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Lamivudine

Dosage Form: tablet, film coated

WARNING: LACTIC ACIDOSIS, POSTTREATMENT EXACERBATIONS OF HEPATITIS B IN CO-INFECTED PATIENTS, DIFFERENT FORMULATIONS OF Lamivudine.

Lactic Acidosis and Severe Hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Lamivudine and other antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.1)].


Exacerbations of Hepatitis B

Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued Lamivudine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue Lamivudine and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.2)].
 
Important Differences among Lamivudine-containing Products

Lamivudine tablets (used to treat HIV-1 infection) contain a higher dose of the active ingredient (Lamivudine) than EPIVIR-HBV® tablets and oral solution (used to treat chronic HBV infection). Patients with HIV-1 infection should receive only dosage forms appropriate for treatment of HIV-1 [see Warnings and Precautions (5.2)].

Indications and Usage for Lamivudine


Lamivudine tablets are a nucleoside analogue indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection. Limitation of use: The dosage of this product is for HIV-1 and not for HBV.

Lamivudine Dosage and Administration

Adult Patients

  • The recommended oral dose of Lamivudine tablets in HIV-1-infected adults is 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily, in combination with other antiretroviral agents. 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)].
  • Lamivudine tablets may be taken with or without food.

Pediatric Patients

Lamivudine tablets are available as scored tablets for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. Before prescribing Lamivudine tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow Lamivudine tablets, the oral solution formulation should be prescribed. The recommended oral dosage of Lamivudine tablets for HIV-1-infected pediatric patients is presented in Table 1.

Table 1. Dosing Recommendations for Lamivudine Scored (150 mg) Tablets in Pediatric Patients
Weight
(kg)
Twice-daily Dosing Regimen Using Scored 150 mg Tablet
AM Dose
PM Dose
Total Daily Dose
14 to <20
½  tablet (75 mg)
½ tablet (75 mg)
150 mg
≥20 to <25
½  tablet (75 mg)
1 tablet (150 mg)
225 mg
≥25
1 tablet (150 mg)
1 tablet (150 mg)
300 mg

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

Patients with Renal Impairment


Dosing of Lamivudine tablets 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 Lamivudine Tablets in Adults and Adolescents (Greater than or Equal to 25 kg) in Accordance with Creatinine Clearance

Creatinine Clearance (mL/min)
Recommended Dosage of Lamivudine Tablets
   ≥50
   150 mg twice daily or 300 mg once daily
   30 to 49
   150 mg once daily
   15 to 29
   150 mg first dose, then 100 mg once daily
   5 to 14
   150 mg first dose, then 50 mg once daily
   <5
   50 mg first dose, then 25 mg once daily

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

Although there are insufficient data to recommend a specific dose adjustment of Lamivudine tablets 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



  • Lamivudine Scored Tablets

150 mg, are white to off-white, film-coated, oval shaped tablets, debossed with ‘66’ and ‘Y’ on either side of the score line on one side and plain with a score line on the other side.


  • Lamivudine Tablets

300 mg, are white to off-white, film-coated, oval shaped tablets, debossed with ‘67 Y’ on one side and plain on the other side.

Contraindications


Lamivudine tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., anaphylaxis) to any of the components of the product.

Warnings and Precautions

Lactic Acidosis/Severe Hepatomegaly with Steatosis


Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Lamivudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular 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).

Patients with HIV-1 and Hepatitis B Virus Co-infection


Posttreatment Exacerbations of Hepatitis

In clinical trials in non-HIV-1-infected patients treated with Lamivudine for chronic hepatitis B, 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. There is insufficient evidence to determine whether re-initiation of Lamivudine alters the course of posttreatment exacerbations of hepatitis.

Important Differences among Lamivudine-containing Products

Lamivudine tablets contain a higher dose of the same active ingredient (Lamivudine) than EPIVIR-HBV tablets and EPIVIR-HBV oral solution. EPIVIR-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of Lamivudine in EPIVIR-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 EPIVIR-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, Lamivudine oral solution or another product containing the higher dose of Lamivudine should be used as part of an appropriate combination regimen.

Emergence of Lamivudine-resistant HBV

In non-HIV-1-infected patients treated with Lamivudine for chronic hepatitis B, emergence of Lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see full prescribing information for EPIVIR-HBV for additional information). Emergence of hepatitis B virus variants associated with resistance to Lamivudine has also been reported in HIV-1-infected patients who have received Lamivudine-cotaining antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

Use with Other Lamivudine- and Emtricitabine-containing Products

Lamivudine is one of multiple Lamivudine-containing products. Concomitant administration of Lamivudine with other products containing Lamivudine is not recommended. Concomitant use of Lamivudine with emtricitabine-containing products is also not recommended.

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 complete prescribing information for interferon and ribavirin.

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)].

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 system responds 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.

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.

Adverse Reactions


The following adverse reactions are discussed in greater detail in other sections of the labeling:


Clinical Trials Experience in Adult Subjects

Because 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 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)
a Either zidovudine monotherapy or zidovudine in combination with zalcitabine.
Adverse Reaction
Lamivudine 150 mg
Twice Daily
plus RETROVIR
(n = 251)
RETROVIRa
(n = 230)
Body as a Whole
 
 
    Headache
35%
27%
    Malaise & fatigue
27%
23%
    Fever or chills
10%
12%
Digestive
 
 
    Nausea
33%
29%
    Diarrhea
18%
22%
    Nausea & vomiting
13%
12%
    Anorexia and/or decreased appetite
10%
7%
    Abdominal pain
9%
11%
    Abdominal cramps
6%
3%
    Dyspepsia
5%
5%
Nervous System
 
 
    Neuropathy
12%
10%
    Insomnia & other sleep disorders
11%
7%
    Dizziness
10%
4%
    Depressive disorders
9%
4%
Respiratory
 
 
    Nasal signs & symptoms
20%
11%
    Cough
18%
13%
Skin
 
 
    Skin rashes
9%
6%
Musculoskeletal
 
 
    Musculoskeletal pain
12%
10%
    Myalgia
8%
6%
    Arthralgia
5%
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 (5.5)].


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 to 4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Trial (NUCB3007)
a The median duration on study was 12 months.
b Either zidovudine monotherapy or zidovudine in combination with zalcitabine.
c Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine.
ULN = Upper limit of normal.
ND = Not done.
Test
(Threshold Level)
24-Week Surrogate Endpoint
Trialsa
Clinical Endpoint
Triala
Lamivudine plus
RETROVIR
RETROVIRb
Lamivudine plus
Current
Therapy
Placebo plus
Current
Therapyc
Absolute neutrophil count
(<750/mm3)
7.2%
5.4%
15%
13%
Hemoglobin (<8 g/dL)
2.9%
1.8%
2.2%
3.4%
Platelets (<50,000/mm3)
0.4%
1.3%
2.8%
3.8%
ALT (>5 x ULN)
3.7%
3.6%
3.8%
1.9%
AST (>5 x ULN)
1.7%
1.8%
4%
2.1%
Bilirubin (>2.5 x ULN)
0.8%
0.4%
ND
ND
Amylase (>2 x ULN)
4.2%
1.5%
2.2%
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.

Clinical Trials Experience in Pediatric Subjects

Lamivudine oral solution has been studied in 638 pediatric subjects aged 3 months to 18 years in 3 clinical trials.

Selected clinical adverse reactions and physical findings with a greater than or equal to 5% frequency during therapy with Lamivudine 4 mg per kg twice daily plus RETROVIR 160 mg per m2 3 times daily in therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 5.

Table 5.  Selected Clinical Adverse Reactions and Physical Findings (Greater than or Equal to 5% Frequency) in Pediatric Subjects in Trial ACTG300
a  Includes pain, discharge, erythema, or swelling of an ear.
Adverse Reaction
Lamivudine plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
Body as a Whole
 
 
    Fever
25%
32%
Digestive
 
 
    Hepatomegaly
11%
11%
    Nausea & vomiting
8%
7%
    Diarrhea
8%
6%
    Stomatitis
6%
12%
    Splenomegaly
5%
8%
Respiratory
 
 
    Cough
15%
18%
    Abnormal breath sounds/wheezing
7%
9%
Ear, Nose, and Throat
 
 
    Signs or symptoms of earsa
7% 
6%
    Nasal discharge or congestion
8%
11%
Other
 
 
    Skin rashes
12%
14%
    Lymphadenopathy
9%
11%

Pancreatitis

Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric subjects receiving Lamivudine alone or in combination with other antiretroviral agents. In an open-label dose-escalation trial (NUCA2002), 14 subjects (14%) developed pancreatitis while receiving monotherapy with Lamivudine. Three of these subjects died of complications of pancreatitis. In a second open-label trial (NUCA2005), 12 subjects (18%) developed pancreatitis. In Trial ACTG300, pancreatitis was not observed in 236 subjects randomized to Lamivudine plus RETROVIR. Pancreatitis was observed in 1 subject in this trial who received open-label Lamivudine in combination with RETROVIR and ritonavir following discontinuation of didanosine monotherapy [see Warnings and Precautions (5.5)].

Paresthesias and Peripheral Neuropathies

Paresthesias and peripheral neuropathies were reported in 15 subjects (15%) in Trial NUCA2002, 6 subjects (9%) in Trial NUCA2005, and 2 subjects (less than 1%) in Trial ACTG300.

Selected laboratory abnormalities experienced by therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 6.

Table 6. Frequencies of Selected Grade 3 to 4 Laboratory Abnormalities in Pediatric Subjects in Trial ACTG300
ULN = Upper limit of normal.
Test
(Threshold Level)
Lamivudine plus
RETROVIR
Didanosine
Absolute neutrophil count (<400/mm3)
8%
3%
Hemoglobin (<7 g/dL)
4%
2%
Platelets (<50,000/mm3)
1%
3%
ALT (>10 x ULN)
1%
3%
AST (>10 x ULN)
2%
4%
Lipase (>2.5 x ULN)
3%
3%
Total Amylase (>2.5 x ULN)
3%
3%

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


Neonates

Limited short-term safety information is available from 2 small, uncontrolled trials in South Africa in neonates receiving Lamivudine with or without zidovudine for the first week of life following maternal treatment starting at Week 38 or 36 of gestation [see Clinical Pharmacology (12.3)]. Selected adverse reactions reported in these neonates included increased liver function tests, anemia, diarrhea, electrolyte disturbances, hypoglycemia, jaundice and hepatomegaly, rash, respiratory infections, and sepsis; 3 neonates died (1 from gastroenteritis with acidosis and convulsions, 1 from traumatic injury, and 1 from unknown causes). Two other nonfatal gastroenteritis or diarrhea cases were reported, including 1 with convulsions; 1 infant had transient renal insufficiency associated with dehydration. The absence of control groups limits assessments of causality, but it should be assumed that perinatally exposed infants may be at risk for adverse reactions comparable to those reported in pediatric and adult HIV-1-infected patients treated with Lamivudine-containing combination regimens. Long-term effects of in utero and infant Lamivudine exposure are not known.

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.

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, posttreatment exacerbation of hepatitis B [see Boxed Warning, Warnings and Precautions (5.1, 5.2)].

Hypersensitivity

Anaphylaxis, urticaria.

Musculoskeletal

Muscle weakness, CPK elevation, rhabdomyolysis.

Skin

Alopecia, pruritus.

Drug Interactions


Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim). No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of Lamivudine.

Interferon- and Ribavirin-based Regimens


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, 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 [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3)].

Zalcitabine


Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of Lamivudine in combination with zalcitabine is not recommended.

Trimethoprim/Sulfamethoxazole (TMP/SMX)


No change in dose of either drug is recommended. There is no information regarding the effect on Lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP.

Drugs with No Observed Interactions with Lamivudine


A drug interaction trial showed no clinically significant interaction between Lamivudine and zidovudine.

USE IN SPECIFIC POPULATIONS

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 U.S. 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 U.S. 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 embryo-lethality 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.

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.

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 [see Dosage and Administration (2.2), Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.2)].

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, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, because Lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

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)].

Overdosage


There is no known antidote for Lamivudine. One case of an adult ingesting 6 g of Lamivudine was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. Two cases of pediatric overdose were reported in Trial ACTG300. One case involved a single dose of 7 mg per kg of Lamivudine; the second case involved use of 5 mg per kg of Lamivudine twice daily for 30 days. There were no clinical signs or symptoms noted in either case. Because a negligible amount of Lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a Lamivudine overdose event. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.

Lamivudine Description


Lamivudine(also known as 3TC) is a synthetic nucleoside analogue with activity against HIV-1 and HBV. The chemical name of Lamivudine is (2R,cis)-4-amino-l-(2-hydroxymethyl-l,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. It has the following structural formula:



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

Lamivudine tablets are for oral administration. Each scored 150 mg film-coated tablet and 300 mg film-coated tablet contains 150 mg and 300 mg of Lamivudine and the following inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

Lamivudine - Clinical Pharmacology

Mechanism of Action


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

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.

Absorption and Bioavailability:
Lamivudine was rapidly absorbed after oral administration in HIV-1-infected subjects. 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 1.5 following 15 days of oral administration of 2 mg per kg twice daily.

Effects of Food on Oral Absorption:
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; therefore, Lamivudine tablets may be administered with or without food.

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 man, the only known metabolite of Lamivudine is the trans-sulfoxide metabolite. Within 12 hours after a single oral dose of Lamivudine in 6 HIV-1-infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined.



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 to 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•hr/mL)
11 + 1.7
48 ± 19
157 ± 74
   C1/F (mL/min)
464 ± 76
114 ± 34
36 ± 11

Exposure (AUC), Cmax, and half-life increased with diminishing renal function (as expressed by creatinine clearance). Apparent total oral clearance (Cl/F) of Lamivudine decreased as creatinine clearance decreased. 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.

It is not known whether Lamivudine can be removed by continuous (24-hour) hemodialysis.

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

Hepatic Impairment:
The pharmacokinetic properties of Lamivudine have been determined in adults with impaired hepatic function. Pharmacokinetic parameters were not altered by diminishing hepatic function; therefore, no dose adjustment for Lamivudine is required for patients with impaired hepatic function. Safety and efficacy of Lamivudine have not been established in the presence of decompensated liver disease.

Pediatric Patients: The pharmacokinetics of Lamivudine have been studied after either single or repeat doses of Lamivudine tablets in 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 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 (6.2)].

Additional pediatric use information for patients aged 3 months and above is approved for ViiV Healthcare Company’s EPIVIR® (Lamivudine) tablets. 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 have not been studied [see Use 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 (5.4)].



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 (5.4)].



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 [see Drug Interactions (7.3)].

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 h) [see Drug Interactions (7.4)].

Microbiology


Mechanism of Action

Intracellularly, Lamivudine is phosphorylated to its active 5'-triphosphate metabolite, Lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is the inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. 3TC-TP is a weak inhibitor of mammalian DNA polymerases α, β, and γ.

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) using standard susceptibility assays. EC50 values (50% effective concentrations) were in the range of 0.003 to 15 µM (1 µM = 0.23 mcg per mL). HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.429 µM (range: 0.2 to 2.007 µM) from Virco (n = 92 baseline samples from COLA40263) and 2.35 µM (range: 1.37 to 3.68 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of Lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.12 µM, and against HIV-2 isolates from 0.003 to 0.12 µM in peripheral blood mononuclear cells. Ribavirin (50 µM) decreased the anti-HIV-1 activity of Lamivudine by 3.5 fold in MT-4 cells. In HIV-1-infected MT-4 cells, Lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity. Please see the full prescribing information for EPIVIR-HBV for information regarding the inhibitory activity of Lamivudine against HBV.

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 (Ml84V/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. In some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with Lamivudine and zidovudine. Combination therapy with Lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.

Lamivudine-resistant HBV isolates develop substitutions (rtM204V/I) in the YMDD motif of the catalytic domain of the viral reverse transcriptase. rtM204V/I substitutions are frequently accompanied by other substitutions (rtV173L, rtL180M) which enhance the level of Lamivudine resistance or act as compensatory mutations improving replication efficiency. Other substitutions detected in Lamivudine-resistant HBV isolates include: rtL80I and rtAl81T. Similar HBV mutants have been reported in HIV-1-infected subjects who received Lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus [see Warnings and Precautions (5.2)].

Cross-resistance

Lamivudine-resistant HIV-1 mutants were cross-resistant to didanosine (ddI) and zalcitabine (ddC). In some subjects treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple reverse transcriptase inhibitors, including Lamivudine, have emerged.

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 0 of 22 subjects contained treatment-emergent amino acid substitutions associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), isolates from 10 of 22 subjects contained treatment-emergent amino acid substitutions associated with efavirenz resistance (L100I, K101E, K103N, V108I, or Y181C), and isolates from 8 of 22 subjects contained a treatment-emergent Lamivudine resistance-associated substitution (M184I or M184V).

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

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


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

Trial EPV40001: Fifty subjects received zidovudine 300 mg twice daily plus abacavir 300 mg twice daily plus Lamivudine 300 mg once daily and 50 subjects received zidovudine 300 mg plus abacavir 300 mg plus Lamivudine 150 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 Ml84V alone. On-therapy isolates from subjects (n = 6) receiving Lamivudine twice daily showed that isolates from 2 subjects had Ml84V alone, and isolates from 2 subjects harbored the Ml84V 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.

Nonclinical Toxicology

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) those observed in humans at the recommended therapeutic dose for HIV-1 infection.

Mutagenesis

Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, 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.

Clinical Studies


The use of Lamivudine 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 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.



Table 9. Number of Subjects (%) with at Least One HIV-1 Disease Progression Event or Death
aAn investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.
Endpoint
Current Therapy
(n = 460)
Lamivudine plus
Current Therapy
(n = 896)
Lamivudine 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%)

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.



Table 10. Outcomes of Randomized Treatment through 48 Weeks (Intent-to-Treat)
a Achieved confirmed plasma HIV-1 RNA less than 400 copies per 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.
Outcome
Lamivudine 300 mg
Once Daily
plus RETROVIR
plus Efavirenz
(n = 278)
Lamivudine 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%

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.

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 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.

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

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


How Supplied/Storage and Handling


Lamivudine Scored Tablets, 150 mg are white to off-white, film-coated, oval shaped tablets, debossed with ‘66’ and ‘Y’ on either side of the score line on one side and plain with a score line on the other side.

                  Bottle of 60 Tablets                                      NDC 65862-552-60
                  Carton of 60 (6 x 10) Unit-dose Tablets       NDC 65862-552-10

Lamivudine Tablets, 300 mg
are white to off-white, film-coated, oval shaped tablets, debossed with ‘67 Y’ on one side and plain on the other side.

                  Bottle of 30 Tablets                                        NDC 65862-553-30
                  Carton of 30 (3 x 10) Unit-dose Tablets         NDC 65862-553-10

Recommended Storage:

Store at
20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Lactic Acidosis/Hepatomegaly

Inform patients that some HIV medicines, including Lamivudine, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see Warnings and Precautions (5.1)].

HIV-1/HBV Co-infection

Inform patients co-infected with HIV-1 and HBV that deterioration of liver disease has occurred in some cases when treatment with Lamivudine was discontinued. Advise patients to discuss any changes in regimen with their physician [see Warnings and Precautions (5.2)].

Differences in Formulations of Lamivudine

Advise patients that Lamivudine tablets contain a higher dose of the same active ingredient (Lamivudine) as EPIVIR-HBV tablets and oral solution. If a decision is made to include Lamivudine in the HIV-1 treatment regimen of a patient co-infected with HIV-1 and HBV, the formulation and dosage of Lamivudine in Lamivudine tablets (not EPIVIR-HBV) should be used [see Warnings and Precautions (5.2)].

Use with Other Lamivudine-and Emtricitabine-containing Products

Lamivudine should not be coadministered with drugs containing Lamivudine or emtricitabine, including COMBIVIR (Lamivudine/zidovudine) tablets, EPZICOM (abacavir sulfate and Lamivudine) tablets, TRIUMEQ (dolutegravir, abacavair, Lamivudine), TRIZIVIR (abacavir sulfate, Lamivudine, and zidovudine), ATRIPLA (efavirenz, emtricitabine, and tenofovir), EMTRIVA (emtricitabine), STRIBILD (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate), TRUVADA (emtricitabine and tenofovir), or COMPLERA (rilpivirine/emtricitabine/tenofovir) [see Warnings andPrecautions (5.3)].

HIV-1/HCV Co-infection

Inform patients with HIV-1/HCV co-infection that 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 [see Warnings and Precautions (5.4)].

Risk of Pancreatitis

Advise parents or guardians to monitor pediatric patients for signs and symptoms of pancreatitis [see Warnings and Precautions (5.5)].

Redistribution/Accumulation of Body Fat

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including Lamivudine, and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.7)].

Information about HIV-1 Infection

Lamivudine is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illness. Patients should be told that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician when using Lamivudine.

Patients should be informed to take all HIV medications exactly as prescribed. If you miss a dose of Lamivudine tablets, take it as soon as you remember. Do not take 2 doses at the same time. If you are not sure about your dosing, call your healthcare provider.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.


  • Do not re-use or share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
  • Continue to practice safer sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood.
  • Female patients should be advised not to breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

PATIENT INFORMATION

Lamivudine Tablets
(la miv' ue deen)

What is the most important information I should know about Lamivudine tablets?

Lamivudine tablets 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 Lamivudine tablets or similar medicines (nucleoside analogs). Lactic acidosis is a serious medical emergency that can lead to death. Lactic acidosis can be hard to identify early because the symptoms could seem like symptoms of other health problems. 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

  • Severe liver problems. Severe liver problems can happen in people who take Lamivudine tablets or similar medicines. In some cases these liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis) when you take Lamivudine tablets. Call your healthcare provider right away if you get any of the following signs 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 severe liver problems if you are female, very overweight (obese), or have been taking nucleoside analog medicines for a long time or have risks for liver problems.

  • Worsening of hepatitis B infection. If you have HIV-1 (Human Immunodeficiency Virus) and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking Lamivudine tablets. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease from HBV can be serious and may lead to death.
  • Do not run out of Lamivudine tablets. Refill your prescription or talk to your healthcare provider before your Lamivudine tablets are all gone.
  • Do not stop Lamivudine tablets without first talking to your healthcare provider.
  • If you stop taking Lamivudine tablets, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver.

What are Lamivudine tablets?

Lamivudine tablets are a prescription HIV-1 medicine used with other antiretroviral medicines to treat HIV-1 infections in adults and children aged 3 months and older. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).

Lamivudine tablets (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.

It is not known if Lamivudine tablets are safe and effective in children under 3 months of age.

When used with other antiretroviral medicines to treat HIV-1 infection, Lamivudine tablets
may help:

  • reduce the amount of HIV-1 in your blood. This is called “viral load”.
  • increase the number of CD4+ (T) cells in your blood, which help fight off other infections

Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).

Lamivudine tablets do not cure HIV-1 infection or AIDS.
You must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses.

Avoid doing things that can spread HIV-1 infection to others:

  • Do not share or re-use needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
  • Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood.

Ask your healthcare provider if you have any questions about how to prevent passing HIV to other people.

Who should not take Lamivudine tablets?

Do not take Lamivudine tablets
if you are allergic to Lamivudine or any of the ingredients in Lamivudine tablets. See “What are the ingredients in Lamivudine tablets?”

Do not take Lamivudine tablets if you also take:

  • other medicines that contain Lamivudine (COMBIVIR®, EPIVIR-HBV®, EPZICOM®, TRIZIVIR®,TRIUMEQ®)
  • medicines that contain emtricitabine (ATRIPLA®, COMPLERA®, EMTRIVA®, STRIBILD®, TRUVADA®)

What should I tell my healthcare provider before taking Lamivudine tablets?

Before you take Lamivudine tablets, tell your healthcare provider if you:

  • have or had liver problems, including hepatitis B or C infection.
  • have kidney problems.
  • have any other medical condition.
  • are pregnant or plan to become pregnant. Taking Lamivudine tablets during pregnancy has not been associated with an increased risk of birth defects. Tell your healthcare provider if you become pregnant while taking Lamivudine tablets.

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 Lamivudine tablets.
    • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
    • Talk to 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-the counter medicines, vitamins, and herbal supplements. Keep a list of your medicines to show your healthcare provider and pharmacist. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take Lamivudine tablets with other medicines.

How should I take Lamivudine tablets?

  • Take Lamivudine tablets exactly as your healthcare provider tells you.
  • Do not change your dose or stop taking Lamivudine tablets without talking with your healthcare provider.
  • For children 3 months and older, your healthcare provider will prescribe a dose of Lamivudine tablets based on your child’s body weight.
  • Take Lamivudine tablets by mouth, with or without food.
  • Tell your healthcare provider if you have trouble swallowing tablets. Lamivudine tablets also comes as a liquid (oral solution).
  • Do not skip doses. If you miss a dose of Lamivudine tablets, take it as soon as you remember. Do not take 2 doses at the same time. If you are not sure about your dosing, call your healthcare provider.
  • If you take too much Lamivudine, call your healthcare provider or go to the nearest hospital emergency room right away. It is important to stay under your healthcare provider’s care while taking Lamivudine tablets.

What are the possible side effects of Lamivudine tablets?

Lamivudine tablets can cause serious side effects. See “What is the most important information I should know about Lamivudine tablets?”.

  • Use with interferon and ribavirin-based treatment. Worsening of liver disease that has sometimes led to 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 Lamivudine tablets and interferon with or without ribavirin, tell your healthcare provider if you have any new symptoms.
  • Risk of inflammation of the pancreas (pancreatitis). Children may be at risk for developing pancreatitis during treatment with Lamivudine tablets 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 Lamivudine tablets 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 starting your HIV-1 medicine.
  • Changes in body fat can happen in people who take HIV-1 medicines. These changes may include 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 problems are not known.

The most common side effects of Lamivudine tablets in adults include:

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

The most common side effects of Lamivudine tablets 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 Lamivudine tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Lamivudine tablets?

  • Store Lamivudine tablets at room temperature between 20° to 25°C (68° to 77°F)

Keep Lamivudine tablets and all medicines out of the reach of children.

General information about the safe and effective use of Lamivudine tablets.

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

If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Lamivudine tablets that is written for health professionals.

For more information call Aurobindo Pharma USA, Inc. at 1-866-850-2876.

What are the ingredients in Lamivudine tablets?

Active ingredient:
Lamivudine

Inactive ingredients:
hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

This Patient Information has been approved by the U.S. Food and Drug Administration.

The brands listed are trademarks of their respective owners and are not trademarks of the Aurobindo Pharma Limited. The makers of these brands are not affiliated with and do not endorse the Aurobindo Pharma Limited or its products.

Manufactured for:
Aurobindo Pharma USA, Inc.
2400 Route 130 North
Dayton, NJ 08810

Manufactured by:
Aurobindo Pharma Limited
Unit-VII (SEZ)
Mahaboob Nagar (Dt)-509302
India

Revised: 07/2015

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 150 mg (60 Tablets Bottle)


NDC 65862-552-60
Lamivudine Tablets
150 mg
Rx only           60 Tablets
AUROBINDO 


PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 150 mg Blister Carton (6 x 10 Unit-dose)


NDC 65862-552-10
Lamivudine Tablets 150 mg
Rx only           60 (6 x 10) Unit-dose Tablets
AUROBINDO


PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 300 mg (30 Tablets Bottle)


NDC 65862-553-30
Lamivudine Tablets
300 mg
Rx only           30 Tablets
AUROBINDO 


PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 300 mg Blister Carton (3 x 10 Unit-dose)


NDC 65862-553-10
Lamivudine Tablets 300 mg
Rx only           30 (3 x 10) Unit-dose Tablets
AUROBINDO


Lamivudine 
Lamivudine tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:65862-552
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Lamivudine (Lamivudine) Lamivudine 150 mg
Inactive Ingredients
Ingredient Name Strength
HYPROMELLOSE 2910 (5 MPA.S)  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POLYETHYLENE GLYCOL 400  
POLYSORBATE 80  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
TITANIUM DIOXIDE  
Product Characteristics
Color WHITE (White to Off-white) Score 2 pieces
Shape OVAL Size 12mm
Flavor Imprint Code 66;Y
Contains         
Packaging
# Item Code Package Description
1 NDC:65862-552-60 60 TABLET, FILM COATED in 1 BOTTLE
2 NDC:65862-552-10 6 BLISTER PACK in 1 CARTON
2 10 TABLET, FILM COATED in 1 BLISTER PACK
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA202032 11/17/2011
Lamivudine 
Lamivudine tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:65862-553
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Lamivudine (Lamivudine) Lamivudine 300 mg
Inactive Ingredients
Ingredient Name Strength
HYPROMELLOSE 2910 (5 MPA.S)  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POLYETHYLENE GLYCOL 400  
POLYSORBATE 80  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
TITANIUM DIOXIDE  
Product Characteristics
Color WHITE (White to Off-white) Score no score
Shape OVAL Size 16mm
Flavor Imprint Code 67;Y
Contains         
Packaging
# Item Code Package Description
1 NDC:65862-553-30 30 TABLET, FILM COATED in 1 BOTTLE
2 NDC:65862-553-10 3 BLISTER PACK in 1 CARTON
2 10 TABLET, FILM COATED in 1 BLISTER PACK
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA202032 11/17/2011
Labeler - Aurobindo Pharma Limited (650082092)
Establishment
Name Address ID/FEI Operations
Aurobindo Pharma Limited 650381903 ANALYSIS(65862-552, 65862-553), MANUFACTURE(65862-552, 65862-553)
Establishment
Name Address ID/FEI Operations
Aurobindo Pharma Limited 918917626 API MANUFACTURE(65862-552, 65862-553)
Revised: 07/2015
 
Aurobindo Pharma Limited
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