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epoetin
Drug Monograph
Drug Name | Mechanism of Action and Pharmacokinetics | Indications and Status | Adverse Effects | Dosing | Administration
Guidelines | Special Precautions | Interactions | Recommended Clinical Monitoring | Supplementary Public Funding | References | Disclaimer A ­ Drug Name
epoetin SYNONYM(S): EPO; epoetin alfa; Erythropoietin; r­HuEPO
COMMON TRADE NAME(S): Eprex ® (Janssen­Ortho)
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B ­ Mechanism of Action and Pharmacokinetics
Erythropoietin is a glycoprotein produced in the kidney, which stimulates the division and differentiation of committed erythroid progenitors in the bone marrow. Epoetin is a recombinant 165 amino acid glycoprotein with an identical sequence to natural erythropoietin. It is used for the non­emergency increase/ maintenance of red cell levels and to decrease the need for transfusions in patients who do not have other reversible anemias such as iron or folate deficiencies, hemolysis or gastrointestinal bleeding. Clinical trials in a number of tumour types suggest an adverse effect (poorer progression­free survival/survival) in patients treated with epoetin. Absorption
Oral: no
Bioavailability Distribution
Peak serum erythropoietin concentrations achieved within 4­24 hours following subcutaneous injection of epoetin, and serum concentrations remain above baseline for 2­4 days. Peak serum drug concentrations appear to be reduced (by up to 40­70% compared with the first­dose peak) with multiple­dose administration of the drug. Cross blood brain barrier? PPB Metabolism
SC: Approximately 20%. Erythropoetin may be degraded by peptidases in the skin.
yes
Unlikely
The metabolic fate of endogenous erythropoietin and the recombinant hormone (i.e. epoetin) is poorly understood. Disialylation (removal of the Any use of the information is subject, at all times, to CCO’s Terms and Conditions.
CCO Formulary - March 2013
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oligosaccharide side chains) of epoetin appears to occur mainly in the liver. The inactive metabolite appears to undergo hepatic clearance via metabolic pathways and/or binding.
Elimination
Active metabolites Inactive metabolites no
Desialylated epoetin
Half­life Urine 25­39 hours
<10% (unchanged)
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C ­ Indications and Status
Health Canada Approvals:
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Treatment of anemia in cancer patients with metastatic or advanced non­myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy (for a minimum of 2 months). Not indicated with other anti­cancer therapy. The risk­benefit must be carefully considered and discussed with each patient. [See Health Canada Advisories: Important Safety Information on Erythropoiesis­Stimulating Agents, Aranesp® (darbepoetin alfa) and Eprex® (epoetin)].
Refer to the product monograph for non­oncology indications approved by Health Canada. back to top
D ­ Adverse Effects
Emetogenic potential: Not applicable Extravasation Potential: Not applicable The following table contains adverse effects reported mainly in cancer patients where the incidence is greater than placebo.
ORGAN SITE
Cardiovascular SIDE EFFECT* (%)
Arterial thromboembolism
Heart failure
Hypertension (may be severe)
Venous thromboembolism
Gastrointestinal Constipation (10%)
Diarrhea (15%)
ONSET**
E
E
I E
E
E
E
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CCO Formulary - March 2013
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General Nausea, vomiting (35%)
E
Edema (14%)
E
Flu­like symptoms (22%)
Hematological I E
Pure red cell aplasia (very rare)
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Thrombocytosis (rare)
E
Hypersensitivity Anaphylaxis (rare)
I
Injection site Injection site reaction (erythema, burning ­ mild to moderate)
I
Nervous System Dizziness (10%)
Headache (temporary or related to hypertension)
E
I E
Seizure (1%)
E
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post­marketing, phase 1 studies, isolated data or anecdotal reports.
Dose­limiting side effects are underlined. ** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
The most frequent adverse reaction during treatment with epoetin is a dose­dependent increase in blood pressure or aggravation of existing hypertension, especially with a rapid increase in hematocrit, and is most commonly seen in patients with chronic renal failure. Grade 4 hypertension has been reported. Antihypertensive therapy may be required. Patients with uncontrolled hypertension should not be treated with epoetin. If blood pressure cannot be controlled, erythropoietin should be discontinued until blood pressure control is re­established. Thrombotic/vascular events, such as myocardial ischemia, myocardial infarction, cerebrovascular accidents (cerebral hemorrhage and cerebral infarction), transient ischemic attacks, deep venous thrombosis, arterial thrombosis, pulmonary emboli, aneurysms, retinal thrombosis, clotting of vascular access (A­V fistula) and clotting of an artificial kidney have been reported in patients receiving epoetin. Patients with pre­existing vascular disease and/or at risk for thrombosis should be monitored closely. This increased risk of thrombotic events may be associated with treatment to higher hemoglobin concentrations, and/or higher rates of rise of hemoglobin. Recent clinical study results have suggested higher risks of death and serious cardiovascular adverse events when patients with cancer or renal failure were treated to target hemoglobin levels of greater than 120 g/L. Also refer to CCO Practice Guidelines: Treatment of Anemia with Erythropoietic Agents in Patients with Cancer.
Flu­like signs and symptoms such as dizziness, drowsiness, fever, headaches, joint and muscle pains, and weakness have occurred, especially at the start of treatment.
In post­marketing reports, pure red cell aplasia (PRCA) has been reported in chronic renal failure patients after months to years of treatment with recombinant erythropoietins. Erythropoietin antibody­mediated PRCA is very rare with the currently available formulations of epoetin. Any use of the information is subject, at all times, to CCO’s Terms and Conditions.
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Patients who present with a sudden lack of response should be investigated for PRCA.
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E ­ Dosing
Refer to protocol by which patient is being treated. Red cell transfusion is the preferred method of managing anemia in cancer patients. Epoetin should only be used where red cell transfusions are not appropriate in patients and only for patients receiving cytotoxic therapy for more than 2 months.
Other causes of anemia should be excluded before instituting therapy with epoetin. Iron status should be evaluated for all patients prior to and during treatment and iron supplementation should be administered if necessary. Transferrin saturation should be at least 20%, and serum ferritin levels should be at least 100 ng/mL. Supplemental iron, e.g. oral elemental iron or intravenous iron is recommended to increase and maintain transferrin saturation to levels that will adequately support epoetin­stimulated erythropoiesis. The dose of ESA must be titrated to gradually increase the hemoglobin concentration (not more than 10 g/L in any 2­week period) to the lowest level sufficient to avoid blood transfusions. Hemoglobin levels during ESA treatment should not exceed 120 g/L. Blood pressure should be adequately controlled prior to initiation of epoetin therapy, and must be closely monitored and controlled during treatment.
Adults:
Chemotherapy­induced anemia in patients with non­myeloid malignancies: Starting dose: 150 IU/kg SC 3 times weekly or 40,000 IU SC once weekly
Do not initiate if hemoglobin levels ≥ 100 g/L. Discontinue following the completion of chemotherapy or if no response (no ↓ in RBC transfusion or ↑ in hemoglobin) after 8 weeks of therapy
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Dose titration ­ 3 times weekly dosing: Observation
After 4 weeks
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Hemoglobin has not increased by ≥ 10 g/L No reduction in transfusion requirements Hemoglobin ↑ > 10 g/L in a 2­week period or reaches a level needed to avoid transfusions
Hemoglobin > 120 g/L or exceeds level needed to avoid transfusions
Action
May ↑ to 300 IU/kg SC 3 times weekly. If no response after 4 weeks, discontinue.
Reduce dose by 25%# from previous dose
Hold until ≤ 120g/L and then restart with a 25%# dose reduction from previous dose
# from Eprex® product monograph. The Hematology Disease Site Group recommends a 50% dose reduction when the hemoglobin rise exceeds 10 g/L in any 2­week period or when the hemoglobin concentration exceeds 120 g/L. Refer to CCO Practice Guidelines: Treatment of Anemia with Erythropoietic Agents in Patients with Cancer. Dose titration ­ Weekly dosing: Observation
After 4 weeks
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Hemoglobin has not increased by ≥ 10 g/L No reduction in transfusion requirements Hemoglobin ↑ > 10 g/L in a 2­week period or reaches level needed to avoid transfusions
Hemoglobin > 120 g/L or exceeds level needed to avoid transfusions
Action
May ↑ to 60000 IU/wk SC. If no response after 4 weeks, discontinue.
Reduce dose by 25%# from previous dose
Hold until ≤ 120g/L and then restart with a 25%# dose reduction from previous dose
# from Eprex® product monograph. The Hematology Disease Site Group recommends a 50% dose reduction when the hemoglobin rise exceeds 10 g/L in any 2­week period or when the hemoglobin concentration exceeds 120 g/L. Refer to CCO Practice Guidelines: Treatment of Anemia with Erythropoietic Agents in Patients with Cancer. Any use of the information is subject, at all times, to CCO’s Terms and Conditions.
CCO Formulary - March 2013
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General dose modifications: Toxicity
Anaphylaxis or severe allergic reaction
Antibody­mediated anemia (ie. PRCA) Blood pressure not controlled by pharmacologic or dietary restrictions
Action
Discontinue
Discontinue; DO NOT switch to other erythropoietic agents as cross­reactivity may occur
Discontinue, until blood pressure controlled Dosage with Hepatic Impairment:
No information found. The safety and efficacy of epoetin have not been studied in patients with hepatic impairment.
Dosage with Renal Impairment:
Based on information to date, the use of epoetin in predialysis patients does not accelerate the rate of progression of renal insufficiency.
Dosage in the elderly:
No data available.
Children:
Epoetin is indicated in infants and children form 1 month old to up to 16 years of age for treatment of anemia associated with CRF requiring dialysis, but there are no approved indications in oncology.
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F ­ Administration Guidelines
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Refrigerate (2­8°C) but do not freeze. Protect from exposure to light. Do not shake. Subcutaneous self­administration (or administered by home caregiver); drug available by outpatient prescription. Do not administer by intravenous infusion or mix with other drugs The maximum volume per injection site should be 1 mL. For larger volumes, use more than one injection site. The injections should be given in the limbs or the anterior abdominal wall. Single use pre­filled syringes are human serum albumin free, containing glycine and polysorbate 80 as stabilizers and no preservative. Any use of the information is subject, at all times, to CCO’s Terms and Conditions.
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G ­ Special Precautions
Other:
Epoetin results in increased risk of death, cardiac events, thromboembolic disorders and shortens survival (overall and progression­free). Epoetin should only be used if a) red cell transfusion is not appropriate, b) hemoglobin < 100 g/L, c) with cytotoxic chemotherapy being administered for more than 2 months and d) where the risk­benefit has been carefully considered. Epoetin must be discontinued when the cytotoxic therapy is completed.
Epoetin is contraindicated in patients who developed pure red cell aplasia (PRCA) following treatment with any erythropoiesis regulating hormone, with uncontrolled hypertension, with known hypersensitivity to mammalian cell­derived products, or any component in epoetin preparation, and who for any reason cannot receive adequate antithrombotic treatment. It is also contraindicated in patients with severe arterial disease such as myocardial infarction or cerebrovascular accident. Use with caution in patients with seizures, risk factors for thrombosis, and with known porphyria. Use of epoetin is not recommended in patients with grossly elevated serum erythropoietin levels (i.e. > 200 mU/mL). No safety and efficacy data are available in patients with underlying hematologic diseases (ie. thalassemia, sickle cell disease, MDS).
Recent clinical trials suggest a possible tumour promoter effect. Although not mutagenic and not teratogenic, epoetin is embryotoxic and fetotoxic. Epoetin should be given to a pregnant woman only if potential benefit justifies the potential risk to the fetus. The possibility of potential pregnancy should be discussed and the need for contraception evaluated. Since menses have resumed in CRF patients after epoetin therapy, adequate contraception should be used during epoetin treatment, and for at least 6 months after treatment cessation. As it is not known whether epoetin is excreted in human milk, breast feeding is not recommended.
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H ­ Interactions
No evidence indicates that treatment with epoetin alters the metabolism of other drugs.
AGENT
Cyclosporine
EFFECT
MECHANISM
MANAGEMENT
↓ therapeutic effect of Cyclosporine is bound Monitor levels of by RBC
cyclosporine
cyclosporine
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CCO Formulary - March 2013
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Drugs that decrease erythropoiesis
May ↓ response to epoetin alfa
May counteract with erythropoietin
Avoid
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I ­ Recommended Clinical Monitoring
Recommended Clinical Monitoring l
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Neutralizing antibodies if sudden loss of response occurs
Serum vitamin B12 and folate; baseline Iron evaluation (includes transferrin saturation and serum ferritin); baseline and regular
Hemoglobin / hematocrit (discontinue when hemoglobin ≥ 120g/L); once weekly until stabilized and periodically thereafter
After dose adjustment, weekly hemoglobin/hematocrit for at least 2­6 weeks until stabilized, then periodically after
Blood pressure; baseline and regular
Clinical assessment for thromboembolism; regular
Grade toxicity using the current NCI­CTCAE (Common Terminology Criteria for Adverse Events) version back to top
J ­ Supplementary Public Funding
Exceptional Access Program (EAP Website)
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Anemia in palliative cancer patients, with specific criteria Anemia secondary to MDS, with specific criteria ODB Limited Use (ODB Formulary)
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Patients with cancer diagnosis and receiving chemotherapy, with specific criteria back to top
K ­ References
CCO Practice Guidelines: Treatment of Anemia with Erythropoietic Agents in Patients with Cancer
Any use of the information is subject, at all times, to CCO’s Terms and Conditions.
CCO Formulary - March 2013
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Epoetin alfa: AHFS Drug Information. American Society of Health­System Pharmacists, 2009. FDA Drug Warning Letter: Additional Trials Showing Increased Mortality and/or Tumor Progression with Epogen®/Procrit® and Aranesp®. March 7th, 2008 (Amgen and Ortho­Biotech)
Health Canada endorsed important safety information on erythropoiesis­stimulating agents (ESAs): Aranesp® (darbepoetin alfa) and Eprex® (epoetin alfa). April 16th, 2007
Product Monograph: Eprex® (epoetin alfa). Janssen­Ortho Inc., June 22, 2011. Xenocostas A, Cheung WK, Farrell F et al. The pharmacokinetics of erythropoietin in the cerebrospinal fluid after intravenous administration of recombinant human erythropoietin. Eur J Clin Pharmacol 2005; 61(3): 189­95. March 2013: Added public funding info; revised Jan 2012 back to top
L ­ Disclaimer
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up­to­date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary. The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time. Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as­is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability. CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO Any use of the information is subject, at all times, to CCO’s Terms and Conditions.
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and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary. back to top
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