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Zidovudine

State of Florida DOH Central Pharmacy

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ZIDOVUDINE . See full prescribing information for ZIDOVUDINE. Initial U.S. Approval 1987RECENT MAJOR CHANGES2.1BOXED WARNINGWARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS. See full prescribing information for complete boxed warning.   Hematologic toxicity including neutropenia and severe anemia have been associated with the use of zidovudine. (5.1) Symptomatic myopathy associated with prolonged use of zidovudine. (5.2) Lactic acidosis and severe 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) INDICATIONS AND USAGE  Treatment of Human Immunodeficiency Virus (HIV-1) infection in combination with other antiretroviral agents. (1.1) Prevention of maternal-fetal HIV-1 transmission. (1.2) DOSAGE AND ADMINISTRATION Treatment of HIV-1 infection: (2.1) Prevention of maternal-fetal HIV-1 transmission: (2.2) Patients with severe anemia and/or neutropenia: (2.3) Renal Impairment – Recommended dosage in hemodialysis or peritoneal dialysis patients is 100 mg every 6 to 8 hours. (2.4) DOSAGE FORMS AND STRENGTHS(3)CONTRAINDICATIONS(4)WARNINGS AND PRECAUTIONS Hematologic toxicity/bone marrow suppression including neutropenia and severe anemia have been associated with the use of zidovudine. (5.1) Symptomatic myopathy associated with prolonged use of zidovudine. (5.2) Lactic acidosis and severe 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) 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. (5.4) Hepatic decompensation, (some fatal), has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with/without ribavirin. Discontinue zidovudine as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.4) Zidovudine should not be administered with other zidovudine-containing combination products. (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 commonly reported adverse reactions (incidence ≥15%) in adult HIV-1 clinical studies were headache, malaise, nausea, anorexia, and vomiting. (6.1) The most commonly reported adverse reactions (incidence ≥15%) in pediatric HIV-1 clinical studies were fever, cough, and digestive disorders.  (6.1) The most commonly reported adverse reactions in neonates (incidence ≥15%) in the prevention of maternal-fetal transmission of HIV-1 clinical trial were anemia and neutropenia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Stavudine: Concomitant use with zidovudine should be avoided. (7.1) Doxorubicin: Use with zidovudine should be avoided. (7.2) Bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. (7.3) USE IN SPECIFIC POPULATIONS(8.1)


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS


Zidovudine has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced HIV-1 disease [see Warnings and Precautions (5.1)] .

Prolonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions (5.2)] .
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including 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)].

1 INDICATIONS AND USAGE

1.1 Treatment of HIV-1


1.2 Prevention of Maternal-Fetal HIV-1 Transmission


[see Dosage and Administration (2.2)]. 
  • antepartum therapy of HIV-1 infected mothers
  • intrapartum therapy of HIV-1 infected mothers
  • post-partum therapy of HIV-1 exposed neonate.



  • In most cases, zidovudine tablets for prevention of maternal-fetal HIV-1 transmission should be given in combination with other antiretroviral drugs.
  • Prevention of HIV-1 transmission in women who have received zidovudine tablets for a prolonged period before pregnancy has not been evaluated.
  • Because the fetus is most susceptible to the potential teratogenic effects of drugs during the first 10 weeks of gestation and the risks of therapy with zidovudine tablets during that period are not fully known, women in the first trimester of pregnancy who do not require immediate initiation of antiretroviral therapy for their own health may consider delaying use; this indication is based on use after 14 weeks gestation.

2 DOSAGE AND ADMINISTRATION

2.1 Treatment of HIV-1 Infection


Adults:

Pediatric Patients (6 weeks to <18 years of age):  Healthcare professionals should pay special attention to accurate calculation of the dose of zidovudine tablets, transcription of the medication order, dispensing information, and dosing instructions to minimize risk for medication dosing errors. 

Prescribers should calculate the appropriate dose of zidovudine tablets for each child based on body weight (kg) and should not exceed the recommended adult dose.

Before prescribing zidovudine tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a zidovudine tablet, the zidovudine syrup formulation should be prescribed.

The recommended dosage in pediatric patients 6 weeks of age and older and weighing ≥4 kg is provided in Table 1. Zidovudine syrup should be used to provide accurate dosage when whole tablets are not appropriate.
Table 1: Recommended Pediatric Dosage of Zidovudine Tablets

   Body Weight
          (kg)
      Total Daily 
         Dose  
   Dosage Regimen and Dose   

   b.i.d.   
   t.i.d.   

4 to <9
24 mg/kg/day
   12 mg/kg   
   8 mg/kg   

≥9 to <30
18 mg/kg/day
   9 mg/kg   
   6 mg/kg   

≥30
600 mg/day
   300 mg   
   200 mg   
Alternatively, dosing for zidovudine tablets can be based on body surface area (BSA) for each child. The recommended oral dose of zidovudine tablets is 480 mg/m2/day in divided doses (240 mg/m2 twice daily or 160 mg/m2 three times daily). In some cases the dose calculated by mg/kg will not be the same as that calculated by BSA.

2.2 Prevention of Maternal-Fetal HIV-1 Transmission




Maternal Dosing:[see Clinical Studies (14.3)]

Neonatal Dosing:

2.3 Patients With Severe Anemia and/or Neutropenia


3[see Warnings and Precautions (5.1)]

2.4 Patients With Renal Impairment


End-Stage Renal Disease:[see Clinical Pharmacology (12.3) ]

2.5 Patients With Hepatic Impairment


3 DOSAGE FORMS AND STRENGTHS


Zidovudine Tablets USP, 300 mg

4 CONTRAINDICATIONS


5 WARNINGS AND PRECAUTIONS

5.1 Hematologic Toxicity/Bone Marrow Suppression


3t

[see Dosage and Administration (2.3)]

5.2 Myopathy


5.3 Lactic Acidosis/Severe Hepatomegaly With Steatosis


5.4 Use With Interferon- and Ribavirin-Based Regimens in HIV-1/HCV Co-Infected Patients


In vitro [see Clinical Pharmacology (12.3) ]



5.5 Use With Other Zidovudine-Containing Products


®®

5.6 Immune Reconstitution Syndrome


Mycobacterium avium Pneumocystis jirovecii

5.7 Fat Redistribution


6 ADVERSE REACTIONS

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:


Table 2. Percentage (%) of Patients With Adverse Reactions* in Asymptomatic HIV-1 Infection (ACTG 019)
* Reported in ≥5% of study population.
†  Not statistically significant versus placebo.


   Adverse Reaction
   Zidovudine 500 mg/day 
                (n = 453)
    Placebo  
   (n = 428)

   Body as a whole   

       Asthenia   

       Headache   

       Malaise   
 

                 9%†

                 63%   

                 53%
 

      6%

      53%

      45%

   Gastrointestinal     

       Anorexia   

       Constipation   

       Nausea   

       Vomiting    
 

                 20%

                 6%†

                 51%

                 17%
    

      11%

      4%

      30%

      10%




Table 3. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients With Asymptomatic HIV-1 Infection (ACTG 019)
ULN = Upper limit of normal.


Test
(Abnormal Level) 
    Zidovudine   
    500 mg/day 
      (n = 453)   
    
    Placebo   
   (n = 428)   

   Anemia (Hgb<8 g/dL)

   Granulocytopenia (<750 cells/mm3)

   Thrombocytopenia (platelets<50,000/mm3) 

   ALT (>5 x ULN)

   AST (>5 x ULN)
1%

2%

0%

3%

1%
<1%

2%

<1%

3%

2%

Pediatrics:

Study ACTG300:  2
Table 4. 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
    EPIVIR plus   
      Zidovudine
        (n = 236)
    Didanosine   
     (n = 235)

   Body as a whole

      Fever

 

25%
 

32%

   Digestive

      Hepatomegaly

      Nausea & vomiting

      Diarrhea

      Stomatitis

      Splenomegaly
 

11%

8%

8%

6%

5%
 

11%

7%

6%

12%

8%

   Respiratory

      Cough

      Abnormal breath sounds/wheezing
 

15%

7%
 

18%

9%

   Ear, Nose, and Throat

       Signs or symptoms of ears*

      Nasal discharge or congestion

 

7%

8%
 

6%

11%

   Other

      Skin rashes

      Lymphadenopathy

 

12%

9%
 

14%

11%


Table 5. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric Patients in Study ACTG300
ULN = Upper limit of normal.
ANC = Absolute neutrophil count.

Test
(Abnormal Level)
     EPIVIR plus   
       Zidovudine

   Didanosine   

   Neutropenia (ANC<400 cells/mm3)     

   Anemia (Hgb<7 g/dL)

   Thrombocytopenia (platelets<50,000/mm3)   

   ALT (>10 x ULN)

   AST (>10 x ULN)

   Lipase (>2.5 x ULN)

   Total amylase (>2.5 x ULN)

8%

4%

1%

1%

2%

3%

3%
3%

2%

3%

3%

4%

3%

3%

2

Use for the Prevention of Maternal-Fetal Transmission of HIV-1:3in utero

6.2 Postmarketing Experience




Body as a Whole:[see Warnings and Precautions (5.6)]

Cardiovascular:,

Endocrine:

Eye:

Gastrointestinal:

General:

Hemic and Lymphatic:

Hepatobiliary Tract and Pancreas:

Musculoskeletal:

Nervous:

Respiratory:

Skin:

Special Senses:

Urogenital:

7 DRUG INTERACTIONS

7.1 Antiretroviral Agents


Stavudine:in vitro

Nucleoside Analogues Affecting DNA Replication:in vitro

7.2 Doxorubicin


in vitro

7.3 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents


8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy




Pregnancy Category C.

[see Clinical Studies (14.3)]r

[see Clinical Studies (14.3)]

[see Nonclinical Toxicology (13.2)]

Antiretroviral Pregnancy Registry:

8.3 Nursing Mothers


[see Clinical Pharmacology (12.3)]

8.4 Pediatric Use


Zidovudine has been studied in HIV-1-infected pediatric patients ≥6 weeks of age who had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-1-related immunosuppression. Zidovudine has also been studied in neonates perinatally exposed to HIV-1 [see Dosage and Administration (2.1), Adverse Reactions (6.1) , Clinical Pharmacology (12.3), Clinical Studies (14.2), (14.3)].

8.5 Geriatric Use


8.6 Renal Impairment


[see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment


[see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

10 OVERDOSAGE


OD

11 DESCRIPTION



Zidovudine
101354

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action


[see Clinical Pharmacology (12.4)]

12.3 Pharmacokinetics


Absorption and Bioavailability:
Table 6. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients
* Median [range].
†Approximate range.


Parameter
           Mean ± SD
  (except where noted)   

  Oral bioavailability (%)

              64 ± 10
               (n = 5)

  Apparent volume of distribution (L/kg)  

             1.6 ± 0.6
               (n = 8)

  Plasma protein binding (%)

<38

  CSF: plasma ratio*

       0.6 [0.04 to 2.62] 
              (n = 39)

  Systemic clearance (L/hr/kg)

            1.6 ± 0.6
              (n = 6)

  Renal clearance (L/hr/kg)

           0.34 ± 0.05 
               (n = 9)

  Elimination half-life (hr)†

              0.5 to 3
              (n = 19)

Distribution:

Metabolism and Elimination:

Effect of Food on Absorption:

Special Populations:Renal Impairment: 
Table 7. Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal Impairment*
*Data are expressed as mean ± standard deviation.

   

              Parameter
       Control Subjects
  (Normal Renal Function) 
                (n = 6) 

  Patients With Renal 
        Impairment 
           (n = 14)

  CrCl (mL/min)

120 ± 8
18 ± 2

  Zidovudine AUC (ng•hr/mL) 

1,400 ± 200
3,100 ± 300

  Zidovudine half-life (hr)

1 ± 0.2
1.4 ± 0.1

Hemodialysis and Peritoneal Dialysis:[see Dosage and Administration (2.4)]

Hepatic Impairment:[see Dosage and Administration (2.5)]

Pediatric Patients:

Patients 3 Months to 12 Years of Age:2[see Dosage and Administration (2.1)]

Patients <3 Months of Age:  in utero[see Dosage and Administration (2.2)]
Table 8. Zidovudine Pharmacokinetic Parameters in Pediatric Patients*
*Data presented as mean ± standard deviation except where noted.
†Median [range].

   Parameter
   Birth to 14 Days  
          of Age
   14 Days to 3 Months 
            of Age
   3 Months to 12 Years 
               of Age

   Oral bioavailability (%)
         89 ± 19 
        (n = 15)
               61 ± 19 
              (n = 17)
            65 ±  24 
            (n = 18)

   CSF:plasma ratio
        no data
            no data
    0.68 [0.03 to 3.25]†  
            (n = 38)

   CL (L/hr/kg)
       0.65 ±  0.29 
        (n = 18)
          1.14 ± 0.24
            (n = 16)
         1.85 ± 0.47 
            (n = 20)

   Elimination half-life (hr)
        3.1 ± 1.2 
        (n = 21)
           1.9 ± 0.7 
           (n = 18)
            1.5 ±  0.7 
           (n = 21)

Pregnancy:  [see Use in Specific Populations (8.1)].



Nursing Mothers:  [see Use In Specific Populations (8.3) ]

Geriatric Patients:

Gender: 

Drug Interactions:[See Drug Interactions (7)]
Table 9. Effect of Coadministered Drugs on Zidovudine AUC* 
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED WITH
COADMINISTRATION OF THE FOLLOWING DRUGS.
↑ = 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.

  
  Coadministered Drug and Dose 

  
           Zidovudine
               Dose
    
 
        n          
                 Zidovudine
               Concentrations
   Concentration 
             of
  Coadministered 
           Drug

  AUC
Variability

  Atovaquone
  750 mg q 12 hr with food
200 mg q 8 hr
   14
↑AUC 31%
       Range
  23% to 78%†

↔

  Fluconazole
  400 mg daily
200 mg q 8 hr
   12
↑AUC 74%
      95% CI:
   54% to 98% 

Not Reported

  Lamivudine
  300 mg q 12 hr
         single 200 mg
   12
↑AUC 13%
      90% CI:
   2% to 27% 

↔

  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 130%† 

Not Assessed

Phenytoin: 

Ribavirin:  In vitro [see Warnings and Precautions (5.4)].

12.4 Microbiology


Mechanism of Action:

Antiviral Activity:50905050

Resistance:

Cross-Resistance:

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility












+/-in vitro



a

13.2 Reproductive and Developmental Toxicology Studies


in vitro

14 CLINICAL STUDIES


14.1 Adults


Combination Therapy:

®

Monotherapy:3

14.2 Pediatric Patients


310
Table 10. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death)

 

           Endpoint
     EPIVIR plus 
      Zidovudine
       (n = 236)
  Didanosine 
    (n = 235)

  HIV disease progression or death (total)  

        Physical growth failure

        Central nervous system deterioration

        CDC Clinical Category C

        Death
15 (6.4%)

7 (3%)

4 (1.7%)

2 (0.8%)

2 (0.8%)
37 (15.7%)

6 (2.6%)

12 (5.1%)

8 (3.4%)

11 (4.7%)

14.3 Prevention of Maternal-Fetal HIV-1 Transmission


33t

16 HOW SUPPLIED/STORAGE AND HANDLING

Zidovudine Tablets USP, 300 mg are white colored, biconvex, round, film-coated tablets debossed with ‘D’ on one side and ‘11’ on other side

They are supplied by State of Florida DOH Central Pharmacy as follows:

NDC Strength Quantity/Form Color Source Prod. Code
53808-0812- 300 mg 30 Tablets in a Blister Pack white 65862-024

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

17 PATIENT COUNSELING INFORMATION

17.1 Information About Therapy With Zidovudine


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

Common Adverse Reactions:[see Adverse Reactions (6)]

Drug Interactions:

Redistribution/Accumulation of Body Fat:[see Warnings and Precautions (5.6)]

Pregnancy:in utero



Information About Therapy With Zidovudine:








Aurobindo Pharma USA, Inc.




Aurobindo Pharma Limited

This Product was Repackaged By:

State of Florida DOH Central Pharmacy
104-2 Hamilton Park Drive
Tallahassee, FL 32304
United States

Label Image 300 mg

Zidovudine

Zidovudine

ZIDOVUDINE TABLET, FILM COATED

Product Information

Product Type Human prescription drug label with highlights Item Code (Source) NDC:53808-0812(NDC:65862-024)
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
Zidovudine ZIDOVUDINE 300 mg

Inactive Ingredients

Ingredient Name Strength
hypromellose
MAGNESIUM STEARATE
cellulose, microcrystalline
polyethylene glycol
SODIUM STARCH GLYCOLATE TYPE A POTATO
titanium dioxide

Product Characteristics

Color Size Imprint Code Shape
white 10 mm D;11 ROUND

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:53808-0812-1 30 in 1 BLISTER PACK

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077267 2009-07-01


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