Interferons, Alpha (Systemic)

This monograph includes information on the following:

1) Interferon Alfa-2a, Recombinant
2) Interferon Alfa-2b, Recombinant
3) Interferon Alfa-n1(lns)  *
4) Interferon Alfa-n3 

VA CLASSIFICATION
Primary: IM404
Secondary: AN900

Commonly used brand name(s): Alferon N4; Intron A2; Roferon-A1; Wellferon3.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Biological response modifier—

antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Leukemia, hairy cell (treatment)—Recombinant interferon alfa-2a, recombinant interferon alfa-2b, and interferon alfa-n1 (lns) are indicated for treatment of hairy cell leukemia in splenectomized or nonsplenectomized patients {01} {06} {16} {17} {106} {108} {110} {111} {113}. [ Interferon alfa-n3] is also indicated for treatment of hairy cell leukemia {92}.

Condyloma acuminatum (treatment)— Recombinant interferon alfa-2b1, interferon alfa-n1 (lns), and interferon alfa-n3 are indicated by intralesional injection for treatment of refractory or recurrent external condyloma acuminatum (genital warts) {33} {34} {35} {36} {54} {55} {113} {114}.

Hepatitis, chronic, active (treatment)—[ Recombinant interferon alfa-2a]1, recombinant interferon alfa-2b, interferon alfa-n1 (lns)1 , and [interferon alfa-n3] are indicated for treatment of non-A, non-B/C hepatitis in patients 18 years of age or older with compensated liver disease who have a history of blood or blood product exposure and/or are HCV (hepatitis C virus) antibody positive {93} {103} {115}. Safety and efficacy have not been established for treatment of patients with decompensated liver disease or for immune suppressed transplant recipients {115}. Use is not recommended in patients with autoimmune hepatitis or a history of autoimmune disease {115}.
—Available data indicate that serum transaminase activity and markers of viral activity are reduced during alpha interferon treatment, although abnormalities may recur when treatment is withdrawn. Long-term effects of alpha interferon on development of chronic hepatitis are not established. {93}

Hepatitis B, chronic (treatment)— Recombinant interferon alfa-2b1 is indicated for treatment of chronic hepatitis B in patients 18 years of age or older with compensated liver disease and hepatitis B virus (HBV) replication. Patients must test positive for hepatitis B serum antigen for at least 6 months and have HBV replication with elevated serum alanine aminotransferase. {154}

Kaposi"s sarcoma, AIDS-associated (treatment)— Recombinant interferon alfa-2a and recombinant interferon alfa-2b are indicated for treatment of AIDS-associated Kaposi"s sarcoma {10} {13} {33} {34} {36} {42} {43} {44} {45} {46} {47} {71} {72} {73} {74} {75} {76} {103} {105} {107} {112} in selected patients 18 years of age and older {105} {107}. Interferon alfa-n1 (lns)1 and [interferon alfa-n3 ] are also indicated for this indication {92}.

Carcinoma, bladder (treatment)— Interferon alfa-n1 (lns)1and [interferon alfa-n3 ] are indicated for the treatment of superficial bladder carcinoma (intravesically) {33} {84} {85} {92}.

Note: Recombinant interferon alfa-2a and recombinant interferon alfa-2b have been studied, in combination therapy, for intravesical use in the treatment of bladder carcinoma {136} {137} {138} {139} {140} (Evidence rating: IIID). Although some medical experts agree that these medications may be useful in the management of bladder carcinoma, others state there is not enough medical literature or clinical experience to consider the use of these alpha interferons for this indication outside of a clinical trial setting {153}.


Carcinoma, renal (treatment) or
Leukemia, chronic myelocytic (treatment)—[ Recombinant interferon alfa-2a], [ recombinant interferon alfa-2b]1 , interferon alfa-n1 (lns)1 , and [interferon alfa-n3 ] are indicated for the treatment of renal carcinoma {20} {21} {33} {36} {48} {49} {50} {83} {92} {104} and chronic myelocytic leukemia {32} {33} {36} {53} {61} {62} {92} {104}.

Papillomatosis, laryngeal (treatment)—[ Recombinant interferon alfa-2b]1, interferon alfa-n1 (lns), and [interferon alfa-n3] are indicated for treatment of laryngeal papillomatosis {33} {34} {36} {92}, including juvenile laryngeal papilloma {89} {113}.

Lymphomas, non-Hodgkin"s (treatment)
Malignant melanoma (treatment)
Multiple myeloma (treatment) or
Mycosis fungoides (treatment)—[ Recombinant interferon alfa-2a]1, recombinant interferon alfa-2b1 , interferon alfa-n1 (lns)1 , and [interferon alfa-n3] are indicated for treatment of non-Hodgkin"s lymphomas, especially follicular small cleaved cell lymphoma (nodular poorly differentiated types) {05} {11} {19} {22} {30} {33} {36} {37} {38} {39} {40} {41} {59} {60} {65} {92} {94}, malignant melanoma {12} {14} {15} {33} {34} {36} {51} {52} {56} {57} {58} {75} {77} {78} {79} {80} {81} {82} {92} {154}, multiple myeloma {18} {33} {34} {36} {63} {64} {65} {66} {67} {68} {69} {70} {92}, and mycosis fungoides {11} {19} {33} {36} {92}.

[Carcinoid tumors (treatment)]1—Alpha interferons are indicated as reasonable medical therapy in the management of carcinoid tumors {145} {146} {147} {148} {149} {150} {151} {152} {153} (Evidence rating: IID).

[Carcinoma, ovarian, epithelial (treatment) ]1 or
[Carcinoma, skin (treatment)]—Alpha interferons are indicated for treatment of epithelial ovarian (intraperitoneal administration) {09} {109} and skin (recombinant interferon alfa-2b) {09} {29} carcinomas.

[Polycythemia vera (treatment)]1—Recombinant interferon alfa-2a and recombinant interferon alfa-2b are indicated as reasonable medical therapy at some point in the management of polycythemia vera {124} {125} {126} {127} {128} {129} {153} (Evidence rating: IIID). However, these medications are not recommended for first-line treatment.

[Thrombocytosis, essential (treatment) ]1—Alpha interferons are indicated for treatment of essential thrombocytosis {09} {25}.

—Although efficacy of all alpha interferons for various indications appears to be similar, differences in relative efficacy for a particular indication may exist.

Acceptance not established
Recombinant interferon alfa-2b, in combination therapy, has been studied for use in the treatment of cervical carcinoma {141} {142} {143} {144} (Evidence rating: IIID). Some medical experts consider this agent to be reasonable medical therapy at some point in the management of advanced cervical carcinoma (although it is not recommended as first-line treatment) {153}. However, other experts state that there is not enough medical literature or clinical experience to consider the use of recombinant interferon alfa-2b for the treatment of cervical carcinoma outside of a clinical trial setting {153}.

Recombinant interferon alfa-2a and recombinant interferon alfa-2b have been studied, in combination therapy, for use in the treatment of esophageal carcinoma {118} {119} {120} {121} {122} {123} (Evidence rating: IIID). However, medical experts agree that, at this point in time, there is not enough medical literature or clinical experience to consider the use of these medications for the treatment of esophageal carcinoma outside of a clinical trial setting {153}.

Unaccepted
Recombinant interferon alfa-2a and recombinant interferon alfa-2b, in combination therapy, have been shown in several studies to be ineffective in the treatment of colorectal carcinoma {130} {131} {132} {133} {134} {135} {153} (Evidence rating: IIC). Their use is not recommended.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Interferon alfa-2a, recombinant: Synthetic. A protein chain of 165 amino acids produced by a recombinant DNA process {01} {106} {108} {110} {111} involving genetically engineered Escherichia coli {01} {02} {07} {106} {108} {110} {111}. Has a lysine group at position 23 {33}. Purification procedure includes affinity chromatography using a murine monoclonal antibody {01} {07} {106} {108} {110} {111}. Contains only a single alpha interferon subtype.
    Interferon alfa-2b, recombinant: Synthetic. A protein chain of 165 amino acids produced by a recombinant DNA process {01} {106} {108} {110} {111} involving genetically engineered Escherichia coli {01} {02} {07} {106} {108} {110} {111}. Has an arginine group at position 23 {33}. Purification is done by proprietary methods {01} {07} {106} {108} {110} {111}. Contains only a single alpha interferon subtype.
    Interferon alfa-n1 (lns): A highly purified blend of natural human alpha interferons, obtained from human lymphoblastoid cells following induction with Sendai virus {113}. Is a mixture of natural alpha interferon subtypes, but in different proportions than in human leukocyte interferon {113}.
    Interferon alfa-n3: A highly purified mixture of up to 14 natural human alpha interferon subtypes {95}. A protein chain of approximately 166 amino acids {114}. Manufactured from pooled units of human leukocytes that have been induced by incomplete infection with an avian virus (Sendai virus) to produce interferon alfa-n3 {114}. The manufacturing process includes immunoaffinity chromatography with a murine monoclonal antibody, acidification (pH 2) for 5 days at 4 °C, and gel filtration chromatography {114}.

Chemical group—
    Interferon alfa-n1 and -n3: Naturally occurring alpha interferons.
    Interferon alfa-2a and -2b, recombinant: Related to naturally occurring alpha interferons.
    Interferons are produced and secreted by cells in response to viral infections or various synthetic and biologic inducers {01} {03} {19} {106} {108} {110} {111}; alpha interferons are produced mainly by leukocytes {02} {19}.

Mechanism of action/Effect:

In general, interferons have antiviral, antiproliferative, and immunomodulatory activities {01} {02} {03} {07} {106} {108} {110} {111}. Antiviral and antiproliferative actions are thought to be related to alterations in synthesis of RNA, DNA, and cellular proteins, including oncogenes {87} {88} {89}. The exact mechanism of antineoplastic activity is unknown, but may be related to any of these three actions.

Antiviral—Inhibit virus replication in virus-infected cells {01} {106} {108} {110} {111}.

Antiproliferative—Suppress cell proliferation {01} {106} {108} {110} {111}.

Immunomodulatory—Enhance phagocytic activity of macrophages and augment specific cytotoxicity of lymphocytes for target cells {01} {106} {108} {110} {111}.

Absorption:

Intralesional—Plasma concentrations achieved are below detectable levels; however, systemic effects have been reported, indicating some systemic absorption {114}.

Intramuscular and subcutaneous—Greater than 80% {01} {24} {106} {108} {110} {111}.

Biotransformation:

Renal, complete {01} {106} {108} {110} {111}. Alpha interferons are totally filtered through the glomeruli and undergo rapid proteolytic degradation during tubular reabsorption {117}.

Half-life:


Recombinant interferon alfa-2a:

Intramuscular: 6 to 8 hours {08} {96}.

Intravenous infusion: 3.7 to 8.5 (mean 5.1) hours {117}.



Recombinant interferon alfa-2b:

Intramuscular or subcutaneous: 2 to 3 hours {115}.



Interferon alfa-n1:

Intravenous infusion: About 8 hours {113}.


Note: Accumulation may occur with daily intramuscular dosing {02} {07} {117}.


Onset of action:

Hepatitis, chronic, active—Normalization of serum alanine aminotransferase (ALT) concentrations may occur as early as 2 weeks after initiation of treatment {115}, although 6 months of treatment is usually recommended {115}.

Time to peak concentration:


Recombinant interferon alfa-2a (single dose):

Intramuscular: 3.8 hours {117}.

Subcutaneous: 7.3 hours {117}.



Recombinant interferon alfa-2b (single dose):

Intramuscular or subcutaneous: 3 to 12 hours {115}.


Time to peak effect

Condyloma acuminatum—4 to 8 weeks after initiation of treatment {115}.

Elimination:
    With systemic use—Renal {03} {07} {117}; metabolites almost completely reabsorbed in renal tubules {113} {117}, with only negligible amounts of unchanged alpha interferon reappearing in systemic circulation {03} {07} {117}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to any alpha interferon may also be sensitive to any other alpha interferon {117}.

Patients sensitive to mouse immunoglobulin may also be sensitive to recombinant interferon alfa-2a {117}.

Patients sensitive to mouse immunoglobulin, egg protein, or neomycin may also be sensitive to interferon alfa-n3 {114}.

Carcinogenicity

Studies have not been done in either animals or humans {01} {106} {108} {110} {111} {114}.

Mutagenicity

Results of Ames tests and in vitro treatment of human lymphocyte cultures with recombinant alpha interferon at noncytotoxic concentrations showed no evidence of mutagenicity. However, both genotoxicity and protection from chromosomal abnormalities produced by gamma rays have been reported in association with human leukocyte interferon in vitro . {117}

Pregnancy/Reproduction
Fertility—
In humans, alpha interferon has been shown to affect the menstrual cycle and decrease serum estradiol and progesterone concentrations in adult females {114} {115}.

In Macaca mulatta (rhesus) monkeys given high doses (e.g., in the case of interferon alfa-n3, 326 times the average intralesional dose [120 times the maximum recommended dose]) intramuscularly daily, recombinant alpha interferon has been shown to cause menstrual cycle changes; normal menstrual rhythm returned when alpha interferon was withdrawn {114} {117}.

For interferon alfa-2a, recombinant: Has been shown to cause reversible {86} menstrual irregularities, including prolonged or shortened menstrual periods and erratic bleeding with anovulation, in Macaca mulatta (rhesus) monkeys {117} given 5 million and 25 million Units per kg of body weight per day.

For interferon alfa-n3: No menstrual changes were reported in humans {114}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {113} {114} {115} {117}.


For interferon alfa-2a, recombinant

Studies in Macaca mulatta (rhesus) monkeys at doses approximately 20 to 500 times the therapeutic human dose found a significant increase in abortifacient activity but no evidence of teratogenic activity. {117}

FDA Pregnancy Category C.



For interferon alfa-2b, recombinant

Studies in Macaca mulatta (rhesus) monkeys at doses of 90 and 180 times the intramuscular or subcutaneous dose of 2 million Units per square meter of body surface area found an abortifacient effect {115}.

FDA Pregnancy Category C.



For interferon alfa-n1 (lns)

Studies have not been done in animals {113}.



For interferon alfa-n3

Studies have not been done in animals {114}.

FDA Pregnancy Category C.


Breast-feeding

It is not known whether alpha interferon is distributed into breast milk {113} {114} {115}; in mice, mouse interferons are distributed into milk {115}. However, because of the potential for serious adverse effects in nursing infants, avoidance of breast-feeding should be considered while alpha interferon is being administered {115}.

Pediatrics

Appropriate studies on the relationship of age to the effects of alpha interferons have not been performed in the pediatric population.



Adolescents

Alpha interferons have been shown to affect the menstrual cycle in animals and decrease serum estradiol and progesterone concentrations in human females {115}. These effects should be kept in mind when considering alpha interferon treatment in adolescent females {115}.


Geriatrics


Although appropriate studies on the relationship of age to the effects of alpha interferons have not been performed in the geriatric population, neurotoxicity {01} {106} {108} {110} {111} and cardiotoxicity {02} may be more likely to occur in the elderly, who may have underlying central nervous system (CNS) and cardiac function impairment {33}. In addition, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving alpha interferons.


Dental

The bone marrow depressant effects of alpha interferons may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal and patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Interferon alfa-2a and alfa-2b may cause stomatitis and discomfort. Use of interferon alfa-2a or alfa-2b may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
The following information applies to systemic use.

Alcohol or
CNS depression–producing medications (see Appendix II )    (concurrent use may enhance the CNS depressant effects of either these medications or alpha interferon {01} {106} {108} {110} {111} {113})


Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of interferon may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of alpha interferon, if necessary, should be based on blood counts)


Bone marrow depressants, other (see Appendix II ) or
Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)

{01}{106}{108}{110}{111}

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values

Note: The following information applies to systemic use.

Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT]) and
Lactate dehydrogenase    (serum values may be increased; dose-related; reversible on withdrawal of alpha interferon {02} {07} {08} {10} {12} {17} {18} {21} {22} {23} {115})


Blood pressure    (mild and transient increase may occur {01} {07} {106} {108} {110} {111}; hypotension is more likely and may occur during administration or up to 2 days after administration {01} {10} {23} {106} {108} {110} {111})


Hemoglobin concentrations and
Hematocrit    (may be decreased {01} {23} {106} {108} {110} {111})


Leukocyte counts (including neutrophils) and
Platelet counts    (may be decreased {01} {02} {04} {06} {07} {08} {10} {11} {12} {16} {18} {19} {21} {22} {23} {27} {28} {106} {108} {110} {111}; dose-related)


Prothrombin time (PT) and
Partial thromboplastin time (PTT)    (may be increased by recombinant interferon alfa-2b; dose-related {01} {106} {108} {110} {111})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Autoimmune disease, history of    (caution is recommended because alpha interferon may increase the activity of the immune system and thereby worsen the condition {97}; use for treatment of non-A, non-B/C hepatitis or hepatitis B is not recommended {97} {154})


Bone marrow depression    (may be exacerbated {01} {106} {108} {110} {111})


» Cardiac disease, severe, including recent myocardial infarction {19} {23} {114} {115} {117} or
» Diabetes mellitus prone to ketoacidosis {115} or
» Ischemic disorders or{155}
» Pulmonary disease {05} {114} {115}    (may be exacerbated as a result of the stress of the fever and chills that occur in most patients receiving alpha interferon)

    (the risk of cardiotoxicity of alpha interferon may be increased in patients with a history of cardiac disease {02}; myocardial infarction has been reported rarely {23} {30} {117})


» Chickenpox, existing or recent, including recent exposure or
» Herpes zoster    (risk of severe generalized disease)


» CNS function, compromised {01} {106} {108} {110} {111} {113} or
» Psychiatric conditions, severe, or history of {113} {115} or
» Seizure disorders {23} {114}    (risk of severe CNS side effects {23})


Hepatic disease, severe {113} {117}    (alpha interferons may elevate serum hepatic enzyme concentrations)


Herpes labialis, history of    (may be reactivated {01} {106} {108} {110} {111})


» Infectious disorders    (alfa interferons may aggravate fatal or life-threatening infectious disorders )

{155}
Renal disease, severe {113} {117}    (may be exacerbated by fever and dehydration caused by alpha interferon {89})


» Sensitivity to alpha interferon {107} {114} {115}
Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy.
For treatment of non-A, non-B/C hepatitis, or hepatitis B (in addition to the above):
» Thyroid function impairment    (recombinant interferon alfa-2b has been reported to cause thyroid function abnormalities {115} {154}; serum thyroid-stimulating hormone [TSH] concentrations must be within normal limits before initiation of treatment {115} {154})


For recombinant interferon alfa-2b and interferon alfa-n3 only (in addition to the above):
Coagulation disorders {115} {91}    (caution is recommended; recombinant interferon alfa-2b may prolong PT and PTT)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


Note: The following information applies to systemic use.

Alanine aminotransferase (ALT [SGPT]) values and
Aspartate aminotransferase (AST [SGOT]) values and
Bilirubin concentrations, serum and
Lactate dehydrogenase (LDH) values    (recommended prior to initiation of therapy and at periodic intervals during therapy)


Blood pressure measurements    (recommended at periodic intervals {33})


Electrocardiogram (ECG)    (recommended prior to initiation of therapy and at periodic intervals during therapy in patients with cardiac disease or advanced malignancy {01} {106} {108} {110} {111})


» Blood count, complete (CBC)
» Hematocrit or hemoglobin and
» Platelet count and
» Total and, if appropriate, differential leukocyte count     (determinations recommended prior to initiation of therapy and at periodic intervals during therapy)

    (alfa interferon therapy should be discontinued in patients who develop severe decreases in neutrophil or platelet counts)

{155}
Liver biopsy    (recommended prior to discontinuing alpha interferon treatment when hepatic enzyme values return to normal {102})


Neuropsychiatric monitoring    (recommended especially in patients receiving high doses of alpha interferon {117})


Thyroid-stimulating hormone (TSH) concentrations, serum    (recommended prior to initiation of treatment for non-A, non-B/C hepatitis, or hepatitis B and if symptoms of thyroid function impairment occur during treatment {115} {154})




Side/Adverse Effects

Table 1. Side/Adverse Effects


Note: Most side/adverse effects, except the flu-like syndrome, are dose-related {99}. They are usually mild to moderate {100} at systemic doses less than 10 million Units per day {12}; hematologic and hepatic toxicities tend to be more frequent with doses above 10 million Units, and cardiovascular and neurologic toxicities tend to be more frequent with doses above 30 million Units {115}. However, patient sensitivity varies {89}.
Reduced blood pressure occurs frequently with systemic use but is rarely symptomatic {01} {10} {23} {106} {108} {110} {111}; hypotension may occur during administration or up to two days after therapy, and may require supportive therapy including fluid replacement to maintain intravascular volume {115}; hypertension may occur but is usually mild and transient {01} {07} {106} {108} {110} {111}.
Development of neutralizing antibodies has been reported. Relationship of the presence of neutralizing antibodies to loss of antitumor effects {89} is controversial; a possible correlation with titer of neutralizing antibodies has been suggested but not confirmed. Differences in frequency of antibody formation have been reported among alpha interferons but relative frequency has not been studied prospectively. Differences may be related to the differences in the sensitivity of tests used in antibody detection {01} {02} {07} {18} {23} {101} {106} {108} {110} {111}, as well as to disease state, dose, schedule, and route of administration.



The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive: *
Indication {99}
Hairy cell
leukemia
Other
malignancies
Condyloma
acuminatum
Kaposi"s
sarcoma
Hepatitis
Those indicating need for medical attention
Anemia (usually asymptomatic)
N/A
M
L
M
M
Autoimmune disorders including: vasculitis, arthritis, hemolytic anemia, and erythematosus syndrome{155}
 
R
R
R
R
R
Cardiotoxicity (chest pain {01} {23} {106} {108} {110} {111}, irregular heartbeat {01} {106} {108} {110} {111})
Note: Arrhythmias are usually supraventricular {01} {106} {108} {110} {111}.
R
R
U
R
R
Hepatotoxicity (usually asymptomatic)
L
L
L
M
L
Hyperthyroidism or hypothyroidism (usually asymptomatic)
U
U
U
U
R
Ischemic attacks, transient (headache, numbness or tingling in arms or legs, trouble speaking){155}
R
R
R
R
R
Leukopenia (usually asymptomatic; rarely, fever or chills, cough or hoarseness, lower back or side pain, painful or difficult urination)
N/A
M
M
M
M
Neurotoxicity (confusion {01} {11} {19} {23} {106} {108} {110} {111}, mental depression {01} {11} {19} {23} {32} {106} {108} {110} {111}, nervousness {01} {11} {106} {108} {110} {111}, trouble in sleeping {01} {32} {106} {108} {110} {111}, trouble in thinking or concentrating {02} {26} {32} )
L
L
L
L
L
Note: Usually reversible after withdrawal {26}; in some patients, especially the elderly or those treated with high doses, stupor, obtundation, and coma have occurred {01} {02} {12} {18} {26} {32} {106} {108} {110} {111}.
         
Peripheral neuropathy (numbness or tingling of fingers, toes, or face) {01} {02} {07} {18} {21} {22} {23} {106} {108} {110} {111}
L
L
L
L
R
Thrombocytopenia (usually asymptomatic; rarely, unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)
N/A
M
L
M
M
Those indicating need for medical attention only if they continue or are bothersome
Blurred vision
 
L
L
L
L
L
Change in taste {01} or metallic taste {89}
 
M
M
R
M
R
Cold sores or stomatitis (sores in mouth and on lips)
L
L
R
R
R
Diarrhea {01} {02} {07} {08} {18} {23} {106} {108} {110} {111}
M
M
L
M
M
Dizziness {01} {07} {23} {106} {108} {110} {111}
Note: Dizziness is a CNS effect.
M
M
L
M
L
Dry mouth {01} {08} {21} {106} {108} {110} {111}
M
M
R
M
L
Dry skin or itching {01} {07} {21} {106} {108} {110} {111}
L
L
L
L
L
Flu-like syndrome (aching muscles {01} {02} {07} {10} {21} {22} {23} {32} {106} {108} {110} {111} {114}, fever and chills {01} {02} {05} {06} {07} {10} {11} {16} {17} {18} {19} {21} {22} {23} {32} {106} {108} {110} {111}, headache {01} {02} {07} {10} {22} {23} {32} {106} {108} {110} {111}, general feeling of discomfort or illness {113} {114} {115}; less frequently, joint pain {01} {02} {23} {32} {106} {108} {110} {111}, back pain {113} {114} {115})
M
M
M
M
M
Note: Occurs in most patients; most pronounced in first week of treatment and gradually reduced, as a result of tachyphylaxis, within 2 to 4 weeks with continued treatment. {01} {02} {06} {11} {19} {21} {22} {31} {106} {108} {110} {111} {114}
         
Increased sweating
 
L
L
L
L
L
Leg cramps
 
L
L
L
U
R
Loss of appetite {01} {02} {06} {07} {08} {11} {12} {15} {17} {18} {19} {21} {22} {23} {31} {106} {108} {110} {111}
M
M
L
M
M
Note: Loss of appetite tends to become more prominent with continued treatment {01} {12} {106} {108} {110} {111} and may necessitate dosage reduction; usually resolves within 4 weeks after withdrawal of alpha interferon. {22}
         
Nausea or vomiting {01} {02} {07} {10} {17} {18} {22} {23} {106} {108} {110} {111}
M
M
M
M
M
Note: Nausea or vomiting usually resolves within 3 to 5 days after withdrawal of alpha interferon. {22}
         
Skin rash {01} {23} {106} {108} {110} {111}
M
M
L
M
L
Unusual tiredness {01} {02} {06} {07} {08} {10} {11} {12} {15} {16} {19} {21} {22} {23} {26} {31} {32} {106} {108} {110} {111}
M
M
M
M
M
Note: Unusual tiredness tends to become more prominent with continued treatment and may necessitate dosage reduction; usually resolves several weeks after withdrawal of alpha interferon.
         
Weight loss {01} {07} {08} {15} {19} {21} {23} {32} {106} {108} {110} {111}
R
R
R
L
R
Those not indicating need for medical attention
 
         
Loss of hair, partial {01} {07} {17} {19} {23} {32} {106} {108} {110} {111}
L
L
U
M
M
Note: Hair growth returns promptly after withdrawal of alpha interferon {07}.
         
* Differences in frequency of occurrence may reflect either lack of clinical-use data or actual pharmacologic distinctions among agents (although their pharmacologic similarity suggests that side effects occurring with one may occur with the others). M = more frequent; L = less frequent; R = rare; U = unknown; X = does not occur; N/A = not applicable.




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Interferons, Alpha (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to alpha interferons

Pregnancy—Abortifacient effects found in rhesus monkeys





Breast-feeding—Possible need to avoid breast-feeding during alpha interferon therapy because of risk of serious adverse effects in the nursing infant



Use in adolescents—
Possible effects on menstrual cycle






Use in the elderly—Risk of cardiotoxic and neurotoxic effects may be increased
Other medical problems, especially history of autoimmune disease, severe cardiac disease, chickenpox, compromised CNS function, diabetes mellitus, herpes zoster, history of psychiatric disease, infectious disorders pulmonary disease, seizure disorders, and thyroid function impairment

Proper use of this medication
» Compliance with therapy

» Reading patient directions carefully with regard to:    —Preparation of the injection
   —Use of disposable syringes
   —Proper administration technique
   —Stability of the injection


Importance of ample fluid intake to reduce risk of hypotension

Administration at bedtime to minimize inconvenience of fatigue

» Proper dosing
Missed dose: Skipping missed dose and going back to regular schedule; not doubling doses; checking with physician

» Proper storage

Precautions while using this medication
» Importance of close monitoring by physician

» Not changing brands of interferon without consulting physician because of differences in dosage

» Caution in taking alcohol or other CNS depressants during therapy

» Caution when driving or doing anything else requiring alertness because of possible fatigue and dizziness

» Frequency of fever and flu-like symptoms; possible need for acetaminophen before and after a dose is given

Caution if bone marrow depression occurs
» Avoiding exposure to persons with bacterial infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occur

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur


Side/adverse effects
Signs of potential side effects, especially arthritis, cardiotoxicity,erythematosus syndrome, hemolytic anemia, neurotoxicity, peripheral neuropathy, leukopenia, thrombocytopenia and vasculitis

Possibility of minor hair loss; normal hair growth should return after treatment has ended


General Dosing Information
Strengths and dosages of recombinant interferon alfa-2a and alfa-2b, interferon alfa-n1, and interferon alfa-n3 are expressed in terms of Units. Units are determined by comparison of the antiviral activity of the interferon with the activity of the international reference preparation of human leukocyte interferon established by the World Health Organization (WHO). {01} {106} {108} {110} {111}

Patients receiving alpha interferon should be under supervision of a physician experienced in immunomodulatory and/or cancer chemotherapy.

It is recommended that the patient be premedicated with acetaminophen at the time of alpha interferon dosing and that the acetaminophen be continued as needed to treat fever and headache {01} {10} {12} {19} {23} {24} {30} {106} {108} {110} {111}. Dosage reduction of alpha interferon may be necessary if headache persists.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests. In some cases, it may be difficult to distinguish fever due to infection from fever associated with the flu-like syndrome.

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of alpha interferons. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and any aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required. {98}

For systemic use
The subcutaneous route of administration is recommended for patients with thrombocytopenia or at risk for bleeding {01} {06} {106} {108} {110} {111}.

If severe adverse effects occur, dosage reduction by 50% or temporary withdrawal of alpha interferon is recommended {10} {11} {19} {30} {32} {115}.

It is recommended that patients be well hydrated, especially during initial treatment with alpha interferon, to reduce the risk of hypotension associated with fluid depletion {115}. Hypotension may require supportive treatment, including fluid replacement to maintain intravascular volume {10} {115}.

INTERFERON ALFA-2a, RECOMBINANT

Summary of Differences


Pharmacology/pharmacokinetics:
Source—Synthetic; produced by a recombinant DNA process. Purification procedure includes affinity chromatography using a murine monoclonal antibody {07} {117}. Single alpha interferon subtype.


Half-life—
Intramuscular: 6 to 8 hours.

Intravenous infusion: 3.7 to 8.5 hours.



Time to peak concentration (single dose)—
Intramuscular: 3.8 hours.

Subcutaneous: 7.3 hours.




Parenteral Dosage Forms

INTERFERON ALFA-2a, RECOMBINANT, INJECTION

Usual adult dose
Hairy cell leukemia
Induction: Intramuscular or subcutaneous, 3 million Units per day for sixteen to twenty-four weeks.

Maintenance: Intramuscular or subcutaneous, 3 million Units three times per week.

Kaposi's sarcoma, AIDS-associated


Induction:
Intramuscular or subcutaneous, 36 million Units (1 mL) per day for ten to twelve weeks {105}, or

Intramuscular or subcutaneous, 3 million Units per day on Days 1 to 3, 9 million Units per day on Days 4 to 6, and 18 million Units per day on Days 7 to 9, followed by 36 million Units (1 mL) per day for the remainder of the ten- to twelve-weeks induction period {105}.



Maintenance:
Intramuscular or subcutaneous, 36 million Units (1 mL) three times per week {105}.



Note: A variety of dosage schedules of interferon have been used for the unlabeled indications. Since these regimens are still largely investigational, the prescriber should consult the medical literature in choosing a specific dosage.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


3 million Units per mL (Rx) [Roferon-A (sodium chloride) (albumin) (phenol)]


6 million Units per mL (18 million Units per vial) (Rx) [Roferon-A (sodium chloride) (albumin) (phenol)]


10 million Units per mL (9 million Units per 0.9-mL vial) (Rx) [Roferon-A (sodium chloride) (albumin) (phenol)]


36 million Units per mL (Rx) [Roferon-A (sodium chloride) (albumin) (phenol)]

Note: The 10-million-Units-per-mL and 36-million-Units-per-mL strengths are for use for treatment of AIDS-associated Kaposi's sarcoma. They should not be used for treatment of hairy cell leukemia. {105}


Canada—


3 million Units per mL (Rx) [Roferon-A (sodium chloride) (albumin) (phenol)]


6 million Units per mL (Rx) [Roferon-A (phenol)]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer. Protect from freezing.

Note: Do not shake.
When dispensing for self-administration by the patient, make sure that patient instructions are included and that the patient understands how to prepare and administer the injection, including proper use of disposable syringes.
Interferon alfa-2a, -2b, -n1, and -n3 are not interchangeable {115}.



INTERFERON ALFA-2a, RECOMBINANT, FOR INJECTION

Usual adult dose
Hairy cell leukemia
Induction: Intramuscular or subcutaneous, 3 million Units per day for sixteen to twenty-four weeks.

Maintenance: Intramuscular or subcutaneous, 3 million Units three times per week.


Note: A variety of dosage schedules of interferon have been used for the unlabeled indications. Since these regimens are still largely investigational, the prescriber should consult the medical literature in choosing a specific dosage.


Usual pediatric dose
Dosage has not been established.

Size(s) usually available:
U.S.—


18 million Units (Rx) [Roferon-A (diluent contains sodium chloride, albumin, phenol)]

Canada—


18 million Units (Rx) [Roferon-A (diluent contains sodium chloride, albumin, phenol)]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer. Protect from freezing {117}.

Preparation of dosage form:
Interferon alfa-2a, recombinant, for injection is prepared for parenteral use by adding 3 mL of diluent (containing sodium chloride, albumin, and phenol) provided by the manufacturer and swirling gently to dissolve, producing a solution containing 6 million Units per mL. {01} {112}

Stability:
Reconstituted solution of interferon alfa-2a, recombinant, for injection should be used within 30 days and stored between 2 and 8 °C (36 and 46 °F).

Note: When dispensing for self-administration by the patient, make sure that patient instructions are included and that the patient understands how to prepare and administer the injection, including proper use of disposable syringes.
Interferon alfa-2a, -2b, -n1, and -n3 are not interchangeable {115}.



INTERFERON ALFA-2b, RECOMBINANT

Summary of Differences


Pharmacology/pharmacokinetics:
Source—Synthetic; produced by a recombinant DNA process. Purification is done by proprietary methods {01} {07} {106} {108} {110} {111}. Single alpha interferon subtype.

Half-life—Intramuscular or subcutaneous: 2 to 3 hours.

Time to peak concentration—Intramuscular or subcutaneous: 3 to 12 hours.



Precautions:


Laboratory value alterations—
Nadir of leukocyte and platelet counts is at 3 to 5 days, with recovery within 3 to 5 days after withdrawal.

Prothrombin time (PT) and partial thromboplastin time (PTT) may be increased.



Medical considerations/contraindications—
Caution in coagulation disorders.




Parenteral Dosage Forms

INTERFERON ALFA-2b, RECOMBINANT, FOR INJECTION

Usual adult dose
Hairy cell leukemia
Intramuscular or subcutaneous, 2 million Units per square meter of body surface area three times per week.

Condyloma acuminatum1
Intralesional, 1 million Units (using only the 10-million-Units-per-mL strength) per wart (up to five warts) three times a week on alternate days for three weeks {115}. If response is not satisfactory twelve to sixteen weeks after the initial treatment course, a second course may be given {115}. Patients with six to ten warts may be given a second (sequential) course of treatment at the same dose to treat up to five additional warts per course; for patients with more than ten warts, additional courses may be given as needed with up to five additional warts per course {115}.

Kaposi's sarcoma, AIDS-associated
Intramuscular or subcutaneous, 30 million Units (using 50-million-Units-per-mL strength) per square meter of body surface area three times a week {107}.

Hepatitis, chronic, active
Non-A, non-B/C hepatitis: Intramuscular or subcutaneous, 3 million Units three times per week {115}. Patients who relapse may be re-treated with the same dose to which they had previously responded {115}.

Hepatitis B, chronic1
Intramuscular or subcutaneous, 30 to 35 million Units per week, either as 5 million Units per day or 10 million Units three times per week, for sixteen weeks {154}.

Malignant melanoma1
Induction: Intravenous infusion, 20 million Units per square meter of body surface area for five consecutive days per week for four weeks {154}.
Maintenance: Subcutaneous, 10 million Units per square meter of body surface area three times per week for forty-eight weeks {154}.


Note: A variety of dosage schedules of interferon have been used for the unlabeled indications. Since these regimens are still largely investigational, the prescriber should consult the medical literature in choosing a specific dosage.


Usual pediatric dose
Safety and efficacy have not been established {115}.

Size(s) usually available:
U.S.—


3 million Units (Rx) [Intron A (albumin)]


5 million Units (Rx) [Intron A (albumin)]


10 million Units (Rx) [Intron A (albumin)]


18 million Units (Rx) [Intron A (albumin)]


25 million Units (Rx) [Intron A (albumin)]


50 million Units (Rx) [Intron A (albumin)]

Note: The 10-million-Unit size is the only one that should be used for treatment of condyloma acuminatum. Dilution of the other available sizes (3, 5, 18, 25, or 50 million Units) that would be required for intralesional use with the volume of diluent recommended for preparing an intralesional injection would produce a hypertonic solution {115} {154}.
The 50-million-Unit size is a special formulation for use for treatment of AIDS-associated Kaposi's sarcoma or malignant melanoma. It should not be used for treatment of hairy cell leukemia or condyloma acuminatum {107} {154}.


Canada—


3 million Units (Rx) [Intron A (albumin)]


5 million Units (Rx) [Intron A (albumin)]


10 million Units (Rx) [Intron A (albumin)]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
Interferon alfa-2b, recombinant, for injection is prepared for parenteral use by adding the appropriate amount of diluent (in the U.S., bacteriostatic water for injection provided by the manufacturer; in Canada, either sterile water for injection or bacteriostatic water for injection) and agitating gently {115} {116} {154} to dissolve, producing a clear, colorless to light yellow solution.

Size
(Units)
Diluent
(mL)
Final concentration
(Units/mL)
U.S.—
   
For treatment of hairy cell leukemia
 
3 million
1
3 million
5 million
1
5 million
10 million
2
5 million
25 million
5
5 million
For treatment of condyloma acuminatum
 
10 million
1
10 million
For treatment of AIDS-associated Kaposi's sarcoma
 
50 million
1
50 million
For treatment of malignant melanoma (induction or maintenance phase)
 
3 million
1
3 million
5 million
1
5 million
10 million
1
10 million
18 million
1
18 million
25 million
5
5 million
50 million
1
50 million
For treatment of chronic hepatitis B
 
5 million
1
5 million
10 million
1
10 million
For treatment of chronic active non-A, non-B/C hepatitis
 
3 million
1
3 million
Canada—
   
3 million
1
3 million
5 million
1
5 million
10 million
1
10 million


Stability:
Reconstituted solutions of interferon alfa-2b, recombinant, prepared with sterile water for injection are stable for 24 hours when stored between 2 and 8 °C (36 and 46 °F) {116}; solutions prepared with bacteriostatic water for injection are stable for 1 month when stored between 2 and 8 °C (36 and 46 °F) {115}.

Note: When dispensing for self-administration by the patient, make sure that patient instructions are included and that the patient understands how to prepare and administer the injection, including proper use of disposable syringes.
Interferon alfa-2a, -2b, -n1, and -n3 are not interchangeable {115}.



INTERFERON ALFA-n1 (LNS)

Summary of Differences


Pharmacology/pharmacokinetics:
Source—Obtained from pooled units of human lymphoblastoid cells following induction with Sendai virus. Mixture of natural alpha interferon subtypes, but in different proportions than in human leukocyte interferon.

Half-life—Intravenous infusion: About 8 hours.



Parenteral Dosage Forms

INTERFERON ALFA-n1 (LNS) INJECTION

Usual adult dose
Hairy cell leukemia
Induction: Intramuscular or subcutaneous, 3 million Units per day for sixteen to twenty-four weeks.

Maintenance: Intramuscular or subcutaneous, 3 million Units three times per week.

Condyloma acuminatum
Intramuscular or subcutaneous, 1 to 3 million Units per square meter of body surface area five times a week for two weeks, followed by three times a week for four weeks {113}. The same dose is then continued every other day or three times a week for one month {113}.

Note: As an adjunct to laser surgery or cryosurgery, the dose is 1 million Units per square meter of body surface area intramuscularly or subcutaneously per day for seven days prior to and seven days following surgical resection of the lesions {113}.



Note: A variety of dosage schedules of interferon have been used for the unlabeled indications. Since these regimens are still largely investigational, the prescriber should consult the medical literature in choosing a specific dosage.


Usual pediatric dose
Hairy cell leukemia or
Condyloma acuminatum
Dosage has not been established.

Juvenile laryngeal papillomatosis


For children older than 1 year of age:
Body surface area less than 0.5 square meter—Intramuscular or subcutaneous, 1.5 million Units per day for twenty-eight days, followed by maintenance dosage three times a week for at least six months {113}.

Body surface area 0.5–1 square meter—Intramuscular or subcutaneous, 3 million Units per day for twenty-eight days, followed by maintenance dosage three times a week for at least six months {113}.

Body surface area greater than 1 square meter—Intramuscular or subcutaneous, 5 million Units per day for twenty-eight days, followed by maintenance dosage three times a week for at least six months {113}.



Size(s) usually available:
U.S.—
Not commercially available.

Canada—


3 million Units (Rx) [Wellferon]


10 million Units (Rx) [Wellferon]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer. Protect from light {113}.

Note: Interferon alfa-2a, -2b, -n1, and -n3 are not interchangeable {115}.



INTERFERON ALFA-n3

Summary of Differences


Pharmacology/pharmacokinetics:
Source—Obtained from pooled units of human leukocytes that have been induced to produce interferon alfa-n3. Contains up to 14 natural alpha interferon subtypes. Human leukocyte interferon.



Precautions:
Medical considerations/contraindications—Caution in coagulation disorders.



Parenteral Dosage Forms

INTERFERON ALFA-n3 INJECTION

Usual adult dose
Condyloma acuminatum
Intralesional (at the base of the wart, preferably using a 30 gauge needle), 250,000 Units two times a week for up to eight weeks {114}.


Note: For large warts, it may be injected at several points around the periphery of the wart, using a total dose of 250,000 Units {114}.
Safety and efficacy of more than one 8-week course have not been established {114}.
A variety of dosage schedules of interferon have been used for the unlabeled indications. Since these regimens are still largely investigational, the prescriber should consult the medical literature in choosing a specific dosage.


Usual adult prescribing limits
2.5 million Units per treatment session {01} {106} {108} {110} {111}.

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


5 million Units per mL (Rx) [Alferon N (phenol 3.3 mg per mL) (human albumin 1 mg per mL)]

Canada—
Not commercially available.

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer. Protect from freezing.

Note: Do not shake.
Interferon alfa-2a, -2b, -n1, and -n3 are not interchangeable.




Revised: 09/12/2001



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  1. Reviewers" consensus on monograph revision of 6/98.
  1. Intron A package insert (Schering—US), Rev 3/98, Rec 6/98.
  1. Product Information: Roferon®-A, interferon alfa-2a, recombinant, Roche, Nutley, NJ (Revised 03/2001) Reviewed 08/2001.
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