RETACRIT (Page 4 of 11)

5.3 Hypertension

RETACRIT is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of epoetin alfa, approximately 25% of patients on dialysis required initiation of or increases in antihypertensive therapy; hypertensive encephalopathy and seizures have been reported in patients with CKD receiving epoetin alfa.

Appropriately control hypertension prior to initiation of and during treatment with RETACRIT. Reduce or withhold RETACRIT if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions [see Patient Counseling Information (17)].

5.4 Seizures

Epoetin alfa products, including RETACRIT, increase the risk of seizures in patients with CKD. During the first several months following initiation of RETACRIT, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms or change in seizure frequency.

5.5 Lack or Loss of Hemoglobin Response to RETACRIT

For lack or loss of hemoglobin response to RETACRIT, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA [see Warnings and Precautions (5.6)]. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to RETACRIT therapy [see Dosage and Administration (2.2)].

5.6 Pure Red Cell Aplasia

Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with epoetin alfa. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which RETACRIT is not approved).

If severe anemia and low reticulocyte count develop during treatment with RETACRIT, withhold RETACRIT and evaluate patients for neutralizing antibodies to erythropoietin. Contact Hospira, Inc., a Pfizer Company (1-800-438-1985) to perform assays for binding and neutralizing antibodies. Permanently discontinue RETACRIT in patients who develop PRCA following treatment with RETACRIT or other erythropoietin protein drugs. Do not switch patients to other ESAs.

5.7 Serious Allergic Reactions

Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with epoetin alfa products. Immediately and permanently discontinue RETACRIT and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.

5.8 Severe Cutaneous Reactions

Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including epoetin alfa) in the postmarketing setting. Discontinue RETACRIT therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.

5.9 Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative

RETACRIT from multiple-dose vials contains benzyl alcohol and is contraindicated for use in neonates, infants, pregnant women, and lactating women [see Contraindications (4)]. In addition, do not mix RETACRIT with bacteriostatic saline (which also contains benzyl alcohol) when administering RETACRIT to these patient populations [see Dosage and Administration (2)].

Serious and fatal reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including RETACRIT multiple-dose vials. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. There is a potential for similar risks to fetuses and infants exposed to benzyl alcohol in utero or in breast-fed milk, respectively. RETACRIT multiple-dose vials contain 8.5 mg of benzyl alcohol per mL. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.1, 8.2, and 8.4)].

5.10 Risks in Patients with Phenylketonuria

Phenylalanine can be harmful to patients with phenylketonuria (PKU). RETACRIT contains phenylalanine, a component of aspartame. Each 1 mL single-dose vial of 2,000, 3,000, 4,000, and 10,000 Units of epoetin alfa-epbx injection contains 0.5 mg of phenylalanine. Before prescribing RETACRIT to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including RETACRIT.

5.11 Dialysis Management

Patients may require adjustments in their dialysis prescriptions after initiation of RETACRIT. Patients receiving RETACRIT may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

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 Reaction Epoetin 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 Reactions Epoetin 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 Reaction Epoetin 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 Reaction Epoetin 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 Reaction Study S1 Study S2
Epoetin alfa 300 U/kg Epoetin alfa 100 U/kg Placebo Epoetin 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%

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