EPOETIN ALFA, EPOETIN BETA, ERYTHROPOIETIN, EPO, r-HUEPO

Chemistry - A biosynthetic form of the glycoprotein human hormone erythropoietin, epoetin alfa(EPO) has a molecular weight of approximately 30, 000. It is commercially available as a sterile, preservative-free, colorless solution. Sodium chloride solution is added to adjust tonicity and isbuffered with sodium citrate:citric acid. Human albumin (2.5 mg per vial) is also added to thesolution.

Storage, Stability, Compatibility

The injectable solution should be stored in the refrigerator (2-8°C); do not freeze. Do not shake the solution as denaturation of the protein with resultant loss of activity may occur. If light exposure is limited to 24 hours or less, no effects on potency shouldoccur. When stored as directed, the solution has an expiration of date of 2 years after manufacture.
Do not mix with other drugs or use the same IV tubing where other drugs are running. Because the solution contains no preservatives, the manufacturer recommends using each vial only as a single use.
A method of diluting the Amgen product to facilitate giving very small dosages has been described (Grodsky 1994). Using a 1:20 dilution (1 part Epogen® to 19 parts bacteriostatic normal saline does not require any additional albumin to prevent binding of the drug to container. No data is available commenting on this dilution's stability.

Pharmacology - EPOETIN ALFA, EPOETIN BETA, ERYTHROPOIETIN, EPO, r-HUEPO

Erythropoietin is a naturally occurring substance produced in the kidney and is considered a hormone as it regulates erythropoiesis. It stimulates erythrocyte production by stimulating the differentiation and proliferation of committed red cel precursors. EPO also stimulates the release of reticulocytes.
Recombinant Human EPO alfa (r-HuEPO-alpha) serves as a substitute for endogenous EPO, primarily in patients with renal disease. It is believed that various uremic toxins may be responsiblefor the decreased production of EPO by the kidney.
Uses, Indications - EPO has been used to treat dogs and cats for anemia associated with chronicrenal failure. Some clinicians state that because of the expense and potential risks associated with itsuse, PCV's should be in the "teens" before considering beginning EPO therapy.

Pharmacokinetics - EPOETIN ALFA, EPOETIN BETA, ERYTHROPOIETIN, EPO, r-HUEPO

EPO is only absorbed after parenteral administration. It s unclear whether thedrug crosses the placenta or enters milk. The drug's metabolic fate is unknown. In patients withchronic renal failure, half lives are prolonged approximately 20% over those with normal renalfunction.

Contraindications, Precautions, Reproductive Safety

EPO is contraindicated in patients withuncontrolled hypertension or in those who are hypersensitive to it (see Adverse Effects below).
EPO cannot be recommended for use in equines.
Some teratogenic effects (decrease in body weight gain, delayed ossification, etc ) have been notedin pregnant rats given high dosages. Rabbits receiving 500 mg/kg during days 6-18 of gestationshowed no untoward effects on offspring. However, use during pregnancy only when benefitsoutweigh the potential risks.

Adverse Effects, Warnings

In dogs and cats, the most troublesome aspect of EPO therapy is thedevelopment of autoantibodies with resultant resistance to further treatment. Perhaps up to 30% ofall patients will develop antibodies significant enough to cause profound anemia, arrestment oferythropoiesis and transfusion dependency. Should a patient develop refractory anemia whilereceiving adequate EPO doses and have normal iron metabolism, a bone marrow aspirate should beconsidered. A myeloid:erythroid ratio of greater than 6 predicts significant autoantibody formationand contraindicates further EPO therapy. Some clinicians believe that the drug (EPO) should bewithdrawn if PCV starts to drop while on therapy.
Other effects reported include systemic hypertension, seizures and iron depletion. Local reactionsat injection sites (which may be a predictor of antibody formation), fever, arthralgia, andmucocutaneous ulcers are also possible. Other effects that have been noted that may be a result ofthe animal's disease (or compounded by such), include cardiac disease (may be related to hypertension associated with chronic renal failure). In humans, hyperkalemia, seizures, and iron deficiency have been reported.
Overdosage, Acute Toxicity - Acute overdoses appear to be relatively free of adverse effects.
Single doses of up to 1600 Units/kg in humans demonstrated no untoward signs of toxicity.
Chronic overdoses may lead to polycythemia or other adverse effects. Cautious phlebotomy may beemployed should polycythemia occur.

Drug Interactions

Androgens (e.g., nandrolone) may potentially increase the response to
EPO (Note: this effect has not been confirmed in well-controlled studies nor has the safety of thiscombination been determined). One case report has noted that EPO and desmopressin used together reduced the bleeding time in one human patient with end-stage renal disease. Probenecidhas been demonstrated to reduce the renal tubular excretion of EPO; clinical significance is unclearat this time.
Laboratory Considerations - No laboratory interactions of major clinical importance have yetbeen described. EPO can affect several lab test values via its pharmacologic effect. See
Pharmacology, Adverse Effects and Monitoring Parameters sections for more details.