2.1 Recommended Dosage for Adult Patients

The recommended dosage of LAMIVUDINE 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)].

2.2 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 (up to a maximum of 300 mg daily), administered in combination with other antiretroviral agents.

Once daily dosing in pediatric patients 3 months of age and older in combination with other antiretroviral agents for the treatment of HIV-1 infection.

LAMIVUDINE 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 LAMIVUDINE scored tablets, pediatric patients should be assessed for the ability to swallow tablets. For patients unable to safely and reliably swallow LAMIVUDINE tablets, the oral solution formulation should be prescribed [see Warnings and Precautions (5.6)]. The recommended oral dosage of LAMIVUDINE tablets for HIV-l-infected pediatric patients is presented in Table 1.

Additional pediatric use information for patients aged 3 months and above is approved for ViiV Healthcare Company’s EPIVIR® (lamivudine) tablets and oral solution. However, due to ViiV Healthcare Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.3 Patients with Renal Impairment

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

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

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

5.1 Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering LAMIVUDINE to any patient with known risk factors for liver disease; however, cases also have been reported in patients with no known risk factors. Treatment with LAMIVUDINE should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

5.2 Patients with and Hepatitis B Virus Co-infection

Posttreatment Exacerbations of Hepatitis

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Important Differences among Lamivudine-containing Products

LAMIVUDINE tablets contain a higher dose of the same active ingredient (lamivudine) than LAMIVUDINE-HBV tablets. LAMIVUDINE-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of lamivudine in LAMIVUDINE-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. If treatment with LAMIVUDINE-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment. If a decision is made to administer lamivudine to patients co-infected with HIV-1 and HBV, LAMIVUDINE tablets, or another product containing the higher dose of lamivudine should be used as part of an appropriate combination regimen.

Emergence of Lamivudine-resistant HBV

Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV (see full prescribing information for LAMIVUDINE-HBV). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

5.3 Use with Interferon- and Ribavirin-based Regimens

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients[see Clinical Pharmacology (12.3)], hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and LAMIVUDINE should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of LAMIVUDINE should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). See the full prescribing information for interferon and ribavirin.

5.4 Pancreatitis

In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, LAMIVUDINE should be used with caution. Treatment with LAMIVUDINE should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)].

5.5 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including LAMIVUDINE. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus,Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.6 Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution

Pediatric subjects who received LAMIVUDINE oral solution concomitantly with other antiretroviral oral solutions at any time in the ARROW trial had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving LAMIVUDINE tablets[see Clinical Pharmacology (12.3),Microbiology (12.4),Clinical Studies (14.2)].

LAMIVUDINE 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. Consider more frequent monitoring of HIV-1 viral load when treating with LAMIVUDINE oral solution.

5.7 Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

6.1 Clinical Trials Experience

Clinical Trials Experience in Adult SubjectsBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The safety profile of LAMIVUDINE in adults is primarily based on 3,568 HIV-1-infected subjects in 7 clinical trials.The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea, and cough.Selected clinical adverse reactions in greater than or equal to 5% of subjects during therapy with LAMIVUDINE 150 mg twice daily plus RETROVIR® 200 mg 3 times daily for up to 24 weeks are listed in Table 3. Table 3. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002)Adverse ReactionLAMIVUDINE 150 mgTwice Dailyplus RETROVIR(n = 251)RETROVIRaEither zidovudine monotherapy or zidovudine in combination with zalcitabine.(n = 230)Body as a WholeHeadache35%27%Malaise & fatigue27%23%Fever or chills10%12%DigestiveNausea33%29%Diarrhea18%22%Nausea & vomiting13%12%Anorexia and/or decreased appetite10%7%Abdominal pain9%11%Abdominal cramps6%3%Dyspepsia5%5%Nervous SystemNeuropathy12%10%Insomnia & other sleep disorders11%7%Dizziness10%4%Depressive disorders9%4%RespiratoryNasal signs & symptoms20%11%Cough18%13%SkinSkin rashes9%6%MusculoskeletalMusculoskeletal pain12%10%Myalgia8%6%Arthralgia5%5%Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult subjects (0.3%) who received LAMIVUDINE in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007 [see Warnings and Precautions (5.4)].LAMIVUDINE 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in subjects receiving LAMIVUDINE 300 mg once daily or LAMIVUDINE 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) for 48 weeks were similar. Selected laboratory abnormalities observed during therapy are summarized in Table 4.Table 4. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Trial (NUCB3007)ULN = Upper limit of normal.ND = Not done.Test (Threshold Level)24-Week Surrogate EndpointClinical Endpoint TrialThe median duration on study was 12 months.LAMIVUDINE plus RETROVIREither zidovudine monotherapy or zidovudine in combination with zalcitabine.LAMIVUDINE plus Current TherapyCurrent therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine.Placebo plus Current TherapyAbsolute neutrophil count(<750/mm3)7.2%5.415%13%Hemoglobin (<8.0 g/dL)2.9%1.82.2%3.4%Platelets (<50,000/mm3)0.4%1.32.8%3.8%ALT (>5.0 x ULN)3.7%3.63.8%1.9%AST (>5.0 x ULN)1.7%1.84.0%2.1%Bilirubin (>2.5 x ULN)0.8%0.4NDNDAmylase (>2.0 x ULN)4.2%1.52.2%1.1%The frequencies of selected laboratory abnormalities reported in subjects receiving LAMIVUDINE 300 mg once daily or LAMIVUDINE 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of LAMIVUDINE.Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine.

Body as a Whole

Redistribution/accumulation of body fat [see Warnings and Precautions (5.7)].

Endocrine and Metabolic

Hyperglycemia.

a. General:

Weakness.

Hemic and Lymphatic

Anemia (including pure red cell aplasia and severe anemias progressing on therapy).

Hepatic and Pancreatic

Lactic acidosis and hepatic steatosis, [see Warnings and Precautions (5.1)], post treatment exacerbation of hepatitis B.[see Warnings and Precautions (5.2)].

Hypersensitivity

Anaphylaxis, urticaria.

Musculoskeletal

Muscle weakness, CPK elevation, rhabdomyolysis.

Skin

Alopecia, pruritus.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LAMIVUDINE during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

Risk Summary

Available 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 of 2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Lamivudine produced embryonic toxicity in rabbits at a dose that produced similar human exposures as the recommended clinical dose. The relevance of animal findings to human pregnancy registry data is not known.

Data

Human Data: Based on prospective reports from the Antiretroviral Pregnancy Registry of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,300 exposed in the first trimester), there was no difference between lamivudine and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population of the MACDP. The prevalence of defects in the first trimester was 3.1% (95% CI: 2.6% to 3.7%).

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials 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 trials 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, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg per mL (150 mg twice daily) and 2.1 to 5.2 mcg per mL (300 mg twice daily).

Animal Data: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans.

8.2 Lactation

Risk Summary

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 HIV-1 transmission mothers should be instructed not to breastfeed.

8.4 Pediatric Use

The safety and effectiveness of LAMIVUDINE in combination with other antiretroviral agents have been established in pediatric patients aged 3 months and older. LAMIVUDINE 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 because pediatric subjects who received LAMIVUDINE oral solution had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving LAMIVUDINE tablets in the ARROW trial [see Dosage and Administration (2.2),Warnings and Precautions (5.6),Adverse Reactions (6.1),Clinical Pharmacology (12.3),Clinical Studies (14.2)].

8.6 Patients with Impaired Renal Function

Reduction of the dosage of LAMIVUDINE is recommended for patients with impaired renal function

[see Dosage and Administration (2.3),Clinical Pharmacology (12.3)].

8.5 Geriatric Use

Clinical trials of LAMIVUDINE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.In general, caution should be exercised in the administration of LAMIVUDINE in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease orother drug therapy [see Dosage and Administration (2.3),Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Lamivudine is an antiviral agent [see Microbiology (12.4)].

12.3 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 LAMIVUDINE 300-mg tablet once daily for 7 days compared with the LAMIVUDINE 150-mg tablet twice daily for 7 days were assessed in a crossover trial in 60 healthy subjects. LAMIVUDINE 300 mg once daily resulted in lamivudine exposures that were similar to LAMIVUDINE 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. 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: LAMIVUDINE tablets 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); Cmaxin 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 oraldose 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 studies 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).

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 (2.3)].

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 LAMIVUDINE in pediatric subjects. Pediatric subjects receiving lamivudine oral tablets achieved plasma concentrations comparable to or slightly higher than those observed in adults. The absolute bioavailability of both LAMIVUDINE tablets and oral solution are lower in children than adults. The relative bioavailability of LAMIVUDINE 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.

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 (6.1)].

Additional pediatric use information for patients aged 3 months and above is approved for ViiV Healthcare Company’s EPIVIR® (lamivudine) tablets and oral solution. However, due to ViiV Healthcare Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Geriatric Patients: The pharmacokinetics of lamivudine after administration of LAMIVUDINE to subjects over 65 years of age have not been studied[seeUse in Specific Populations (8.5)].

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

Race: There are no significant 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 (5.3)].

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 (5.3)].

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).

12.4 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) 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 isoleucine or valine (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. Dosing LAMIVUDINE 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 (I or V) [see Clinical Studies (14.2)].

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.

Mutagenesis

Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg per kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-1 infection.

Impairment of Fertility

In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

14.1 Adult Subjects

Clinical Endpoint Trial:

NUCB3007 (CAESAR) was a multi-center, 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 LAMIVUDINE or LAMIVUDINE 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.

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 multi-center, double-blind, controlled trial in which subjects were randomized 1:1 to receive LAMIVUDINE 300 mg once daily or LAMIVUDINE 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, EPV20001 12 (Intent-to-Treat)

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 LAMIVUDINE 300 mg once daily and 63% for subjects receiving LAMIVUDINE 150 mg twice daily. Median increases in CD4+ cell counts were 144 cells per mm3 at Week 48 in subjects receiving LAMIVUDINE 300 mg once daily and 146 cells per mm3 for subjects receiving LAMIVUDINE 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.

1

An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.Achieved confirmed plasma HIV-1 RNA less than 400 copies/mL and maintained through 48 weeks.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.Includes consent withdrawn, lost to follow-up, protocol violation, data outside the trial-defined schedule, and randomized but never initiated treatment.Roche AMPLICOR HIV-1 MONITOR.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.

2

An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.Achieved confirmed plasma HIV-1 RNA less than 400 copies/mL and maintained through 48 weeks.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.Includes consent withdrawn, lost to follow-up, protocol violation, data outside the trial-defined schedule, and randomized but never initiated treatment.Roche AMPLICOR HIV-1 MONITOR.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.

14.2 Pediatric Subjects

Clinical Endpoint Trial:

ACTG300 was a multi-center, randomized, double-blind trial that provided for comparison of LAMIVUDINE 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 LAMIVUDINE plus RETROVIR and 9.2 months for subjects receiving didanosine monotherapy. Results are summarized in Table 11.

Additional pediatric use information for patients aged 3 months and above is approved for ViiV Healthcare Company’s EPIVIR® (lamivudine) tablets and oral solution. However, due to ViiV Healthcare Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.