Lamivudine and Zidovudine description, usages, side effects, indications, overdosage, supplying and lots more!

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Lamivudine and Zidovudine

Aurobindo Pharma Limited

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use lamivudine and zidovudine safely and effectively. See full prescribing information for lamivudine and zidovudine tablets USP. Lamivudine and Zidovudine Tablets USPInitial U.S. Approval: 1997 RECENT MAJOR CHANGES(5.8)BOXED WARNINGWARNING: RISK OF HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B See full prescribing information for complete boxed warning. Hematologic toxicity including neutropenia and anemia have been associated with the use of zidovudine, one of the components of lamivudine and zidovudine. (5.1) Symptomatic myopathy associated with prolonged use of zidovudine. (5.2) Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including zidovudine. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.3) 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, a component of lamivudine and zidovudine. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. (5.4) INDICATIONS AND USAGE(1)DOSAGE AND ADMINISTRATION Adults and Adolescents weighing ≥30 kg: 1 tablet twice daily. (2.1) Pediatrics: Dosage should be based on body weight not to exceed adult doses. (2.2) Lamivudine and Zidovudine tablets, a fixed-dose product, should not be prescribed for pediatric patients weighing less than 30 kg or patients requiring dosage adjustment, such as those with renal or hepatic impairment, or patients experiencing dose-limiting adverse reactions. (2.3) DOSAGE FORMS AND STRENGTHS(3)CONTRAINDICATIONS(4)WARNINGS AND PRECAUTIONS See boxed warning for information about the following: Hematologic toxicity, symptomatic myopathy, lactic acidosis and severe hepatomegaly, and severe acute exacerbations of hepatitis B. (5.1, 5.2, 5.3, 5.4) Lamivudine and Zidovudine should not be administered with other lamivudine- or zidovudine-containing products or emtricitabine-containing products. (5.5) Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with/without ribavirin. Discontinue lamivudine and zidovudine as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.6) Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and zidovudine is not advised. (5.6) Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. (5.7) Immune reconstitution syndrome (5.8) and redistribution/accumulation of body fat (5.9) have been reported in patients treated with combination antiretroviral therapy. Side Effects Most commonly reported adverse reactions (incidence greater than or equal to 15%) in adult and pediatric HIV-1 clinical studies of combination lamivudine and zidovudine were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, 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 Concomitant use with the following drugs should be avoided: Stavudine (7.1), zalcitabine (7.1), doxorubicin. (7.2) Bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. (7.3) USE IN SPECIFIC POPULATIONS Pregnancy: Physicians are encouraged to register patients in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263. (8.1) Nursing Mothers: HIV-1 infected mothers in the United States should not breastfeed to avoid potential postnatal transmission of HIV-1. (8.3)


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B


Hematologic Toxicity: Zidovudine, one of the 2 active ingredients in lamivudine and zidovudine tablets, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease [see Warnings and Precautions (5.1)].

Myopathy: Prolonged use of zidovudine has been associated with symptomatic myopathy [see
Warnings and Precautions (5.2)].

Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been
reported with the use of nucleoside analogues alone or in combination, including lamivudine, zidovudine, and other antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.3)].

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 HIV-1 and have discontinued lamivudine, which is one component of lamivudine and zidovudine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine and zidovudine and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.4)].

1 INDICATIONS AND USAGE


2 DOSAGE AND ADMINISTRATION

2.1 Adults and Adolescents Weighing ≥30 kg


2.2 Pediatric Patients




®®

2.3 Patients Requiring Dosage Adjustment


3 DOSAGE FORMS AND STRENGTHS


Lamivudine and Zidovudine Tablets,

4 CONTRAINDICATIONS


5 WARNINGS AND PRECAUTIONS

5.1 Hemotologic Toxicity/Bone Marrow Suppression


3[see Adverse Reactions (6.1)].

5.2 Myopathy


5.3 Lactic Acidosis/Hepatomegaly With Steatosis


5.4 Patients With HIV-1 and Hepatitis B Virus Co-infection


Posttreatment Exacerbations of Hepatitis:

Important Differences Among Lamivudine-Containinq Products:®

Emergence of Lamivudine-Resistant HBV:

5.5 Use With Other, Lamivudine-, Zidovudine-, and/or Emtricitabine-Containing Products


®®®®®®®TM

5.6 Use With Interferon- and Ribavirin-Based Regimens


In vitro[see Clinical Pharmacology (12.3)],

5.7 Pancreatitis


[see Adverse Reactions (6.1)].

5.8 Immune Reconstitution Syndrome


Mycobacterium avium Pneumocystis jirovecii

disorders

5.9 Fat Redistribution


6 ADVERSE REACTIONS

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

6.1 Clinical Trials Experience




Lamivudine Plus Zidovudine Administered As Separate Formulations:

Table 1. Selected Clinical Adverse Reactions (≥5% Frequency) in 4 Controlled Clinical Trials With EPIVIR 300 mg/day and RETROVIR 600 mg/day
Adverse Reaction EPIVIR plus RETROVIR
(n = 251)
   Body as a whole
 
      Headache
35%
      Malaise & fatigue
27%
      Fever or chills
10%
   Digestive
      Nausea
33%
      Diarrhea
18%
      Nausea & vomiting
13%
      Anorexia and/or decreased appetite
10%
      Abdominal pain
9%
      Abdominal cramps
6%
      Dyspepsia
5%
   Nervous system
      Neuropathy
12%
      Insomnia & other sleep disorders
11%
      Dizziness
10%
      Depressive disorders
9%
   Respiratory
      Nasal signs & symptoms
20%
      Cough
18%
   Skin
      Skin rashes
9%
   Musculoskeletal
      Musculoskeletal pain
12%
      Myalgia
8%
      Arthralgia
5%
[see Warnings and Precautions (5.7)].



Table 2. Frequencies of Selected Laboratory Abnormalities Among Adults in 4 Controlled Clinical Trials of EPIVIR 300 mg/day plus RETROVIR 600 mg/day*
Test
(Abnormal Level)
EPIVIR plus RETROVIR
% (n)
ULN = Upper limit of normal.
ANC = Absolute neutrophil count.
n = Number of patients assessed.
* Frequencies of these laboratory abnormalities were higher in patients with mild laboratory abnormalities at baseline.
   Neutropenia (ANC<750/mm3)
7.2% (237)
   Anemia (Hgb<8 g/dL)
2.9% (241)
   Thrombocytopenia (platelets<50,000/mm3)
0.4% (240)
   ALT (>5 x ULN)
3.7% (241)
   AST (>5 x ULN)
1.7% (241)
   Bilirubin (>2.5x ULN)
0.8% (241)
   Amylase (>2 x ULN)
4.2% (72)

6.2 Postmarketing Experience




Body as a Whole:[see Warnings and Precautions (5.9)].

Cardiovascular:

Endocrine and Metabolic:

Gastrointestinal:

General:

Hemic and Lymphatic:

Hepatic and Pancreatic:[see Boxed Warning, Warnings and Precautions (5.3), (5.4) , (5.7)].

Hypersensitivity:

Musculoskeletal:

Nervous:

Respiratory:

Skin:

7 DRUG INTERACTIONS


[see Clinical Pharmacology (12.3)].

7.1 Antiretroviral Agents


Lamivudine: Zalcitabine:

Zidovudine: Stavudine: in vitro

Nucleoside Analogues Affecting DNA Replication:
in vitro

7.2 Doxorubicin


Zidovudine:in vitro

7.3 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents


Zidovudine:

7.4 Interferon- and Ribavirin-Based Regimens


Lamivudine:[see Warnings and Precautions (5.5) , Clinical Pharmacology (12.3)].

7.5 Trimethoprim/Sulfamethoxazole (TMP/SMX)


Lamivudine:

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy




Fetal Risk Summary:

Antiretroviral Pregnancy Registry:

Clinical Considerations:[see Clinical Studies (14.2) ].





Data:Human Data: Lamivudine:

Zidovudine:
[see Clinical Studies (14.2)]. 



Animal Data: Lamivudine:
[see Nonclinical Toxicology (13.2)].

Zidovudine: 
[see Nonclinical Toxicology (13.2)].

8.3 Nursing Mothers




8.4 Pediatric Use


8.5 Geriatric Use


8.6 Renal Impairment


8.7 Hepatic Impairment


10 OVERDOSAGE


Lamivudine and Zidovudine:

Lamivudine:


Zidovudine:
OD

11 DESCRIPTION


Lamivudine and Zidovudine:



Lamivudine:81133
Lamivudine and Zidovudine


Zidovudine:101354
Lamivudine and Zidovudine


12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action


[see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics


Pharmacokinetics in Adults:Lamivudine and Zidovudine: 

Lamivudine: 


Zidovudine: 
Table 3. Pharmacokinetic Parameters* for Lamivudine and Zidovudine in Adults
Parameter Lamivudine Zidovudine
* Data presented as mean ± standard deviation except where noted.
Median [range].
Children.
§ Adults.
Approximate range.
   Oral bioavailability (%)
86 ± 16
N=12
64 ± 10
n = 5
   Apparent volume of distribution (L/kg)
1.3 ± 0.4
N = 20
1.6 ± 0.6
n = 8
   Plasma protein binding (%)
<36
<38
   CSF:plasma ratio
0.12 [0.04 to 0.47]
n = 38
0.6 [0.04 to 2.62]
N = 39§
   Systemic clearance (L/hr/kg)
0.33 ± 0.06
N = 20
1.6 ± 0.6
n = 6
   Renal clearance (L/hr/kg)
0.22 ± 0.06
N = 20
0.34 ± 0.05
n = 9
   Elimination half-life (hr)
5 to 7
0.5 to 3

Effect of Food on Absorption of Lamivudine and Zidovudine: 

Special Populations:

Pregnancy:
  See Use in Specific Populations (8.1).

Lamivudine and Zidovudine


Zidovudine: 


Nursing Mothers:
  See Use in Specific Populations (8.3).

Pediatric Patients:

Geriatric Patients:

Gender:

Race:Lamivudine: 

Zidovudine: 


Drug Interactions:See Drug Interactions (7).



Lamivudine Plus Zidovudine: 

Table 4. Effect of Coadministered Drugs on Lamivudine and Zidovudine AUC*
Note: ROUTINE DOSE MODIFICATION OF LAMIVUDINE AND ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Drugs That May Alter Lamivudine Blood Concentrations
Coadministered Drug
and Dose
Lamivudine
Dose
      n       Lamivudine
Concentrations
Concentration of
Coadministered
Drug
AUC Variability
↑ = Increase; ↓= Decrease; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval.
* This table is not all inclusive.
Estimated range of percent difference.
   Nelfinavir
   750 mg q 8 hr x 7 to 10 days
single 150 mg
11
↑AUC 10%
95% CI:
l% to 20%

   Trimethoprim 160 mg/Sulfamethoxazole
   800 mg daily x 5 days
single 300 mg
14
↑AUC 43%
90% CI:
32% to 55%

Drugs That May Alter Zidovudine Blood Concentrations
Coadministered Drug
and Dose
Zidovudine
Dose
n
Zidovudine
Concentrations

Concentration of
Coadministered
Drug
AUC
Variability
   Atovaquone
      750 mg q l2 hr with food
200 mg q 8 hr
14
↑AUC 31%
Range
23% to 78%


   Clarithromycin
  500 mg daily
100 mg q 4 hr x 7 days
4
↓AUC 12%
Range
↓34% to ↑14%
Not Reported
   Fluconazole
      400 mg daily
200 mg q 8 hr
12
↑AUC 74%
95% CI:
54% to 98%
Not Reported
   Methadone
      30 to 90 mg daily
200 mg q 4 hr
9
↑AUC 43%
Range
16% to 64%

   Nelfinavir
      750 mg q 8 hr x 7 to 10 days
single 200 mg
11
↓AUC 35%
Range
28% to 41%

   Probenecid
      500 mg q 6 hr x 2 days
2 mg/kg q 8 hr x 3 days
3
↑AUC
106%
Range
100% to
170%
Not Assessed
   Rifampin
      600 mg daily x 14 days
200 mg q 8 hr
x 14 days
8
↓AUC
47%
90% CI:
41% to 53%
Not Assessed
   Ritonavir
      300 mg q 6 hr x 4 days
200 mg q 8 hr
x 4 days
9
↓ AUC
25%
95% CI:
15% to 34%

   Valproic acid
      250 mg or 500 mg q 8 hr x 4 days
100 mg q 8 hr
x 4 days
6
↑AUC
80%
Range
64% to l30%
Not Assessed
Ribavirin: In vitro[see Warnings and Precautions (5.5)].

12.4 Microbiology


Mechanism of Action: Lamivudine:

Zidovudine:


Antiviral ActivityLamivudine Plus Zidovudine:

Lamivudine:
505050

Zidovudine:
50905050

Resistance: Lamivudine Plus Zidovudine Administered As Separate Formulations:



Lamivudine:


Zidovudine:


Cross-Resistance:

Lamivudine Plus Zidovudine:


Lamivudine:


Zidovudine:

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


Carcinogenicity: Lamivudine:

Zidovudine:











Mutagenicity: Lamivudine: +/-in vitro

Zidovudine:
+/-in vitro

Impairment of Fertility: Lamivudine:

Zidovudine: 

13.2 Reproductive and Developmental Toxicology Studies


Lamivudine:

Zidovudine:in vitro

14 CLINICAL STUDIES


Clinical Pharmacology (12.3)

14.1 Adults


Lamivudine Plus Zidovudine:3
Table 5. Number of Patients (%) With At Least 1 HIV-1 Disease-Progression Event or Death
Endpoint Current Therapy
(n = 460)
EPIVIR
plus Current Therapy
(n = 896)
EPIVIR
Plus a NNRTI*
plus Current Therapy
(n = 460)
* An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.
   HIV-1 progression or death
90 (19.6%)
86 (9.6%)
41 (8.9%)
   Death
27 (5.9%)
23 (2.6%)
14 (3%)

14.2 Prevention of Maternal-Fetal HIV-1 Transmission


33

16 HOW SUPPLIED/STORAGE AND HANDLING


Lamivudine and Zidovudine Tablets USP,



Store at

17 PATIENT COUNSELING INFORMATION

17.1 Advice for the Patient


Neutropenia and Anemia[see Boxed Warning, Warnings and Precautions (5.1)].

Myopathy:[see Warnings and Precautions (5.2)]

Lactic Acidosis/Hepatomegaly:[see Warnings and Precautions (5.3)]

HIV‑1/HBV Co‑Infection:[see Warnings and Precautions (5.4)]

Use With Other Lamivudine-, Zidovudine-, and/or Emtricitabine‑Containing Products:[see Warnings and Precautions (5.5)].

HIV‑1/HCV Co‑Infection:[see Warnings and Precautions (5.6)]

Drug Interactions:[see Drug Interactions (7.3)]

Redistribution/Accumulation of Body Fat:[see Warnings and Precautions (5.9)]

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 and zidovudine are 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/300 mg (60 Tablet Bottle)


NDC 65862-597-60
Lamivudine and Zidovudine Tablets USP
150 mg/300 mg
Rx only                                    60 Tablets
AUROBINDO
Lamivudine and Zidovudine

Lamivudine and Zidovudine

Lamivudine and Zidovudine TABLET, FILM COATED

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:65862-597
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
LAMIVUDINE LAMIVUDINE 150 mg
Zidovudine ZIDOVUDINE 300 mg

Inactive Ingredients

Ingredient Name Strength
SILICON DIOXIDE
HYPROMELLOSE 2910 (6 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) 17 mm J;58 CAPSULE

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:65862-597-60 60 in 1 BOTTLE

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA202418 2012-05-15


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