Epogen

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]
• Increased mortality and/or increased risk of tumor progression or recurrence in Patients With Cancer [see WARNINGS AND PRECAUTIONS]
• Hypertension [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• PRCA [see WARNINGS AND PRECAUTIONS]
• Serious allergic reactions [see WARNINGS AND PRECAUTIONS]

Clinical Trial 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.

Adult Patients

Three double-blind, placebo-controlled studies, including 244 patients with CKD on dialysis, were used to identify the adverse reactions to Epogen. 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 Epogen. 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 Epogen-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

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% Epogen and 1% placebo) [see WARNINGS AND PRECAUTIONS].

The adverse reactions with a reported incidence of ≥ 5% in Epogen-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

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% Epogen and 0% placebo) and myocardial infarction (0.8% Epogen and 0% placebo) [see WARNINGS AND PRECAUTIONS].

Pediatric Patients

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

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

For the combined Epogen 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 Epogen 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 HIV-infected patients, adverse reactions with an incidence of ≥ 1% in patients treated with Epogen were:

Table 5: Adverse Reactions in Zidovudine-treated HIV-infected Patients

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 Epogen 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 Epogen-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 Epogen-treatment group was 158 white (94%) and 10 black (6%). Epogen 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 Epogen-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:

Table 6: Adverse Reactions in Cancer 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 Epogen and 103 (22%) patients were randomly assigned to receive placebo. Epogen 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 Epogen treatment groups, a total of 90 (25%) and 268 (75%) women between the ages of 29 and 89 years were enrolled. The racial distribution of the combined Epogen 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 Epogen-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

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Epogen. 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]
• PRCA [see WARNINGS AND PRECAUTIONS]
• Serious allergic reactions [see WARNINGS AND PRECAUTIONS]
• Injection site reactions, including irritation and pain
• Porphyria

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. 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].

The incidence 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 to Epogen with the incidence of antibodies to other products may be misleading.

• Amgen Inc

Contact your doctor if you miss a dose of epoetin alfa.

Use Epogen as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into the fatty part of the skin.
• It may be given as a shot into a vein.
• To gain the most benefit, do not miss doses.
• Keep using this medicine as you have been told by your doctor or other health care provider, even if you feel well.
• If you will be giving yourself the shot, your doctor or nurse will teach you how to give the shot.
• Follow how to use as you have been told by the doctor or read the package insert.
• Do not shake.
• Do not use if it has been shaken.
• Wash your hands before and after use.
• Do not use if the solution is cloudy, leaking, or has particles.
• Do not use if solution changes color.
• Do not use if it has been frozen.
• Do not give into red or irritated skin.
• Throw away needles in a needle/sharp disposal box. Do not reuse needles or other items. When the box is full, follow all local rules for getting rid of it. Talk with a doctor or pharmacist if you have any questions.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

Epogen is contraindicated in patients with:

• Uncontrolled hypertension [see Warnings and Precautions (5.3)]
  
• Pure red cell aplasia (PRCA) that begins after treatment with Epogen or other erythropoietin protein drugs [see Warnings and Precautions (5.6)]
  
• Serious allergic reactions to Epogen [see Warnings and Precautions (5.7)]

Epogen from multiple-dose vials contains benzyl alcohol and is contraindicated in:

• Neonates, infants, pregnant women, and nursing mothers.  Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients.  When therapy with Epogen is needed in neonates and infants, use single-dose vials; do not admix with bacteriostatic saline containing benzyl alcohol [see Use in Specific Populations (8.1, 8.3, 8.4)].

Epogen overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of Epogen dosage and/or with phlebotomy, as clinically indicated [see Pharmacodynamics (12.2)].  Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions (5.3)].

Epogen may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Other drugs may interact with epoetin alfa, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

You should not use this medication if you are allergic to epoetin alfa or darbepoetin alfa or (Aranesp), or if:

• you have untreated or uncontrolled high blood pressure;

• you have had pure red cell aplasia (PRCA, a type of anemia) after using darbepoetin alfa or epoetin alfa; or

• you use an epoetin alfa multi-dose vial and you are pregnant or breast-feeding.

Do not use epoetin alfa from a multi-dose vial when giving medicine to a baby. The multi-dose vial contains an ingredient that can cause serious side effects or death in very young infants or premature babies.

Epoetin alfa may shorten remission time in some people with head and neck cancer who are also being treated with radiation. Epoetin alfa may also shorten survival time in certain people with breast cancer, non-small cell lung cancer, head and neck cancer, cervical cancer, or lymphoid cancer. Talk with your doctor about your individual risk.

To make sure epoetin alfa is safe for you, tell your doctor if you have:

• heart disease, high blood pressure;

• kidney disease (or if you are on dialysis);

• a seizure disorder; or

• a history of stroke, heart attack, or blood clots.

Using epoetin alfa during pregnancy could harm the unborn baby. Tell your doctor if you are pregnant or if you become pregnant while using this medicine.

It is not known whether epoetin alfa passes into breast milk or if it could affect the nursing baby. Tell your doctor if you are breast-feeding.

Do not use epoetin alfa from a multi-dose vial if you are pregnant or breast-feeding.

Epoetin alfa is made from human plasma (part of the blood) which may contain viruses and other infectious agents. Donated plasma is tested and treated to reduce the risk of it containing infectious agents, but there is still a small possibility it could transmit disease. Talk with your doctor about the risks and benefits of using this medication.

Call your doctor for instructions if you miss a dose of epoetin alfa.

Other drugs may interact with epoetin alfa, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.