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INTERFERONS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Interferons are naturally occurring, species specific, proteins or glycoproteins that are "biological response mediators" that are produced by cells in response to an event.
    B) Interferon is thought to play a role in immune modulation, cell differentiation and proliferation, antiviral activity and possibly direct cytotoxicity.

Specific Substances

    A) Human leukocyte interferon
    1) cantell type interferon
    2) buffy coat interferon
    3) natural leukocyte interferon
    4) IFN-c
    5) HuIFN-Le
    6) IFN-alpha
    7) IFN-alfa
    8) Le interferon, type I
    Alpha-A-interferon
    1) interferon alfa-2a
    2) recombinant leukocyte A interferon
    3) rIFN-A
    4) IFLrA
    5) RO-22-8181
    6) IFN-alpha-2a
    7) CAS 76543-88-9
    8) Molecular Formula: C860-H1353-N227-O225-S9
    Alpha-2-interferon
    1) interferon alfa-2b
    2) IFN-alpha 2
    3) rIFN-alfa 2
    4) SCH 30500
    5) IFN-alfa-2b
    6) CAS 99210-65-8
    7) Molecular Formula: C860-H1353-N229-O255-S9
    8) YM-14090
    Interferon alfa-2c
    1) Mixture of natural alpha-interferons
    Human lymphoblastoid interferon
    1) interferon alfa-nl
    2) HLBI
    3) Hu IFN-alpha (Ly)
    4) IFN-alpha-nl
    5) CL-884
    6) NSC 339140
    Interferon alfa-n3
    1) Mixture of natural alpha-interferons
    Interferon-beta synonyms
    1) Fibroblast interferon
    2) beta interferon
    3) beta-IFN
    4) beta-seron 17 IFN
    5) beta ser 17 IFN
    6) F interferon, type I
    T Lymphocyte interferon
    1) immune interferon
    2) gamma interferon
    3) IFN-gamma
    4) interferon, type II
    5) II F
    6) CAS 82115-62-6
    Interferon gamma-1b
    1) CAS 98059-61-1
    2) Molecular Formula: C734-H1166-N204-O216-S5

Available Forms Sources

    A) FORMS
    1) The following interferon have been used: interferon alfa-2A; interferon alfa-2b; interferon alfacon-1; interferon beta, natural; interferon beta-1a; interferon beta-1b; interferon gamma; interferon gamma-1b; peginterferon alfa-2a; peginterferon alfa-2b.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) There are few reports of human overdose with interferons. There is no specific antidote. The following information is based on clinical trials at various doses, dosing frequencies, and routes of administration.
    B) An acute syndrome of effects is well described following interferon administration. The acute effects are described as "flu-like" symptoms of fever, chills, tachycardia, headache, malaise, and myalgias.
    C) Dizziness, light-headedness, seizures, nasal congestion, sinus drainage, and urinary urgency are reported less frequently.
    D) The severity of the reaction is based on many factors including age, performance status, type of interferon, dose, and route of administration.
    0.2.3) VITAL SIGNS
    A) Tachycardia, hypotension, and fever may occur.
    0.2.4) HEENT
    A) Nasal congestion, dry mouth, and sore throat may be noted.
    0.2.5) CARDIOVASCULAR
    A) Tachycardia and transient hypotension occur frequently.
    B) Myocardial infarction and congestive heart failure have been reported after prolonged use of interferon in patients with pre-existing cardiac disease.
    0.2.6) RESPIRATORY
    A) Pulmonary edema, respiratory insufficiency, and pneumonitis have been reported.
    0.2.7) NEUROLOGIC
    A) Somnolence, lethargy, confusion, mental laziness, and extreme fatigue have been reported with doses greater than 100 million Units. Spastic paraplegias have also been reported in pediatric patients.
    0.2.8) GASTROINTESTINAL
    A) "Flu-like" symptoms are common. Anorexia, diarrhea, nausea, vomiting, and aberrant taste may occur.
    0.2.10) GENITOURINARY
    A) Reversible renal insufficiency and vaginal bleeding have been reported.
    0.2.12) FLUID-ELECTROLYTE
    A) Hyperkalemia and hypocalcemia may occur with high doses.
    0.2.13) HEMATOLOGIC
    A) A decrease may be seen in erythrocytes, leukocytes, granulocytes, lymphocytes, and platelets. Coagulation abnormalities may occur.
    0.2.14) DERMATOLOGIC
    A) Skin eruptions or rashes may occur.
    0.2.15) MUSCULOSKELETAL
    A) Weakness, myalgias, rhabdomyolysis and arthralgias have been reported.
    0.2.20) REPRODUCTIVE
    A) All interferons are classified as FDA pregnancy category C. Isolated cases of spontaneous abortions have occurred with interferon use during pregnancy. There is evidence of abortifacient activity in monkeys treated with interferons. There are no adequate and well-controlled studies of interferon use in humans. It is unknown whether interferons are excreted in human breast milk. High doses of interferons have caused reversible menstrual irregularities in female monkeys.

Laboratory Monitoring

    A) Monitor CBC, electrolytes, renal and liver function tests, ECG and blood pressure.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Interferons are proteins and will be broken down in the gut on oral ingestion.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) The range of toxicity is not known. Single doses greater than 100 to 200 million units and continuous daily doses of 1 to 3 million units for 7 months have been associated with severe, dose-limiting toxicities.

Clinical Effects

Summary Of Exposure

    A) There are few reports of human overdose with interferons. There is no specific antidote. The following information is based on clinical trials at various doses, dosing frequencies, and routes of administration.
    B) An acute syndrome of effects is well described following interferon administration. The acute effects are described as "flu-like" symptoms of fever, chills, tachycardia, headache, malaise, and myalgias.
    C) Dizziness, light-headedness, seizures, nasal congestion, sinus drainage, and urinary urgency are reported less frequently.
    D) The severity of the reaction is based on many factors including age, performance status, type of interferon, dose, and route of administration.

Vital Signs

    3.3.1) SUMMARY
    A) Tachycardia, hypotension, and fever may occur.
    3.3.3) TEMPERATURE
    A) FEVER is commonly observed with the other flu-like symptoms. Tolerance may develop with daily dosing of alpha and beta interferons (Sarna et al, 1986; Krown, 1986).
    B) Mild fever (37.5 C), myalgias, shivers, and mild tachycardia developed in an adult who injected 264 mcg to 308 mcg of IFN beta-1a subcutaneously(Falcone et al, 2005).
    3.3.4) BLOOD PRESSURE
    A) HYPOTENSION may occur during the first 24 hours following administration of interferon (Balmer, 1985; Quesada et al, 1986).
    1) One patient inadvertently received interferon alfa-2a intravenously rather than interferon alfa-2b and experienced severe hypotension that resolved once the infusion was stopped. It is not known whether the effect was due directly to interferon alfa-2a or due to the IV administration of a preparation not recommended for IV administration (Hanson & Leggette, 1997).
    B) HYPERTENSION - Interferon alfa therapy has occasionally induced hypertensive episodes (Priestman, 1980).

Heent

    3.4.1) SUMMARY
    A) Nasal congestion, dry mouth, and sore throat may be noted.
    3.4.3) EYES
    A) Excessive growth of eyelashes has been reported (Quesada et al, 1986; Balmer, 1985).
    3.4.5) NOSE
    A) Nasal congestion and sinus discharge may occur (Quesada et al, 1986; Sriskandan et al, 1986).
    3.4.6) THROAT
    A) SORE THROAT has been reported with gamma interferon (Sriskandan et al, 1986).
    B) Altered taste and dry mouth may occur (Balmer, 1985; Krown, 1986; Sriskandan et al, 1986).

Cardiovascular

    3.5.1) SUMMARY
    A) Tachycardia and transient hypotension occur frequently.
    B) Myocardial infarction and congestive heart failure have been reported after prolonged use of interferon in patients with pre-existing cardiac disease.
    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has been frequently reported in association with the acute flu-like syndrome (Quesada et al, 1986; Spiegel, 1986).
    2) WITH POISONING/EXPOSURE
    a) Mild tachycardia (heart rate 100 beats/minute) was reported in an adult who injected 264 mcg to 308 mcg of IFN beta-1a subcutaneously(Falcone et al, 2005).
    B) RIGHT HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Those patients with a limited heart reserve may be at risk for developing congestive heart failure during the initial flu-like syndrome (Quesada et al, 1986).
    C) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) Myocardial infarction has been reported in patients with pre-existing cardiac disease (Quesada et al, 1986; Oldham, 1983).
    D) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Paroxysmal atrial tachycardia, atrial fibrillation, and premature ventricular contractions have been reported mostly in older patients with evidence of pre-existing heart disease (Oldham, 1983).
    b) CARDIAC ECTOPY - There is a single case report of cardiac ectopy improvement with gamma interferon therapy (Friess et al, 1986).
    c) LACK OF ADVERSE EFFECT
    1) There is no evidence that interferons have direct arrhythmogenicity or cardiotoxicity (Spiegel, 1986; Oldham, 1983).

Respiratory

    3.6.1) SUMMARY
    A) Pulmonary edema, respiratory insufficiency, and pneumonitis have been reported.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Pulmonary edema was reported on autopsy of a 69-year-old woman with a history of coronary artery disease treated with 3.2 million Units of gamma interferon by a 6 hour continuous IV infusion (Kurzrock et al, 1986).
    B) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) A transient, less than 20% decrease in peak expiratory flow was associated with administration of inhaled natural leukocyte interferon alfa (60,000,000 International Units to 120,000,000 International Units) from a dosimeter-equipped jet nebulizer in 2 patients (Kinnula et al, 1989).
    C) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) Interferon-induced interstitial pneumonitis has been reported in one patient after receiving a total dose of 600 million International Units (Wolf et al, 1997). The pneumonitis resolved following discontinuation of the interferon and administration of corticosteroids, bronchodilators, and diuretics.

Neurologic

    3.7.1) SUMMARY
    A) Somnolence, lethargy, confusion, mental laziness, and extreme fatigue have been reported with doses greater than 100 million Units. Spastic paraplegias have also been reported in pediatric patients.
    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) Fatigue, weakness, tiredness, absence of motivation, mental laziness, lack of desire to participate in normal activities, somnolence, and anorexia may occur (Quesada et al, 1986; Balmer, 1985; Sriskandan et al, 1986).
    b) PEDIATRIC - Fifty-three children (all less then 3 years of age at treatment initiation) being treated with interferon alfa-2b for severe hemangiomas were evaluated for toxicities. Dosing was 100,000 International Units/kg/day in children less than 0.6 m(2) and 3 million International Units/m(2)/day in children greater than or equal to 0.6 m(2). Grade 1 (mild) neurologic toxicity (agitation, irritability, problems with sleep) was seen in 46 patients, grade 2 (moderate) toxicity was seen in 18 patients, and grade 3 (severe) toxicity (agitation, lethargy) was seen in 4 patients. Forty-two patients received formal neurologic exams after therapy had concluded, and 10 of these children had abnormal examinations with 1 child having spastic diplegia (Dubois et al, 1999).
    B) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue has been reported as a dose-limiting toxicity and may continue for several weeks after discontinuation of interferon administration (Balmer, 1985; Quesada et al, 1986; Epstein, 1985; Kirkwood et al, 2002).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache is frequently reported after interferon administration and may continue after interferon therapy is discontinued (Sriskandan et al, 1986).
    D) ELECTROENCEPHALOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Diffuse slowing of the alpha rhythm with appearance of delta and theta waves can occur and is consistent with a diffuse encephalopathy. Level of interferon in the spinal fluid has not been found to correlate with EEG changes. These changes are usually reversible within days (Quesada et al, 1986) and occur at doses greater than 100 million Units (Farkkila et al, 1984; Anon, 1983; Kurzrock et al, 1986).
    E) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Paresthesias may occur and are more likely to occur in those patients previously exposed to vinca alkaloids (Quesada et al, 1986).
    F) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been reported in patients taking IFN-alpha (Quesada et al, 1986; Janssen et al, 1990).
    b) CASE REPORT - A 62-year-old male experienced photosensitive seizures shortly after initiation of IFN-alpha therapy for maintenance treatment of multiple myeloma. An EEG, performed 2 years after beginning IFN-alpha therapy, showed a photoparoxysmal response to intermittent photic stimulation. The seizures disappeared after discontinuation of IFN-alpha therapy (Brouwers et al, 1999).
    G) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS - Parkinsonian signs were reported in 2 patients being treated with intravenous gamma interferon (Kurzrock et al, 1986).
    H) NEURALGIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 63-year-old male developed neuralgic amyotrophy with initial complaints beginning 3 weeks after alpha-2 interferon therapy was initiated.
    1) Interferon was discontinued and improvement was noted on follow-up at 6 months. Polyneuropathy was present on neurologic examination prior to interferon treatment (Bernsen et al, 1988).
    I) SPASTIC PARALYSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT (PEDIATRIC) - A 2-year-old male developed spastic diplegia (consistent with upper motor neuron lesion) that was associated with interferon therapy for juvenile laryngeal papilloma.
    1) He received human leukocyte interferon in doses of 1 to 3 million International Units intramuscularly daily, nearly continuously, for 7 months when it was noted that he began to move on all fours (Vesikari et al, 1988).
    b) Other cases of spastic paraplegia have been reported in pediatric patients treated with interferon alfa-2a for hemangiomas. One group reported 5 cases, representing 10% of their patients, developing spastic paraplegias, indicating that interferon use in pediatric patients with hemangiomas should be limited to hemangiomas that are life- and function-threatening (Enjolras, 1998).

Gastrointestinal

    3.8.1) SUMMARY
    A) "Flu-like" symptoms are common. Anorexia, diarrhea, nausea, vomiting, and aberrant taste may occur.
    3.8.2) CLINICAL EFFECTS
    A) INFLUENZA-LIKE ILLNESS
    1) WITH THERAPEUTIC USE
    a) In high-dose interferon alfa-2b trials, 94% of patients reported some degree of "flu-like" symptom (fever, chills/rigors, myalgia, headache, nausea, vomiting), and 48% of patients had grade 3 or 4 toxicity (Kirkwood et al, 2002).
    b) PEDIATRIC - Fifty-three children (all less then 3 years of age at treatment initiation) being treated with interferon alfa-2b for severe hemangiomas were evaluated for toxicities. Dosing was 100,000 International Units/kg/day in children less than 0.6 m(2) and 3 million International Units/m(2)/day in children greater than or equal to 0.6 m(2). Grade 1 (mild) "flu-like" symptoms occurred in 50 patients, grade 2 (moderate) symptoms occurred in 25 patients, and grade 3 (severe) symptoms were reported in 2 patients (Dubois et al, 1999).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting occur more frequently at interferon doses greater than 10 million Units. Rarely is it necessary to treat the vomiting with antiemetics (Quesada et al, 1986; Sriskandan et al, 1986).
    C) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) A salty or metallic taste has been described at the start of interferon therapy and at high doses (Quesada et al, 1986).
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea may be severe at high doses (Quesada et al, 1986).
    E) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia is commonly reported (Balmer, 1985; Quesada et al, 1986; Sriskandan et al, 1986; Kirkwood et al, 2002).
    F) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) Flatulence was commonly reported during the second infusion of gamma-interferon (Sriskandan et al, 1986).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In a high-dose interferon alfa-2b trial, liver function abnormalities were reported in 63% of patients, and 14% to 29% of patients in cooperative group trials had grade 3 or 4 toxicity (Kirkwood et al, 2002).
    b) PEDIATRIC - Fifty-three children (all less then 3 years of age at treatment initiation) being treated with interferon alfa-2b for severe hemangiomas were evaluated for toxicities. Dosing was 100,000 International Units/kg/day in children less than 0.6 m(2) and 3 million International Units/m(2)/day in children greater than or equal to 0.6 m(2). Grade 1 (mild) alteration of liver enzymes was seen in 8 patients, grade 2 (moderate) was seen in 26 patients, grade 3 (severe) was seen in 22 patients, and grade 4 (unacceptable) was seen in 3 patients. All abnormal laboratory results were transient and reversible (Dubois et al, 1999).
    B) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Markedly elevated AST and ALT levels (374 Units/L and 260 Units/L, respectively) developed in a 43-year-old male with hepatitis C approximately 4 weeks after beginning IFN-alpha therapy. The liver enzyme levels dropped significantly after IFN-alpha treatment was stopped, but greatly increased (AST of 1038 Units/L) after treatment was restarted. The patient also complained of fatigue and recurrent vomiting. A diagnosis of hepatic failure was made and the patient recovered following liver transplantation. The explanted liver showed micronodular cirrhosis with dense inflammatory infiltration with foci of necrosis and signs of intracytoplasmic and intracanalicular cholestasis (Lock et al, 1999).

Genitourinary

    3.10.1) SUMMARY
    A) Reversible renal insufficiency and vaginal bleeding have been reported.
    3.10.2) CLINICAL EFFECTS
    A) ALBUMINURIA
    1) WITH THERAPEUTIC USE
    a) Proteinuria has been reported. There are no reports of documented renal toxicity (Balmer, 1985; Spiegel, 1986).
    B) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Kidney function deterioration has been reported in patients with preexisting renal damage receiving interferon alfa therapy (Averbuch et al, 1984).
    C) SEMEN EXAM: ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Impaired spermatogenesis has been reported with interferon alfa-2b for hairy cell leukemia (Balmer, 1985).
    D) FINDING OF VAGINAL BLEEDING
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 19-year-old woman treated with 8 million International Units every other day interferon beta-1b developed severe vaginal bleeding and was admitted with a hemoglobin of 3.9 g/dL. The bleeding resolved one day after withdrawal of interferon(Pakulski & DiMarco, 1997).

Hematologic

    3.13.1) SUMMARY
    A) A decrease may be seen in erythrocytes, leukocytes, granulocytes, lymphocytes, and platelets. Coagulation abnormalities may occur.
    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) A decrease of about 50% below baseline leukocyte count occurs at all doses and usually occurs within hours of exposure (Quesada et al, 1986).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In high-dose interferon alfa-2b trials, 92% of patients displayed neutropenia, and 26% to 60% of patients had grade 3 or 4 toxicity (Kirkwood et al, 2002).
    b) PEDIATRIC - Fifty-three children (all less then 3 years of age at treatment initiation) being treated with interferon alfa-2b for severe hemangiomas were evaluated for toxicities. Dosing was 100,000 International Units/kg/day in children less than 0.6 m(2) and 3 million International Units/m(2)/day in children greater than or equal to 0.6 m(2). Hematologic toxicities, manifesting mainly as neutropenia and mild anemia, were frequently reported. Grade 1 (mild) toxicity developed in 32 patients, grade 2 (moderate) toxicity developed in 28 patients, grade 3 (severe) toxicity developed in 16 patients, and grade 4 (unacceptable) toxicity developed in 6 patients. No infections or febrile neutropenia events requiring hospitalization were reported (Dubois et al, 1999).
    C) APLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Aplastic anemia has been reported in a single patient (Mangan et al, 1985).
    D) BLOOD COAGULATION PATHWAY FINDING
    1) WITH THERAPEUTIC USE
    a) Reversible coagulation abnormalities were reported with high-dose continuous infusions of human lymphoblastoid interferon (Balmer, 1985; Krown, 1986).
    E) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia and anemia can occur with therapeutic use of all alpha interferons.

Dermatologic

    3.14.1) SUMMARY
    A) Skin eruptions or rashes may occur.
    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Mild alopecia may occur (Quesada et al, 1986).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Maculopapular eruptions are most commonly reported and are usually of short duration (Quesada et al, 1986).
    b) Allergic contact dermatitis has been reported from beta-interferon used as eye drops (Pigatto et al, 1991).
    C) ERYTHEMA
    1) WITH POISONING/EXPOSURE
    a) Diffuse erythema of the limbs and trunk developed in an adult who injected 264 mcg to 308 mcg of IFN beta-1a subcutaneously(Falcone et al, 2005).
    D) HERPES SIMPLEX
    1) WITH THERAPEUTIC USE
    a) Herpes simplex lesions may be reactivated at onset of interferon therapy and heal despite continuation of therapy (Balmer, 1985; Borden et al, 1982).
    E) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus was reported during treatment with beta and gamma interferon (Sarna et al, 1986; Sriskandan et al, 1986).
    F) MEE'S LINE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Mees-beau lines were reported several weeks following alpha-2 interferon therapy in a 63-year-old male (Bernsen et al, 1988).

Musculoskeletal

    3.15.1) SUMMARY
    A) Weakness, myalgias, rhabdomyolysis and arthralgias have been reported.
    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) Muscular weakness may occur with the fatigue neurotoxic syndrome (Balmer, 1985). Weakening of tendon reflexes and tone may occur at high doses (Farkkila et al, 1984).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgias are commonly reported following interferon administration (Quesada et al, 1986) Dvoretzky, 1990).
    2) WITH POISONING/EXPOSURE
    a) Myalgias developed in an adult who injected 264 mcg to 308 mcg of IFN beta-1a subcutaneously(Falcone et al, 2005).
    C) INCREASED MUSCLE TONE
    1) WITH THERAPEUTIC USE
    a) Hand cramps were reported in two patients treated with gamma interferon (Sriskandan et al, 1986).
    D) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Severe arthralgias, without clinical evidence of arthritis, were reported with IV administered recombinant gamma interferon (Kurzrock et al, 1986).
    E) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) Fatal rhabdomyolysis and multiple organ failure was associated with adjuvant high-dose interferon alfa in a patient with malignant melanoma. His symptoms began 4 days after taking recombinant IFN alfa-2b, 20 million International Units/m(2)/day (Reinhold et al, 1997).
    F) EATON-LAMBERT SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 41-year-old man experienced a sudden onset of high fever, severe bone pain, and muscle weakness after receiving interferon alfa and hydroxyurea for 4 months for chronic phase of chronic myeloid leukemia. In addition, tendon reflexes were absent bilaterally. Bone marrow specimens revealed the characteristic features of necrosis without any sign of blast crisis. A high level of tumor necrosis factor alpha was found in the marrow plasma. Electromyographic findings showed characteristic pattern of the Lambert-Eaton syndrome. Following treatment with high-dose corticosteroids, symptoms resolved completely (Kumakura et al, 1998).
    G) MYOSITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 50-year-old woman experienced a slowly progressive proximal muscle weakness of the lower extremities, followed by generalized fatigue and the insidious development of proximal muscle weakness of the upper extremities 2 months after receiving interferon alpha-2b 4.5 x 10(6) Units/day. Neurologic examination showed atrophy of the proximal muscle and symmetric proximal muscle weakness. Electromyography revealed widespread myopathic changes, with polyphasia and spontaneous activity (fibrillation potentials and positive sharp waves) in proximal and distal muscles. Biopsy of the quadriceps muscle showed several endomysial inflammatory infiltrates with invasion of non-necrotic muscle fibers, expression of major histocompatibility complex class I antigens on the sarcolemma, several ragged-red fibers, and reduced cytochrome c oxidase staining. Following the discontinuation of interferon alpha-2b, her condition improved gradually (Hengstman et al, 2000).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) ABNORMAL ANTI-DIURETIC HORMONE
    1) WITH THERAPEUTIC USE
    a) CASE SERIES - Syndrome of inappropriate antidiuretic hormone secretion was reported in 6 patients with amyotrophic lateral sclerosis following high-dose human leukocyte interferon (100 to 200 million International Units/day) by intravenous infusion (Farkkila et al, 1984).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANTI-NUCLEAR FACTOR POSITIVE
    1) WITH THERAPEUTIC USE
    a) Antibodies have been detected and can nullify both toxic and therapeutic effects to various degrees (Krown, 1986; Quesada et al, 1986; Spiegel, 1986). Antibodies are usually observed in low titers and have not clinically changed the dosing regimen.

Reproductive

    3.20.1) SUMMARY
    A) All interferons are classified as FDA pregnancy category C. Isolated cases of spontaneous abortions have occurred with interferon use during pregnancy. There is evidence of abortifacient activity in monkeys treated with interferons. There are no adequate and well-controlled studies of interferon use in humans. It is unknown whether interferons are excreted in human breast milk. High doses of interferons have caused reversible menstrual irregularities in female monkeys.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) PEGINTERFERON ALFA-2A
    a) At the time of this review, no data were available to assess the teratogenic potential of this agent in humans (Prod Info PEGASYS(R) subcutaneous injection solution, 2011).
    2) PEGINTERFERON ALFA-2B
    a) At the time of this review, no data were available to assess the teratogenic potential of this agent in humans (Prod Info SYLATRON(TM) subcutaneous injection powder, 2011; Prod Info PegIntron(R) subcutaneous injection, powder for solution, 2011).
    3) PEGINTERFERON BETA-1A
    a) At the time of this review, no data were available to assess the teratogenic potential of this agent in humans (Prod Info PLEGRIDY(TM) subcutaneous injection, Jul).
    B) ANIMAL STUDIES
    1) INTERFERON ALFA-2A
    a) There was no evidence of teratogenicity when female monkeys were given doses of 1, 5, or 25 million international units/kg/day (approximately 20 to 500 times the human weekly dose based on body surface area comparison) on gestation day 22 to 70 or treated with 25 million international units/kg/day during late fetal development (gestation day 79 to 100) (Prod Info ROFERON-A(R) subcutaneous injection, 2008).
    2) INTERFERON BETA-1A
    a) There was no evidence of teratogenicity or other adverse effects on fetal development when pregnant monkeys were given interferon beta doses that were 100 times the recommended weekly human dose (based on body surface area) (Prod Info AVONEX(R) intramuscular injection, 2013). There was also no evidence of fetal malformations or teratogenicity when interferon beta-1a was given to pregnant monkeys at doses approximately 1, 2, and 7 times the maximum recommended cumulative weekly human dose either during organogenesis (gestation day 21 to 89) or later during pregnancy (gestation day 90 to term) (Prod Info Rebif(R) subcutaneous injection, 2013).
    3) INTERFERON BETA-1B
    a) There was no evidence of teratogenicity when female monkeys were given doses up to 0.42 mg/kg/day on gestation days 20 to 70. Lower doses were not studied in monkeys (Prod Info BETASERON(R) powder for subcutaneous injection, 2008).
    4) PEGINTERFERON BETA-1A
    a) No signs of teratogenicity were observed when subQ interferon beta was administered to monkeys every other day during early pregnancy (Prod Info PLEGRIDY(TM) subcutaneous injection, Jul)
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) PEGINTERFERON ALFA-2A
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info PEGASYS(R) subcutaneous injection solution, 2011).
    2) PEGINTERFERON ALFA-2B
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info SYLATRON(TM) subcutaneous injection powder, 2011; Prod Info PegIntron(R) subcutaneous injection, powder for solution, 2011).
    3) PEGINTERFERON BETA-1A
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info PLEGRIDY(TM) subcutaneous injection, Jul).
    B) PREGNANCY CATEGORY
    1) The manufacturers have classified INTERFERON ALFA-2A, INTERFERON ALFACON-1, INTERFERON BETA-1A, INTERFERON BETA-1B, PEGINTERFERON ALFA-2A, PEGINTERFERON ALFA-2B, and PEGINTERFERON BETA-1A as FDA pregnancy category C (Prod Info BETASERON subcutaneous injection, 2014; Prod Info AVONEX(R) intramuscular injection, 2013; Prod Info EXTAVIA(R) subcutaneous injection, 2012; Prod Info SYLATRON(TM) subcutaneous injection powder, 2011; Prod Info PegIntron(R) subcutaneous injection, powder for solution, 2011; Prod Info PEGASYS(R) subcutaneous injection solution, 2011; Prod Info ROFERON-A(R) subcutaneous injection, 2008; Prod Info INFERGEN(R) subcutaneous injection, 2006; Prod Info Rebif(R) subcutaneous injection, 2013; Prod Info PLEGRIDY(TM) subcutaneous injection, Jul).
    2) PEGINTERFERON ALFA-2A USE IN COMBINATION WITH RIBAVIRIN: Concomitant use with ribavirin is classified as pregnancy category X. If peginterferon alfa-2a is used in combination with ribavirin by women of childbearing potential and men, 2 forms of adequate contraception should be used during treatment and for at least 6 months following discontinuation (Prod Info PEGASYS(R) subcutaneous injection solution, 2011).
    3) PEGINTERFERON ALFA-2B USE IN COMBINATION WITH RIBAVIRIN: Concomitant use with ribavirin is classified as FDA pregnancy category X. If peginterferon alfa-2b is used in combination with ribavirin by women of childbearing potential and men, 2 forms of adequate contraception should be used and monthly pregnancy tests should be performed during treatment and for 6 months after discontinuation (Prod Info PegIntron(R) subcutaneous injection, 2013).
    C) SPONTANEOUS ABORTION
    1) INTERFERON BETA-1A
    a) In 2 efficacy studies, there were 2 spontaneous abortions and 5 pregnancies carried to term among 7 women treated with interferon beta-1a during pregnancy (Prod Info Rebif(R) subcutaneous injection, 2009).
    2) INTERFERON BETA-1B
    a) There are no adequate or well controlled studies of interferon beta-1b use during human pregnancy. However, spontaneous abortions have been reported in 4 women administered interferon beta-1b during clinical trials. Abortifacient effects were observed in pregnant rhesus monkeys administered interferon beta-1b 0.028 to 0.42 mg/kg/day during organogenesis. Until additional data are available, interferon beta-1b should be used during pregnancy only if the potential maternal benefit outweighs the potential fetal risk (Prod Info BETASERON subcutaneous injection, 2014; Prod Info EXTAVIA(R) subcutaneous injection, 2012).
    D) LACK OF EFFECT
    1) A total of 9 women treated with interferon-alfa during pregnancy have been described in brief reports, and all delivered healthy, developmentally normal infants (Briggs et al, 1994).
    2) Two HIV-seropositive pregnant women who were scheduled for abortions were given a single intramuscular dose of interferon-alfa. Blood samples taken simultaneously from the mothers and fetuses along with amniotic fluid showed no detectable interferon-alfa in the fetal blood or amniotic fluid (Pons et al, 1995).
    E) ANIMAL STUDIES
    1) INTERFERON ALFA-2A
    a) Dose-related abortifacient activity was reported when female monkeys where given doses of 1, 5, or 25 million international units/kg/day (approximately 20 to 500 times the human weekly dose based on body surface area comparison) on gestation day 22 to 70. Abortifacient activity was also reported in 2 of 6 pregnant monkeys treated with 25 million international units/kg/day during late fetal development (gestation day 79 to 100) (Prod Info ROFERON-A(R) subcutaneous injection, 2008).
    2) INTERFERON ALFA-2B
    a) Interferon alfa-2b had abortifacient effects in rhesus monkeys treated with 90 to 360 times the human dose (Briggs et al, 1994).
    3) INTERFERON ALFACON-1
    a) In hamsters and monkeys, interferon alfacon-1 has been shown to have embryolethal or abortifacient effects at doses that were 135 times and 9 to 81 times (based on body surface area) the human dose, respectively (Prod Info INFERGEN(R) subcutaneous injection, 2006).
    4) INTERFERON BETA-1A
    a) Abortifacient activity was evident after 3 to 5 doses of interferon beta that were each 100 times the recommended weekly human dose (based on a body surface area comparison). No abortifacient effects were observed in monkeys treated at 2 times the recommended weekly human dose (Prod Info AVONEX(R) intramuscular injection, 2013). In another study, there were non-dose-related increases in spontaneous abortions and fetal and neonatal deaths when interferon beta-1a was given to pregnant monkeys at a dose of approximately 1, 2, and 7 times the maximum recommended cumulative weekly human dose either during organogenesis (gestation day 21 to 89) or later during pregnancy (gestation 90 to term) (Prod Info Rebif(R) subcutaneous injection, 2013).
    5) INTERFERON BETA-1B
    a) In pregnant rhesus monkeys, administration of interferon beta-1b doses between 0.028 and 0.42 mg/kg/day during organogenesis (gestation days 20 through 70) had a dose-related abortifacient effect. The low-effect dose is approximately 3 times the recommended human dose of 0.25 mg (based on a mg/m(2) body surface area). A no-effect dose for embryofetal development was not established (Prod Info BETASERON subcutaneous injection, 2014; Prod Info EXTAVIA(R) subcutaneous injection, 2012).
    6) PEGINTERFERON ALFA-2A
    a) Non-pegylated interferon alfa-2a treatment resulted in an statistically significant increase in abortions in Rhesus monkeys given doses approximately 20 to 500 times the recommended weekly human dose. It should be assumed that peginterferon alfa-2a will have similar abortifacient potential (Prod Info PEGASYS(R) subcutaneous injection solution, 2011).
    7) PEGINTERFERON ALFA-2B
    a) The teratogenic potential of peginterferon alfa-2b in animals has not been studied. Non-pegylated interferon alfa-2b has been shown to have abortifacient effects in rhesus monkeys at an estimated human equivalent dose of 5 to 10 million international units (IU)/kg (Prod Info PegIntron(R) subcutaneous injection, powder for solution, 2011) which is approximately equal to the human dose of 79 to 158 mcg/kg/week (Prod Info SYLATRON(TM) subcutaneous injection powder, 2011).
    8) PEGINTERFERON BETA-1A
    a) When subQ interferon was administered to monkeys every other day during early pregnancy, spontaneous abortions occurred after 3 to 5 doses (Prod Info PLEGRIDY(TM) subcutaneous injection, Jul)
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) INTERFERON BETA-1B
    a) Lactation studies have not been conducted with interferon beta-1b and it is not known whether interferon beta-1b is excreted into human breast milk. The potential for adverse effects in the nursing infant from exposure to the drug are unknown. Due to the lack of human safety information and the potential for adverse effects in the nursing infant, it is recommended that either breastfeeding or interferon beta-1b be discontinued, taking into consideration the importance of the drug to the mother (Prod Info BETASERON subcutaneous injection, 2014; Prod Info EXTAVIA(R) subcutaneous injection, 2012).
    2) PEGINTERFERON ALFA-2A
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info PEGASYS(R) subcutaneous injection solution, 2011).
    3) PEGINTERFERON ALFA-2B
    a) It is not known whether peginterferon alfa-2b is excreted into human breast milk. No reports describing the use of peginterferon alfa-2b during human lactation are available and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Due to the lack of human safety information, the manufacturer suggests a decision be made whether to discontinue the treatment or discontinue nursing the infant, taking into consideration the importance of the drug to the mother (Prod Info SYLATRON(TM) subcutaneous injection powder, 2011; Prod Info PegIntron(R) subcutaneous injection, powder for solution, 2011). A case report suggests that interferon alfa (non-pegylated) is minimally elevated in human breast milk even following large doses of 30 million international units IV over 30 minutes (Kumar et al, 2000a).
    4) PEGINTERFERON BETA-1A
    a) It is unknown if peginterferon beta-1a is excreted in human breast milk. Therefore, exercise caution when administering this drug to a woman who is breastfeeding (Prod Info PLEGRIDY(TM) subcutaneous injection, Jul).
    B) LACK OF EFFECT
    1) INTERFERON BETA-1A
    a) Based on 1 case report, interferon is likely too large a molecule to transfer into maternal milk in clinically significant amounts. The patient received a dose of interferon alfa-2b 30 million International Units for the treatment of malignant melanoma, while the amount of interferon transferred into human milk was only slightly elevated (1551 International Units/mL) when compared with control milk (1249 International Units/mL) (Kumar et al, 2000).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) INTERFERON BETA-1A
    a) Female monkeys had menstrual irregularities, anovulation, and decreased serum progesterone levels after 8 to 15 doses of subQ interferon beta 50 mcg/kg over the course of one menstrual cycle; however, the effects were reversible after drug discontinuation. Eight to 15 doses of 1.25 mcg/kg (approximately 2 times the recommended weekly human dose of 30 mcg on a mg/m(2) basis) produced no adverse effects on fertility (Prod Info AVONEX(R) intramuscular injection, 2013). In another study of female monkeys, 6 months of subQ doses up to 9 times the recommended weekly human dose produced no effects on either menstrual cycling or serum estradiol levels. Male monkeys administered the same doses had no observed adverse effects on sperm count, motility, morphology, or function (Prod Info Rebif(R) subcutaneous injection, 2013).
    2) PEGINTERFERON ALFA-2A
    a) Female cynomolgus monkeys given subcutaneous injections of 600 mcg/kg/dose (approximately 180 times the recommended weekly human dose for a 60 kg person) every other day for 1 month experienced prolonged menstrual cycles and/or amenorrhea. Administration of peginterferon alfa-2a every other day at 100 mcg/kg (approximately 30 times the recommended human dose) did not have an effect on reproductive hormone status or duration of the menstrual cycle. Both a decrease and delay in the peak 17 beta-estradiol and progesterone levels following administration of peginterferon alfa-2a to female monkeys accompanied menstrual cycle irregularities. Discontinuation of treatment resulted in the return of a normal menstrual cycle (Prod Info PEGASYS(R) subcutaneous injection solution, 2011).
    b) There are no adequate or well-controlled studies on the effects of peginterferon alfa-2a on male fertility. However, Rhesus monkeys treated for 5 months with non-pegylated interferon alfa-2a at doses up to 25 x 10(6) international units/kg/day experienced no fertility-related adverse effects (Prod Info PEGASYS(R) subcutaneous injection solution, 2011).
    3) PEGINTERFERON ALFA-2B
    a) Reversible irregularities in cynomolgus monkey menstrual cycles were observed following subcutaneous injections of 4239 mcg/m(2) of body surface area every other day for 1 month (approximately 345 times the recommended weekly human dose based on body surface area). No effects on cycle duration or reproductive hormone status were seen following doses of 262 mcg/m(2) every other day (approximately 21 times the weekly human dose) (Prod Info PegIntron(R) subcutaneous injection, powder for solution, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CBC, electrolytes, renal and liver function tests, ECG and blood pressure.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Renal and liver function tests should be monitored as well as electrolytes.
    B) HEMATOLOGIC
    1) Complete blood count should be monitored.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor ECG and blood pressure.

Methods

    A) IMMUNOASSAY
    1) Human alpha-interferon can be identified by a specific and sensitive immunoradiometric assay (Chard et al, 1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.

Monitoring

    A) Monitor CBC, electrolytes, renal and liver function tests, ECG and blood pressure.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastric decontamination is NOT necessary following oral ingestion. Interferons are proteins and probably would be digested in the gut (Scott, 1982).
    6.5.3) TREATMENT
    A) SUPPORT
    1) The acute syndrome of fever, chills, malaise, and myalgias can be managed by acetaminophen or non-steroidal anti-inflammatory agents.
    2) Fatigue is a common incapacitating effect of high-dose interferon that may last for weeks following an exposure. The only treatment is probably rest.
    B) HYPOTENSIVE EPISODE
    1) Hypotension is usually transient and usually requires no treatment.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis did not significantly alter the kinetics of interferon alpha in one report (Hirsch et al, 1983).

Range Of Toxicity

Summary

    A) The range of toxicity is not known. Single doses greater than 100 to 200 million units and continuous daily doses of 1 to 3 million units for 7 months have been associated with severe, dose-limiting toxicities.

Therapeutic Dose

    7.2.1) ADULT
    A) INTERFERON ALFA-2A
    1) 3 to 9 million international units SUBQ daily or 3 times weekly, depending on indication (Prod Info ROFERON-A(R) subcutaneous injection, 2008)
    2) Interferon alfa-2a 36 million international units daily for 10 to 12 weeks SUBQ or IM has been used for patients with Kaposi's sarcoma (Prod Info Roferon-A(R), 2001). However, as of September 10, 2003, interferon alfa-2a (Roferon-A(R)) is no longer FDA approved for Kaposi's sarcoma, per the manufacturer's request (US Food and Drug Administration, 2003).
    B) INTERFERON ALFA-2B
    1) CONDYLOMA ACUMINATUM
    a) 1 million international units (0.1 mL per lesion) intralesionally 3 times/wk on alternate days for 3 weeks; maximum 5 lesions per course; may repeat a second course at 12 to 16 weeks (Prod Info INTRON(R) A intramuscular injection, subcutaneous injection, intralesional injection, intravenous injection, 2014)
    2) MALIGNANT MELANOMA
    a) induction, 20 million international units/m(2) IV over 20 minutes 5 consecutive days/week for 4 weeks; maintenance, 10 million international units/m(2) subQ 3 times/week for 48 weeks (Prod Info INTRON(R) A intramuscular injection, subcutaneous injection, intralesional injection, intravenous injection, 2014)
    3) FOLLICULAR LYMPHOMA
    a) 5 million international units subQ 3 times/wk for up to 18 months (Prod Info INTRON(R) A intramuscular injection, subcutaneous injection, intralesional injection, intravenous injection, 2014)
    4) CHRONIC HEPATITIS B
    a) 5 million international units IM/subQ daily OR 10 million international units IM/subQ 3 times/wk for 16 weeks (30 to 35 million international units per week) (Prod Info INTRON(R) A intramuscular injection, subcutaneous injection, intralesional injection, intravenous injection, 2014)
    5) CHRONIC HEPATITIS C
    a) 3 million international units IM/subQ 3 times/ wk for 16 weeks; for patients responding to therapy, treatment should be extended to 18 to 24 months (Prod Info INTRON(R) A intramuscular injection, subcutaneous injection, intralesional injection, intravenous injection, 2014)
    6) HAIRY CELL LEUKEMIA
    a) 2 million international units/m(2) IM/subQ 3 times/wk for up to 6 months (Prod Info INTRON(R) A intramuscular injection, subcutaneous injection, intralesional injection, intravenous injection, 2014)
    7) KAPOSI'S SARCOMA ASSOCIATED WITH AIDS
    a) 30 million international units/m(2) IM/subQ 3 times/wk until disease progression or maximal response is achieved after 16 weeks (Prod Info INTRON(R) A intramuscular injection, subcutaneous injection, intralesional injection, intravenous injection, 2014)
    C) INTERFERON ALFACON-1
    1) 9 to 15 mcg SUBQ up to 3 times weekly, alone or in combination with ribavirin, depending on indication (Prod Info INFERGEN(R) subcutaneous injection, 2010)
    D) INTERFERON BETA-1A
    1) Avonex(R): 30 mcg IM once weekly; to prevent adverse effects, 7.5 mcg IM once weekly initially, increase by 7.5 mcg/wk to full dose (Prod Info AVONEX(R) intramuscular injection, 2012)
    2) Rebif(R): 4.4 to 44 mcg SUBQ 3 times/wk (Prod Info Rebif(R) subcutaneous injection, 2009)
    E) INTERFERON BETA-1B
    1) 0.0625 to 0.25 mg SUBQ every other day; MAXIMUM DOSE of 0.25 mg every other day (Prod Info EXTAVIA(R) subcutaneous injection, 2009; Prod Info BETASERON(R) powder for subcutaneous injection, 2008)
    F) INTERFERON GAMMA-1B
    1) BODY SURFACE AREA GREATER THAN 0.5 m(2): The recommended dose is 50 mcg/m(2) (1 million International Units/m(2)) subQ 3 times weekly (Prod Info ACTIMMUNE(R) subcutaneous injection, 2015)
    2) BODY SURFACE AREA LESS THAN OR EQUAL TO 0.5 m(2): The recommended dose is 1.5 mcg/kg subQ 3 times weekly (Prod Info ACTIMMUNE(R) subcutaneous injection, 2015).
    G) PEGINTERFERON ALFA-2A
    1) 180 mcg SUBQ once a week for 24 or 48 weeks as a monotherapy or in combination with antivirals; duration depends on indication, genotype, and concurrent antivirals (Prod Info PEGASYS(R) subcutaneous injection, 2014)
    H) PEGINTERFERON ALFA-2B
    1) COMBINATION THERAPY WITH RIBAVIRIN: 1.5 mcg/kg/wk SUBQ (Prod Info PegIntron(R) subcutaneous injection powder for solution, 2011)
    2) MONOTHERAPY: 1 mcg/kg/wk (Prod Info PegIntron(R) subcutaneous injection powder for solution, 2011) to 6 mcg/kg/wk SUBQ (Prod Info SYLATRON(TM) subcutaneous injection powder, 2011)
    7.2.2) PEDIATRIC
    A) INTERFERON ALFA-2A
    1) Interferon alfa-2a was tolerated in 1 trial of 15 children with Philadelphia chromosome-positive (Ph-positive), adult-type chronic myelogenous leukemia (CML) receiving doses between 2.5 to 5 million international units/m(2)/day IM. In another study, severe adverse effects including death were noted in children with previously untreated, Ph-negative, juvenile CML, who received interferon doses of 30 million international units/m(2)/day (Prod Info ROFERON-A(R) subcutaneous injection, 2008).
    B) INTERFERON ALFA-2B
    1) CHRONIC HEPATITIS B: 1 TO 17 YEARS: 3 million international units/m(2) subQ 3 times/wk for the first week, then 6 million international units/m(2) subQ 3 times/wk; total duration of therapy 16 to 24 weeks; maximum 10 million international units 3 times/wk (Prod Info INTRON(R) A intramuscular injection, subcutaneous injection, intralesional injection, intravenous injection, 2014)
    C) INTERFERON ALFACON-1
    1) Safety and effectiveness have not been established in patients under 18 years of age (Prod Info INFERGEN(R) subcutaneous injection, 2010).
    D) INTERFERON BETA-1A
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info AVONEX(R) intramuscular injection, 2012; Prod Info Rebif(R) subcutaneous injection, 2009).
    E) INTERFERON BETA-1B
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info EXTAVIA(R) subcutaneous injection, 2009).
    F) INTERFERON GAMMA-1B
    1) BODY SURFACE AREA GREATER THAN 0.5 m(2): The recommended dose is 50 mcg/m(2) (1 million International Units/m(2)) subQ 3 times weekly (Prod Info ACTIMMUNE(R) subcutaneous injection, 2015)
    2) BODY SURFACE AREA LESS THAN OR EQUAL TO 0.5 m(2): The recommended dose is 1.5 mcg/kg subQ 3 times weekly (Prod Info ACTIMMUNE(R) subcutaneous injection, 2015).
    G) PEGINTERFERON ALFA-2A
    1) LESS THAN 5 YEARS OF AGE: Safety and effectiveness have not been established (Prod Info PEGASYS(R) subcutaneous injection, 2014).
    2) 5 YEARS AND OLDER: 180 mcg/1.73 m(2) x BSA SUBQ once a week for 24 or 48 weeks, to a MAXIMUM DOSE of 180 mcg, in combination with ribavirin; duration depends on genotype (Prod Info PEGASYS(R) subcutaneous injection, 2014)
    H) PEGINTERFERON ALFA-2B
    1) COMBINATION THERAPY WITH RIBAVIRIN
    a) LESS THAN 3 YEARS OF AGE: Safety and effectiveness have not been established (Prod Info PegIntron(R) subcutaneous injection powder for solution, 2011)
    b) 2 YEARS AND OLDER: 60 mcg/m(2)/wk SUBQ with ribavirin (guideline dosing) (Ghany et al, 2009)
    c) 3 YEARS AND OLDER: 60 mcg/m(2)/wk SUBQ with ribavirin (Prod Info PegIntron(R) subcutaneous injection powder for solution, 2011)
    2) MONOTHERAPY
    a) Safety and effectiveness have not been established in patients under 18 years of age (Prod Info SYLATRON(TM) subcutaneous injection powder, 2011).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal dose is unknown.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) DOSE RELATED SEVERITY - High-dose interferon regimens have shown similar toxicities to those reported with low dose regimens but the toxicities tend to be more severe.
    2) MAXIMUM TOLERATED DOSE -
    a) The maximum tolerated dose varies from patient to patient but probably is about 100 to 200 million units of alpha interferon.
    b) Previous radiation therapy or chemotherapy may lower the maximum tolerated dose. Chemotherapy and radiation therapy are thought to act synergistically with interferon therapy.
    3) A 63-year-old male developed bilateral neuralgic amyotrophy and Mees-Beau lines following alpha-2 interferon therapy in doses up to 30 million international units daily by intramuscular gluteal injections (Bernsen et al, 1988).
    4) A 2-year-old male developed spastic diplegia (consistent with upper motor neuron lesion) that was associated with interferon therapy for juvenile laryngeal papilloma. He received human leukocyte interferon in doses of 1 to 3 million international units intramuscularly daily, nearly continuously, for 7 months when it was noted that he began to move on all fours (Vesikari et al, 1988).
    5) An adult developed mild flu-like symptoms lasting 24 hours after injecting 264-308 micrograms IFN beta-1a subcutaneously(Falcone et al, 2005).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Toxic serum/blood concentrations have not been identified.
    b) Doses greater than 100 million units/square meter usually result in severe toxicities.
    c) Peak concentration following a single dose of 36 million units of Interferon Alfa-2a (Balmer, 1985):
    1) 40 minute intravenous infusion: 10,400 to 17,470 picograms/milliliter
    2) IM: 1668 to 2372 picograms/milliliter
    3) SC: 1253 picograms/milliliter
    d) OVERDOSE: An adult injected 264 to 308 micrograms IFN beta-1a subcutaneously. He developed mild flu- like illness lasting 24 hours. Interferon beta-1a serum concentrations 24 and 48 hours after injection were 8.1 and 9.9 international units/mL, respectively. The 24-hour concentration may have been artificially low because the sample was not frozen (Falcone et al, 2005).
    e) INHALATION: Inhaled natural leukocyte interferon alfa (120,000,000 international units) from a dosimeter-equipped jet nebulizer resulted in circulating interferon concentrations ranging from 11 to 35 international units of interferon/milliliter of serum for at least 12 hours (Kinnula et al, 1989).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Interferons are biological response mediators. They are proteins produced by cells in response to interferon inducers such as certain synthetic polycarboxylates, double-stranded RNA, endotoxin, or viruses. They do not directly destroy tumor cells or virus; they stimulate existing host defenses.
    B) Interferons induce enzymes systems which interfere with viral reproduction. Interferons have direct inhibitory effects on protein and DNA synthesis which may play a role in their antitumor effects (Balmer, 1985). Exact mechanisms are being investigated.

Physicochemical

Physical Characteristics

    A) Interferons are naturally-occurring, small protein molecules that consist of approximately 166 amino acids (Prod Info INFERGEN(R) subcutaneous injection, 2006; Prod Info ALFERON N(R) injection, 2006; Prod Info Rebif(R) subcutaneous injection, 2009; Prod Info AVONEX(R) IM Injection, 2008).
    B) INTERFERON ALFA-2A is a colorless solution (Prod Info ROFERON-A(R) subcutaneous injection, 2008).
    C) INTERFERON ALFA-2B is water soluble. The solution for injection is clear and colorless; the powder for injection is white to cream-colored and the reconstituted solution is clear and colorless to light yellow (Prod Info INTRON(R) A IM, IV, subcutaneous injection, 2008).
    D) INTERFERON ALFA-N3 is a clear, colorless solution (Prod Info ALFERON N(R) injection, 2006).
    E) INTERFERON ALFACON-1 is a clear, colorless solution (Prod Info INFERGEN(R) subcutaneous injection, 2006).
    F) INTERFERON BETA-1A is formulated as a white to off-white powder for injection or as a clear, colorless solution for injection (Prod Info Rebif(R) subcutaneous injection, 2009; Prod Info AVONEX(R) IM Injection, 2008).
    G) INTERFERON BETA-1B is formulated as a white to off-white powder for injection (Prod Info BETASERON(R) powder for subcutaneous injection, 2008).
    H) INTERFERON GAMMA-1B is a clear, colorless solution (Prod Info ACTIMMUNE(R) injection, 2007).
    I) PEGINTERFERON ALFA-2A is a colorless to light yellow injectable solution (Prod Info PEGASYS(R) subcutaneous injection solution, 2011).
    J) PEGINTERFERON ALFA-2B is a white to off-white powder with a specific activity of approximately 0.7 x 10(8) international units/mg of protein (Prod Info SYLATRON(TM) subcutaneous injection powder, 2011).
    K) PEGINTERFERON BETA-1A is a clear solution for subQ injection (Prod Info PLEGRIDY(TM) subcutaneous injection solution, 2014).

Ph

    A) INTERFERON ALFA-N3: 7.4 (Prod Info ALFERON N(R) injection, 2006)
    B) INTERFERON ALFACON-1: 5 to 9 (Prod Info INFERGEN(R) subcutaneous injection, 2006)
    C) INTERFERON BETA-1A: approximately 7.3 (Avonex(R) reconstituted IM solution); approximately 4.8 (Avonex(R) prefilled IM syringe) (Prod Info AVONEX(R) IM Injection, 2008)
    D) PEGINTERFERON ALFA-2A: 5.5 to 6.5 (Prod Info PEGASYS(R) subcutaneous injection solution, 2011)
    E) PEGINTERFERON BETA-1A: approximately 4.8 (Prod Info PLEGRIDY(TM) subcutaneous injection solution, 2014)

Molecular Weight

    A) Interferons have molecular weights ranging from 15,000 to 27,600 daltons (Prod Info INTRON(R) A IM, IV, subcutaneous injection, 2008).
    B) INTERFERON ALFA-2B: 19,271 daltons (Prod Info INTRON(R) A IM, IV, subcutaneous injection, 2008)
    C) INTERFERON BETA-1A: approximately 22,500 daltons (Prod Info Rebif(R) subcutaneous injection, 2009; Prod Info AVONEX(R) IM Injection, 2008)
    D) INTERFERON BETA-1B: approximately 18,500 daltons (Prod Info BETASERON(R) powder for subcutaneous injection, 2008)
    E) PEGINTERFERON ALFA-2A: approximately 60,000 daltons (Prod Info PEGASYS(R) subcutaneous injection solution, 2011)
    F) PEGINTERFERON ALFA-2B: approximately 31,000 daltons (Prod Info SYLATRON(TM) subcutaneous injection powder, 2011)
    G) PEGINTERFERON BETA-1A: approximately 44,000 daltons (Prod Info PLEGRIDY(TM) subcutaneous injection solution, 2014)

References

General Bibliography

    1) Anon: "Toxicity" of interferon (editorial). Lancet 1983; 1:1256.
    2) Averbuch SD, Austin HA III, & Sherwin SA: Acute interstitial nephritis with the nephrotic syndrome following recombinant leukocyte a interferon therapy for mycosis fungoides. N Engl J Med 1984; 310:32-35.
    3) Balmer CM: The new alpha interferons. Drug Intell Clin Pharm 1985; 19:887-893.
    4) Bernsen PL, Wong Chung RE, & Vingerhoets HM: Bilateral neuralgic amyotrophy induced by interferon treatment. Arch Neurol 1988; 45:449-451.
    5) Bino T, Edery H, & Gertler A: Involvement of the kidney in catabolism of human leukocyte interferon. J Gen Virol 1982; 59:39-45.
    6) Bocci V, Pacini A, & Muscettola M: Renal filtration, absorption, and catabolism of human alpha interferon. J Interfer Res 1981; 1:347-352.
    7) Borden EC, Holland JF, & Dao TL: Leukocyte-derived interferon (alpha) in human breast carcinoma. Ann Intern Med 1982; 97:1-6.
    8) Briggs GG, Freeman RK, & Yaffe SJ: Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 4th ed, Williams & Wilkins, Baltimore, MD, 1994.
    9) Brouwers PJ, Bosker RJ, & Schaafsma MR: Photosensitive seizures associated with interferon alfa-2a (letter). Ann Pharmacother 1999; 33:113-114.
    10) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    11) Chard T, Craig PH, & Menabawey M: Alpha interferon in human pregnancy. Br J Obstet Gynecol 1986; 93:1145-1149.
    12) Cummins JM, Beilharz MW, & Krakowka S: Oral use of interferon. J Interferon Cytokine Res 1999; 19:853-857.
    13) Dubois J, Hershon L, Carmant L, et al: Toxicity profile of interferon alfa-2b in children: A prospective evaluation. J Pediatr 1999; 135(6):782-785.
    14) Enjolras O: Neurotoxicity of interferon alfa in children treated for hemangiomas (letter). J Am Acad Dermatol 1998; 1037-1038.
    15) Epstein LB: Update on interferon. Immunol Allerg Pract 1985; 7:19-26.
    16) Falcone NP, Nappo A, & Neuteboom B: Interferon beta-1a overdose in a multiple sclerosis patient. Ann Pharmacother 2005; 39:1950 - 1952.
    17) Farkkila M, Iivanainen M, & Roine R: Neurotoxic and other side effects of high-dose interferon in amyotrophic lateral sclerosis. Acta Neurol Scand 1984; 69:42-46.
    18) Fent K & Zbinden G: Toxicity of interferon and interleukin. Trends Pharmacol Sci 1987; 8:100-105.
    19) Friess GG, Brown TD, & Wrenn RC: Improvement in cardiac ectopy during gamma interferon infusion: a case report. Cancer Treat Rep 1986; 70:1463-1464.
    20) Ghany MG, Strader DB, Thomas DL, et al: Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49(4):1335-1374.
    21) Hanson DS & Leggette CT: Severe hypotension following inadvertent intravenous administration of interferon alfa-2a (letter). Ann Pharmacother 1997; 31:371-372.
    22) Hengstman GJ, Vogels OJ, terLaak HJ, et al: Myositis during long-term interferon-alpha treatment. Neurology 2000; 54(11):2186-.
    23) Hirsch MS, Tolkoff-Rubin NE, & Kelly AP: Pharmacokinetics of human and recombinant leukocyte interferon in patients with chronic renal failure who are undergoing hemodialysis (letter). J Infect Dis 1983; 148:335.
    24) Hutchinson V & Cummins JM: Low-dose oral interferon in patient with AIDS (letter). Lancet 1987; 2:1530-1531.
    25) Janssen HLA, Berk L, & Vermeulen M: Seizures associated with low-dose alpha-interferon (letter). Lancet 1990; 2:1580.
    26) Kinnula V, Mattson K, & Cantell K: Pharmacokinetics and toxicity of inhaled human interferon-a in patients with lung cancer. J Interfer Res 1989; 9:419-423.
    27) Kirkwood JM, Bender C, Agarwala S, et al: Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J Clin Oncol 2002; 20(17):3703-3718.
    28) Krown SE: Interferons and interferon inducers in cancer treatment. Seminars Oncol 1986; 13:207-217.
    29) Kumakura S, Ishikura H, & Kobayashi S: Bone marrow necrosis and the Lambert-Eaton syndrome associated with interferon alfa treatment. N Engl J Med 1998; 338(3):199-200.
    30) Kumar AR, Hale TW, & Mock RE: Transfer of interferon alfa into human breast milk. J Hum Lact 2000; 16:226-228.
    31) Kumar AR, Hale TW, & and Mock RE: Transfer of interferon alfa into human breast milk. J Hum Lact 2000a; 16(3):226-228.
    32) Kurzrock R, Quesada JR, & Rosenblum MG: Phase I study of IV administrated recombinant gamma interferon in cancer patients. Cancer Treat Rep 1986; 70:1357-1364.
    33) Lock G, Reng CM, & Graeb C: Interferon-induced hepatic failure in a patient with hepatitis C (letter). Amer J Gastroenterol 1999; 94:2570-2571.
    34) Mangan KF, Zidar B, & Shadduck RK: Interferon-induced aplasia: evidence for T-cell-mediated suppression of hematopoiesis and recovery after treatment with horse antihuman thymocyte globulin. Am J Hematol 1985; 19:401-413.
    35) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    36) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    37) Oldham RR: Toxic effects of interferon (letter). Science 1983; 219:902.
    38) Pakulski LA & DiMarco LM: Severe vaginal bleeding associated with recombinant interferon beta-1b. Ann Pharmacother 1997; 31:50-52.
    39) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    40) Pigatto PD, Bigardi A, & Legori A: Allergic contact dermatitis from beta-interferon in eyedrops. Contact Dermatitis 1991; 25:199-200.
    41) Pons JC, Lebon P, & Frydman R: Pharmacokinetics of interferon-alpha in pregnant women and fetoplacental passage. Fetal Diagn Ther 1995; 10:7-10.
    42) Priestman TJ: Initial evaluation of human lymphoblastoid interferon in patients with advanced malignant disease. Lancet 1980; 2:113-118.
    43) Product Information: ACTIMMUNE(R) injection, interferon gamma-1b injection. Intermune,Inc, Brisbane, CA, 2007.
    44) Product Information: ACTIMMUNE(R) subcutaneous injection, interferon gamma-1b subcutaneous injection. HZNP USA Inc. (per FDA), Roswell, GA, 2015.
    45) Product Information: ALFERON N(R) injection, interferon alfa N3 injection. Hemispherx Biopharma Inc, Philadelphia, PA, 2006.
    46) Product Information: AVONEX(R) IM Injection, interferon beta-1a IM Injection. Biogen Idec Inc., Cambridge, MA, 2008.
    47) Product Information: AVONEX(R) intramuscular injection, interferon beta 1a intramuscular injection. Biogen Idec Inc. (per FDA), Cambridge, MA, 2013.
    48) Product Information: AVONEX(R) intramuscular injection, interferon beta-1a intramuscular injection. Biogen Idec Inc. (per manufacturer), Cambridge, MA, 2012.
    49) Product Information: BETASERON subcutaneous injection, interferon beta 1b subcutaneous injection. Bayer HealthCare Pharmaceuticals Inc. (per FDA), Whippany, NJ, 2014.
    50) Product Information: BETASERON(R) powder for subcutaneous injection, interferon beta 1b powder for subcutaneous injection. Bayer Healthcare Pharmaceuticals Inc, Montville, NJ, 2008.
    51) Product Information: EXTAVIA(R) subcutaneous injection, interferon beta 1b subcutaneous injection. Novartis Pharmaceuticals Corporation (per manufacturer), East Hanover, NJ, 2012.
    52) Product Information: EXTAVIA(R) subcutaneous injection, interferon beta-1b subcutaneous injection. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2009.
    53) Product Information: INFERGEN(R) subcutaneous injection, interferon alfacon-1 subcutaneous injection. Three Rivers Pharmaceuticals, LLC, Warrendale, PA, 2010.
    54) Product Information: INFERGEN(R) subcutaneous injection, interferon alfacon-1 subcutaneous injection. Valeant Pharmaceuticals North America, Costa Mesa, CA, 2006.
    55) Product Information: INTRON(R) A IM, IV, subcutaneous injection, interferon alfa-2b recombinant IM, IV, subcutaneous injection. Schering-Plough, Kenilworth, NJ, 2008.
    56) Product Information: INTRON(R) A intramuscular injection, subcutaneous injection, intralesional injection, intravenous injection, interferon alfa 2b recombinant intramuscular injection, subcutaneous injection, intralesional injection, intravenous injection. Schering Corporation (per FDA), Whitehouse Station, NJ, 2014.
    57) Product Information: PEGASYS(R) subcutaneous injection solution, peginterferon alfa-2a subcutaneous injection solution. Genentech USA, Inc., South San Francisco, CA, 2011.
    58) Product Information: PEGASYS(R) subcutaneous injection, peginterferon alfa-2a subcutaneous injection. Genentech USA, Inc. (per manufacturer), South San Francisco, CA, 2014.
    59) Product Information: PLEGRIDY(TM) subcutaneous injection solution, peginterferon beta-1a subcutaneous injection solution. Biogen Idec Inc. (per FDA), Cambridge, MA, 2014.
    60) Product Information: PLEGRIDY(TM) subcutaneous injection, peginterferon beta 1a subcutaneous injection. Biogen Idec Inc.(per FDA), Cambridge, MA, Jul.
    61) Product Information: PegIntron(R) subcutaneous injection powder for solution, peginterferon alfa-2b subcutaneous injection powder for solution. Schering Corporation (per FDA), Whitehouse Station, NJ, 2011.
    62) Product Information: PegIntron(R) subcutaneous injection, peginterferon alfa 2b subcutaneous injection. Schering Corporation (per FDA), Whitehouse Station, NJ, 2013.
    63) Product Information: PegIntron(R) subcutaneous injection, powder for solution, peginterferon alfa-2b subcutaneous injection, powder for solution. Schering Corporation, Whitehouse Station, NJ, 2011.
    64) Product Information: ROFERON-A(R) subcutaneous injection, interferon alfa-2a recombinant subcutaneous injection. Hoffman-La Roche Inc, Nutley, NJ, 2008.
    65) Product Information: Rebif(R) subcutaneous injection, interferon beta 1a subcutaneous injection. EMD Serono, Inc. and Pfizer Inc. (per FDA), Rockland, MA, 2013.
    66) Product Information: Rebif(R) subcutaneous injection, interferon beta-1a subcutaneous injection. EMD Serono, Inc., Rockland, MA, 2009.
    67) Product Information: Roferon-A(R), interferon alfa-2a recombinant. Roche Laboratories, Nutley, NJ, 2001.
    68) Product Information: SYLATRON(TM) subcutaneous injection powder, peginterferon alfa-2b subcutaneous injection powder. Schering Corporation, Kenilworth, NJ, 2011.
    69) Quesada JR, Talpaz M, & Rios A: Clinical toxicity of interferons in cancer patients: a review. J Clin Oncol 1986; 4:234-243.
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    71) Sarna G, Pertcheck M, & Figlin R: Phase I study of recombinant beta ser 17 interferon in the treatment of cancer. Cancer Treat Rep 1986; 70:1365-1372.
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    75) Sumpio BE, Ernstoff MS, & Kirkwood JM: Urinary excretion of interferon, albumin, and beta 2-microglobulin during interferon treatment. Cancer Res 1984; 44:3599-3603.
    76) Tamura S, Warabi Y, & Matsubara S: Severe liver dysfunction possibly caused by the combination of interferon beta-1b therapy and melilot (sweet clover) supplement. J Clin Pharm Ther 2012; 37(6):724-725.
    77) US Food and Drug Administration: FDA letter regarding interferon alfa-2a and Kaposi's sarcoma indication. US Food and Drug Administration. Rockville, MD. 2003. Available from URL: http://www.fda.gov/cder/foi/appletter/2003/103145-5026ltr.pdf.
    78) Vesikari T, Nuutila A, & Cantell K: Neurologic sequelae following interferon therapy of juvenile laryngeal papilloma. Acta Paediatr Scand 1988; 77:619-622.
    79) Wadler S, Lyver A, & Wiernik PH: Clinical toxicities of the combination of 5-fluorouracil and recombinant interferon alfa-2a: an unusual toxicity profile. Oncol Nurs Forum 1989; 16(Suppl):12-15.
    80) Wills RJ, Dennis S, & Spiegel HE: Interferon kinetics and adverse reactions after intravenous, intramuscular, and subcutaneous injection. Clin Pharmacol Ther 1984; 35:722-727.
    81) Wolf Y, Haddad R, Jossipov J, et al: Alpha-interferon induced severe pneumonitis. J Toxicol Clin Toxicol 1997; 35:113-114.