacokinetics in Adults:
The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg/day administered to HBV-infected patients.
The steady-state pharmacokinetic properties of the Epivir (Lamivudine) 300-mg tablet once daily for 7 days compared with the Epivir (Lamivudine) 150-mg tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. Epivir (Lamivudine) 300 mg once daily resulted in lamivudine exposures that were similar to Epivir (Lamivudine) 150 mg twice daily with respect to plasma AUC; however, C was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUCand C; however, trough values were lower compared with the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.
Absorption and Bioavailability:
The accumulation ratio of lamivudine in HIV-1-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2 mg/kg twice daily.
Effects of Food on Oral Absorption:
Distribution:
Binding of lamivudine to human plasma proteins is low (
Metabolism:
Elimination:
In most single-dose studies in HIV-1-infected patients, HBV-infected patients, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. In HIV-1-infected patients, total clearance was 398.5 ± 69.1 mL/min (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg/kg.
Exposure (AUC∞), C, and half-life increased with diminishing renal function (as expressed by creatinine clearance). Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. T was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment .
Based on a study in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from a mean of 64 to 88 mL/min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration. Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis.
It is not known whether lamivudine can be removed by continuous (24-hour) hemodialysis.
The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known.
Hepatic Impairment:
Pediatric Patients:
Systemic clearance decreased with increasing age in pediatric patients, as shown in Figure 1.
Figure 1. Systemic Clearance (L/hr•kg) of Lamivudine in Relation to Age
After oral administration of lamivudine 4 mg/kg twice daily to 11 pediatric patients ranging from 4 months to 14 years of age, C was 1.1 ± 0.6 mcg/mL and half-life was 2.0 ± 0.6 hours. (In adults with similar blood sampling, the half-life was 3.7 ± 1 hours.) Total exposure to lamivudine, as reflected by mean AUC values, was comparable between pediatric patients receiving an 8-mg/kg/day dose and adults receiving a 4-mg/kg/day dose.
Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric patients after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose. At the dose of 8 mg/kg/day, CSF lamivudine concentrations in 8 patients ranged from 5.6% to 30.9% (mean ± SD of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg/mL.
Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants up to 1 week of age in 2 studies in South Africa. In these studies, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric patients (>3 months of age) studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges >3 months old .
Gender:
Race:
Mechanism of Action:
Antiviral Activity:
Resistance:
HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from patients. Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.
Lamivudine-resistant HBV isolates develop substitutions (rtM204V/I) in the YMDD motif of the catalytic domain of the viral reverse transcriptase. rtM204V/I substitutions are frequently accompanied by other substitutions (rtV173L, rtL180M) which enhance the level of lamivudine resistance or act as compensatory mutations improving replication efficiency. Other substitutions detected in lamivudine-resistant HBV isolates include: rtL80I and rtA181T. Similar HBV mutants have been reported in HIV-1-infected patients who received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus .
Cross-Resistance:
Genotypic analysis of on-therapy isolates from 22 patients identified as virologic failures in the lamivudine once-daily group showed that isolates from 0/22 patients contained treatment-emergent amino acid substitutions associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), isolates from 10/22 patients contained treatment-emergent amino acid substitutions associated with efavirenz resistance (L100I, K101E, K103N, V108I, or Y181C), and isolates from 8/22 patients contained a treatment-emergent lamivudine resistance-associated substitution (M184I or M184V).
Genotypic analysis of on-therapy isolates from patients (n = 22) in the lamivudine twice-daily treatment group showed that isolates from 1/22 patients contained treatment-emergent zidovudine resistance substitutions, isolates from 7/22 contained treatment-emergent efavirenz resistance substitutions, and isolates from 5/22 contained treatment-emergent lamivudine resistance substitutions.
Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n = 13) receiving lamivudine once daily showed that isolates from 12/13 patients were susceptible to zidovudine; isolates from 8/13 patients exhibited a 25- to 295-fold decrease in susceptibility to efavirenz, and isolates from 7/13 patients showed an 85- to 299-fold decrease in susceptibility to lamivudine.
Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n = 13) receiving lamivudine twice daily showed that isolates from all 13 patients were susceptible to zidovudine; isolates from 3/13 patients exhibited a 21- to 342-fold decrease in susceptibility to efavirenz, and isolates from 4/13 patients exhibited a 29- to 159-fold decrease in susceptibility to lamivudine.
Study EPV40001:
Genotypic analysis of on-therapy HIV-1 isolates from patients (n = 9) in the lamivudine once-daily treatment group showed that isolates from 6 patients had an abacavir and/or lamivudine resistance-associated substitution M184V alone. On-therapy isolates from patients (n = 6) receiving lamivudine twice daily showed that isolates from 2 patients had M184V alone, and isolates from 2 patients harbored the M184V substitution in combination with zidovudine resistance-associated amino acid substitutions.
Phenotypic analysis of on-therapy isolates from patients (n = 6) receiving lamivudine once daily showed that HIV-1 isolates from 4 patients exhibited a 32- to 53-fold decrease in susceptibility to lamivudine. HIV-1 isolates from these 6 patients were susceptible to zidovudine.
Phenotypic analysis of on-therapy isolates from patients (n = 4) receiving lamivudine twice daily showed that HIV-1 isolates from 1 patient exhibited a 45-fold decrease in susceptibility to lamivudine and a 4.5-fold decrease in susceptibility to zidovudine.
Epivir (Lamivudine) Clinical Studies
The use of Epivir (Lamivudine) is based on the results of clinical studies in HIV-1-infected patients in combination regimens with other antiretroviral agents. Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-1 RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials.
Clinical Endpoint Study:
Dose Regimen Comparison Surrogate Endpoint Studies in Therapy-Naive Adults:
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Figure 2. Virologic Response Through Week 48, EPV20001(Intent-to-Treat)
a
b
The proportions of patients with HIV-1 RNA
A small, randomized, open-label pilot study, EPV40001, was conducted in Thailand. A total of 159 treatment-naive adult patients (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells/mm, median plasma HIV-1 RNA 4.8 logcopies/mL) were enrolled. Two of the treatment arms in this study provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily. In intent-to-treat analyses of 48-week data, the proportions of patients with HIV-1 RNA below 400 copies/mL were 61% (33/54) in the group randomized to once-daily lamivudine and 75% (39/52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-1 RNA below 50 copies/mL were 54% (29/54) in the once-daily lamivudine group and 67% (35/52) in the all-twice-daily group; and the median increases in CD4+ cell counts were 166 cells/mm in the once-daily lamivudine group and 216 cells/mm in the all-twice-daily group.
Clinical Endpoint Study:
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3
3
3
3
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Epivir (Lamivudine) How Supplied/storage And Handling
White, diamond-shaped, scored, film-coated tablets debossed with “GX CJ7” on both sides.
Bottle of 60 tablets (NDC 0173-0470-01) with child-resistant closure.
Gray, modified diamond-shaped, film-coated tablets engraved with “GX EJ7” on one side and plain on the reverse side.
Bottle of 30 tablets (NDC 0173-0714-00) with child-resistant closure.
Recommended Storage:
Store Epivir (Lamivudine) Tablets at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
A clear, colorless to pale yellow, strawberry-banana-flavored liquid, contains 10 mg of lamivudine in each 1 mL.
Plastic bottle of 240 mL (NDC 0173-0471-00) with child-resistant closure. This product does not require reconstitution.
Recommended Storage:
Store in tightly closed bottles at 25°C (77°F) [see USP Controlled Room Temperature].
Epivir (Lamivudine)
Epivir (Lamivudine)
Epivir (Lamivudine)
