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Lamivudine

Aurobindo Pharma Limited

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use lamivudine safely and effectively. See full prescribing information for lamivudine tablets. Lamivudine TabletsInitial U.S. Approval: 1995 RECENT MAJOR CHANGES(5.6)BOXED WARNINGWARNING: LACTIC ACIDOSIS, POSTTREATMENT EXACERBATIONS OF HEPATITIS 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-1) 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-1. (5.2) INDICATIONS AND USAGE(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 tablets must be adjusted in accordance with renal function. (2.3) DOSAGE FORMS AND STRENGTHS Tablets: 300 mg (3) Tablets: Scored 150 mg (3) CONTRAINDICATIONS(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 hepatotoxicity 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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS(7.2)USE IN SPECIFIC POPULATIONS Pregnancy: Physicians are encouraged to register patients in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263. (8.1)


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

WARNING: RISK OF LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B IN CO-INFECTED PATIENTS UPON DISCONTINUATION OF LAMIVUDINE, 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)].

1 INDICATIONS AND USAGE


2 DOSAGE AND ADMINISTRATION

2.1 Adults and Adolescents >16 years of age


[see Warnings and Precautions (5.2)].

2.2 Pediatric Patients




Table 1. Dosing Recommendations for Lamivudine Tablets in Pediatric Patients

Weight (kg) 
 
Dosage Regimen Using Scored
150 mg Tablet
Total
Daily Dose
AM Dose
PM Dose
   14 to 21
½ tablet (75 mg)
½ tablet (75 mg)
150 mg
   >21 to <30
½ tablet (75 mg)
1 tablet (150 mg)
225 mg
   ≥30
1 tablet (150 mg)
1 tablet (150 mg)
300 mg

2.3 Patients With Renal Impairment


[see Clinical Pharmacology (12.3)]

Table 2. Adjustment of Dosage of Lamivudine Tablets in Adults and Adolescents (≥30 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
   30-49
   150 mg once daily
   15-29
   150 mg first dose, then 100 mg once daily
   5-14
   150 mg first dose, then 50 mg once daily
   <5
   50 mg first dose, then 25 mg once daily



3 DOSAGE FORMS AND STRENGTHS



  • Lamivudine Scored Tablets


  • 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.

4 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


Posttreatment Exacerbations of Hepatitis:

Important Differences Among Lamivudine-Containing Products:®®®

Emergence of Lamivudine-Resistant HBV:

5.3 Use With Other Lamivudine- and Emtricitabine-Containing Products


® ® ® TM

5.4 Use With Interferon- and Ribavirin-Based Regimens


In vitro[see Clinical Pharmacology (12.3)],

5.5 Pancreatitis


[see Adverse Reactions (6.1) ].

5.6 Immune Reconstitution Syndrome


Mycobacterium avium Pneumocystis jirovecii

and

5.7 Fat Redistribution


6 ADVERSE REACTIONS



6.1 Clinical Trials Experience




Adults - Clinical Trials in HIV-1:



®
Table 3. Selected Clinical Adverse Reactions (≥5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002)
*Either zidovudine monotherapy or zidovudine in combination with zalcitabine.

Adverse Reaction
Lamivudine 150 mg
Twice Daily
plus RETROVIR
(n = 251)
RETROVIR*
(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: [see Warnings and Precautions (5.5)].

Lamivudine
300 mg Once Daily:



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 Endpoint Study (NUCB3007)
* The median duration on study was 12 months.
Either zidovudine monotherapy or zidovudine in combination with zalcitabine.
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 Studies*
Clinical Endpoint Study*
Lamivudine plus
RETROVIR
RETROVIR
Lamivudine plus
Current Therapy
Placebo plus
Current Therapy
   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%


Pediatric Patients – Clinical Trials in HIV-1:

2

Table 5. Selected Clinical Adverse Reactions and Physical Findings (≥5% Frequency) in Pediatric Patients in Study ACTG300
*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 ears*
7%
6%
      Nasal discharge or congestion
8%
11%
   Other
      Skin rashes
12%
14%
      Lymphadenopathy
9%
11%
Pancreatitis: [see Warnings and Precautions (5.5) ].

Paresthesias and
Peripheral Neuropathies:



Table 6. Frequencies of Selected Grade 3 to 4 Laboratory Abnormalities in Pediatric Patients in Study 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%
Neonates - Clinical Trials in HIV-1:[see Clinical Pharmacology (12.3)]in utero

6.2 Postmarketing Experience




Body as a Whole:[see Warnings and Precautions (5.7)]

Endocrine and Metabolic:

General:

Hemic and Lymphatic:

Hepatic and Pancreatic:[see Boxed Warning, Warnings and Precautions (5.1, 5.2)]

Hypersensitivity:

Musculoskeletal:

Skin:

7 DRUG INTERACTIONS


7.1 Interferon- and Ribavirin-Based Regimens


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

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

Teratogenic Effects






[see Nonclinical Toxicology (13.2)].

Antiretroviral Pregnancy Registry:

8.3 Nursing Mothers




8.4 Pediatric Use


[see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)]

8.5 Geriatric Use


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

8.6 Patients With Impaired Renal Function


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

10 OVERDOSAGE


11 DESCRIPTION


81133
Lamivudine


12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action


[see Clinical Pharmacology (12.4)]

12.3 Pharmacokinetics


Pharmacokinetics in Adults



24,ssmax,ss 24,ssmax24,ss

Absorption and Bioavailability:
maxmax



Effects of Food on Oral Absorption:
maxmaxmax

Distribution:


In vitro





½

Special PopulationsRenal Impairment:

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
maxmax[see Dosage and Administration (2.3)]







Hepatic Impairment:


Pediatric Patients:



Lamivudine
max



[see Adverse Reactions (6.1)].

Geriatric Patients: [see Use in Specific Populations (8.5)]

Gender:


Race:


Drug InteractionsInterferon Alfa: [see Warnings and Precautions (5.4)]

In vitro[see Warnings and Precautions (5.4)]

[see Drug Interactions (7.3)]

Zidovudine:
[see Drug Interactions (7.4)]

12.4 Microbiology


Mechanism of Action:

Antiviral Activity:505050

Resistance:



[see Warnings and Precautions (5.2)].

Cross-Resistance:

Genotypic and Phenotypic Analysis of On-Therapy HIV-1 Isolates From Patients With Virologic Failure:  Study EPV20001:  1010









Study EPV40001: 
1010





13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


in vitroin vitroin vivo

13.2 Reproductive Toxicology Studies


14 CLINICAL STUDIES


14.1 Adults


Clinical Endpoint Study:33

Table 8. Number of Patients (%) With at Least One HIV-1 Disease Progression Event or Death
*An 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
NNRTI* 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 Studies: Dual Nucleoside Analogue Studies:

Dose Regimen Comparison Surrogate Endpoint Studies in Therapy-Naive Adults:
3 310
Lamivudine
Table 9. Outcomes of Randomized Treatment Through 48 Weeks (Intent-to-Treat)
* Achieved confirmed plasma HIV-1 RNA <400 copies/mL and maintained through 48 weeks.
Achieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48.
Includes consent withdrawn, lost to follow-up, protocol violation, data outside the study-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)
   Responder*
67%
65%
   Virologic failure
8%
8%
   Discontinued due to clinical progression   
<1%
0%
   Discontinued due to adverse events   
6%
12%
   Discontinued due to other reasons‡    
18%
14%
33

31033

14.2 Pediatric Patients


Clinical Endpoint Study:3333310

Table 10. Number of Patients (%) 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%)

16 HOW SUPPLIED/STORAGE AND HANDLING


Lamivudine Scored Tablets, 150 mg




Lamivudine Tablets, 300 mg





Store at

17 PATIENT COUNSELING INFORMATION

17.1 Advice for the Patient


Lactic Acidosis/Hepatomegaly:[see Warnings and Precautions (5.1)]

HIV-1/HBV Co-infection:[see Warnings and Precautions (5.2)]

Differences in Formulations of Lamivudine:[see Warnings and Precautions (5.2)]

Use With Other Lamivudine- and Emtricitabine-Containing Products:[see Warnings and Precautions (5.3)]

HIV-1/HCV Co-infection:[see Warnings and Precautions (5.4)]

Risk of Pancreatitis:[see Warnings and Precautions (5.5)]

Redistribution/Accumulation of Body Fat:[see Warnings and Precautions (5.7)]

Information About HIV-1 Infection:
  • 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.








Aurobindo Pharma USA, Inc.




Aurobindo Pharma Limited




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


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

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
Lamivudine

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


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

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

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 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 Size Imprint Code Shape
WHITE (White to Off-white) 12 mm 66;Y OVAL

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:65862-552-60 60 in 1 BOTTLE
2 10 in 1 BLISTER PACK
3 NDC:65862-552-10 6 in 1 CARTON

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA202032 2011-11-17


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 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 Size Imprint Code Shape
WHITE (White to Off-white) 16 mm 67;Y OVAL

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:65862-553-30 30 in 1 BOTTLE
2 10 in 1 BLISTER PACK
3 NDC:65862-553-10 3 in 1 CARTON

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA202032 2011-11-17


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