Interferon-α

Trade Names
α-interferon, IFN-α, Interferon-α 2a, Roferon Interferon-α 2b, Intron A

Classification
Immunotherapy

Category
Biologic response modifier agent

Drug Manufacturer
Roche (Roferon), Schering (Intron A)

Mechanism of Action

• Precise mechanism of antitumor action remains unknown.
• Direct antiproliferative effects on tumor cell mediated by:
  • Induction of 2′5′–oligoadenylate synthetase and protein kinase leading to decreased translation and inhibition of tumor cell protein synthesis.
  • Induction of differentiation.
  • Prolongation of the cell cycle.
  • Modulation of oncogene expression.
• Indirect induction of host antitumor mechanisms mediated by:
  • Induced activity of at least four immune effector cells, including cytotoxic T cells, helper T cells, NK cells, and macrophages.
  • Enhancement of tumor surface expression of critical antigens that are recognized by the immune system.
  • Inhibition of angiogenesis through decreased expression of various angiogenic factors.

Mechanism of Resistance

• Development of neutralizing antibodies to interferon-α.
• Decreased expression of cell surface receptors to interferon-α.

Absorption
Not available for oral use and is administered only via the parenteral route. Approximately 80%–90% of interferon-α is absorbed into the systemic circulation after IM or SC injection. Peak plasma levels are achieved in 4 hours after intramuscular injection and 7 hours after subcutaneous administration.

Distribution
Does not cross the blood-brain barrier. Binding to plasma proteins has not been well characterized.

Metabolism
Interferon-α is catabolized by renal tubule cells to various breakdown products. The major route of elimination is through the kidneys by both glomerular filtration and tubular secretion. Hepatic metabolism and biliary excretion play only a minor role in drug clearance. The elimination half-life is approximately 2–7 hours and depends on the specific route of drug administration.

Indications

1. Malignant melanoma―adjuvant therapy.
2. Chronic myelogenous leukemia―chronic phase.
3. Hairy cell leukemia.
4. AIDS-related Kaposi's sarcoma.
5. Cutaneous T-cell lymphoma.
6. Multiple myeloma.
7. Low-grade, non-Hodgkin's lymphoma.
8. Renal cell cancer.
9. Hemangioma.

Dosage Range

1. Chronic myelogenous leukemia: 9 million IU SC or IM daily.
2. Hairy cell leukemia: 3 million IU SC or IM daily for 16–24 weeks.
3. Malignant melanoma: 20 million IU/m² IV, 5 times weekly for 4 weeks, then 10 million IU/m² SC, 3 times weekly for 48 weeks.
4. Kaposi's sarcoma: 36 million IU SC or IM daily for 12 weeks.

Drug Preparation

• Available in solution form in single-dose vials of 3, 6, 9, and 36 million units for intramuscular or subcutaneous use. Also available in single-use prefilled syringes of 3, 6, and 9 million units for subcutaneous use.
• Do NOT freeze or shake vials.
• Stable for 1 month under refrigeration.

Drug Interaction 1
Cyclophosphamide―Metabolic activation of cyclophosphamide and its subsequent antitumor effects may be inhibited as interferon-α inhibits the liver cytochrome P450 system.

Drug Interaction 2
Phenytoin, phenobarbital―Effects of phenytoin and phenobarbital may be increased as interferon-α inhibits the liver P450 system. Drug levels must be monitored closely and dose adjustments made accordingly.

Drug Interaction 3
Live vaccines―Vaccination with live vaccines is contraindicated during and for at least 3 months after completion of interferon therapy.

Special Considerations

1. Use with caution in patients with pre-existing cardiac, pulmonary, CNS, hepatic, and/or renal impairment as they are at increased risk for developing serious and sometimes fatal reactions.
2. Contraindicated in patients with history of autoimmune disease, autoimmune hepatitis, or in those who have received immunosuppressive therapy for organ transplants.
3. Contraindicated in patients with a known allergy to benzyl alcohol as the injectable solution form contains benzyl alcohol.
4. Use with caution in patients with myelosuppression or those who are receiving concurrent agents known to cause myelosuppression.
5. Use with caution in patients with a history of depression and/or other psychological disorders. Routine neuropsychiatric monitoring of all patients on interferon-α is recommended.
6. Use with caution in older patients (> 65 years of age) as they are at increased risk for developing fatigue and neurologic toxicities secondary to interferon-α.
7. Premedicate patient with acetaminophen to reduce the risk and/or severity of flulike symptoms, including fever and chills. In the event that acetaminophen is unsuccessful, indomethacin can be used.
8. Pregnancy category C.

Toxicity 1
Flulike symptoms with fever, chills, headache, myalgias, and arthralgias. Occur in 80%–90% of patients, usually beginning a few hours after the first injection and lasting for up to 8–9 hours. Incidence decreases with subsequent injections. Can be controlled with acetaminophen and/or indomethacin.

Toxicity 2
Fatigue and anorexia are dose-limiting with chronic administration.

Toxicity 3
Somnolence, confusion, or depression. Patients > 65 years of age are much more susceptible to the neurologic sequelae of interferon-α.

Toxicity 4
Myelosuppression with mild leukopenia and thrombocytopenia. Reversible upon discontinuation of therapy.

Toxicity 5
Mild, transient elevations in serum transaminases. Dose-dependent toxicity observed more frequently in the presence of pre-existing liver abnormalitites.

Toxicity 6
Renal toxicity is uncommon and is manifested by mild proteinuria and hypocalcemia. Acute renal failure and nephrotic syndrome have been reported in rare instances.

Toxicity 7
Alopecia, skin rash, pruritus with dry skin, and irritation at the injection site.

Toxicity 8
Cardiotoxicity in the form of chest pain, arrhythmias, and congestive heart failure. Uncommon and almost always reversible.

Toxicity 9
Impotence, decreased libido, menstrual irregularities, and an increased incidence of spontaneous abortions.

Toxicity 10
Rare cases of autoimmune disorders, including thrombocytopenia, vasculitis, Raynaud's disease, lupus, rheumatoid arthritis, and rhabdomyolysis.

Toxicity 11
Retinopathy with cotton-wool spots and small hemorrhages. Usually asymptomatic and resolves upon termination of therapy.