Epivir

Name: Epivir

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Reviewed on 9/22/2016 References Reference: FDA Prescribing Information

Uses

This drug 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. Lamivudine belongs to a class of drugs known as nucleoside reverse transcriptase inhibitors-NRTI.Lamivudine is not a cure for HIV infection. To decrease your risk of spreading HIV disease to others, do all of the following: (1) continue to take all HIV medications exactly as prescribed by your doctor, (2) always use an effective barrier method (latex or polyurethane condoms/dental dams) during all sexual activity, and (3) 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.OTHER This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.This medication may also be used in combination with other HIV medications to reduce the risk of getting HIV infection after contact with the virus. Consult your doctor for more details.A lower-strength lamivudine product is used for hepatitis B infection in people without HIV infection.

Description

EPIVIR (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 C8H11N3O3S and a molecular weight of 229.3 g per mol. It has the following structural formula:

Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg per mL in water at 20°C.

EPIVIR 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 oral solution is for oral administration. One milliliter (1 mL) of EPIVIR oral solution contains 10 mg of lamivudine (10 mg per 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).

Clinical pharmacology

Mechanism Of Action

Lamivudine is an antiretroviral agent [see Microbiology].

Pharmacokinetics

Pharmacokinetics In Adults

The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1-infected adult subjects after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg per kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg per kg.

The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg per day administered to HBV-infected subjects.

The steady-state pharmacokinetic properties of the EPIVIR 300-mg tablet once daily for 7 days compared with the EPIVIR 150-mg tablet twice daily for 7 days were assessed in a crossover trial in 60 healthy subjects. EPIVIR 300 mg once daily resulted in lamivudine exposures that were similar to EPIVIR 150 mg twice daily with respect to plasma AUC24,ss; however, Cmax,ss 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 AUC24,ss and Cmax24,ss; 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 pharmacokinetics of lamivudine was evaluated in 12 adult HIV-1-infected subjects dosed with lamivudine 150 mg twice daily in combination with other antiretroviral agents. The geometric mean (95% CI) for AUC(0-12) was 5.53 (4.58, 6.67) mcg.h per mL and for Cmax was 1.40 (1.17, 1.69) mcg per mL.

Absorption And Bioavailability

Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. After oral administration of 2 mg per kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg per mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg per kg.

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 per kg twice daily.

Effects Of Food On Oral Absorption

EPIVIR tablets and oral solution may be administered with or without food. An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1-infected subjects on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax: 3.2 ± 1.3 hours) compared with the fasted state (Tmax: 0.9 ± 0.3 hours); Cmax in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC∞) in the fed and fasted states.

Distribution

The apparent volume of distribution after IV administration of lamivudine to 20 subjects was 1.3 ± 0.4 L per kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.

Binding of lamivudine to human plasma proteins is low (less than 36%). In vitro studies showed that over the concentration range of 0.1 to 100 mcg per mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.

Metabolism

Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). Serum concentrations of this metabolite have not been determined. Lamivudine is not significantly metabolized by cytochrome P450 enzymes.

Elimination

The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL per min (mean ± SD). In 20 HIV-1-infected subjects given a single IV dose, renal clearance was 280.4 ± 75.2 mL per min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine.

In most single-dose trials in HIV-1-infected subjects, HBV-infected subjects, 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 subjects, total clearance was 398.5 ± 69.1 mL per 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 per kg.

Special Populations

Renal Impairment: The pharmacokinetic properties of lamivudine have been determined in a small group of HIV-1-infected adults with impaired renal function (Table 7).

Table 7: Pharmacokinetic Parameters (Mean ± SD) after a Single 300-mg Oral Dose of Lamivudine in 3 Groups of Adults with Varying Degrees of Renal Function

Parameter Creatinine Clearance Criterion (Number of Subjects)
> 60 mL/min
(n = 6)
10-30 mL/min
(n = 4)
< 10 mL/min
(n = 6)
Creatinine clearance (mL/min) 111 ± 14 28 ± 8 6 ± 2
Cmax (mcg/mL) 2.6 ± 0.5 3.6 ± 0.8 5.8 ± 1.2
AUC∞ (mcg•h/mL) 11.0 ± 1.7 48.0 ± 19 157 ± 74
Cl/F (mL/min) 464 ± 76 114 ± 34 36 ± 11

Tmax 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 [see DOSAGE AND ADMINISTRATION].

Based on a trial in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from a mean of 64 to 88 mL per 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.

The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known.

Hepatic Impairment: The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function. Pharmacokinetic parameters were not altered by diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.

Pregnancy: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. 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.

Pediatric Patients: The pharmacokinetics of lamivudine have been studied after either single or repeat doses of EPIVIR in 210 pediatric subjects. Pediatric subjects receiving lamivudine oral solution according to the recommended dosage regimen achieved approximately 25% lower plasma concentrations of lamivudine compared with HIV-1-infected adults. Pediatric subjects receiving lamivudine oral tablets achieved plasma concentrations comparable to or slightly higher than those observed in adults. The absolute bioavailability of both EPIVIR tablets and oral solution are lower in children than adults. The relative bioavailability of EPIVIR oral solution is approximately 40% lower than tablets containing lamivudine in pediatric subjects despite no difference in adults. The mechanisms for the diminished absolute bioavailability of lamivudine and relative bioavailability of lamivudine solution are unknown.

The pharmacokinetics of lamivudine dosed once daily in HIV-1-infected pediatric subjects aged 3 months through 12 years was evaluated in 3 trials (PENTA-15 [n = 17], PENTA 13 [n = 19], and ARROW PK [n = 35]). All 3 trials were 2-period, crossover, open-label pharmacokinetic trials of twice-versus once-daily dosing of abacavir and lamivudine. These 3 trials demonstrated that once-daily dosing provides similar AUC0-24 to twice-daily dosing of lamivudine at the same total daily dose when comparing the dosing regimens within the same formulation (i.e., either the oral solution or the tablet formulation). The mean Cmax was approximately 80% to 90% higher with lamivudine once-daily dosing compared with twice-daily dosing.

Table 8: Pharmacokinetic Parameters (Geometric Mean [95% CI]) after Repeat Dosing of Lamivudine in 3 Pediatric Trials

  Trial (Number of Subjects)
ARROW PK
(n = 35)
PENTA-13
(n = 19)
PENTA-15
(n = 17)a
Age Range 3-12 years 2-12 years 3-36 months
Formulation Tablet Solution and Tabletb Solution
Parameter Once Daily Twice Daily Once Daily Twice Daily Once Daily Twice Daily
Cmax (mcg/mL) 3.17 (2.76, 3.64) 1.80 (1.59, 2.04) 2.09 (1.80, 2.42) 1.11 (0.96, 1.29) 1.87 (1.65, 2.13) 1.05 (0.88, 1.26)
AUC(0-24) (mcg•h/mL) 13.0 (11.4, 14.9) 12.0 (10.7, 13.4) 9.80 (8.64, 11.1) 8.88 (7.67, 10.3) 8.66 (7.46, 10.1) 9.48 (7.89, 11.4)
a n = 16 for PENTA-15 Cmax.
b Five subjects in PENTA-13 received lamivudine tablets.

Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric subjects after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose. At the dose of 8 mg per kg per day, CSF lamivudine concentrations in 8 subjects 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 per mL.

Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants aged up to 1 week in 2 trials in South Africa. In these trials, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric subjects (aged over 3 months) studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges over 3 months old [see ADVERSE REACTIONS].

Geriatric Patients: The pharmacokinetics of lamivudine after administration of EPIVIR to subjects over 65 years have not been studied [see Use in Specific Populations].

Gender: There are no significant or clinically relevant gender differences in lamivudine pharmacokinetics.

Race: There are no significant or clinically relevant racial differences in lamivudine pharmacokinetics.

Drug Interactions

Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects [see WARNINGS AND PRECAUTIONS].

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects [see WARNINGS AND PRECAUTIONS].

Trimethoprim/Sulfamethoxazole: Lamivudine and TMP/SMX were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC∞, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used in treat PCP.

Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).

Microbiology

Mechanism Of Action

Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue.

Antiviral Activity

The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC50 values against HIV-2 isolates (n = 4) ranged from 0.003 to 0.120 microM in PBMCs. Lamivudine was not antagonistic to all tested anti-HIV agents.

Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.

Resistance

Lamivudine-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis showed that the resistance was due to a specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine to either valine or isoleucine (M184V/I).

HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from subjects. Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12 weeks.

Genotypic And Phenotypic Analysis Of On-Therapy HIV-1 Isolates From Subjects With Virologic Failure

Trial EPV20001: Fifty-three of 554 (10%) subjects enrolled in EPV20001 were identified as virological failures (plasma HIV-1 RNA level greater than or equal to 400 copies per mL) by Week 48. Twenty-eight subjects were randomized to the lamivudine once-daily treatment group and 25 to the lamivudine twice-daily treatment group. The median baseline plasma HIV-1 RNA levels of subjects in the lamivudine once-daily group and lamivudine twice-daily group were 4.9 log10 copies per mL and 4.6 log10 copies per mL, respectively.

Genotypic analysis of on-therapy isolates from 22 subjects identified as virologic failures in the lamivudine once-daily group showed that isolates from 8 of 22 subjects contained a treatment-emergent lamivudine resistance-associated substitution (M184V or M184I), isolates from 0 of 22 subjects contained treatment-emergent amino acid substitutions associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), and isolates from 10 of 22 subjects contained treatment-emergent amino acid substitutions associated with efavirenz resistance (L100I, K101E, K103N, V108I, or Y181C).

Genotypic analysis of on-therapy isolates from subjects (n = 22) in the lamivudine twice-daily treatment group showed that isolates from 5 of 22 subjects contained treatment-emergent lamivudine resistance substitutions, isolates from 1 of 22 subjects contained treatment-emergent zidovudine resistance substitutions, and isolates from 7 of 22 subjects contained treatment-emergent efavirenz resistance substitutions.

Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from subjects (n = 13) receiving lamivudine once daily showed that isolates from 7 of 13 subjects showed an 85-to 299-fold decrease in susceptibility to lamivudine, isolates from 12 of 13 subjects were susceptible to zidovudine, and isolates from 8 of 13 subjects exhibited a 25-to 295-fold decrease in susceptibility to efavirenz.

Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from subjects (n = 13) receiving lamivudine twice daily showed that isolates from 4 of 13 subjects exhibited a 29-to 159-fold decrease in susceptibility to lamivudine, isolates from all 13 subjects were susceptible to zidovudine, and isolates from 3 of 13 subjects exhibited a 21-to 342-fold decrease in susceptibility to efavirenz.

Trial EPV40001: Fifty subjects received lamivudine 300 mg once daily plus zidovudine 300 mg twice daily plus abacavir 300 mg twice daily and 50 subjects received lamivudine 150 mg plus zidovudine 300 mg plus abacavir 300 mg all twice-daily. The median baseline plasma HIV-1 RNA levels for subjects in the 2 groups were 4.79 log10 copies per mL and 4.83 log10 copies per mL, respectively. Fourteen of 50 subjects in the lamivudine once-daily treatment group and 9 of 50 subjects in the lamivudine twice-daily group were identified as virologic failures.

Genotypic analysis of on-therapy HIV-1 isolates from subjects (n = 9) in the lamivudine once-daily treatment group showed that isolates from 6 subjects had an abacavir and/or lamivudine resistance-associated substitution M184V alone. On-therapy isolates from subjects (n = 6) receiving lamivudine twice daily showed that isolates from 2 subjects had M184V alone, and isolates from 2 subjects harbored the M184V substitution in combination with zidovudine resistance-associated amino acid substitutions.

Phenotypic analysis of on-therapy isolates from subjects (n = 6) receiving lamivudine once daily showed that HIV-1 isolates from 4 subjects exhibited a 32-to 53-fold decrease in susceptibility to lamivudine. HIV-1 isolates from these 6 subjects were susceptible to zidovudine.

Phenotypic analysis of on-therapy isolates from subjects (n = 4) receiving lamivudine twice daily showed that HIV-1 isolates from 1 subject exhibited a 45-fold decrease in susceptibility to lamivudine and a 4.5-fold decrease in susceptibility to zidovudine.

Pediatrics: Pediatric subjects receiving lamivudine oral solution concomitantly with other antiretroviral oral solutions (abacavir, nevirapine/efavirenz, or zidovudine) in ARROW developed viral resistance more frequently than those receiving tablets. At randomization to once-daily or twice-daily dosing of EPIVIR plus abacavir, 13% of subjects who started on tablets and 32% of subjects who started on solution had resistance substitutions. The resistance profile observed in pediatrics is similar to that observed in adults in terms of the genotypic substitutions detected and relative frequency, with the most commonly detected substitutions at M184 (V or I) [see Clinical Studies].

Cross-Resistance

Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors (NRTIs). Lamivudine-resistant HIV-1 mutants were cross-resistant in cell culture to didanosine (ddI). Cross-resistance is also expected with abacavir and emtricitabine as these select M184V substitutions.

Clinical Studies

The use of EPIVIR is based on the results of clinical trials in HIV-1-infected subjects 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.

Adult Subjects

Clinical Endpoint Trial

NUCB3007 (CAESAR) was a multicenter, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1. A total of 1,816 HIV-1-infected adults with 25 to 250 CD4+ cells per mm³ (median = 122 cells per mm³) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on trial was 12 months. Results are summarized in Table 9.

Table 9:  Number of Subjects (%) with at Least One HIV-1 Disease Progression Event or Death

Endpoint Current Therapy
(n = 460)
EPIVIR plus Current Therapy
(n = 896)
EPIVIR plus an NNRTIa plus Current Therapy
(n = 460)
HIV-1 progression or death
Death
90 (19.6%)
27 (5.9%)
86 (9.6%)
23 (2.6%)
41 (8.9%)
14 (3.0%)
a An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.

Surrogate Endpoint Trials

Dual Nucleoside Analogue Trials: Principal clinical trials in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine. These trials demonstrated the antiviral effect of lamivudine in a 2-drug combination. More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple-drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression.

Dose Regimen Comparison Surrogate Endpoint Trials in Therapy-Naive Adults: EPV20001 was a multicenter, double-blind, controlled trial in which subjects were randomized 1:1 to receive EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily. A total of 554 antiretroviral treatment-naive HIV-1-infected adults enrolled: male (79%), white (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells per mm³ (median = 362 cells per mm³), and median baseline plasma HIV-1 RNA of 4.66 log10 copies per mL. Outcomes of treatment through 48 weeks are summarized in Figure 1 and Table 10.

Figure 1: Virologic Response through Week 48, EPV20001a,b (Intent-to-Treat)

a Roche AMPLICOR HIV-1 MONITOR.
b Responders at each visit are subjects who had achieved and maintained HIV-1 RNA less than 400 copies per mL without discontinuation by that visit.

Table 10: Outcomes of Randomized Treatment through 48 Weeks (Intent-to-Treat)

Outcome EPIVIR 300 mgOnce Daily plus RETROVI Rplus Efavirenz
(n = 278)
EPIVIR 150 mg Twice Dailyplus RETROVI Rplus Efavirenz
(n = 276)
Respondera 67% 65%
Virologic failureb 8% 8%
Discontinued due to clinical progression < 1% 0%
Discontinued due to adverse events 6% 12%
Discontinued due to other reasonsc 18% 14%
a Achieved confirmed plasma HIV-1 RNA less than 400 copies per mL and maintained through 48 weeks.
b Achieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48.
c Includes consent withdrawn, lost to follow-up, protocol violation, data outside the trial-defined schedule, and randomized but never initiated treatment.

The proportions of subjects with HIV-1 RNA less than 50 copies per mL (via Roche Ultrasensitive assay) through Week 48 were 61% for subjects receiving EPIVIR 300 mg once daily and 63% for subjects receiving EPIVIR 150 mg twice daily. Median increases in CD4+ cell counts were 144 cells per mm³ at Week 48 in subjects receiving EPIVIR 300 mg once daily and 146 cells per mm³ for subjects receiving EPIVIR 150 mg twice daily.

A small, randomized, open-label pilot trial, EPV40001, was conducted in Thailand. A total of 159 treatment-naive adult subjects (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells per mm³, median plasma HIV-1 RNA 4.8 log10 copies per mL) were enrolled. Two of the treatment arms in this trial 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 subjects with HIV-1 RNA below 400 copies per mL were 61% (33 of 54) in the group randomized to once-daily lamivudine and 75% (39 of 52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-1 RNA below 50 copies per mL were 54% (29 of 54) in the once-daily lamivudine group and 67% (35 of 52) in the all-twice-daily group; and the median increases in CD4+ cell counts were 166 cells per mm³ in the once-daily lamivudine group and 216 cells per mm³ in the all-twice-daily group.

Pediatric Subjects

Clinical Endpoint Trial

ACTG300 was a multicenter, randomized, double-blind trial that provided for comparison of EPIVIR plus RETROVIR (zidovudine) with didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects were enrolled in these 2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-white. The mean baseline CD4+ cell count was 868 cells per mm³ (mean: 1,060 cells per mm³ and range: 0 to 4,650 cells per mm³ for subjects aged less than or equal to 5 years; mean: 419 cells per mm³ and range: 0 to 1,555 cells per mm³ for subjects aged over 5 years) and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies per mL. The median duration on trial was 10.1 months for the subjects receiving EPIVIR plus RETROVIR and 9.2 months for subjects receiving didanosine monotherapy. Results are summarized in Table 11.

Table 11: Number of Subjects (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death)

Endpoint EPIVIR plus RETROVIR
(n = 236)
Didanosine
(n = 235)
HIV-1 disease progression or death (total) 15 (6.4%) 37 (15.7%)
  Physical growth failure 7 (3.0%) 6 (2.6%)
  Central nervous system deterioration 4 (1.7%) 12 (5.1%)
  CDC Clinical Category C 2 (0.8%) 8 (3.4%)
  Death 2 (0.8%) 11 (4.7%)

Once-Daily Dosing

ARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1-infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing EPIVIR and abacavir, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks on treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of EPIVIR and abacavir, in combination with a third antiretroviral drug, for an additional 96 weeks. Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Virologic suppression was not a requirement for participation: at baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared with 71% of subjects in the once-daily cohort.

The proportion of subjects with HIV-1 RNA of less than 80 copies per mL through 96 weeks is shown in Table 12. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.

Table 12: Virologic Outcome of Randomized Treatment at Week 96a (ARROW Randomization 3)

Outcome EPIVIR plus Abacavir
Twice-Daily Dosing
(n = 333)
EPIVIR plus Abacavir
Once-Daily Dosing
(n = 336)
HIV-1 RNA < 80 copies/mLb 70% 67%
HIV-1 RNA ≥80 copies/mLc 28% 31%
No virologic data
Discontinued due to adverse event or death 1% < 1%
Discontinued study for other reasonsd 0% < 1%
Missing data during window but on study 1% 1%
a Analyses were based on the last observed viral load data within the Week 96 window.
b Predicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96.
c Includes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol.
d Other includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing).

Analyses by formulation demonstrated the proportion of subjects with HIV-1 RNA of less than 80 copies per mL at randomization and Week 96 was higher in subjects who had received tablet formulations (75% [458/610] and 72% [434/601]) than in those who had received any solution formulations at any time (52% [29/56] and 54% [30/56]), respectively. These differences were observed in each different age group evaluated.

Patient information

EPIVIR®
(EP-i-veer)
(lamivudine) Tablets

EPIVIR®
(EP-i-veer)
(lamivudine) Oral Solution

What is the most important information I should know about EPIVIR?

EPIVIR can cause serious side effects, including:

  • Build-up of an acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take EPIVIR. Lactic acidosis is a serious medical emergency that can cause death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:
    • feel very weak or tired
    • unusual (not normal) muscle pain
    • trouble breathing
    • stomach pain with nausea and vomiting
    • feel cold, especially in your arms and legs
    • feel dizzy or light-headed
    • have a fast or irregular heartbeat
  • Serious liver problems can happen in people who take EPIVIR. In some cases these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:
    • your skin or the white part of your eyes turns yellow (jaundice)
    • dark or “tea-colored” urine
    • light-colored stools (bowel movements)
    • loss of appetite for several days or longer
    • nausea
    • pain, aching, or tenderness on the right side of your stomach area

You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight (obese), or have been taking nucleoside analog medicines for a long time.

  • Worsening of hepatitis B virus in people who have HIV-1 infection. If you have HIV-1 (Human Immunodeficiency Virus type 1) and hepatitis B virus (HBV) infection, your HBV may get worse (flareup) if you stop taking EPIVIR. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease can be serious and may lead to death.
    • Do not run out of EPIVIR. Refill your prescription or talk to your healthcare provider before your EPIVIR is all gone.
    • Do not stop EPIVIR without first talking to your healthcare provider.
    • If you stop taking EPIVIR, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver.
  • Resistant Hepatitis B Virus (HBV). If you have HIV-1 and hepatitis B, the hepatitis B virus can change (mutate) during your treatment with EPIVIR and become harder to treat (resistant).
  • Use with interferon and ribavirin-based regimens. Worsening of liver disease that has caused death has happened in people infected with both HIV-1 and hepatitis C virus who are taking antiretroviral medicines and are also being treated for hepatitis C with interferon with or without ribavirin. If you are taking EPIVIR and interferon with or without ribavirin, tell your healthcare provider if you have any new symptoms.

What is EPIVIR?

EPIVIR is a prescription medicine used together with other antiretroviral medicines to treat Human Immunodeficiency Virus (HIV-1) infection.

HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).

EPIVIR tablets and oral solution (used to treat HIV-1 infection) contain a higher dose of the same active ingredient (lamivudine) than is in the medicine EPIVIR-HBV tablets and oral solution (used to treat HBV). If you have both HIV-1 and HBV, you should not use EPIVIR-HBV to treat your infections. The safety and effectiveness of EPIVIR have not been established in children under 3 months of age.

Who should not take EPIVIR?

Do not take EPIVIR if you are allergic to lamivudine or any of the ingredients in EPIVIR. See the end of this Patient Information leaflet for a complete list of ingredients in EPIVIR.

What should I tell my healthcare provider before taking EPIVIR?

Before you take EPIVIR, tell your healthcare provider if you:

  • have or have had liver problems, including hepatitis B or C virus infection.
  • have kidney problems.
  • have diabetes. Each 15-mL dose (150 mg) of EPIVIR oral solution contains 3 grams of sucrose.
  • are pregnant or plan to become pregnant. Taking EPIVIR during pregnancy has not been associated with an increased risk of birth defects. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
    Pregnancy Registry. There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.
  • are breastfeeding or plan to breastfeed. Do not breastfeed if you take EPIVIR.
    • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Talk with your healthcare provider about the best way to feed your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements.

Some medications interact with EPIVIR. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. You can ask your healthcare provider or pharmacist for a list of medicines that interact with EPIVIR.

Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take EPIVIR with other medicines.

How should I take EPIVIR?

  • Take EPIVIR exactly as your healthcare provider tells you to take it.
  • If you miss a dose of EPIVIR, take it as soon as you remember. Do not take 2 doses at the same time or take more than what your healthcare provider tells you to take.
  • Stay under the care of a healthcare provider during treatment with EPIVIR.
  • EPIVIR may be taken with or without food.
  • For children 3 months and older, your healthcare provider will prescribe a dose of EPIVIR based on your child's body weight.
  • Tell your healthcare provider if you or your child has trouble swallowing tablets. EPIVIR also comes as a liquid (oral solution).
  • Do not run out of EPIVIR. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.
  • If you take too much EPIVIR, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of EPIVIR?

  • EPIVIR can cause serious side effects including:
  • See “What is the most important information I should know about EPIVIR?”
  • Risk of inflammation of the pancreas (pancreatitis). Children may be at risk for developing pancreatitis during treatment with EPIVIR if they:
    • have taken nucleoside analogue medicines in the past
    • have a history of pancreatitis
    • have other risk factors for pancreatitis

Call your healthcare provider right away if your child develops signs and symptoms of pancreatitis including severe upper stomach-area pain, with or without nausea and vomiting. Your healthcare provider may tell you to stop giving EPIVIR to your child if their symptoms and blood test results show that your child may have pancreatitis.

  • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking EPIVIR.
  • Changes in body fat can happen in people who take HIV-1 medicines. These changes may include an increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.

The most common side effects of EPIVIR in adults include:

  • headache
  • nausea
  • generally not feeling well
  • tiredness
  • nasal signs and symptoms
  • diarrhea
  • cough

The most common side effects of EPIVIR in children include fever and cough.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of EPIVIR. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store EPIVIR?

  • Store EPIVIR tablets and oral solution at room temperature between 68°F to 77°F (20°C to 25°C).
  • Keep bottles of EPIVIR oral solution tightly closed.

Keep EPIVIR and all medicines out of the reach of children.

General information about the safe and effective use of EPIVIR.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use EPIVIR for a condition for which it was not prescribed. Do not give EPIVIR to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about EPIVIR that is written for health professionals.

For more information, go to www.viivhealthcare.com or call 1-877-844-8872.

What are the ingredients in EPIVIR?

Active ingredient: lamivudine

Inactive ingredients: EPIVIR scored 150-mg film-coated tablets: hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

EPIVIR 300-mg film-coated tablets: black iron oxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

EPIVIR oral solution: artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben, propylene glycol, propylparaben, sodium citrate (dihydrate), and sucrose (200 mg per mL).

Epivir Dosage

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

  • the condition being treated
  • other medical conditions you have
  • other medications you are taking
  • how you respond to this medication
  • your kidney function
  • your weight
  • your height
  • your age
  • your gender

Adults, for the treatment of HIV:

  • The recommended dose of Epivir (lamivudine) in HIV infected adults and adolescents over 16 years of age is 300 mg daily, taken by mouth, as either 150 mg twice daily or 300 mg once daily.
  • The dose may be decreased if you have kidney problems. 

Children, for the treatment of HIV:

  • The recommended dose of Epivir (lamivudine) oral solution in HIV infected children 3 months to 16 years of age is based on the child's weight. The recommendation is 4 mg/kg twice daily or 8 mg/kg once daily (up to a maximum of 300 mg daily), taken by mouth, in combination with other antiretroviral agents.
  • Children weighing at least 14 kg, can be given Epivir (lamivudine) tablets.

 

Other Requirements

  • Store Epivir tablets at room temperature between 15° to 30°C (59° to 86°F).
  • Epivir oral solution does not require refrigeration, but should be stored tightly closed in a cool place.
  • Keep this and all medicines out of the reach of children.

What is the most important information i should know about lamivudine (epivir, epivir hbv)?

You should not take lamivudine if you are allergic to it.

The Epivir brand of lamivudine (for treating HIV) should not be taken together with any HIV combination medicine that contains lamivudine or emtricitabine. This includes Atripla, Combivir, Complera, Emtriva, Epzicom, Trizivir, and Truvada.

The Epivir-HBV brand of lamivudine (for treating hepatitis B) should not be taken together with any other medication that contains lamivudine, which includes Combivir, Epivir, Epzicom, and Trizivir.

Before taking lamivudine, tell your doctor if you have kidney disease, liver disease, a history of pancreatitis, or if you have used a medicine similar to lamivudine in the past, such as abacavir (Ziagen), didanosine (Videx), emtricitabine (Atripla, Complera, Emtriva, Truvada), stavudine (Zerit), tenofovir (Viread), zalcitabine (Hivid), or zidovudine (Retrovir).

Some people develop lactic acidosis while taking lamivudine. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.

If you have hepatitis B you may develop liver symptoms after you stop taking this medication, even months after stopping. Your doctor may want to check your liver function for several months after you stop using lamivudine. Visit your doctor regularly.

Lamivudine can also cause severe or life-threatening effects on your liver or pancreas. Call your doctor at once if you have any of these symptoms while taking lamivudine: severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Epivir tablets and liquid contain a higher dose of lamivudine than Epivir-HBV. Each time you get a refill of this medication, be sure you have received the correct brand to treat your condition.

What should i avoid while taking lamivudine (epivir, epivir hbv)?

Taking this medication will not prevent you from passing HIV to other people. Avoid having unprotected sex or sharing razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Uses For Epivir

Lamivudine is used in combination with other medicines for the treatment of the infection caused by the human immunodeficiency virus (HIV). HIV is the virus that causes acquired immune deficiency syndrome (AIDS).

Lamivudine will not cure or prevent HIV infection or AIDS. It helps keep HIV from reproducing and appears to slow down the destruction of the immune system. This may help delay the development of serious health problems usually related to AIDS or HIV disease from occurring. Lamivudine will not keep you from spreading HIV to other people. People who receive this medicine may continue to have other problems usually related to AIDS or HIV disease.

Lamivudine is also used to treat chronic (long-term) hepatitis B virus (HBV) infection.

This medicine is available only with your doctor's prescription.

Before Using Epivir

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of lamivudine for the treatment of HIV infection in children 3 months to 16 years of age. However, safety and efficacy have not been established in children younger than 3 months of age.

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of lamivudine for the treatment of chronic hepatitis B infection in children 2 to 17 years of age. However, safety and efficacy have not been established in children younger than 2 years of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of lamivudine in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving lamivudine.

Pregnancy

Pregnancy Category Explanation
All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Dasabuvir
  • Orlistat

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Diabetes—The oral solution contains sucrose, which can make this condition worse.
  • Kidney disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.
  • Liver disease—Use with caution. May make this condition worse.
  • Pancreatitis (inflammation or swelling of the pancreas), history of—Epivir® should be used with caution. May make this condition worse.

Proper Use of lamivudine

This section provides information on the proper use of a number of products that contain lamivudine. It may not be specific to Epivir. Please read with care.

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine comes with a patient information leaflet. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Epivir® and Epivir-HBV® both contain the same medicine, but Epivir® has more medicine in each tablet or dose of liquid. Use only the brand of this medicine that your doctor prescribed. If you have HIV or AIDS, you need to use Epivir®. If you have hepatitis B but you do not have HIV or AIDS, you can use Epivir-HBV®.

Your doctor may want to test you for HIV before you start using Epivir-HBV® and during your treatment. Your medicine may need to be changed based on these test results.

It is important to take Epivir® as part of a combination regimen. Take all of the medicines your doctor prescribed at the right time of day. This will make your medicines work better.

Keep taking lamivudine for the full time of treatment, even if you or your child begin to feel better. Do not stop taking it without checking first with your doctor. When your supply of the medicine is running low, contact your doctor or pharmacist ahead of time. Do not allow yourself to run out of the medicine.

If you are using the oral liquid, use a specially marked measuring spoon, dosing syringe, or medicine cup to measure each dose accurately. The average household teaspoon may not hold the right amount of liquid.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage forms (solution or tablets):
    • For treatment of hepatitis B infection:
      • Adults—100 milligrams (mg) once a day.
      • Children 2 to 17 years of age—Dose is based on body weight and must be determined by your doctor. The dose is usually 3 milligrams (mg) per kilogram (kg) of body weight per day. The doctor may increase your dose as needed. However, the dose is usually not more than 100 mg per day. If your child cannot swallow the tablets, he or she may take the oral liquid.
      • Children younger than 2 years of age—Use and dose must be determined by your doctor.
    • For treatment of HIV infection or AIDS:
      • Adults and children 17 years of age and older—300 milligrams (mg) once a day or 150 mg two times a day.
      • Children 3 months to 16 years of age—
        • Solution: Dose is based on body weight and must be determined by your doctor. The dose is usually 4 milligrams (mg) per kilogram (kg) of body weight taken two times a day, or 8 mg per kg once a day. The doctor may increase your dose as needed. However, the dose is usually not more than 150 mg two times a day, taken with other HIV medicines.
        • Tablets: Dose is based on body weight and must be determined by your doctor. The dose is usually 150 to 300 mg per day. If your child weighs at least 14 kg, it is preferred that he or she take the scored tablet.
      • Children younger than 3 months of age—Use and dose must be determined by your doctor.

Note: Patients that require treatment for both hepatitis B and either AIDS or HIV should follow the dosing schedule for HIV or AIDS.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Indications and Usage for Epivir

Epivir is a nucleoside analogue indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection.

Limitations of Use:

• The dosage of this product is for HIV‑1 and not for HBV.

Epivir Dosage and Administration

Recommended Dosage for Adult Patients

The recommended dosage of Epivir in HIV‑1-infected adults is 300 mg daily, administered as either 150 mg taken orally twice daily or 300 mg taken orally once daily with or without food. If lamivudine is administered to a patient infected with HIV‑1 and HBV, the dosage indicated for HIV‑1 therapy should be used as part of an appropriate combination regimen [see Warnings and Precautions (5.2)].

Recommended Dosage for Pediatric Patients

The recommended dosage of Epivir oral solution in HIV‑1-infected pediatric patients aged 3 months and older is 4 mg per kg taken orally twice daily or 8 mg per kg taken orally once daily (up to a maximum of 300 mg daily), administered in combination with other antiretroviral agents. Consider HIV-1 viral load and CD4+ cell count/percentage when selecting the dosing interval for patients initiating treatment with oral solution [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)].

Epivir scored tablet is the preferred formulation for HIV‑1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. Before prescribing Epivir scored tablets, pediatric patients should be assessed for the ability to swallow tablets. For patients unable to safely and reliably swallow Epivir tablets, the oral solution formulation should be prescribed [see Warnings and Precautions (5.6)]. The recommended oral dosage of Epivir tablets for HIV‑1-infected pediatric patients is presented in Table 1.

Table 1. Dosing Recommendations for Epivir Scored (150-mg) Tablets in Pediatric Patients

Weight

(kg)

Once-Daily Dosing Regimena

Twice-Daily Dosing Regimen Using Scored 150-mg Tablet

AM Dose

PM Dose

Total Daily Dose

14 to <20

1 tablet (150 mg)

½ tablet (75 mg)

½ tablet (75 mg)

150 mg

≥20 to <25

1½ tablets (225 mg)

½ tablet (75 mg)

1 tablet (150 mg)

225 mg

≥25

2 tablets (300 mg)b

1 tablet (150 mg)

1 tablet (150 mg)

300 mg

a Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment [see Clinical Studies (14.2)].

b Patients may alternatively take one 300-mg tablet, which is not scored.

Patients with Renal Impairment

Dosing of Epivir is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2 [see Clinical Pharmacology (12.3)].

Table 2. Adjustment of Dosage of Epivir in Adults and Adolescents (Greater than or Equal to 25 kg) in Accordance with Creatinine Clearance

Creatinine Clearance (mL/min)

Recommended Dosage of Epivir

≥50

150 mg twice daily or 300 mg once daily

30-49

150 mg once daily

15-29

150 mg first dose, then 100 mg once daily

5-14

150 mg first dose, then 50 mg once daily

<5

50 mg first dose, then 25 mg once daily

No additional dosing of Epivir is required after routine (4-hour) hemodialysis or peritoneal dialysis.

Although there are insufficient data to recommend a specific dose adjustment of Epivir in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered.

Dosage Forms and Strengths

• Epivir Scored Tablets

Epivir scored tablets contain 150 mg of lamivudine. The tablets are white, diamond-shaped, scored, film-coated tablets debossed with “GX CJ7” on both sides.

• Epivir Tablets

Epivir tablets contain 300 mg of lamivudine. The tablets are gray, modified diamond-shaped, film-coated, and engraved with “GX EJ7” on one side and plain on the reverse side.

• Epivir Oral Solution

Epivir oral solution contains 10 mg of lamivudine per 1 mL. The solution is a clear, colorless to pale yellow, strawberry-banana flavored liquid.

Clinical Studies

The use of Epivir is based on the results of clinical trials in HIV‑1-infected subjects 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.

Adult Subjects

Clinical Endpoint Trial

NUCB3007 (CAESAR) was a multicenter, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of Epivir or Epivir plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1. A total of 1,816 HIV‑1-infected adults with 25 to 250 CD4+ cells per mm3 (median = 122 cells per mm3) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on trial was 12 months. Results are summarized in Table 9.

Table 9. Number of Subjects (%) with at Least One HIV-1 Disease Progression Event or Death

Endpoint

Current Therapy

(n = 460)

Epivir plus

Current Therapy

(n = 896)

Epivir plus an

NNRTIa plus Current

Therapy

(n = 460)

HIV-1 progression or death

90 (19.6%)

86 (9.6%)

41 (8.9%)

Death

27 (5.9%)

23 (2.6%)

14 (3.0%)

aAn investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.

Surrogate Endpoint Trials

Dual Nucleoside Analogue Trials: Principal clinical trials in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine. These trials demonstrated the antiviral effect of lamivudine in a 2-drug combination. More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple-drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression.

Dose Regimen Comparison Surrogate Endpoint Trials in Therapy-Naive Adults: EPV20001 was a multicenter, double-blind, controlled trial in which subjects were randomized 1:1 to receive Epivir 300 mg once daily or Epivir 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily. A total of 554 antiretroviral treatment-naive HIV‑1-infected adults enrolled: male (79%), white (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells per mm3 (median = 362 cells per mm3), and median baseline plasma HIV-1 RNA of 4.66 log10 copies per mL. Outcomes of treatment through 48 weeks are summarized in Figure 1 and Table 10.

Figure 1. Virologic Response through Week 48, EPV20001a,b (Intent-to-Treat)

a Roche AMPLICOR HIV-1 MONITOR.

bResponders at each visit are subjects who had achieved and maintained HIV-1 RNA less than 400 copies per mL without discontinuation by that visit.

Table 10. Outcomes of Randomized Treatment through 48 Weeks (Intent-to-Treat)

Outcome

Epivir 300 mg Once Daily

plus RETROVIR plus Efavirenz

(n = 278)

Epivir 150 mg Twice Daily

plus RETROVIR plus Efavirenz

(n = 276)

Respondera

67%

65%

Virologic failureb

8%

8%

Discontinued due to clinical progression

<1%

0%

Discontinued due to adverse events

6%

12%

Discontinued due to other reasonsc

18%

14%

aAchieved confirmed plasma HIV-1 RNA less than 400 copies per mL and maintained through 48 weeks.

bAchieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48.

cIncludes consent withdrawn, lost to follow-up, protocol violation, data outside the trial-defined schedule, and randomized but never initiated treatment.

The proportions of subjects with HIV-1 RNA less than 50 copies per mL (via Roche Ultrasensitive assay) through Week 48 were 61% for subjects receiving Epivir 300 mg once daily and 63% for subjects receiving Epivir 150 mg twice daily. Median increases in CD4+ cell counts were 144 cells per mm3 at Week 48 in subjects receiving Epivir 300 mg once daily and 146 cells per mm3 for subjects receiving Epivir 150 mg twice daily.

A small, randomized, open‑label pilot trial, EPV40001, was conducted in Thailand. A total of 159 treatment‑naive adult subjects (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells per mm3, median plasma HIV‑1 RNA 4.8 log10 copies per mL) were enrolled. Two of the treatment arms in this trial 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 subjects with HIV‑1 RNA below 400 copies per mL were 61% (33 of 54) in the group randomized to once‑daily lamivudine and 75% (39 of 52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV‑1 RNA below 50 copies per mL were 54% (29 of 54) in the once‑daily lamivudine group and 67% (35 of 52) in the all‑twice‑daily group; and the median increases in CD4+ cell counts were 166 cells per mm3 in the once‑daily lamivudine group and 216 cells per mm3 in the all‑twice‑daily group.

Pediatric Subjects

Clinical Endpoint Trial

ACTG300 was a multicenter, randomized, double-blind trial that provided for comparison of Epivir plus RETROVIR (zidovudine) with didanosine monotherapy. A total of 471 symptomatic, HIV‑1-infected therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects were enrolled in these 2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-white. The mean baseline CD4+ cell count was 868 cells per mm3 (mean: 1,060 cells per mm3 and range: 0 to 4,650 cells per mm3 for subjects aged less than or equal to 5 years; mean: 419 cells per mm3 and range: 0 to 1,555 cells per mm3 for subjects aged over 5 years) and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies per mL. The median duration on trial was 10.1 months for the subjects receiving Epivir plus RETROVIR and 9.2 months for subjects receiving didanosine monotherapy. Results are summarized in Table 11.

Table 11. Number of Subjects (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death)

Endpoint

Epivir plus RETROVIR

(n = 236)

Didanosine

(n = 235)

HIV-1 disease progression or death (total)

15 (6.4%)

37 (15.7%)

   Physical growth failure

7 (3.0%)

6 (2.6%)

   Central nervous system deterioration

4 (1.7%)

12 (5.1%)

   CDC Clinical Category C

2 (0.8%)

8 (3.4%)

   Death

2 (0.8%)

11 (4.7%)

Once-Daily Dosing

ARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV–1-infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing Epivir and abacavir, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks on treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of Epivir and abacavir, in combination with a third antiretroviral drug, for an additional 96 weeks. Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Virologic suppression was not a requirement for participation: at baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared with 71% of subjects in the once-daily cohort.

The proportion of subjects with HIV-1 RNA of less than 80 copies per mL through 96 weeks is shown in Table 12. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.

Table 12. Virologic Outcome of Randomized Treatment at Week 96a (ARROW Randomization 3)

Outcome

Epivir plus Abacavir Twice-Daily Dosing

(n = 333)

Epivir plus Abacavir Once-Daily Dosing

(n = 336)

HIV-1 RNA <80 copies/mLb

70%

67%

HIV-1 RNA ≥80 copies/mLc

28%

31%

No virologic data

Discontinued due to adverse event or death

1%

<1%

Discontinued study for other reasonsd

0%

<1%

Missing data during window but on study

1%

1%

aAnalyses were based on the last observed viral load data within the Week 96 window.

bPredicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96.

cIncludes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol.

dOther includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing).

Analyses by formulation demonstrated the proportion of subjects with HIV-1 RNA of less than 80 copies per mL at randomization and Week 96 was higher in subjects who had received tablet formulations (75% [458/610] and 72% [434/601]) than in those who had received any solution formulations at any time (52% [29/56] and 54% [30/56]), respectively. These differences were observed in each different age group evaluated.

(web3)