Epogen Side Effects

Generic Name: epoetin alfa

Please note - some side effects for Epogen may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Epogen - for the Consumer

Epogen

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Epogen:

Cough; headache; joint or bone pain; mild muscle pain; mild pain or redness at the injection site; muscle spasms; nausea; trouble sleeping; vomiting; weight loss.

Seek medical attention right away if any of these SEVERE side effects occur when using Epogen:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); calf or leg pain, redness, tenderness, or swelling; chest, jaw, or left arm pain; confusion; coughing up blood; depression; fainting; fast or irregular heartbeat; fever, chills, or sore throat; muscle pain, weakness, or cramping; new or worsening pale skin color, or tiredness or weakness; numbness of an arm or leg; one-sided weakness; seizures; severe or persistent pain or irritation at the injection site; shortness of breath; sudden, severe headache, dizziness, or vomiting; sudden trouble walking, or loss of balance or coordination; swelling of the fingers, ankles, or legs; swelling or soreness of the mouth or tongue; symptoms of high blood sugar (eg, increased thirst, hunger, or urination; drowsiness; flushing; rapid breathing; fruit-like breath odor); trouble swallowing; vision or speech problems; weight gain.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Epogen Side Effects - for the Professional

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 (5.1)]
• Increased mortality and/or increased risk of tumor progression or recurrence in Patients With Cancer [see Warnings and Precautions (5.3)]
• Hypertension [see Warnings and Precautions (5.4)]
• Seizures [see Warnings and Precautions (5.5)]
• PRCA [see Warnings and Precautions (5.7)]
• Serious allergic reactions [see Warnings and Precautions (5.8)]

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.

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 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

Adverse Reaction	Epogen-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% Epogen and 1% placebo) [see Warnings and Precautions (5.1)].

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

Adverse Reactions	Epogen-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% Epogen and 0% placebo) and myocardial infarction (0.8% Epogen 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 HIV-infected Patients

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

Adverse Reaction	Epogen (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

Cancer Patients 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 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

Adverse Reaction	Epogen (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 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

* Study included patients undergoing orthopedic surgery treated with Epogen or placebo for 15 days. † Study included patients undergoing orthopedic surgery treated with Epogen 600 U/kg weekly for 4 weeks or 300 U/kg daily for 15 days. ‡ DVTs were determined by clinical symptoms.
	Study S1			Study S2
	Epogen 300 U/kg	Epogen 100 U/kg	Placebo	Epogen 600 U/kg x 4 weeks	Epogen 300 U/kg x 15 days
Adverse Reaction	(n = 112)*	(n = 101)*	(n = 103)*	(n = 73)†	(n = 72)†
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%

Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified during postmarketing use of Epogen:

• Seizures [see Warnings and Precautions (5.5)]
• PRCA [see Warnings and Precautions (5.7)]
• Serious allergic reactions [see Warnings and Precautions (5.8)]
• 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 (5.7)].

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.

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Side Effects by Body System - for Healthcare Professionals

Immunologic

Immunologic side effects including neutralizing antibodies to erythropoietin, in association with pure red cell aplasia (PRCA) or severe anemia (with or without cytopenias) have been reported.

General

Epoetin alfa generally has been well tolerated. A flu-like syndrome has been reported in 5% of patients receiving intravenous injections of epoetin alfa. This syndrome includes low-grade fever, arthralgias, myalgias, and flank pain. These symptoms may be managed by subcutaneous administration or a slower rate of intravenous administration. Many patients receiving epoetin alfa have serious underlying conditions and it is sometimes difficult to discern true drug toxicity from disease activity.

The most frequently reported adverse effects observed in patients on dialysis were hypertension, headache, tachycardia, nausea and vomiting, clotted vascular access, shortness of breath, hyperkalemia, and diarrhea. In zidovudine treated HIV patients, the incidence of epoetin alfa side effects were not statistically significant from those in the placebo group and were consistent with disease progression. Diarrhea and edema occurred at a statistically significant greater incidence (compared to placebo) in cancer patients on chemotherapy.

Cardiovascular

The development or exacerbation of hypertension in patients with chronic renal failure is of concern. Epoetin alfa associated hypertension does not appear to depend on preexisting hypertension and one study suggests a relationship between new onset hypertension and an hematocrit of less than 20%. The mechanism for development of hypertension has not been established, but may be due to increased blood viscosity as red cell production increases or increased peripheral resistance as the anemia is corrected. Therapeutic endpoints should be approached slowly and preexisting hypertension should be controlled prior to initiating therapy.

Cardiovascular side effects have been reported the most frequently. These have included hypertension, myocardial infarction, and tachycardia. Up to 35% of patients with hypertension due to chronic renal failure may require additional antihypertensive medication or an adjustment of an existing regimen.

Deep vein thrombosis has been reported in at least one patient receiving 20,000 units three times a week.

Increased mortality has been observed in cardiac patients (ischemic heart disease or congestive heart failure) on hemodialysis with a target hematocrit of 42% compared to similar patients with a target hematocrit of 30% (mortality rate 35% and 29%, respectively). The incidence of nonfatal myocardial infarctions, vascular access thrombosis, and all other thrombotic events was also increased in patients randomized to the higher target hematocrit. Maintenance of hematocrit levels between 30% and 36% is recommended.

A significant increase in thrombosis and mortality has been associated with the use of epoetin alfa (compared to placebo) in patients without renal failure undergoing coronary bypass surgery. In patients receiving epoetin who are at risk for thrombosis, the risk versus benefit of therapy should be individually evaluated.

Hematologic

Hematologic side effects have included incidences of vascular access thrombosis. All other thrombotic events were increased in cardiac patients randomized to a target hematocrit (HCT) of 42% compared to a target HCT of 30%. Maintenance of HCT levels between 30% and 36% is recommended.

A significant increase in thrombosis and mortality has been associated with the use of epoetin alfa (compared to placebo) in patients without renal failure undergoing coronary bypass surgery. In patients requiring epoetin who are at risk for thrombosis, the risk versus benefit of therapy should be individually evaluated.

Iron deficiency has occurred in most patients due to incorporation of iron into newly synthesized red blood cells. Supplemental iron may be necessary.

Arteriovenous shunt clotting may occur in hemodialysis patients due to increased blood viscosity and decreased bleeding time, however, the incidence does not appear to be greater than in hemodialysis patients not receiving epoetin alfa. Clotting within the dialyzer has resulted in a 25% increase in heparin anticoagulation requirements during hemodialysis.

Iron stores are readily incorporated into new red blood cells as hemoglobin is produced during the acute phase of drug therapy. Iron deficiency diminishes the therapeutic effect of the drug. Iron replacement is necessary in nearly all patients treated with epoetin alfa, and iron status should be evaluated prior to initiating therapy and at regular intervals. A transferrin saturation of less than 20% or a serum ferritin level of less than 100 mcg/L suggests inadequate iron stores and a need for iron replacement therapy.

Nervous system

Nervous system side effects have included headache (15%) and seizures (to 5%).

Seizures have occurred primarily in the first three months of therapy and may have been associated with a increase in hematocrit or blood pressure. Neurologic monitoring and evaluation during epoetin alfa therapy is recommended in patients with a history of seizure activity. Therapeutic endpoints should be approached slowly to minimize seizure risks.

Psychiatric

Psychiatric side effects have rarely included hallucinations among the dialysis patients treated with epoetin alfa.

Oncologic

Oncologic side effects, particularly with myeloid tumors, may occur due to epoetin alfa's growth factor activity.

Erythropoietin receptors have been found to be present on the surface of some malignant cell lines and tumor biopsy specimens. However, there is insufficient data to establish whether use of epoetin products have an adverse effect on time to tumor progression or progression-free survival.

Gastrointestinal

Gastrointestinal side effects have included nausea, vomiting, and diarrhea, but these have not occurred at an incidence significantly greater than reported in placebo groups amongst patients with chronic renal failure and HIV-infected patients treated with zidovudine. Diarrhea occurred at a statistically significant greater incidence (compared to placebo) in cancer patients on chemotherapy.

Dermatologic

Dermatologic side effects have rarely included mild and transient skin rashes and urticaria.

Local

Local side effects of epoetin alfa have included pain at the injection site.

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