Lamivudine
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*
- WARNING: RISK OF LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B IN CO-INFECTED PATIENTS UPON DISCONTINUATION OF LAMIVUDINE, DIFFERENT FORMULATIONS OF LAMIVUDINE.
- 1 LAMIVUDINE INDICATIONS AND USAGE
- 2 LAMIVUDINE DOSAGE AND ADMINISTRATION
- 3 DOSAGE FORMS AND 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
- 7 DRUG INTERACTIONS
- 8 USE IN SPECIFIC POPULATIONS
- 10 OVERDOSAGE
- 11 LAMIVUDINE DESCRIPTION
- 12 CLINICAL PHARMACOLOGY
- 13 NONCLINICAL TOXICOLOGY
- 14 CLINICAL STUDIES
- 16 HOW SUPPLIED/STORAGE AND HANDLING
- 17 PATIENT COUNSELING INFORMATION
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 150 mg (60 Tablet Bottle)
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 150 mg Blister Carton (6 x 10 Unit-dose)
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 300 mg (30 Tablet Bottle)
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 300 mg Blister Carton (3 x 10 Unit-dose)
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
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)]
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
- 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-1 and hepatitis C [see Warnings and Precautions (5.4)].
- Pancreatitis [see Warnings and Precautions (5.5)].
6.1 Clinical Trials Experience
Adults - Clinical Trials in HIV-1:
®
*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% |
Lamivudine 300 mg Once Daily:
* 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
*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% |
Paresthesias and Peripheral Neuropathies:
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% |
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
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:
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 |
Hepatic Impairment:
Pediatric Patients:
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
*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
* 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% |
31033
14.2 Pediatric Patients
Clinical Endpoint Study:3333310
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
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 Tablet 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
LamivudineLamivudine TABLET, FILM COATED
|
LamivudineLamivudine TABLET, FILM COATED
|
PLEASE, BE CAREFUL!
Be sure to consult your doctor before taking any medication!