Zidovudine (Page 3 of 9)

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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults

The frequency and severity of adverse reactions associated with the use of zidovudine are greater in patients with more advanced infection at the time of initiation of therapy.

Table 3 summarizes adverse reactions reported at a statistically significant greater incidence for subjects receiving oral Zidovudine in a monotherapy trial.

Table 3. Percentage (%) of Subjects with Adverse Reactions (Greater Than or Equal to 5% Frequency) in Asymptomatic HIV-1 Infection (ACTG 019)
*

Adverse Reaction

Zidovudine 500 mg/day

(n = 453)

Placebo

(n = 428)

Body as a whole

Asthenia

9% *

6%

Headache

63%

53%

Malaise

53%

45%

Gastrointestinal

Anorexia

20%

11%

Constipation

6% *

4%

Nausea

51%

30%

Vomiting

17%

10%

In addition to the adverse reactions listed in Table 3, adverse reactions observed at an incidence of greater than or equal to 5% in any treatment arm in clinical trials (NUCA3001, NUCA3002, NUCB3001 and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia, and neuropathy. Additionally, in these trials hyperbilirubinemia was reported at an incidence of less than or equal to 0.8%.

Selected laboratory abnormalities observed during a clinical trial of monotherapy with oral zidovudine are shown in Table 4.

Table 4. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Subjects 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)

1%

< 1%

Granulocytopenia (< 750 cells/mm 3)

2%

2%

Thrombocytopenia (platelets < 50,000/mm 3)

0%

< 1%

ALT (> 5 x ULN)

3%

3%

AST (> 5 x ULN)

1%

2%

The adverse reactions reported during IV administration of zidovudine injection are similar to those reported with oral administration; neutropenia and anemia were reported most frequently. Long-term IV administration beyond 2 to 4 weeks has not been studied in adults and may enhance hematologic adverse reactions. Local reaction, pain, and slight irritation during IV administration occur infrequently.

Pediatrics

The clinical adverse reactions reported among adult recipients of zidovudine may also occur in pediatric patients.

Trial ACTG 300: Selected clinical adverse reactions and physical findings with a greater than or equal to 5% frequency during therapy with EPIVIR ® (lamivudine) oral suspension 4 mg per kg twice daily plus zidovudine 160 mg per m 2 3 times daily compared with didanosine in therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 5.

Table 5. Selected Clinical Adverse Reactions and Physical Findings (Greater Than or Equal to 5% Frequency) in Pediatric Subjects in Trial ACTG 300
*
Includes pain, discharge, erythema, or swelling of an ear.

Adverse Reaction

EPIVIR plus zidovudine tablets

(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%

Selected laboratory abnormalities experienced by therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 6.

Table 6. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric Subjects in Trial ACTG 300
ULN = Upper limit of normal.
ANC = Absolute neutrophil count.

Test

(Abnormal Level)

EPIVIR plus zidovudine tablets

Didanosine

Neutropenia (ANC < 400 cells/mm 3)

8%

3%

Anemia (Hgb < 7 g/dL)

4%

2%

Thrombocytopenia (platelets < 50,000/mm 3)

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%

Macrocytosis was reported in the majority of pediatric subjects receiving zidovudine 180 mg per m 2 every 6 hours in open-label trials. Additionally, adverse reactions reported at an incidence of less than 6% in these trials were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability, and weight loss.

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