Lamivudine

Camber Pharmaceuticals, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use lamivudine safely and effectively. See full prescribing information for lamivudine.Lamivudine TabletsInitial U.S. Approval: 1995Rx OnlyRECENT MAJOR CHANGESWarnings and Precautions, Immune ---------------(11/2011)Reconstitution Syndrome (5.6)BOXED WARNING WARNING: LACTIC ACIDOSIS, POSTTREATMENT EXACERBATIONS OF HEPATITS B IN CO-INFECTED PATIENTS, DIFFERENT FORMULATIONS OF LAMIVUDINE See full prescribing information for complete boxed warning • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.( 5.1 )• 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-l)and have discontinued lamivudine. Monitor hepatic function closely in these patients and, if appropriate, initiate anti- hepatitis B treatment.( 5.2 )• Patients with HIV-1 infection should receive only dosage forms of lamivudine appropriate for treatment of HIV-l.( 5.2)INDICATIONS AND USAGELamivudine tablet is a nucleoside analogue reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Limitation of Use:The dosage of this product is for HIV-1 and not for HBV. (1)DOSAGE AND ADMINISTRATION• Adults and adolescents >16 years of age: 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily. (2.1)• Pediatric patients 3 months up to 16 years of age: Dosage should be based on body weight. (2.2).• Patients With Renal Impairment: Doses of lamivudine must be adjusted in accordance with renal function. (2.3)DOSAGE FORMS AND STRENGTHS• Tablets: 300 mg (3)• Tablets: Scored 150 mg (3)CONTRAINDICATIONSLamivudine Tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., anaphylaxis) to any of the components of the products. (4)WARNINGS AND PRECAUTIONS• Lactic acidosis and severe hepatomegaly with steatosis: Reported with the use of nucleoside analogues. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatoxicity occur. (5.1)• Severe acute exacerbations of hepatitis: Reported in patients who are co-infected with hepatitis B virus and HIV-1 and discontinued lamivudine. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. (5.2)• Patients with HIV-1 infection should receive only dosage forms of lamivudine appropriate for treatment of HIV-1. (5.2)• Co-infected HIV-1/HBV Patients: Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. (5.2)• Emtricitabine should not be administered concomitantly with lamivudine-containing products. (5.3)• Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving interferon and ribavirin-based regimens. Monitor for treatment- associated toxicities. Discontinue lamivudine as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.4)• Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. (5.5)• Immune reconstitution syndrome (5.6) and redistribution/accumulation of body fat (5.7) have been reported in patients treated with combination antiretroviral therapy.Side Effects• The most common reported adverse reactions (incidence ≥15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. (6.1)• The most common reported adverse reactions (incidence ≥15%) in pediatric patients were fever and cough. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONSZalcitabine is not recommended for use in combination with lamivudine. (7.2)USE IN SPECIFIC POPULATIONSPregnancy: Physicians are encouraged to register patients in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263. (8.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: RISK OF LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B IN CO- INFECTED PATIENTS UPON DISCONTINUATION OF LAMIVUDINE, DIFFERENT FORMULATIONS OF LAMIVUDINE.
• 1 INDICATIONS & USAGE
• 2 DOSAGE & ADMINISTRATION
  • 2.1 Adults and Adolescents >16 years of age
  • 2.2 Pediatric Patients
  • 2.3 Patients With Renal Impairment
• 3 DOSAGE FORMS & STRENGTHS
• 4 LAMIVUDINE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Lactic Acidosis/Severe Hepatomegaly With Steatosis
  • 5.2 Patients With HIV-1 and Hepatitis B Virus Co-infection
  • 5.3 Use With Other Lamivudine- and Emtricitabine-Containing Products
  • 5.4 Use With Interferon- and Ribavirin-Based Regimens
  • 5.5 Pancreatitis
  • 5.6 Immune Reconstitution Syndrome
  • 5.7 Fat Redistribution
• 6 LAMIVUDINE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Interferon- and Ribavirin-Based Regimens
  • 7.2 Zalcitabine
  • 7.3 Trimethoprim/Sulfamethoxazole (TMP/SMX)
  • 7.4 Drugs with No Observed Interactions With lamivudine
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Patients With Impaired Renal Function
• 10 OVERDOSAGE
• 11 LAMIVUDINE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
  • 12.4 Microbiology
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility
  • 13.2 Reproductive Toxicology Studies
• 14 CLINICAL STUDIES
  • 14.1 Adults
  • 14.2 Pediatric Patients
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Advice for the Patient
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

1 INDICATIONS & USAGE

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

2 DOSAGE & ADMINISTRATION

2.1 Adults and Adolescents >16 years of age

The recommended oral dose of lamivudine in HIV-1-infected adults and adolescents >16 years of age 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-l therapy should be used as part of an appropriate combination regimen [see Warnings and Precautions (5.2)].

2.2 Pediatric Patients

Lamivudine is also available as a scored tablet for HIV-l-infected pediatric patients who weigh ≥14 kg 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 Tablets in Pediatric Patients

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)].

Table 2. Adjustment of Dosage of Lamivudine in Adults and Adolescents (≥30 kg) in Accordance With Creatinine Clearance

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.

3 DOSAGE FORMS & STRENGTHS

• Lamivudine Scored Tablets
 150 mg, are white capsule shaped, biconvex, scored film coated tablets debossed with ‘J’ on one side and ‘16’ on the other side, 1 and 6 seperated by a score line.
• Lamivudine Tablets
300 mg, are white capsule shaped, biconvex, film coated tablets debossed with ‘17’ on one side and ‘J’ on the other side.

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 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).

5.2 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. 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, COMBIVIR^® (lamivudine/zidovudine) Tablets, EPZICOM^®(abacavir sulfate and lamivudine) Tablets, or TRIZIVIR^®(abacavir sulfate, lamivudine, and zidovudine) Tablets should be used as part of an appropriate combination regimen.

Emergence of Lamivudine-Resistant HBV:In non-HIV-l-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-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

5.3 Use With Other Lamivudine- and Emtricitabine-Containing Products

Lamivudine should not be administered concomitantly with other lamivudine- containing products including EPIVIR-HBV Tablets,COMBIVIR (lamivudine/zidovudine) Tablets, EPZICOM (abacavir sulfate and lamivudine) Tablets, or TRIZIVIR (abacavir sulfate, lamivudine, and zidovudine) or emtricitabine-containing products, including ATRIPLA^® (efavirenz, emtricitabine, and tenofovir), EMTRIVA^®(emtricitabine), or TRUVADA^® (emtricitabine and tenofovir), or COMPLERA^TM (rilpivirine/emtricitabine/tenofovir).

5.4 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-l/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-l/HCV co-infected patients [see Clinical Pharmacology (12.3) ], hepatic decompensation (some fatal) has occurred in HIV-l/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 >6). See the complete prescribing information for interferon and ribavirin.

5.5 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)].

5.6 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretrovira1 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.

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 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:
• Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.1)].
• Severe acute exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.2)].
• Hepatic decompensation in patients co-infected with HIV-l and Hepatitis C [see Warnings and Precautions (5.4)].
• Pancreatitis [see Warnings and Precautions (5.5)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults - Clinical Trials in HIV-1: The safety profile of lamivudine in adults is primarily based on 3,568 HIV-l-infected patients 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 of in ≥5% of patients during therapy with lamivudine 150 mg twice daily plus zidovudine 200 mg 3 times daily for up to 24 weeks are listed in Table 3.

Table 3. Selected Clinical Adverse Reactions (≥5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) 

^aEither zidovudine monotherapy or zidovudine in combination with zalcitabine.

Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult patients (0.3%) who  received  lamivudine  in  the  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 patients receiving lamivudine 300 mg once daily or lamivudine
150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) for48 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 Studies (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical End point Study (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 didonasine, or zidovudine plus zalcitabine
ULN = Upper limit of normal. ND = Not done.

The frequencies of selected laboratory abnormalities reported in patients receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.

Pediatric Patients - Clinical Trials in HIV-1: Selected clinical adverse reactions and physical findings with a ≥5% frequency during therapy with lamivudine 4 mg/kg twice daily plus zidovudine 160 mg/m² 3 times daily in therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are listed in Table 5.

Table 5. Seleted Clinical Adverse Reactions and Physical Findings (≥5% frequency) in Pediatric Patients in Study ACTG300

^aIncludes pain, discharge, erythema, or swelling of an ear.

Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric patients receiving lamivudine alone or in combination with other antiretroviral agents. In an open-label dose-escalation study (NUCA2002), 14 patients (14%) developed pancreatitis while receiving monotherapy with  lamivudine.  Three  of  these  patients  died of  complications  of  pancreatitis.  In  a second  open-label  study  (NUCA2005),  12  patients  (18%)  developed  pancreatitis.  In Study ACTG300, pancreatitis was not observed in 236 patients randomized to lamivudine plus zidovudine. Pancreatitis was observed in 1 patient in this study who received open- label lamivudine in combination with zidovudine 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 patients (15%) in Study NUCA2002, 6 patients (9%) in Study NUCA2005, and 2 patients (<1%) in Study ACTG300.

Selected laboratory abnormalities experienced by therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are listed in Table 6.

Table 6.  Frequencies of Selected Grade 3 to 4 Laboratory Abnormalities in Pediatric Patients in Study ACTG300

ULN = Upper limit of normal.

Neonates - Clinical Trials in HIV-1: Limited short-term safety information is available  from  2  small,  uncontrolled  studies 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 (1from 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.

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported during postmarketing use of lamivudine. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine.

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

7 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.

7.1 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-l/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV–l/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)].

7.2 Zalcitabine

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

7.3 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.

7.4 Drugs with No Observed Interactions With lamivudine

A drug interaction study showedno clinically significant interaction between lamivudine and zidovudine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic  Effects:  Pregnancy  Category  C.  There  are  no  adequate  and  well- controlled studies of lamivudine in pregnant women. Animal reproduction studies in rats and  rabbits  revealed  no  evidence  of  teratogenicity.  Increased  early  embryolethality occurred in rabbits at exposure levels similar to those in humans. Lamivudine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical studies conducted in South Africa. The study assessed pharmacokinetics in: 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. These studies were not designed or powered to provide efficacy information. Lamivudine pharmacokinetics in the pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, lamivudine amniotic  fluid  specimens  were  collected  following  natural  rupture  of  membranes. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily). It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1- infected patients.

Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus. [see Non clinical Toxicology (13.2)].

Antiretroviral  Pregnancy  Registry:  To  monitor  maternal-fetal  outcomes  of pregnant women exposed to lamivudine, a Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

8.3 Nursing Mothers

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-l infection. Because of the potential for serious adverse reactions in nursing infants and HIV-l transmission, mothers should be instructed not to breastfeed if they are receiving lamivudine.

Lamivudine is excreted into human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.

8.4 Pediatric Use

The safety and effectiveness of twice-daily lamivudine in combination with other antiretroviral agents have been established in pediatric patients 3 months and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)].

8.5 Geriatric Use

Clinical studies 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)].

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)]

10 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 Study ACTG300. One case involved a single dose of 7 mg/kg of lamivudine; the second case involved use of 5 mg/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.

11 DESCRIPTION

Lamivudine USP (also known as 3TC), a synthetic nucleoside analogue with activity against HIV-1 and HBV. The chemical name of lamivudine USP is 2(1H) - Pyrimidinone, 4-amino-1- [2- (hydroxymethyl)-1,3-oxathio-lan-5-yl], (2R-cis)-. It has a molecular formula of C₈H₁₁N₃O₃S and a molecular weight of 229.26. It has the following structural formula:

Lamivudine USP is a white to an off white solid and soluble in water.

Lamivudine tablets are for oral administration. Each film-coated tablet contains 150 mg or 300 mg of lamivudine USP and the following inactive ingredients: crospovidone, isomalt, isopropyl alcohol, magnesium stearate and methylene chloride. The tablets are coated with opadry white containing hypromellose, polyethylene glycol, polysorbate 80 and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

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

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

The steady-state pharmacokinetics 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 study in 60 healthy volunteers. Lamivudine 300 mg once daily resulted in lamivudine exposures that were similar to lamivudine 150 mg twice daily with respect to plasma AUC_24,.ss; however, C _max,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 AUC_24,ss and C_max24,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 clinical significance   of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.

Absorption  and  Bioavailability:  Lamivudine  was  rapidly  absorbed  after  oral administration in HIV-1-infected patients. Absolute bioavailability in 12 adult patients was 86%±16% (mean ± SD) for the 150-mg tablet and 87%±13% for the oral solution. After oral administration of 2 mg/kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (C_max) was 1.5 ±0.5 mcg/mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and C_max increased in proportion to oral dose over the range from 0.25 to 10 mg/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/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  patients  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); C_max 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 patients was 1.3± 0.4 L/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 (<36%). In vitro studies showed  that  over  the  concentration  range  of  0.1  to  100  mcg/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-l-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/min (mean ± SD). In 20 HIV-l-infected patients given a single IV dose, renal clearance was 280.4 ± 75.2 mL/min (mean ± SD), representing 71% ± 16% (mean ±SD) of total clearance of lamivudine.

In most single-dose studies in HIV-1-infected patients, HBV-infected patients, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t1/2) ranged from 5 to 7 hours. In HIV-1-infected patients, total clearance was 398.5 ± 69.1 mL/min (mean ± SD). Oral clearance and elimination half- life were independent of dose and body weight over an oral dosing range of 0.25 to10 mg/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

Exposure (AUC∞), C_max, 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  study  in  otherwise  healthy  subjects  with  impaired  renal  function, hemodialysis increased lamivudine clearance from a mean of 64 to 88 mL/min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single dose administration. Continuous ambulatory peritoneal   dialysis  and  automated   peritoneal   dialysis   have   negligible   effects   on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine  clearance,  that  no  additional  dose  modification  be  made  after  routine hemodialysis or peritoneal dialysis.

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

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

Hepatic Impairment: 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 decompensate liver disease.

Pediatric Patients: In Study NUCA2002, pharmacokinetic properties of lamivudine were assessed in a subset of 57 HIV-1-infected pediatric patients (age range:
4.8 months to 16 years, weight range: 5 to 66 kg) after oral and IV administration of 1, 2,4, 8, 12, and 20 mg/kg/day. The mechanism for the diminished absolute bioavailabilty of lamivudine in infants and children is unknown.

Systemic clearance decreased with increasing age in pediatric patients, as shown in Figure 1.

Figure 1. Systemic Clearance (L/hr•kg) of Lamivudine in Relation to Age

After  oral  administration  of  lamivudine  4  mg/kg  twice  daily  to  11  pediatric patients ranging from 4 months to 14 years of age, C_max was 1.1 ± 0.6 mcg/mL and half- life was 2.0 ± 0.6 hours. (In adults with similar blood sampling, the half-life was 3.7 ± 1 hours.) Total exposure to lamivudine, as reflected by mean AUC values, was comparable  between  pediatric  patients  receiving  an  8-mg/kg/day  dose  and  adults receiving a 4-mg/kg/day dose.

Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric patients after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose. At the dose of 8 mg/kg/day, CSF lamivudine concentrations in 8 patients ranged from 5.6% to 30.9% (mean ± SD of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg/mL.

Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants up to 1 week of age in 2 studies in South Africa. In these studies, lamivudine clearance was substantially reduced in  1-week-old  neonates  relative  to  pediatric  patients  (>3  months  of  age)  studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges >3 months old [see Adverse Reactions (6.1)].

Geriatric Patients: The pharmacokinetics of lamivudine after administration of lamivudine to patients over 65 years of age 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 study 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-l/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-l/HCV co-infected patients [see Warnings and Precautions (5.4)].

Trimethoprim/Sulfamethoxazole: Lamivudine and TMP/SMX were co administered to 14 HIV-1-positive patients in a single-center, open-label, randomized, crossover study. Each patient received treatment with a single 300-mg dose of lamivudine and TMP160  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-l-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr) [see Drug Interactions (7.4)].

12.4 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-l 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 15µM (l µM = 0.23 mcg/mL). HIV-l from therapy-naive subjects with no amino acid substitutions associated with resistance gavemedian EC₅₀ values of 0.429 µM (range: 0.200 to 2.007 µM) from Virco (n = 92 baseline samples from COLA40263) and 2.35 µM (1.37 to 3.68 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC₅₀  values of lamivudine against different HIV-l clades (A-G) ranged from 0.001 to 0.120 µM, and against HIV-2 isolates from 0.003  to  0.120  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 (M184V/I).

HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from  patients.  Susceptibility  of  clinical  isolates  to  lamivudine  and  zidovudine  was monitored in controlled clinical trials. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination  therapy  with  lamivudine  plus  zidovudine  delayed  the  emergence  of mutations conferring resistance to zidovudine.

Lamivudine-resistant  HBV  isolates  develop  substitutions  (rtM204V/I)  in  the YMDD  motif  of  the  catalytic  domain  of  the  viral  reverse  transcriptase.  rtM204V/I substitutions  are  frequently  accompanied  by  other  substitutions  (rtV173L,  rtL180M) which enhance the level of lamivudine resistance or act as compensatory mutations improving  replication  efficiency.  Other  substitutions  detected  in  lamivudine-resistant HBV isolates include: rtL80I and rtA181T. Similar HBV mutants have been reported in HIV-1-infected patients who received lamivudine-containing antiretroviral regimens in the  presence  of  concurrent  infection  with  hepatitis  B  virus  [see  Warnings  and Precautions (5.2)].

Cross-Resistance: Lamivudine-resistant HIV-1 mutants were cross-resistant to didanosine (ddI) and zalcitabine (ddC). In some patients 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 Patients With Virologic Failure: Study EPV20001: Fifty-three of 554 (10%) patients enrolled in EPV20001 were identified as virological failures (plasma HIV-l RNA level ≥400 copies/mL) by Week 48. Twenty-eight patients were randomized to the lamivudine once-daily treatment group and 25 to the lamivudine twice-daily treatment group. The median baseline plasma HIV-l RNA levels of patients in the lamivudine once-daily group and lamivudine twice-daily group were 4.9 log10  copies/mL and 4.6 log10  copies/mL, respectively.

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

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

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

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

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

Genotypic analysis of on-therapy HIV-1 isolates from patients (n = 9) in the lamivudine  once-daily  treatment  group  showed  that  isolates  from  6  patients  had  an abacavir and/or lamivudine resistance-associated substitution M184V alone. On-therapy isolates from patients (n = 6) receiving lamivudine twice daily showed that isolates from 2 patients had M184 and isolates from 2 patients harbored the M184Vsubstitution in combination with zidovudine resistance-associated amino acid substitutions.

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

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

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-l infection. 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/kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-l infection. In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg/kg/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.

13.2 Reproductive Toxicology Studies

Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that for the 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. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.

14 CLINICAL STUDIES

The use of lamivudine is based on the results of clinical studies in HIV-1-infected patients in combination regimens with other antiretroviral agents. Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-l RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials.

14.1 Adults

Clinical Endpoint Study: NUCB3007 (CAESAR) was a multi-center, double-blind, placebo-controlled study comparing continued current therapy (zidovudine alone [62% of  patients]  or  zidovudine  with  didanosine  or  zalcitabine  [38%  of  patients])  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-l-infected adults with 25 to 250 CD4+ cells/mm³  (median = 122 cells/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  study  was  12  months.  Results  are summarized in Table 8.

Table 8. Number of Patients (%) With at Least One HIV-1 Disease Progression Event or Death

^a An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States

Surrogate Endpoint Studies: Dual Nucleoside Analogue Studies: Principal clinical trials  in  the  initial  development  of  lamivudine  compared  lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine. These studies 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 Studies in Therapy-Naive Adults: EPV20001 was a multi-center, double-blind, controlled study in which patients 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%), Caucasian (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells/mm³  (median = 362 cells/mm³), and median baseline plasma HIV-1 RNA of 4.66 log₁₀ copies/mL. Outcomes of treatment through 48 weeks are summarized in Figure 2 and Table 9.

Figure 2. Virologic Response Through Week 48, EPV20001^ab (Intent-to-Treat)

^a Roche AMPLICOR HIV-1 MONITOR.
^b Responders at each visit are patients who had achieved and maintained
HIV-1 RNA<400 copies/mL without discontinuation by that visit.

Table 9. Outcomes of Randomized Treatment Through 48 Weeks (Intent-to- Treat)

^a Achieved confirmed plasma HIV-1 RNA <400 copies/mL and maintained through 48 weeks.
^b Achieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through 
  Week 48.
^c Includes consent withdrawn, lost to followup, protocol violation, data outside the study-defined schedule, and randomized but never initiated treatment.

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

A  small,  randomized,  open-label  pilot  study,  EPV40001,  was  conducted  in Thailand. A total of 159 treatment-naive adult patients (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells/mm³, median plasma HIV-1 RNA  4.8  log₁₀  copies/mL)  were  enrolled.  Two  of  the  treatment  arms  in  this  study provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and  abacavir  300  mg  twice  daily.  In  intent-to-treat  analyses  of  48-week  data,  the proportions of patients with HIV-1 RNA below 400 copies/mL were 61% (33/54) in the group randomized to once-daily lamivudine and 75% (39/52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-l RNA below 50 copies/mL were 54% (29/54) in the once-daily lamivudine group and 67% (35/52) in the all-twice- daily group; and the median increases in CD4+ cell counts were 166 cells/mm³  in the once-daily lamivudine group and 216 cells/mm³ in the all-twice-daily group. 

14.2 Pediatric Patients

Clinical Endpoint Study: ACTG300 was a multi-center, randomized, double-blind study that provided for comparison of lamivudine plus RETROVIR (zidovudine) with didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive (≤56 days of antiretroviral therapy) pediatric patients 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-Caucasian. The mean baseline CD4+ cell count was 868 cells/mm³  (mean: 1,060 cells/mm3 and range: 0 to 4,650 cells/mm3 for patients ≤5 years of age; mean: 419 cells/mm³  and range: 0 to 1,555 cells/mm³  for patients >5 years of age) and the mean baseline plasma HIV-1 RNA was 5.0 log₁₀ copies/mL. The median duration on study was 10.1 months for the patients receiving lamivudine plus zidovudine and 9.2 months for patients receiving didanosine monotherapy.  Results are summarized in Table 10.

Table 10. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease Progression or-Death)

16 HOW SUPPLIED/STORAGE AND HANDLING

Lamivudine Scored Tablets, 150 mg
White capsule shaped, biconvex, scored film coated tablets debossed with ‘J’ on one side and ‘16’ on the other side, 1 and 6 seperated by a score line.

Bottle of 60 tablets NDC 68554-5053-0
Bottle of 600 tablets NDC 68554-5053-1
Blister Card of 10 Unit-dose tablets NDC 68554-5053-2
Blister pack of 100 (10 x 10) Unit-dose tablets NDC 68554-5053-4

Lamivudine Tablets, 300 mg

White capsule shaped, biconvex, film coated tablets debossed with ‘17’ on one side and ‘J’ on the other side.

Bottle of 30 tablets NDC 68554-5054-0
Bottle of 600 tablets NDC 68554-5054-1
Blister Card of 10 Unit-dose tablets NDC 68554-5054-2
Blister pack of 100 (10 x 10) Unit-dose tablets NDC 68554-5054-4

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Preserve in well-closed, light-resistant containers.

17 PATIENT COUNSELING INFORMATION

17.1 Advice for the Patient

Lactic Acidosis/Hepatomegaly: Patients should be informed 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: Patients co-infected with HIV-1 and HBV should be informed that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Patients should be advised to discuss any changes in regimen with their physician [see Warnings and Precautions (5.2)].

Differences in Formulations of Lamivudine: Patients should be advised that lamivudine tablets contain a higher dose of the same active ingredient (lamivudine) as EPIVIR-HBV Tablets. 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 EPIVIR (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, TRIZIVIR (abacavir sulfate, lamivudine, and zidovudine), ATRIPLA (efavirenz, emtricitabine, and tenofovir), EMTRIVA (emtricitabine), TRUVADA (emtricitabine and tenofovir), or COMPLERA (rilpivirine/emtricitabine/tenofovir) [see Warnings and Precautions (5.3)].

HIV-1/HCV Co-Infection: Patients with HIV-1/HCV co-infection should be informed 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: Parents or guardians should be advised to monitor pediatric patients for signs and symptoms of pancreatitis [see Warnings and Precautions (5.5)].

Redistribution/Accumulation of Body Fat: Patients should be informed 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 should remain under the care of a physician when using lamivudine.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
     • Do not 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.
     • Do not have any kind of sex without protection. Always practice safe 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. 
     • Do not breastfeed. Lamivudine is excreted in human breast milk. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Patients should be informed to take all HIV medications exactly as prescribed.

COMBIVIR, EPZICOM and TRIZIVIR are registered trademarks of ViiV Healthcare. 

The other brands listed are trademarks of their respective owners and are not trademarks of Hetero Labs Limited. The makers of these brands are not affiliated with and do not endorse Hetero Labs Limited or its products.

Manufactured for:

Camber Pharmaceuticals, Inc.,

Piscataway, NJ 08854

By:HETERO^TM

Hetero Labs Limited,Unit V, Polepally,           2023525

Jadcherla, Mahaboob Nagar-509 301, India. 

Revised: December 2011

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Lamivudine Tablets 150 mg - Container Label 60s Count

Lamivudine Tablets 150 mg - Blister card 10s

Lamivudine Tablets 150 mg - Blister Carton 100s

Lamivudine Tablets 300 mg - Container Label 30s Count

Lamivudine Tablets 300 mg - Blister Card 10s

Lamivudine Tablets 300 mg - Blister Carton 100s

Lamivudine Lamivudine TABLET, FILM COATED Product Information Product Type Human prescription drug label Item Code (Source) NDC:31722-753 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LAMIVUDINE LAMIVUDINE 150 mg Inactive Ingredients Ingredient Name Strength CROSPOVIDONE ISOMALT ISOPROPYL ALCOHOL MAGNESIUM STEARATE methylene chloride HYPROMELLOSES POLYETHYLENE GLYCOLS polysorbate 80 titanium dioxide Product Characteristics Color Size Imprint Code Shape WHITE 15 mm J;16 CAPSULE Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:31722-753-60 60 in 1 BOTTLE 2 NDC:31722-753-06 600 in 1 BOTTLE 3 NDC:31722-753-31 10 in 1 BLISTER PACK 4 NDC:31722-753-32 100 in 1 CARTON Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203277 2014-01-06

Lamivudine Lamivudine TABLET, FILM COATED Product Information Product Type Human prescription drug label Item Code (Source) NDC:31722-754 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LAMIVUDINE LAMIVUDINE 300 mg Inactive Ingredients Ingredient Name Strength CROSPOVIDONE ISOMALT ISOPROPYL ALCOHOL MAGNESIUM STEARATE methylene chloride HYPROMELLOSES POLYETHYLENE GLYCOLS polysorbate 80 titanium dioxide Product Characteristics Color Size Imprint Code Shape WHITE 19 mm J;17 CAPSULE Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:31722-754-30 30 in 1 BOTTLE 2 NDC:31722-754-06 600 in 1 BOTTLE 3 NDC:31722-754-31 10 in 1 BLISTER PACK 4 NDC:31722-754-32 100 in 1 CARTON Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203277 2014-01-06