RETACRIT™ Adverse Reactions

(epoetin alfa-epbx)

6 ADVERSE REACTIONS

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

Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions (5.1)]
Increased mortality and/or increased risk of tumor progression or recurrence in Patients with Cancer [see Warnings and Precautions (5.2)]
Hypertension [see Warnings and Precautions (5.3)]
Seizures [see Warnings and Precautions (5.4)]
PRCA [see Warnings and Precautions (5.6)]
Serious allergic reactions [see Warnings and Precautions (5.7)]
Severe Cutaneous Reactions [see Warnings and Precautions (5.8)]

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 other drugs and may not reflect the rates observed in practice.

Patients with Chronic Kidney Disease

Adult Patients

Three double-blind, placebo-controlled studies, including 244 patients with CKD on dialysis, were used to identify the adverse reactions to epoetin alfa. In these studies, the mean age of patients was 48 years (range: 20 to 80 years). One hundred and thirty-three (55%) patients were men. The racial distribution was as follows: 177 (73%) patients were white, 48 (20%) patients were black, 4 (2%) patients were Asian, 12 (5%) patients were other, and racial information was missing for 3 (1%) patients.

Two double-blind, placebo-controlled studies, including 210 patients with CKD not on dialysis, were used to identify the adverse reactions to epoetin alfa. In these studies, the mean age of patients was 57 years (range: 24 to 79 years). One hundred and twenty-one (58%) patients were men. The racial distribution was as follows: 164 (78%) patients were white, 38 (18%) patients were black, 3 (1%) patients were Asian, 3 (1%) patients were other, and racial information was missing for 2 (1%) patients.

The adverse reactions with a reported incidence of ≥ 5% in epoetin alfa-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:

Table 3. Adverse Reactions in Patients with CKD on Dialysis
Adverse ReactionEpoetin alfa-treated Patients
(n = 148)
Placebo-treated Patients
(n = 96)

Hypertension

27.7%

12.5%

Arthralgia

16.2%

3.1%

Muscle spasm

7.4%

6.3%

Pyrexia

10.1%

8.3%

Dizziness

9.5%

8.3%

Medical Device Malfunction (artificial kidney clotting during dialysis)

8.1%

4.2%

Vascular Occlusion (vascular access thrombosis)

8.1%

2.1%

Upper respiratory tract infection

6.8%

5.2%

An additional serious adverse reaction that occurred in less than 5% of epoetin alfa-treated dialysis patients and greater than placebo was thrombosis (2.7% epoetin alfa and 1% placebo) [see Warnings and Precautions (5.1)].

The adverse reactions with a reported incidence of ≥ 5% in epoetin alfa-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:

Table 4. Adverse Reactions in Patients with CKD Not on Dialysis
Adverse ReactionsEpoetin alfa-treated Patients
(n = 131)
Placebo-treated Patients
(n = 79)

Hypertension

13.7%

10.1%

Arthralgia

12.2%

7.6%

Additional serious adverse reactions that occurred in less than 5% of epoetin alfa-treated patients not on dialysis and greater than placebo were erythema (0.8% epoetin alfa and 0% placebo) and myocardial infarction (0.8% epoetin alfa and 0% placebo) [see Warnings and Precautions (5.1)].

Pediatric Patients

In pediatric patients with CKD on dialysis, the pattern of adverse reactions was similar to that found in adults.

Zidovudine-treated Patients with HIV-infection

A total of 297 zidovudine-treated patients with HIV-infection were studied in 4 placebo-controlled studies. A total of 144 (48%) patients were randomly assigned to receive epoetin alfa and 153 (52%) patients were randomly assigned to receive placebo. Epoetin alfa was administered at doses between 100 and 200 Units/kg 3 times weekly subcutaneously for up to 12 weeks.

For the combined epoetin alfa treatment groups, a total of 141 (98%) men and 3 (2%) women between the ages of 24 and 64 years were enrolled. The racial distribution of the combined epoetin alfa treatment groups was as follows: 129 (90%) white, 8 (6%) black, 1 (1%) Asian, and 6 (4%) other.

In double-blind, placebo-controlled studies of 3 months duration involving approximately 300 zidovudine-treated patients with HIV-infection, adverse reactions with an incidence of ≥ 1% in patients treated with epoetin alfa were:

Table 5. Adverse Reactions in Zidovudine-treated Patients with HIV-infection
Adverse ReactionEpoetin alfa
(n = 144)
Placebo
(n = 153)

Pyrexia

42%

34%

Cough

26%

14%

Rash

19%

7%

Injection site irritation

7%

4%

Urticaria

3%

1%

Respiratory tract congestion

1%

Not reported

Pulmonary embolism

1%

Not reported

Patients with Cancer on Chemotherapy

The data below were obtained in Study C1, a 16-week, double-blind, placebo-controlled study that enrolled 344 patients with anemia secondary to chemotherapy. There were 333 patients who were evaluable for safety; 168 of 174 patients (97%) randomized to epoetin alfa received at least 1 dose of study drug, and 165 of 170 patients (97%) randomized to placebo received at least 1 placebo dose. For the once weekly epoetin alfa treatment group, a total of 76 men (45%) and 92 women (55%) between the ages of 20 and 88 years were treated. The racial distribution of the epoetin alfa-treatment group was 158 white (94%) and 10 black (6%). Epoetin alfa was administered once weekly for an average of 13 weeks at a dose of 20,000 to 60,000 IU subcutaneously (mean weekly dose was 49,000 IU).

The adverse reactions with a reported incidence of ≥ 5% in epoetin alfa-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:

Table 6. Adverse Reactions in Patients with Cancer
Adverse ReactionEpoetin alfa
(n = 168)
Placebo
(n = 165)

Nausea

35%

30%

Vomiting

20%

16%

Myalgia

10%

5%

Arthralgia

10%

6%

Stomatitis

10%

8%

Cough

9%

7%

Weight decrease

9%

5%

Leukopenia

8%

7%

Bone pain

7%

4%

Rash

7%

5%

Hyperglycemia

6%

4%

Insomnia

6%

2%

Headache

5%

4%

Depression

5%

4%

Dysphagia

5%

2%

Hypokalemia

5%

3%

Thrombosis

5%

3%

Surgery Patients

Four hundred sixty-one patients undergoing major orthopedic surgery were studied in a placebo-controlled study (S1) and a comparative dosing study (2 dosing regimens, S2). A total of 358 patients were randomly assigned to receive epoetin alfa and 103 (22%) patients were randomly assigned to receive placebo. Epoetin alfa was administered daily at a dose of 100 to 300 IU/kg subcutaneously for 15 days or at 600 IU/kg once weekly for 4 weeks.

For the combined epoetin alfa treatment groups, a total of 90 (25%) men and 268 (75%) women between the ages of 29 and 89 years were enrolled. The racial distribution of the combined epoetin alfa treatment groups was as follows: 288 (80%) white, 64 (18%) black, 1 (< 1%) Asian, and 5 (1%) other.

The adverse reactions with a reported incidence of ≥ 1% in epoetin alfa-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:

Table 7. Adverse Reactions in Surgery Patients
Adverse ReactionStudy S1Study S2
Epoetin alfa
300 U/kg
Epoetin alfa
100 U/kg
PlaceboEpoetin alfa
600 U/kg × 4 weeks
Epoetin alfa
300 U/kg × 15 days
(n = 112)*(n = 101)*(n = 103)*(n = 73)(n = 72)
*
Study included patients undergoing orthopedic surgery treated with epoetin alfa or placebo for 15 days.
Study included patients undergoing orthopedic surgery treated with epoetin alfa 600 U/kg weekly for 4 weeks or 300 U/kg daily for 15 days.
DVTs were determined by clinical symptoms.

Nausea

47%

43%

45%

45%

56%

Vomiting

21%

12%

14%

19%

28%

Pruritus

16%

16%

14%

12%

21%

Headache

13%

11%

9%

10%

18%

Injection site pain

13%

9%

8%

12%

11%

Chills

7%

4%

1%

1%

0%

Deep vein thrombosis

6%

3%

3%

0%

0%

Cough

5%

4%

0%

4%

4%

Hypertension

5%

3%

5%

5%

6%

Rash

2%

2%

1%

3%

3%

Edema

1%

2%

2%

1%

3%

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of epoetin alfa. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Seizures [see Warnings and Precautions (5.4)]
PRCA [see Warnings and Precautions (5.6)]
Serious allergic reactions [see Warnings and Precautions (5.7)]
Injection site reactions, including irritation and pain
Porphyria
Severe Cutaneous Reactions [see Warnings and Precautions (5.8)]

6.3 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies to other epoetin alfa products may be misleading.

Neutralizing antibodies to epoetin alfa that cross-react with endogenous erythropoietin and other ESAs can result in PRCA or severe anemia (with or without other cytopenias) [see Warnings and Precautions (5.6)].

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Adverse Reactions

6 ADVERSE REACTIONS

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

Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions (5.1)]
Increased mortality and/or increased risk of tumor progression or recurrence in Patients with Cancer [see Warnings and Precautions (5.2)]
Hypertension [see Warnings and Precautions (5.3)]
Seizures [see Warnings and Precautions (5.4)]
PRCA [see Warnings and Precautions (5.6)]
Serious allergic reactions [see Warnings and Precautions (5.7)]
Severe Cutaneous Reactions [see Warnings and Precautions (5.8)]

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 other drugs and may not reflect the rates observed in practice.

Patients with Chronic Kidney Disease

Adult Patients

Three double-blind, placebo-controlled studies, including 244 patients with CKD on dialysis, were used to identify the adverse reactions to epoetin alfa. In these studies, the mean age of patients was 48 years (range: 20 to 80 years). One hundred and thirty-three (55%) patients were men. The racial distribution was as follows: 177 (73%) patients were white, 48 (20%) patients were black, 4 (2%) patients were Asian, 12 (5%) patients were other, and racial information was missing for 3 (1%) patients.

Two double-blind, placebo-controlled studies, including 210 patients with CKD not on dialysis, were used to identify the adverse reactions to epoetin alfa. In these studies, the mean age of patients was 57 years (range: 24 to 79 years). One hundred and twenty-one (58%) patients were men. The racial distribution was as follows: 164 (78%) patients were white, 38 (18%) patients were black, 3 (1%) patients were Asian, 3 (1%) patients were other, and racial information was missing for 2 (1%) patients.

The adverse reactions with a reported incidence of ≥ 5% in epoetin alfa-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:

Table 3. Adverse Reactions in Patients with CKD on Dialysis
Adverse ReactionEpoetin alfa-treated Patients
(n = 148)
Placebo-treated Patients
(n = 96)

Hypertension

27.7%

12.5%

Arthralgia

16.2%

3.1%

Muscle spasm

7.4%

6.3%

Pyrexia

10.1%

8.3%

Dizziness

9.5%

8.3%

Medical Device Malfunction (artificial kidney clotting during dialysis)

8.1%

4.2%

Vascular Occlusion (vascular access thrombosis)

8.1%

2.1%

Upper respiratory tract infection

6.8%

5.2%

An additional serious adverse reaction that occurred in less than 5% of epoetin alfa-treated dialysis patients and greater than placebo was thrombosis (2.7% epoetin alfa and 1% placebo) [see Warnings and Precautions (5.1)].

The adverse reactions with a reported incidence of ≥ 5% in epoetin alfa-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:

Table 4. Adverse Reactions in Patients with CKD Not on Dialysis
Adverse ReactionsEpoetin alfa-treated Patients
(n = 131)
Placebo-treated Patients
(n = 79)

Hypertension

13.7%

10.1%

Arthralgia

12.2%

7.6%

Additional serious adverse reactions that occurred in less than 5% of epoetin alfa-treated patients not on dialysis and greater than placebo were erythema (0.8% epoetin alfa and 0% placebo) and myocardial infarction (0.8% epoetin alfa and 0% placebo) [see Warnings and Precautions (5.1)].

Pediatric Patients

In pediatric patients with CKD on dialysis, the pattern of adverse reactions was similar to that found in adults.

Zidovudine-treated Patients with HIV-infection

A total of 297 zidovudine-treated patients with HIV-infection were studied in 4 placebo-controlled studies. A total of 144 (48%) patients were randomly assigned to receive epoetin alfa and 153 (52%) patients were randomly assigned to receive placebo. Epoetin alfa was administered at doses between 100 and 200 Units/kg 3 times weekly subcutaneously for up to 12 weeks.

For the combined epoetin alfa treatment groups, a total of 141 (98%) men and 3 (2%) women between the ages of 24 and 64 years were enrolled. The racial distribution of the combined epoetin alfa treatment groups was as follows: 129 (90%) white, 8 (6%) black, 1 (1%) Asian, and 6 (4%) other.

In double-blind, placebo-controlled studies of 3 months duration involving approximately 300 zidovudine-treated patients with HIV-infection, adverse reactions with an incidence of ≥ 1% in patients treated with epoetin alfa were:

Table 5. Adverse Reactions in Zidovudine-treated Patients with HIV-infection
Adverse ReactionEpoetin alfa
(n = 144)
Placebo
(n = 153)

Pyrexia

42%

34%

Cough

26%

14%

Rash

19%

7%

Injection site irritation

7%

4%

Urticaria

3%

1%

Respiratory tract congestion

1%

Not reported

Pulmonary embolism

1%

Not reported

Patients with Cancer on Chemotherapy

The data below were obtained in Study C1, a 16-week, double-blind, placebo-controlled study that enrolled 344 patients with anemia secondary to chemotherapy. There were 333 patients who were evaluable for safety; 168 of 174 patients (97%) randomized to epoetin alfa received at least 1 dose of study drug, and 165 of 170 patients (97%) randomized to placebo received at least 1 placebo dose. For the once weekly epoetin alfa treatment group, a total of 76 men (45%) and 92 women (55%) between the ages of 20 and 88 years were treated. The racial distribution of the epoetin alfa-treatment group was 158 white (94%) and 10 black (6%). Epoetin alfa was administered once weekly for an average of 13 weeks at a dose of 20,000 to 60,000 IU subcutaneously (mean weekly dose was 49,000 IU).

The adverse reactions with a reported incidence of ≥ 5% in epoetin alfa-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:

Table 6. Adverse Reactions in Patients with Cancer
Adverse ReactionEpoetin alfa
(n = 168)
Placebo
(n = 165)

Nausea

35%

30%

Vomiting

20%

16%

Myalgia

10%

5%

Arthralgia

10%

6%

Stomatitis

10%

8%

Cough

9%

7%

Weight decrease

9%

5%

Leukopenia

8%

7%

Bone pain

7%

4%

Rash

7%

5%

Hyperglycemia

6%

4%

Insomnia

6%

2%

Headache

5%

4%

Depression

5%

4%

Dysphagia

5%

2%

Hypokalemia

5%

3%

Thrombosis

5%

3%

Surgery Patients

Four hundred sixty-one patients undergoing major orthopedic surgery were studied in a placebo-controlled study (S1) and a comparative dosing study (2 dosing regimens, S2). A total of 358 patients were randomly assigned to receive epoetin alfa and 103 (22%) patients were randomly assigned to receive placebo. Epoetin alfa was administered daily at a dose of 100 to 300 IU/kg subcutaneously for 15 days or at 600 IU/kg once weekly for 4 weeks.

For the combined epoetin alfa treatment groups, a total of 90 (25%) men and 268 (75%) women between the ages of 29 and 89 years were enrolled. The racial distribution of the combined epoetin alfa treatment groups was as follows: 288 (80%) white, 64 (18%) black, 1 (< 1%) Asian, and 5 (1%) other.

The adverse reactions with a reported incidence of ≥ 1% in epoetin alfa-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:

Table 7. Adverse Reactions in Surgery Patients
Adverse ReactionStudy S1Study S2
Epoetin alfa
300 U/kg
Epoetin alfa
100 U/kg
PlaceboEpoetin alfa
600 U/kg × 4 weeks
Epoetin alfa
300 U/kg × 15 days
(n = 112)*(n = 101)*(n = 103)*(n = 73)(n = 72)
*
Study included patients undergoing orthopedic surgery treated with epoetin alfa or placebo for 15 days.
Study included patients undergoing orthopedic surgery treated with epoetin alfa 600 U/kg weekly for 4 weeks or 300 U/kg daily for 15 days.
DVTs were determined by clinical symptoms.

Nausea

47%

43%

45%

45%

56%

Vomiting

21%

12%

14%

19%

28%

Pruritus

16%

16%

14%

12%

21%

Headache

13%

11%

9%

10%

18%

Injection site pain

13%

9%

8%

12%

11%

Chills

7%

4%

1%

1%

0%

Deep vein thrombosis

6%

3%

3%

0%

0%

Cough

5%

4%

0%

4%

4%

Hypertension

5%

3%

5%

5%

6%

Rash

2%

2%

1%

3%

3%

Edema

1%

2%

2%

1%

3%

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of epoetin alfa. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Seizures [see Warnings and Precautions (5.4)]
PRCA [see Warnings and Precautions (5.6)]
Serious allergic reactions [see Warnings and Precautions (5.7)]
Injection site reactions, including irritation and pain
Porphyria
Severe Cutaneous Reactions [see Warnings and Precautions (5.8)]

6.3 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies to other epoetin alfa products may be misleading.

Neutralizing antibodies to epoetin alfa that cross-react with endogenous erythropoietin and other ESAs can result in PRCA or severe anemia (with or without other cytopenias) [see Warnings and Precautions (5.6)].

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