Ribavirin (Page 4 of 9)

6 ADVERSE REACTIONS

Clinical trials with ribavirin in combination with INTRON A have been conducted in over 7800 subjects from 3 to 76 years of age.

The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of oral therapy. Cardiac and pulmonary reactions associated with anemia occurred in approximately 10% of patients [see Warnings and Precautions (5.2) ].

Greater than 96% of all subjects in clinical trials experienced one or more adverse reactions. The most commonly reported adverse reactions in adult subjects receiving INTRON A in combination with ribavirin were injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. The most common adverse reactions in pediatric subjects, ages 3 and older, receiving ribavirin in combination with INTRON A were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.

The Adverse Reactions section references the following clinical trials:

Ribavirin/INTRON A Combination Therapy trials for adults and pediatrics

Because clinical trials are conducted under widely varying conditions, adverse reactions 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 clinical practice.

6.2 Clinical Trials Experience – Ribavirin/INTRON A Combination Therapy

Adult Subjects

In clinical trials, 19% and 6% of previously untreated and relapse subjects, respectively, discontinued therapy due to adverse reactions in the combination arms compared to 13% and 3% in the interferon arms. Selected treatment-related adverse reactions that occurred in the U.S. trials with greater than or equal to 5% incidence are provided by treatment group (see Table 9). In general, the selected treatment-related adverse reactions were reported with lower incidence in the international trials as compared to the U.S. trials, with the exception of asthenia, influenza-like symptoms, nervousness, and pruritus.

Pediatric Subjects

In clinical trials of 118 pediatric subjects 3 to 16 years of age, 6% discontinued therapy due to adverse reactions. Dose modifications were required in 30% of subjects, most commonly for anemia and neutropenia. In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults. Injection site disorders, fever, anorexia, vomiting, and emotional lability occurred more frequently in pediatric subjects compared to adult subjects. Conversely, pediatric subjects experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea, and pruritus compared to adult subjects. Selected treatment-related adverse reactions that occurred with greater than or equal to 5% incidence among all pediatric subjects who received the recommended dose of ribavirin/INTRON A combination therapy are provided in Table 9.

Table 9: Selected Treatment-Related Adverse Reactions: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects
*
Subjects reporting one or more adverse reactions. A subject may have reported more than one adverse reaction within a body system/organ class category.

Percentage of Subjects

U.S. Previously Untreated Study

U.S. Relapse Study

Pediatric Subjects

24 weeks of treatment

48 weeks of treatment

24 weeks of treatment

48 weeks of treatment

Subjects Reporting Adverse Reactions *

INTRON A/ Ribavirin (N = 228)

INTRON A/ Placebo (N = 231)

INTRON A/ Ribavirin (N = 228)

INTRON A/ Placebo (N = 225)

INTRON A/ Ribavirin (N = 77)

INTRON A/ Placebo (N = 76)

INTRON A/Ribavirin (N = 118)

Application Site Disorders

Injection Site Inflammation

13

10

12

14

6

8

14

Injection Site Reaction

7

9

8

9

5

3

19

Body as a Whole — General Disorders

Headache

63

63

66

67

66

68

69

Fatigue

68

62

70

72

60

53

58

Rigors

40

32

42

39

43

37

25

Fever

37

35

41

40

32

36

61

Influenza-like Symptoms

14

18

18

20

13

13

31

Asthenia

9

4

9

9

10

4

5

Chest Pain

5

4

9

8

6

7

5

Central & Peripheral Nervous System Disorders

Dizziness

17

15

23

19

26

21

20

Gastrointestinal System Disorders

Nausea

38

35

46

33

47

33

33

Anorexia

27

16

25

19

21

14

51

Dyspepsia

14

6

16

9

16

9

< 1

Vomiting

11

10

9

13

12

8

42

Musculoskeletal System Disorders

Myalgia

61

57

64

63

61

58

32

Arthralgia

30

27

33

36

29

29

15

Musculoskeletal Pain

20

26

28

32

22

28

21

Psychiatric Disorders

Insomnia

39

27

39

30

26

25

14

Irritability

23

19

32

27

25

20

10

Depression

32

25

36

37

23

14

13

Emotional Lability

7

6

11

8

12

8

16

Concentration Impaired

11

14

14

14

10

12

5

Nervousness

4

2

4

4

5

4

3

Respiratory System Disorders

Dyspnea

19

9

18

10

17

12

5

Sinusitis

9

7

10

14

12

7

< 1

Skin and Appendages Disorders

Alopecia

28

27

32

28

27

26

23

Rash

20

9

28

8

21

5

17

Pruritus

21

9

19

8

13

4

12

Special Senses, Other Disorders

Taste Perversion

7

4

8

4

6

5

< 1

During a 48 week course of therapy there was a decrease in the rate of linear growth (mean percentile assignment decrease of 7%) and a decrease in the rate of weight gain (mean percentile assignment decrease of 9%). A general reversal of these trends was noted during the 24 week post-treatment period. Long-term data in a limited number of patients, however, suggests that combination therapy may induce a growth inhibition that results in reduced final adult height in some patients [see Warnings and Precautions (5.9) ].

Laboratory Values

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below (see Table 10).

Hemoglobin. Hemoglobin decreases among subjects receiving ribavirin therapy began at Week 1, with stabilization by Week 4. In previously untreated subjects treated for 48 weeks, the mean maximum decrease from baseline was 3.1 g/dL in the U.S. trial and 2.9 g/dL in the international trial. In relapse subjects, the mean maximum decrease from baseline was 2.8 g/dL in the U.S. trial and 2.6 g/dL in the international trial. Hemoglobin values returned to pretreatment levels within 4 to 8 weeks of cessation of therapy in most subjects.

Bilirubin and Uric Acid. Increases in both bilirubin and uric acid, associated with hemolysis, were noted in clinical trials. Most were moderate biochemical changes and were reversed within 4 weeks after treatment discontinuation. This observation occurred most frequently in subjects with a previous diagnosis of Gilbert’s syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.

Table 10: Selected Laboratory Abnormalities During Treatment With Ribavirin and INTRON A: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects

Percentage of Subjects

U.S. Previously Untreated Study

U.S. Relapse Study

Pediatric Subjects

24 weeks of treatment

48 weeks of treatment

24 weeks of treatment

48 weeks of treatment

INTRON A/ Ribavirin (N = 228)

INTRON A/ Placebo (N = 231)

INTRON A/ Ribavirin (N = 228)

INTRON A/ Placebo (N = 225)

INTRON A/ Ribavirin (N = 77)

INTRON A / Placebo (N = 76)

INTRON A/ Ribavirin (N = 118)

Hemoglobin (g/dL)

9.5 to 10.9

24

1

32

1

21

3

24

8.0 to 9.4

5

0

4

0

4

0

3

6.5 to 7.9

0

0

0

0.4

0

0

0

< 6.5

0

0

0

0

0

0

0

Leukocytes (x 109 /L)

2.0 to 2.9

40

20

38

23

45

26

35

1.5 to 1.9

4

1

9

2

5

3

8

1.0 to 1.4

0.9

0

2

0

0

0

0

< 1.0

0

0

0

0

0

0

0

Neutrophils (x 109 /L)

1.0 to 1.49

30

32

31

44

42

34

37

0.75 to

0.99

14

15

14

11

16

18

15

0.5 to 0.74

9

9

14

7

8

4

16

< 0.5

11

8

11

5

5

8

3

Platelets (x 109 /L)

70 to 99

9

11

11

14

6

12

0.8

50 to 69

2

3

2

3

0

5

2

30 to 49

0

0.4

0

0.4

0

0

0

< 30

0.9

0

1

0.9

0

0

0

Total Bilirubin (mg/dL)

1.5 to 3.0

27

13

32

13

21

7

2

3.1 to 6.0

0.9

0.4

2

0

3

0

0

6.1 to 12.0

0

0

0.4

0

0

0

0

> 12.0

0

0

0

0

0

0

0

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