Pharmacokinetics

IFN-α is metabolized by the liver and filtered by the kidneys. However, the body absorbs approximately 80% of the dose. Peak serum concentrations are reached 4 to 8 hours after administration. IFN-α can be administered subcutaneously (subQ), intramuscularly (IM), and intravenously (IV), although subQ and IM are the preferred routes of administration; subQ administration is recommended for patients with platelet counts below 50,000. Interferons-α-n3, -β and -γ are not discussed further because they are not used as antineoplastic agents.

Side Effects and Adverse Reactions

The major side effect of IFN-α is a flulike syndrome. Other effects occur in the gastrointestinal (GI), neurologic, cardiopulmonary, renal, hepatic, hematologic, and dermatologic systems.

The flulike syndrome is characterized by chills, fever, fatigue, malaise, and myalgias (muscle aches). Chills can occur 3 to 6 hours after IFN-α administration and may progress to rigors. A fever as high as 101° F to 104° F (39° C to 40° C) may occur within 30 to 90 minutes after the onset of chills and last 24 hours. Fatigue, malaise, and myalgias are cumulative side effects; fatigue is the dose-limiting toxicity (i.e., the side effect that necessitates a decrease in dose or discontinuation of the drug).

GI side effects include nausea, diarrhea, vomiting, anorexia, taste alterations, and xerostomia (dry mouth). These side effects are mild; anorexia is considered the dose-limiting toxicity for this system.

Neurologic side effects are reversible (after the drug is stopped) and occur in 70% of patients who receive IFN-α. These effects are manifested by mild confusion, somnolence (sleepiness), irritability, poor concentration, seizures, transient aphasia (temporary loss of ability to speak), hallucinations, paranoia, and psychoses. Depression, suicidal ideation, and suicide attempts have occurred in patients taking IFN-α, requiring drug discontinuance.

Cardiopulmonary side effects are dose-related and occur more frequently in older adults and patients with underlying cardiac disease. Side effects include tachycardia, pallor, cyanosis, tachypnea, nonspecific electrocardiographic changes, rare myocardial infarction, and orthostatic hypotension.

Renal and hepatic effects are dose-dependent and usually result in few or no symptoms. The effects are manifested by increased blood urea nitrogen (BUN) and creatinine levels, proteinuria, and elevated transaminases.

Hematologic effects are reversible and dose-limiting. Neutropenia (decreased number of neutrophils in the blood) and thrombocytopenia (decreased number of thrombocytes in the blood) are manifestations of such effects. Neutropenia is usually rare and does not predispose the patient to infection. Thrombocytopenia is more common in patients with hematopoietic (affecting the formation of blood cells) diseases than in those with solid tumors.

Maculopapular rashes of the trunk and extremities, pruritus, irritation at the injection site, desquamation (shedding of epithelial cells of the skin), and alopecia are dermatologic effects of IFN-α. Alopecia can occur after more than 4 months of therapy.

Dosing and Preparation

Roferon-A is supplied in prefilled syringes containing 3 million International Units (IU) per 0.5 mL, 6 million IU per 0.5 mL, and 9 million IU per 0.5 mL. All prefilled syringes must be refrigerated at 36° F to 46° F (2° C to 8° C). The syringes should not be frozen or shaken and must be protected from light.

Administration

The administration of IFN-α is contraindicated in patients with a known hypersensitivity to IFN-α, mouse immunoglobulin, or any component of the product. It should be used cautiously in patients with severe cardiac, renal, or hepatic disease and in those with seizure disorders or central nervous system dysfunction. Manufacturers recommend administering the agent to persons 18 years or older only under the supervision of a qualified physician. Women of childbearing age should use contraceptives while receiving IFN-α because of the agent’s effects on serum estradiol and progesterone concentrations. Studies have not demonstrated fertility or teratogenic effects in men.

It is recommended that baseline and periodic complete blood counts (CBCs) and liver function tests be performed during the course of IFN therapy. Manufacturers suggest that patients undergo IFN therapy for at least 6 months before a decision is made to continue treatment in those who respond or discontinue treatment in those who do not; optimal treatment duration has not been determined. Patients should be well hydrated during IFN therapy, especially during treatment for malignant melanoma, because this minimizes severe side effects. Dose reductions of 50% or drug discontinuation should be considered if severe adverse reactions occur. Concurrent or prior treatment with chemotherapeutic agents or radiation therapy may increase the effectiveness and toxicity of IFN-α.

Pharmacokinetics

Side Effects and Adverse Reactions

It is imperative that the target hemoglobin never exceed 12 g/dL, because the risks of death, serious cardiovascular events, and tumor progression increase at greater values. Close monitoring of hemoglobin response to the ESA and possible dose modification are essential to safe therapy.

The side effects of erythropoietin include hypertension, headache, arthralgias (joint pain), nausea, edema, fatigue, diarrhea, vomiting, chest pain, injection site skin reaction, asthenia (weakness), dizziness, seizures, thrombosis (clots), and allergic reactions. Studies demonstrate that ESA administration is usually well tolerated, and there have been no reports of serious allergic reactions or anaphylaxis. Rare transient skin reactions have been reported. Blood pressure may increase in patients with CRF who receive ESA during the early phase of treatment when the hematocrit (Hct) is on the rise. About 25% of patients with CRF who receive dialysis may require initiation of or increase in antihypertensive therapy. It is postulated that increases in blood pressure may relate to increases in Hct; therefore it is recommended that the dose of ESA be decreased if the Hct increase exceeds 4 points in any 2-week period. Similarly an increase in Hct may cause increased vascular access clotting (clots in the blood vessel at the connection site of the artificial kidney) in hemodialysis patients. Patients may require increased heparinization during ESA therapy to prevent clotting of the artificial kidney. Seizures occurred in patients with CRF who received ESA during clinical trials; activity was particularly evident during the first 90 days of therapy.

Dosing

Procrit should be administered at a starting dose of 50 to 100 units/kg three times a week for patients with CRF. For patients receiving cancer chemotherapy, therapy should not be initiated if the patient’s hemoglobin (Hgb) level is ≥10 g/dL. The Hgb should be monitored on a weekly basis until the level becomes stable. The dose should be titrated for each patient to achieve and maintain the lowest Hgb level sufficient to avoid blood transfusions. The initial recommended dose of Procrit in adults is 150 units/kg 3 times a week or 40,000 units per week given subQ. The dose should be reduced by 25% when the Hgb reaches a level needed to avoid a transfusion or increases >1 g/dL in any 2-week period. The dose should be held if the Hgb exceeds a level needed to avoid transfusion and then restarted at 25% below the previous dose. Aranesp dose is 0.45 mcg/kg subQ every week or 500 mcg subQ every 3 weeks. If the rate of Hgb increase is >1 g/dL in 2 weeks or if the Hgb reaches a level needed to avoid transfusion, the dose should be reduced by 25% of the prior dose. If the Hgb exceeds a level needed to avoid transfusion, the dose should be held until the Hgb approaches a level where transfusion may be required. At this point, the dose should be restarted at 25% of the previous dose. ESAs should be discontinued if after 8 weeks of therapy there is no response as measured by Hgb levels or if transfusions are still required. Otherwise, discontinue ESAs at the completion of the course of chemotherapy.