Interferon Alfa (Antineoplastic) (Monograph)

Drug class: Antineoplastic Agents
- Biologic Response Modifiers
- Cytokines
VA class: AN900
Chemical name: Interferon α2b (human leukocyte clone Hif-SN206 protein moiety reduced)
Molecular formula: C₈₆₀H₁₃₅₃N₂₂₉O₂₅₅S₉
CAS number: 99210-65-8

Introduction

Interferon alfa is a family of proteins and glycoproteins with antiviral, antineoplastic, and immunomodulating activities. Interferon alfa is available in the US as interferon alfa-2b and interferon alfa-n3. Interferon alfa also is available covalently bound to monomethoxy polyethylene glycol (PEG) (i.e., peginterferon alfa). and Peginterferon Alfa 10:00.

Uses for Interferon Alfa (Antineoplastic)

Interferon alfa is used in the treatment of various cancers, including hairy cell leukemia, AIDS-related Kaposi’s sarcoma, follicular non-Hodgkin's lymphoma, and melanoma.

Hairy Cell Leukemia

Interferon alfa (alfa-2a [no longer commercially available in the US], alfa-2b) is used for the treatment of hairy cell leukemia (leukemic reticuloendotheliosis). Results from a limited number of studies in which comparative efficacy was not a specific objective suggest that both interferon subtypes have similar efficacy in patients with this disease.

Therapy with interferon alfa produces complete response in 10% and clinically important tumor regression or disease stabilization (complete or partial responses; overall response) in approximately 80% of patients with hairy cell leukemia, including in previously untreated patients (i.e., those who have not undergone splenectomy) as well as in those with progressive disease in whom splenectomy has been performed. The drug does not appear to be curative. Because of their apparent greater efficacy (i.e., higher complete response rate), cladribine or pentostatin is preferred for most patients with hairy cell leukemia who require treatment. Because of the availability of effective drug therapies, splenectomy is becoming less important as a therapeutic option in patients with hairy cell leukemia. Additional studies and long-term follow-up are needed to elucidate optimal therapy for hairy cell leukemia.

Reductions in splenomegaly and in the number of leukemic cells in peripheral blood generally are the initial signs of response to interferon alfa therapy in patients with hairy cell leukemia. Interferon alfa also may decrease bone marrow hypercellularity and hairy cell infiltrates and result in substantial and sustained improvements in granulocyte and platelet counts in peripheral blood and hemoglobin concentrations. Most patients with hairy cell leukemia have at least one abnormality in their hematologic profile prior to interferon therapy, and response to the drug is characterized by complete or partial normalization of hematologic values, including hemoglobin concentration and granulocyte and platelet counts in peripheral blood and bone marrow. Patients who respond to interferon alfa therapy have an increased performance status, a decreased number of infections as granulocyte counts improve, and substantially reduced requirements for red blood cell and platelet transfusions. Clinical improvement in patients treated with interferon alfa may be apparent within the first month of therapy and usually is apparent within 6 months; however, up to 9–12 months or more of therapy may be required for clinical response.

Clinical response to interferon alfa therapy in hairy cell leukemia generally is similar whether or not the patient has undergone splenectomy, although limited data suggest that response may occur more rapidly in splenectomized patients. In addition, some studies indicate that the incidence of complete remission may be greater in previously untreated patients than in splenectomized patients. Because of the availability of more effective agents such as cladribine and pentostatin, splenectomy is a less important therapeutic option in patients with hairy cell leukemia. Some clinicians suggest that splenectomy may be considered in patients who do not respond to therapy with cladribine, pentostatin, or interferon alfa or when massive splenomegaly or splenic rupture with pain and infection are present. Although interferon alfa generally appears equally effective in patients with mild or severe disease, differences in response rate observed in these studies may have been related to initiation of interferon alfa therapy at an earlier clinical stage of the disease in previously untreated patients. In most patients with substantial splenomegaly, interferon alfa therapy reduces the spleen to normal or near-normal size and produces a reversal of the hematologic abnormalities in peripheral blood that result from hypersplenism. In some of these patients, interferon therapy may reverse hypersplenism which, if not reversed, could have necessitated splenectomy. In those patients who exhibit persistent splenomegaly despite interferon alfa therapy, splenectomy may be required. Limited evidence also suggests that the addition of interferon alfa to antimicrobial therapy in patients with hairy cell leukemia and unresponsive mycobacterial or fungal infections may result in microbiologic and/or clinical cure of the infection, apparently through restoration by interferon alfa of impaired immune function; therefore, some clinicians suggest that interferon may be particularly beneficial and preferable therapy in patients with hairy cell leukemia who have recurrent opportunistic infections.

During the initial 1–3 months of interferon alfa therapy, marked depression in hematopoiesis may occur, as evidenced by a substantial decrease in the monocyte, granulocyte, and polymorphonuclear leukocyte counts in peripheral blood; however, peripheral blood counts generally improve with continued therapy. It has not been established whether the initial transient decrease in circulating granulocytes observed in many patients may increase their risk of infection; however, individuals with hairy cell leukemia have required red blood cell and platelet transfusions during this period of transient myelosuppression. (See Cautions: Precautions and Contraindications.) Interferon alfa therapy does not appear to adversely affect hemoglobin concentration and platelet count in patients with normal pretreatment values of these parameters. Following this initial interferon-induced depression in hematopoiesis, peripheral hematologic parameters generally return to normal over several (e.g., 2–6) months, with platelet count usually returning first, followed by hemoglobin concentration and granulocyte and monocyte counts, and these parameters may continue to improve throughout the initial 9–12 months of therapy.

In addition to restoring peripheral blood counts to normal or near-normal values, interferon alfa produces substantial decreases in the leukemic cell index (the product of the percentages of bone marrow cellularity and leukemic cell infiltrates in the marrow). While return of peripheral blood hematologic values to normal usually occurs after only 2–6 months of therapy, evidence suggests that prolonged (at least 9–12 months) therapy with interferon alfa generally is necessary to decrease leukemic cell infiltration in bone marrow; several patients categorized as having minor responses to interferon therapy reportedly have had a greater than 50% decrease in or complete clearing of leukemic cells in bone marrow despite persistence of neutropenia. Limited evidence suggests that interferon therapy produces a decrease in leukocyte counts in most patients who have leukocytosis prior to therapy.

Interferon alfa may reverse the clinical and laboratory manifestations (e.g., splenomegaly, anemia and other cytopenias, leukemic infiltration) of hairy cell leukemia and has induced objective remissions that may persist for 2 years or longer (range: 0.5 months to longer than 2 years). During the first 3 months following discontinuance of interferon alfa therapy in patients with hairy cell leukemia, an increase in the percentage of leukemic infiltrates in bone marrow frequently is evident. However, this change represents a relative rather than an absolute increase in bone marrow leukemic cells related to the rapid exit of normal myeloid and erythroid precursors from the bone marrow following discontinuance of interferon alfa therapy. Although patients usually are not refractory to a second course of interferon alfa therapy, such therapy generally is not required unless the progressive increase in leukemic infiltrates in bone marrow is accompanied by one or more peripheral blood cytopenias. Deterioration in peripheral blood cell counts does not occur rapidly after discontinuance of interferon alfa therapy; however, within 7–12 months after completion of therapy, peripheral blood platelet and granulocyte counts may decrease to 60% of those achieved at the end of an initial course of therapy. A second course of interferon alfa therapy may be required 2–19 months after completion of the initial course because of this reduction in platelet and granulocyte counts, suggesting that maintenance therapy with interferon alfa may be necessary for prolonged remission in patients with hairy cell leukemia.

Limited evidence suggests that response to interferon alfa therapy during long-term treatment of hairy cell leukemia may be dose related, although conflicting data have been reported. In one study, most patients who received 1 million units/m² of interferon alfa achieved normalization of hematologic values and a reduction in leukemic bone marrow infiltration but had delayed increases in granulocyte count relative to individuals treated with 2 or 4 million units/m²; a few patients achieved only partial responses despite prolonged therapy (i.e., for approximately 1 year). In another study, there was a relatively high incidence of disease progression in patients with hairy cell leukemia who were treated with very low (200,000 units/m²) dosages of interferon alfa, which is unusual in patients treated with standard dosages (e.g., 2 million units/m²) of the drug. Most patients whose disease progressed on this low-dose regimen demonstrated a hematologic response within 3 months of increasing the interferon alfa dosage to that of a standard regimen. While low-dose regimens of interferon alfa are not recommended for initial therapy or for relapse of hairy cell leukemia because of the risk of disease progression and associated neutropenia and thrombocytopenia, low-dose therapy with the drug may prove to be useful for maintenance in patients whose disease is in remission, but additional study and experience are needed.

Response to interferon alfa therapy may be monitored periodically (e.g., monthly) by determining peripheral blood hemoglobin concentration and platelet, granulocyte, and leukemic cell counts in peripheral blood and bone marrow and comparing these with baseline values. Although the manufacturer and some clinicians state that therapy should be discontinued if the patient does not respond within 6 months, other clinicians suggest that therapy be continued for at least 12 months unless there is evidence of disease progression; onset of response has been noted as late as 9–12 months following initiation of treatment in some patients, and limited evidence suggests that prolonged therapy (e.g., 12–18 months or longer) may improve the possibility of a response, including complete remission. However, it has not been established whether achieving complete remission offers any advantage in terms of performance status or survival. In addition, the possible advantage of prolonged maintenance therapy compared with more aggressive induction regimens requires further study.

The optimum duration of interferon alfa therapy for hairy cell leukemia has not been clearly established, although it appears that therapy should continue for at least 6 months. Extending interferon alfa therapy up to a total duration of 18–24 months can maintain therapeutic response during treatment, but does not appear to influence the clinical course of the disease once interferon has been discontinued. Optimum duration of therapy cannot be defined until the biochemical and pharmacologic factors that predict prolonged survival have been identified. Bone marrow histology does not completely normalize in most patients following treatment with interferon alfa, and many (e.g., 20–50%) patients who respond to initial therapy relapse within 6–12 months after discontinuance of the drug. Although limited evidence suggests that early disease relapse following completion of treatment may be more common in patients with severe neutropenia or hyperleukocytosis at the time of diagnosis, other studies have not confirmed a correlation between these baseline hematologic findings and duration of remission. Limited data suggest that the best indicators of relapse following interferon alfa therapy in patients with hairy cell leukemia may be the neutrophil (leukocyte) alkaline phosphatase (NAP or LAP) score and the percentage of hairy cells in bone marrow. In one study, patients whose NAP score was less than 30 had the best prognosis (as measured by time from discontinuance of interferon therapy until further antileukemic therapy was needed); patients with greater than 30% leukemic cells in bone marrow had a poor prognosis, while an NAP score of 30 or greater and 30% or less leukemic cells in bone marrow was associated with an intermediate prognosis. Further studies are needed to determine which clinical and/or laboratory indices are most useful in predicting relapse and the need for subsequent maintenance therapy following interferon therapy or splenectomy.

Limited data are available on long-term survival in patients with hairy cell leukemia treated with interferon alfa. The survival rate at 24–48 months for patients who respond to the drug ranges from approximately 87–94%, while the corresponding survival rate for comparable controls treated with standard therapies, including antineoplastic agents (principally chlorambucil) or supportive care (e.g., transfusions), has ranged from approximately 35–75% at 14–40 months.

AIDS-related Kaposi’s Sarcoma

Interferon alfa (alfa-2a [no longer commercially available in the US], alfa-2b) is used for the palliative treatment of AIDS-related Kaposi’s sarcoma in selected adults, and is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this disease. The likelihood of response to interferon alfa treatment is greater in patients without systemic symptoms who have limited lymphadenopathy and relatively intact immune systems as indicated by CD4⁺ T-cell counts. Patients who have constitutional (“B”) symptoms (e.g., fever, night sweats, weight loss) and/or who have a history of opportunistic infection at the time of diagnosis of Kaposi’s sarcoma generally respond poorly to interferon. For advanced AIDS-related Kaposi’s sarcoma, a liposomal anthracycline (doxorubicin or daunorubicin) or paclitaxel are recommended as drugs of choice.

In contrast to the usual protracted, indolent course of the classic (e.g., Mediterranean) form of Kaposi’s sarcoma, Kaposi’s sarcoma in patients with human immunodeficiency virus (HIV) infection often is rapidly progressive. AIDS-related Kaposi’s sarcoma may progress to multifocal, widespread lesions that involve the skin, oral mucosa, and lymph nodes as well as visceral organs such as the GI tract, lung, liver, and spleen; such lesions often are numerous and may be cosmetically unattractive or disfiguring and accompanied by lymphedema. All patients with AIDS-related Kaposi's sarcoma should be receiving highly active antiretroviral therapy; in some patients, initiation of antiretroviral therapy alone may result in tumor regression and resolution of lesions.

Interferon alfa should not be used in patients with visceral AIDS-related Kaposi’s sarcoma associated with rapidly progressive or life-threatening disease since such patients require rapid cytoreduction, while the response to interferon generally is slow and poor. It has been suggested that disease progression theoretically could occur in such patients secondary to interferon’s immunosuppressive properties.

Although response rates are variable, interferon alfa therapy is associated with clinically important tumor regression or disease stabilization in a substantial proportion of patients with AIDS-related Kaposi’s sarcoma who do not have a history of opportunistic infections or “B” symptoms; major (complete plus partial) responses occur in approximately 20–50% of such patients receiving high-dose (36–54 million units daily) therapy with the drug. The variability in overall response rates may be explained in part by the relative severity of AIDS in patients in different studies, and response rates exceeding 50% may occur in patients with a relatively good prognosis.

Antiretroviral effects of interferon alfa have been demonstrated in vitro and in vivo, and some studies have reported an apparent correlation between these effects (e.g., as evidenced by decreased viral shedding and p24 antigenemia) and clinical response to interferon therapy in patients with AIDS-related Kaposi’s sarcoma. The antiviral effects of interferon alfa have been most prominent in patients with the most competent (in terms of baseline CD4⁺ T-cell counts) immune systems. However, the effects of interferon alfa on immune function are not clearly defined or consistent, since substantial improvement in immunologic status (as measured in vitro) has not been observed when the drug was used alone and progression of immunodeficiency has occurred in some patients during interferon alfa therapy. In responding patients with early AIDS and Kaposi’s sarcoma, interferon alfa reportedly improved quality of life by inducing substantial tumor regression, and such patients also had a lower incidence of opportunistic infection than those not responding to such therapy. Interferon alfa has produced improvement at all disease sites (although not always concomitantly), including skin, lymph nodes, and GI tract, and Kaposi’s lesions generally begin to regress within 4–8 weeks following initiation of therapy.

Response to interferon alfa therapy appears to be related to multiple factors, including pretreatment immune status of the patient, presence of disease symptoms, and interferon dosage. Patients with AIDS-related Kaposi’s sarcoma who are most likely to respond to therapy with interferon alfa are those who have had no prior opportunistic infections and those with relatively normal CD4⁺ T-cell counts, limited lymphadenopathy, and no systemic manifestations (e.g., weight loss, fever, night sweats). Evidence suggests that relative preservation of immune function may be required for interferon alfa to be active as an antitumor agent, and the severity of clinical manifestations in patients with AIDS-related Kaposi’s sarcoma appears to be associated with the degree of immunologic impairment in these patients. Pretreatment determinations of immune function (as assessed by total lymphocyte count, CD4⁺ T-cell counts, and the ratio of CD8⁺ T-cells) frequently have been associated with clinical outcome and response to therapy. Patients with CD4⁺ T-cell counts exceeding 400/ mm³ appear to have the highest response rates (approximately 40–50%) to interferon alfa therapy; in some studies in which pretreatment levels of CD4⁺ T cells were not substantially higher in responding than in nonresponding patients, therapy with interferon alfa was associated with a marked increase in the number of these T cells.

Response of AIDS-related Kaposi’s sarcoma to interferon alfa therapy also appears to be related to interferon dosage, although some evidence that did not show a clear dose effect also has been reported; dosages of 20 million or more units/m² daily appear to be associated with better and more rapid responses than low dosages (e.g., 1–3 million units/m² daily). Initial therapy with high dosages (e.g., 30–50 million units daily) of interferon alfa has produced major responses in approximately 40–45% of patients with less-advanced AIDS (e.g., patients with CD4⁺ T-cell counts exceeding 400/ mm³ who have not experienced severe opportunistic infections); comparable response rates with a somewhat reduced incidence of adverse effects have been achieved when interferon alfa therapy was initiated at a low dosage (e.g., 3 million units daily) and dosage was increased over several days to 36 million units daily. Interferon alfa dosages of less than 3 million units daily generally are not as effective as higher dosages in inducing tumor regression, while dosages exceeding 36 million units (up to a maximum of 54 million units) daily generally have been associated with an unacceptable degree of adverse effects. In one study, patients who responded to therapy with 36 million units of interferon alfa daily during the first month of treatment reportedly developed new lesions when the dosing frequency was decreased to 3 times weekly.

Patients without detectable acid-labile, endogenous interferon activity in serum prior to treatment generally are more likely to respond to therapy with exogenously administered interferon alfa. Initial response to interferon alfa therapy, but not the duration of response or survival, generally has been independent of the stage of Kaposi’s sarcoma (as determined by the location and extent of tumor involvement). Some evidence indicates that the presence of visceral disease or extensive dissemination of the tumor is not necessarily an indicator of poor prognosis to therapy; however, not all sites respond equally (e.g., pulmonary disease may respond relatively poorly). Limited data also suggest that response of cutaneous lesions to interferon alfa therapy in patients with AIDS-related Kaposi’s sarcoma may depend on the cytologic and/or histochemical characteristics of the lesions. Papular and nodular lesions, which are composed principally of endothelial cells, usually undergo partial or complete regression with interferon alfa therapy, while flat hemorrhagic lesions consisting of pericytial cells generally remain unchanged.

The optimum duration of therapy with interferon alfa in patients with AIDS-related Kaposi’s sarcoma has not been determined. The median duration of response for patients receiving therapy with the drug has been approximately 7 months; however, complete and partial responses have persisted for longer than 3 years in some patients who received maintenance therapy for variable periods. Patients who were asymptomatic prior to treatment or who achieved a complete response with therapy generally had more rapid responses and longer durations of remission than symptomatic patients or those who achieved partial responses. Some clinicians suggest that unless an opportunistic infection or severe interferon-associated adverse effects occurs, consideration should be given to continuing interferon alfa therapy indefinitely, with appropriate dosage adjustment, provided a response or disease stabilization is observed; however, the effect of such a regimen on duration of response has not been fully elucidated. In one study, patients who received 6 months of maintenance therapy with interferon alfa after attaining complete responses (i.e., complete gross and histologic clearing of lesions) while on the drug were still disease free 5 months after cessation of maintenance therapy. Further long-term follow-up is needed to determine an optimum duration of interferon alfa therapy for patients with AIDS-related Kaposi’s sarcoma.

No treatment, including interferon alfa, has been shown conclusively to alter the natural history of AIDS-related Kaposi’s sarcoma, although responders generally survive longer than nonresponders and thus the drug appears to affect disease progression. In one clinical study, patients who achieved a major (complete plus partial) response with high-dose (36–54 million units daily) interferon alfa therapy had a median survival exceeding 28 months, while nonresponders had a median survival of only 14 months. In another study in patients receiving an interferon alfa-2b dosage of 30 million units/m² three times weekly, the median survival in responders and nonresponders reportedly was 22.6 and 9.7 months, respectively. Responding patients with a pretreatment CD4⁺ T-cell count exceeding 200 cells/ mm³ reportedly survived longer than responders who had lower baseline CD4⁺ T-cell counts and longer than nonresponders, regardless of their baseline CD4⁺ T-cell counts; median survival was approximately 31 months in patients who had CD4⁺ T-cell counts exceeding 200/ mm³ and only about 9 months in those who had CD4⁺ T-cell counts less than or equal to 200/ mm³. Some limited long-term follow-up data from patients with AIDS-related Kaposi’s sarcoma treated with interferon alfa suggest that patients whose tumors regressed with interferon therapy had a substantial reduction in opportunistic infections and longer survival compared with nonresponders. However, whether these differences in response are attributable to interferon or are part of the natural history of AIDS-related Kaposi’s sarcoma has not been determined. Limited placebo-controlled studies have not shown any effect of interferon alfa on survival in patients with AIDS-related Kaposi’s sarcoma who have had at least one opportunistic infection, although therapy with the drug in such patients has not been extensively evaluated. Some clinicians suggest that cytotoxic antineoplastic therapy may be preferable to interferon alfa treatment in patients with a poor prognosis because antineoplastic therapy is possibly more effective and response more rapid, and there is no evidence that such therapy predisposes these patients to infection or that interferon alfa therapy is superior; in patients with a favorable prognosis, the efficacy of antineoplastic therapy appears to be comparable to that of interferon. Controlled, comparative studies, in which clinical endpoints for survival and time to first opportunistic infection are well defined, and long-term follow-up of patients with early HIV infection and Kaposi’s sarcoma are needed to determine whether interferon alfa or other therapies can produce meaningful improvements in survival and/or quality of life.

Interferon alfa also has been used for the treatment of classic Mediterranean Kaposi’s sarcoma^{† [off-label]}. In at least one patient with laryngeal involvement, the drug produced complete regression of these lesions. However, there is a paucity of information regarding the efficacy of such therapy, and the advanced age of patients with this form of Kaposi’s may limit their tolerance of the drug’s adverse effects. In addition, radiation therapy and/or conventional antineoplastic therapy generally are preferred when treatment is indicated in this form of Kaposi’s.

Non-Hodgkin’s and Cutaneous T-cell Lymphomas

Interferon alfa (alfa-2b) is labeled by the FDA for use in conjunction with anthracycline-containing combination chemotherapy for the treatment of clinically aggressive follicular non-Hodgkin's lymphoma in adults. Interferon alfa also has been used for the treatment of low-grade adult non-Hodgkin’s lymphomas^{† [off-label]} and for the treatment of cutaneous T-cell lymphomas^{† [off-label]}.

Although other agents generally are preferred, the safety and efficacy of interferon alfa-2b in conjunction with a combination chemotherapy regimen has been evaluated for initial treatment in patients with clinically aggressive, large-tumor-burden, stage III/IV follicular non-Hodgkin’s lymphoma. In a randomized, controlled trial, 130 patients received CHVP chemotherapy alone and 135 patients received CHVP therapy and interferon alfa-2b (5 million units subcutaneously 3 times weekly) for 18 months. CHVP chemotherapy consisted of cyclophosphamide 600 mg/m², doxorubicin 25 mg/m², and teniposide 60 mg/m² administered IV on day 1 with oral prednisone (40 mg/m² daily on days 1–5). Treatment consisted of 6 CHVP cycles administered monthly, followed by an additional 6 cycles administered every 2 months for 1 year. Patients in both treatment groups received a total of 12 CHVP cycles over 18 months. The group receiving CHVP and interferon alfa-2b had longer progression-free survival than those receiving CHVP alone (2.9 years versus 1.5 years). After a median follow-up of 6.1 years, the median survival for patients treated with CHVP alone was 5.5 years while median survival for patients treated with CHVP and interferon alfa-2b had not been reached. In 3 other randomized, controlled studies, use of interferon alfa in conjunction with anthracycline-containing combination chemotherapy regimens was associated with prolonged progression-free survival. Differences in overall survival were not consistently observed.

The manufacturer states that efficacy of interferon alfa-2b in the treatment of low-grade, low-tumor-burden follicular non-Hodgkin's lymphoma has not been determined. Interferon alfa given alone has produced objective clinical responses in approximately 40–60% of patients with low-grade lymphocytic adult non-Hodgkin’s lymphomas^{† [off-label]}. However, these diseases typically have a long, indolent course, and improved survival with available therapies, including interferon alfa, in low-grade adult lymphocytic lymphomas has not been documented. Interferon alfa generally appears to have little therapeutic value in intermediate- or high-grade adult non-Hodgkin’s lymphomas^{† [off-label]}, although occasional responses have been reported with high dosages of the drug. Features of B- and T-cell types that might predict response to interferon alfa in non-Hodgkin’s lymphomas have not been identified, and further study is warranted to determine which, if any, subpopulation of patients with higher-grade lymphomas is most likely to benefit from interferon alfa therapy.

Responses to interferon alfa therapy in low-grade lymphocytic adult non-Hodgkin’s lymphomas generally have been noted in patients with advanced disease who have received extensive prior treatment with regimens containing either anthracycline-derivative antineoplastic agents (e.g., doxorubicin) or radiation therapy; objective responses have been noted in approximately 40–50% of patients with advanced low-grade lymphocytic lymphoma refractory to standard treatment regimens, with complete responses occurring in approximately 6–15% of patients. Whether interferon alfa can produce comparable responses in patients with early-stage, low-grade lymphocytic lymphoma who have not received prior therapy has not been established to date; studies are ongoing. Evidence suggests that relatively low doses of interferon alfa (e.g., 2–3 million units/m²) may be as effective as but less toxic than the high doses (e.g., 50 million units/m²) initially used in the treatment of lymphocytic adult non-Hodgkin’s lymphomas^†; however, limited data suggest that patients who experience disease relapse while receiving low doses of interferon alfa may not respond to subsequent therapy with higher doses of the drug.

Systemic therapy with interferon alfa has produced response rates of approximately 40–75% in patients with cutaneous T-cell lymphomas^† (CTCL; e.g., mycosis fungoides, Sézary syndrome). Such responses have been reported in patients who have failed to respond to topical or systemic therapy with other drugs as well as in previously untreated patients; many clinicians consider interferon alfa the most effective single-agent therapy for patients whose disease is refractory to standard treatment (topical mechlorethamine, psoralen plus UVA light, total electron-beam irradiation, antineoplastic agents) for these neoplasms. In one study in a limited number of patients with advanced, refractory CTCL, objective responses lasting 3 to more than 36 months (median duration approximately 5 months) were noted in 45% of patients receiving interferon alfa in an initial dosage of 50 million units/m² IM 3 times weekly. However, as with other non-Hodgkin’s lymphomas, the optimum therapeutic regimen for interferon alfa in patients with CTCL has not been determined, and the effects of the drug on survival when given to patients with earlier stages of the disease and/or in combination with antineoplastic or other therapies are being evaluated. Large cutaneous lesions in patients with CTCL have undergone a substantial decrease in size during interferon alfa therapy, and extracutaneous responses (e.g., reductions in the size of palpable lymph nodes and in the number of circulating malignant cells) have also occurred.

Prognosis for patients with CTCL^† depends on stage of the disease, type of skin lesion, and presence or absence of peripheral blood, lymph node, or visceral involvement; however, responses to interferon alfa appear to be unrelated to disease stage and/or prior therapy. Limited data suggest that response to interferon alfa may depend on dosage and scheduling of the drug. Highest response rates reportedly occur with doses ranging from 6–50 million units. Among patients with CTCL, those with mycosis fungoides appear most responsive to interferon therapy. Complete remissions with interferon alfa therapy have been reported in approximately 10–27% of patients with CTCL, generally in patients receiving high doses (e.g., 50 million units/m²).

Preliminary evidence suggests that the combination of interferon alfa and phototherapy (psoralen plus UVA light irradiation) is effective and generally well tolerated in patients with CTCL^†, although individuals with the more aggressive large-cell variant of the disease may be less likely to respond to this regimen. In one study, intralesional administration^† of low doses of interferon alfa appeared to be more effective than a fivefold higher dose administered IM in patients with plaque-phase mycosis fungoides, suggesting that intralesional concentrations of the drug may be an important determinant of therapeutic response.

Melanoma

Adjuvant Therapy

Interferon alfa (alfa-2a [no longer commercially available in the US], alfa-2b) is used as an adjunct to surgery (within 56 days of surgery) in adults with malignant melanoma who are disease free but at high risk for systemic recurrence. Use of adjuvant therapy with interferon alfa following surgical resection prolongs disease-free but not overall survival in patients at high risk for recurrence of disease, particularly among patients with node-positive melanoma.

In a large randomized trial, patients receiving adjuvant therapy with interferon alfa-2b within 56 days of surgery for deep primary (T4) or regionally metastatic (N1) melanoma had prolonged disease-free and overall survival but experienced substantial toxicity compared with patients receiving surgery alone. Patients with Breslow’s classification greater than 4 mm, and those with any Breslow’s classification with primary or recurrent lymph node involvement, were included in the study. Adjuvant therapy consisted of IV interferon alfa-2b 20 million units/m² 5 days per week for 4 weeks followed by maintenance therapy with 10 million units/m² subcutaneously 3 days per week for 48 weeks. Median overall survival of 3.82 or 2.78 years, respectively, was observed in patients receiving adjuvant interferon alfa therapy or undergoing surgery alone while median time to relapse was 1.72 or 0.98 years, respectively, with such treatment. The estimated 5-year overall survival rate was 46 or 37% in patients receiving adjuvant therapy or undergoing surgery alone, respectively. Although interpretation of the data is limited because stratification was performed to ensure balance rather than to make comparisons between the patient groups, subgroup analysis demonstrated benefit of adjuvant therapy with interferon alfa-2b only among patients with node-positive disease; the small number of patients with node-negative disease enrolled in the trial does not allow any meaningful conclusions regarding efficacy of adjuvant therapy with interferon alfa in this group. Toxicity was substantial with 67% of patients experiencing severe (grade 3) toxicity at some point during the year of treatment; depending on the individual patient and the relative value placed on time spent with toxicity and survival time with relapsed disease, the quality-of-life-adjusted gain in survival time may or may not be significant in patients receiving adjuvant therapy with interferon alfa.

In a subsequent 3-arm randomized trial comparing adjuvant therapy with high-dose IV interferon alfa-2b (followed by maintenance therapy with subcutaneous interferon alfa-2b), adjuvant therapy with low-dose subcutaneous interferon alfa-2b, or observation following surgical resection of deep primary (T4) or primary or recurrent regionally metastatic (N1) melanoma, disease-free survival was prolonged in patients receiving high-dose interferon alfa versus observation; however, overall survival did not differ among the groups. Results from another large trial in patients randomized to receive observation or adjuvant therapy with high-dose IM interferon alfa-2a (no longer commercially available in the US) 3 days a week for 12 weeks following surgery for primary melanomas greater than 1.69 mm in thickness with or without nodal involvement did not detect a difference in recurrence or survival rates, but subset analysis suggested a trend toward increased rate and duration of disease-free survival in patients with node-positive disease receiving adjuvant interferon alfa. Use of adjuvant therapy with interferon alfa may be a reasonable option in selected patients (e.g., those with deep primary tumors or node-positive disease), but further study is needed to establish the role of adjuvant therapy with interferon alfa in patients with high-risk, localized melanoma.

Metastatic Melanoma

Interferon alfa has been used alone for the treatment of metastatic melanoma^† in selected patients. Response rates averaging about 16% (with approximately 4% complete responses) have been reported in patients with metastatic melanoma receiving interferon alfa as a single agent administered daily or 3 times per week.

Monotherapy with IM interferon alfa dosages ranging from 10–20 million units/m² 3 times weekly has been used in patients with metastatic melanoma. However, therapy with interferon alfa alone in tolerable dosages appears unlikely to alter survival in patients with this metastatic disease. The median duration of response following therapy with interferon alfa alone in patients with metastatic melanoma has been reported to be 5 months, but some patients have achieved complete responses lasting longer than 2–3 years. A relatively prolonged course of interferon alfa therapy (i.e., approximately 3 months) may be required to produce responses in patients with metastatic melanoma.

Prognostic factors that reliably identify patients with metastatic melanoma who are likely to respond favorably to interferon alfa therapy have not been identified to date. Most responses to interferon alfa monotherapy have occurred in patients with subcutaneous and small-volume disease. However, long-term responses have been observed in patients with visceral- and nonvisceral-dominant disease, in previously treated and untreated patients, and in those treated with monotherapy or combination drug therapy. Limited data suggest that intralesional therapy with interferon alfa has clinical activity in patients with melanoma, but efficacy of the drug given by this route has not been compared with that of systemic interferon therapy.

Interferon alfa also has been used in combination therapy for the treatment of metastatic melanoma. Results from a small randomized trial suggested that the combination of interferon alfa and dacarbazine was superior to dacarbazine alone, but other studies did not confirm these findings. The addition of interferon alfa did not increase response rate or prolong survival in patients receiving high-dose IV aldesleukin or continuous IV infusion aldesleukin and IV cisplatin for the treatment of metastatic melanoma. The use of interferon alfa and aldesleukin in combination with conventional chemotherapeutic agents (e.g., cisplatin, dacarbazine) is being investigated for the treatment of metastatic melanoma. A large randomized trial is under way to investigate the comparative efficacy and toxicity of concurrent biochemotherapy with interferon alfa-2b, aldesleukin, cisplatin, vinblastine, and dacarbazine versus combination chemotherapy with cisplatin, vinblastine, and dacarbazine.

Basal Cell and Squamous Cell Skin Cancers

Interferon alfa has been used effectively by intralesional injection in the treatment of basal cell carcinoma^†. The response of these lesions to interferon alfa therapy appears to be related to the dose and duration of therapy with the drug, increasing with increasing total dose and duration. While response was poor in patients treated with intralesional injection of 0.9 million units 3 times weekly for 3 weeks in one study and in those treated with a single 10 million-unit dose of a long-acting (protamine zinc) interferon alfa injection in another study, a good response was observed in other studies employing larger total doses and/or more prolonged therapy. In a large, multicenter study, a histologic cure rate exceeding 80% was observed at 1 year in patients receiving intralesional therapy with 1.5 million units of interferon alfa 3 times weekly for 3 weeks. A similar histologic cure rate was observed after 4 months in another study in which patients received intralesional interferon alfa therapy with a long-acting injection at a dosage of 10 million units once weekly for 3 weeks; however, the risk of adverse effects appears to be increased with this regimen compared with the lower-dose, more frequently administered regimen employing the immediate-release injection. As with other (e.g., surgical) therapy, patients treated with intralesional interferon alfa therapy for basal cell carcinoma should be followed closely for evidence of residual cancer. In addition, some clinicians caution that, pending further accumulation of data, the possibility that the lesions occasionally may be transformed into epidermoid cysts by interferon alfa therapy should be considered, since there may be some attendant risk of carcinoma reversion. Although intralesional interferon alfa appears to be safe and effective in the treatment of basal cell carcinoma, and offers the potential for improved cosmetic results and patient acceptance compared with surgical management of this cancer, the role of interferon therapy compared with other therapies (e.g., surgery, cryosurgery, curettage and electrodessication) remains to be more fully elucidated.

Limited evidence also suggests that intralesional therapy with interferon alfa can produce clinical and/or histologic responses in patients with squamous cell carcinoma^† or keratoacanthoma^†. Clinical improvement also has been reported in a limited number of patients with actinic (solar) keratosis^†, which either disappeared or showed histologic improvement with intralesional interferon alfa therapy. However, experience with interferon alfa in the treatment of these skin disorders is less extensive than in the treatment of basal cell carcinoma, and further study is needed to determine the potential role of the drug in the treatment of these disorders.

Chronic Myelogenous Leukemia

Interferon alfa (alfa-2a [no longer commercially available in the US], alfa-2b^†) is used for the treatment of adult-type (Philadelphia chromosome-positive) chronic myelogenous (myelocytic, myeloid) leukemia (CML) in patients who are in the chronic phase of the disease and who have been minimally pretreated (within 1 year of diagnosis). In patients with CML, interferon alfa can produce complete or partial hematologic remissions and cytogenetic responses. Although the cytogenetic responses may be prolonged in some patients, further study and follow-up are needed to determine whether the drug can improve long-term survival in patients with this disease. Limited data suggest that pediatric patients with adult-type CML (i.e., Philadelphia-positive disease) also may exhibit a good therapeutic response to interferon alfa similar to that achieved in adults; however, children with juvenile-type CML^† (i.e., Philadelphia-negative disease) generally are unresponsive to chemotherapy or interferon alfa. (See Pediatric Precautions.)

Complete hematologic remission, generally characterized by relative normalization of leukocyte and platelet counts, reduction in leukocyte alkaline phosphatase concentrations, marked reduction of splenomegaly, and decreased bone marrow cellularity, has been achieved in approximately 22–80% of patients receiving 2–5 million units/m² of interferon alfa daily or 3 times weekly for prolonged periods (e.g., 1–3 years). A cytogenetic response (i.e., suppression of Philadelphia chromosome-positive cells) generally occurs in at least 10–70% of patients achieving complete hematologic remission with interferon alfa therapy. Unlike the transient suppression of the Philadelphia chromosome generally observed with intensive cytotoxic antineoplastic therapy, interferon alfa has produced complete suppression of this chromosome for about 2–8 years or longer in some patients. However, interferon-induced decreases in bone marrow cellularity and suppression of Philadelphia chromosome-positive cells are delayed compared with hematologic improvement, with median times to complete hematologic and cytogenetic remission reported in early studies as 3.4 and 9 months, respectively, but in more recent studies as 5–6.7 and greater than 18 months, respectively. In addition, while the ability of interferon alfa to suppress the malignant Philadelphia chromosome-positive clone and favor reemergence of a normal clone of marrow cells suggests that the drug is potentially curative, only intensive chemotherapy, alone or combined with radiation therapy, followed by bone marrow transplantation has been shown to be curative to date.

Hematologic and cytogenetic responses to interferon alfa therapy appear to be greatest in newly diagnosed, previously untreated patients with low- to intermediate-risk disease (i.e., low to moderately high leukocytosis, splenomegaly, and presence of the Philadelphia chromosome) who have early chronic-phase CML (i.e., those who are treated within 12 months of diagnosis); response rates are approximately fourfold to sixfold higher in the early chronic phase compared with the accelerated and blast phases of the disease. In addition, limited data indicate that response rates to interferon alfa are increased in patients who are white and younger than 60 years of age. Interferon alfa reportedly can control the thrombocytosis that may occur during the initial and/or accelerated phase of CML, but the drug generally has little or no long-term therapeutic effect in the accelerated or blast phase of the disease. However, some evidence indicates that interferon alfa-treated patients with CML who enter blast crisis frequently have a lymphoid blast phenotype, which in a subset of patients appears to be associated with greater response to subsequent antineoplastic therapy, rather than the more typical myeloid blast transformation. There is some evidence to suggest that response to interferon alfa in patients with CML also may be dose related, as evidenced in one study by a higher response rate in patients receiving 5 million versus 2 million units/m² three times weekly; some clinicians suggest an interferon alfa dosage of 5 million units/m² given daily. However, additional study is needed to determine the optimum dosage of interferon alfa in the treatment of CML.

Results of a randomized, multicenter, controlled study in newly diagnosed or minimally treated patients (those who received less than 100 mg of busulfan or less than 50 g of hydroxyurea) with CML demonstrate a longer median survival in patients receiving interferon alfa (44% of patients receiving interferon alfa also received intermittent single-drug chemotherapy) versus those receiving conventional therapy with antineoplastic agents (e.g., hydroxyurea, busulfan). Median survival of 69–72 or 52–55 months, respectively, was reportedly observed in patients receiving interferon alfa or conventional chemotherapy while overall hematologic response rate was 60% (40% had complete response) or 70% (30% had complete response) in patients receiving interferon alfa or conventional chemotherapy, respectively. Usually, cytogenetic responses were only observed in patients who had complete hematologic remissions, and longer survival was observed in patients with cytogenetic response. In addition, the time of disease progression from chronic to blastic phase was 69–72 or 45–46 months in patients receiving interferon alfa or conventional chemotherapy, respectively.

Concomitant administration of interferon alfa-2b^† with cytarabine has been associated with increased survival in patients with CML. Results of a randomized controlled study in previously untreated patients with CML demonstrate a longer survival in patients receiving interferon alfa-2b (5 million units/m² given subcutaneously daily) in combination with cytarabine (20 mg/m² daily for 10 days given subcutaneously 2 weeks after initiation of interferon alfa-2b therapy and monthly thereafter) versus those receiving interferon alfa-2b without cytarabine; patients from both groups also received hydroxyurea 50 mg/kg daily until a complete hematologic remission was achieved. After 3 years, median survival rate of about 86 or 79%, respectively, reportedly was observed in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine while overall hematologic response rate was 66 or 55% in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine, respectively. Major cytogenetic response rate after 12 months was 41 or 24% in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine, respectively. Longer survival was observed in patients with cytogenetic response. Some patients underwent allogeneic or autologous bone marrow transplantation, and the 2-year survival rate after allogeneic bone marrow transplantation was 56 or 59% in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine, respectively, while 2-year survival rate after autologous bone marrow transplantation was 61 or 68% in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine, respectively. Patients who did not have complete hematologic or major cytogenetic responses within 6 or 12 months, respectively, were allowed to cross over to combined treatment with interferon alfa-2b and cytarabine. Among patients who received initial therapy with interferon alfa-2b without cytarabine, but then crossed over to receive combined treatment with interferon alfa-2b and cytarabine, complete and partial responses of 2 and 6%, respectively, were observed.

Further studies and follow-up of previously untreated patients receiving interferon alfa for CML are needed to determine whether the drug alters the natural course of the disease. However, results of several studies indicate that patients with CML who achieve a complete hematologic and cytogenetic response to interferon alfa therapy have a substantially longer survival rate than those who have partial or no response; complete elimination of malignant cells in peripheral blood and bone marrow (as determined by Southern blot and polymerase chain reaction analyses) has been reported following prolonged therapy with the drug. Longer survival usually is associated with slower progression to the blastic phase.

Renal Cell Carcinoma

Overview

Interferon alfa, alone or in combination therapy, is used for the treatment of metastatic renal cell carcinoma^† in selected patients. There is no generally accepted standard drug therapy for metastatic renal cell carcinoma. Because of the poor response to systemic therapy, surgical resection often is included in the management of metastatic renal cell carcinoma.

Various forms of systemic drug therapy, including cytotoxic agents, hormonal agents, and biologic agents (e.g., interferon alfa, aldesleukin, antiangiogenic and other targeted therapy), have been studied in patients with metastatic renal cell carcinoma. Response rates with cytotoxic chemotherapy generally have been poor (10% or less) for any regimen that has been studied in adequate numbers of patients with metastatic renal cell carcinoma. Evidence suggests that the incidence of tumor regression associated with interferon alfa therapy is similar to or possibly greater than that associated with conventional hormonal or antineoplastic drug therapy for this disease, and that adverse effects associated with interferon therapy may be less debilitating than those associated with these therapies. Results of studies with hormonal therapy (e.g., medroxyprogesterone acetate, tamoxifen) has been studied in the treatment of metastatic renal cell carcinoma, results have been disappointing, and these agents are no longer used.

Immunotherapy with interferon alfa or aldesleukin is used for the systemic treatment of metastatic renal cell carcinoma despite low response rates. Interferon alfa produces objective responses in only 5–30% (overall about 10–15%) of patients with metastatic disease^†, and complete responses are uncommon (about 1%). The overall response rates associated with either interferon alfa or aldesleukin monotherapy appear to be similar (10–15 versus 15%, respectively), but evidence suggests that the incidence of complete or durable response is lesser with interferon alfa than with aldesleukin (1 versus 5%). In addition, a survival benefit has been associated with interferon-alfa-containing regimens in patients with metastatic renal cell carcinoma whereas such data are lacking for aldesleukin. Results of large randomized trials and analysis of pooled data from several randomized studies indicate that interferon alfa, used alone or in combination, modestly increases response rates and prolongs survival in patients with metastatic renal cell carcinoma compared with conventional antineoplastic or hormonal agents.

Whether higher response rates or more durable responses are observed in patients with metastatic renal cell carcinoma receiving immunotherapy with cytokines, such as interferon alfa, than in those receiving supportive care only has not been fully established. Results from a randomized, placebo-controlled trial showed no benefit in overall response rate, rate of durable complete response, time to disease progression, or duration of survival with use of the cytokine interferon gamma-1b for metastatic renal cell carcinoma. Most of the evidence for the use of interferon alfa in the treatment of metastatic renal cell carcinoma is based on results from noncomparative, phase II studies; interferon alfa has not been studied in placebo-controlled trials, and evidence from randomized trials comparing interferon alfa monotherapy or interferon alfa-containing regimens with other agents is limited.

Because the prognosis for patients with metastatic renal cell carcinoma is poor and conventional cytokine therapy has minimal activity with substantial toxicity, all patients with this cancer should be considered for inclusion in clinical trials at the time of diagnosis. Supportive care (e.g., adequate analgesia for pain management, surgery for solitary brain metastasis or spinal cord compression, radiation therapy for palliation of metastases, particularly painful bone metastases) remains a mainstay of therapy for patients with metastatic renal cell cancer.

The use of interferon alfa as adjuvant therapy for completely resected, locally advanced renal cell carcinoma did not improve survival or reduce the risk of relapse. No systemic therapy has been shown to reduce the risk of relapse or prolong survival in patients with localized renal cell carcinoma at high risk of recurrence; preliminary results from a small randomized trial suggest that adjuvant therapy with ex vivo activated T cells (ALT) and high-dose cimetidine delays disease recurrence.

Monotherapy for Metastatic Renal Cell Carcinoma

Most evidence for the use of interferon alfa as a single agent for the treatment of metastatic renal cell carcinoma is based on uncontrolled phase II studies. Evidence from controlled, comparative studies evaluating the efficacy of interferon alfa as a single agent versus other agents in the treatment of metastatic renal cell carcinoma is limited.

Although evidence suggests that the incidence of complete or durable response is lesser with interferon alfa (1 versus 5%), the overall response rates associated with either interferon alfa or aldesleukin monotherapy appear to be similar (10–15 versus 15%, respectively). In addition, interferon alfa therapy is less toxic than high-dose aldesleukin therapy, and 2 large randomized trials have demonstrated a survival benefit for interferon-alfa-containing regimens in patients with metastatic renal cell carcinoma

Combination Therapy for Metastatic Renal Cell Carcinoma

Interferon alfa has been used in various combination regimens with other agents including biologic response modifiers (e.g., aldesleukin), and/or conventional chemotherapeutic agents (e.g., fluorouracil, vinblastine) for the treatment of metastatic renal cell carcinoma. According to analysis of pooled data from several randomized studies, higher overall response rate (14 versus 8%) and prolonged survival were observed for regimens containing interferon alfa compared with antineoplastic or hormonal regimens for the treatment of metastatic renal cell carcinoma.

Interferon alfa has been used in combination with aldesleukin for the treatment of metastatic renal cell carcinoma. A collective response rate of about 20% (5% complete responses, 15% partial responses), similar to the overall response rate of 15% observed with aldesleukin monotherapy has been observed in patients with metastatic renal cell carcinoma receiving interferon alfa in combination with aldesleukin.

A retrospective analysis indicates that similar efficacy and less toxicity are observed in patients receiving subcutaneous interferon alfa and subcutaneous aldesleukin compared with continuous IV infusion of aldesleukin alone for advanced renal cell carcinoma. In a large, randomized trial, patients with metastatic renal cell carcinoma receiving subcutaneous interferon alfa-2a (no longer commercially available in the US) combined with continuous IV infusion of aldesleukin had a higher response rate and higher rate of event-free survival at 1 year but no difference in overall survival compared with those receiving either agent alone; less toxicity was observed in patients receiving interferon alfa than in those receiving aldesleukin, either alone or in combination therapy. The low response rates observed for monotherapy with interferon alfa or aldesleukin in this trial may have contributed to the differences observed in comparison with the combination therapy.

Limited evidence from a randomized, phase II trial suggests that the addition of interferon alfa-2b to a high-dose, intermittent IV infusion regimen of aldesleukin did not improve response rate, and incidence of complete response and duration of response appeared to be more favorable for patients receiving high-dose aldesleukin monotherapy for advanced renal cell carcinoma. At a median follow-up of 72 months in another randomized phase II trial, median duration of response was longer (53 versus 14 months) and the rate of progression-free survival at 3 years was higher (13 versus 3%) for patients receiving high-dose IV aldesleukin alone compared with those receiving IV interferon alfa-2b and high-dose IV aldesleukin. Another phase II randomized trial indicates that toxicity is greater but overall survival is not improved when subcutaneous interferon alfa is added to a regimen of subcutaneous aldesleukin. In a randomized trial, no survival difference was observed in patients receiving subcutaneous interferon alfa, subcutaneous aldesleukin, and oral tamoxifen versus oral tamoxifen alone.

Interferon alfa, with or without aldesleukin, also has been used in combination with conventional chemotherapeutic agents (e.g., fluorouracil, vinblastine) for the treatment of metastatic renal cell carcinoma.

In a phase III randomized trial, median survival was prolonged (16.9 versus 9.4 months) and response rate was higher (16.5 versus 2.5%) but grade 4 toxicity was more frequent (18 versus 2%) in patients receiving subcutaneous interferon alfa-2a (no longer commercially available in the US) and IV vinblastine than in those receiving IV vinblastine alone. The role of vinblastine in combination with interferon alfa remains to be established. Variable results have been reported for the benefit versus toxicity of combination regimens with interferon alfa and conventional antineoplastic agents compared with interferon alfa monotherapy. Response rates in patients with advanced renal cell carcinoma are similar or increased when vinblastine is added to interferon alfa therapy, but no difference in survival has been observed; in some studies, increased toxicity has been reported with the addition of vinblastine. No differences in overall response rates, progression-free survival, or overall survival were observed in a large randomized trial of interferon alfa-2a (no longer commercially available in the US) and 13-cis-retinoic acid (isotretinoin) versus interferon alfa-2a alone.

Interferon alfa also has been used in combination with aldesleukin and fluorouracil for the treatment of metastatic renal cell carcinoma. Although early reports from small uncontrolled studies suggested that interferon alfa used in combination with aldesleukin and fluorouracil produced favorable response rates, longer follow-up and subsequent phase II studies did not confirm higher response rates or comparable durability of responses, and some variations of the 3-drug regimen showed substantial toxicity. Results from one randomized trial indicate that the addition of fluorouracil does not improve response rate in patients receiving a regimen of subcutaneous interferon alfa and subcutaneous aldesleukin. In another randomized trial, patients receiving combination therapy with subcutaneous interferon alfa-2a (no longer commercially available in the US), subcutaneous aldesleukin, and IV fluorouracil had higher response rates and prolonged overall and progression-free survival compared with those receiving oral tamoxifen alone. Further study is required to establish the comparative efficacy and toxicity of combination therapy with interferon alfa, aldesleukin, and fluorouracil. In small, uncontrolled studies, the addition of fluorouracil did not appear to improve response rates compared with interferon alfa alone but added toxicities associated with fluorouracil.

Evidence from a randomized trial indicates that the addition of coumarin and cimetidine, potential immunomodulating agents, did not improve response rates or survival duration in patients receiving interferon alfa for metastatic renal cell carcinoma. The addition of aspirin did not enhance or interfere with the efficacy of interferon alfa therapy for metastatic renal cell carcinoma, nor did it lessen overall treatment-associated toxicity. Concomitant treatment with prednisone (10–20 mg daily) reportedly may improve the subjective tolerability of therapy by reducing flu-like symptoms without reducing response rates in patients with renal cell carcinoma receiving interferon alfa at dosages of 18 million units or more 3 times weekly; however, prednisone had little effect on the hepatic toxicity associated with high-dose interferon alfa therapy.

Other Considerations

The optimum dosage and duration of interferon alfa therapy for patients with metastatic renal cell carcinoma have not been established, but limited data suggest that response to the drug may be dose dependent; dosages of interferon alfa ranging from 5–20 million units daily or 3 times weekly appear to be required to achieve optimum response with manageable toxicity. The period from initiation of treatment to occurrence of an objective response averages 3–4 months, and responses to interferon alfa rarely last longer than 2 years.

Although median duration of survival generally appears to be greater in patients with renal cell carcinoma who respond to interferon alfa than in those who do not, it is unclear whether therapy with the drug actually results in a prolonged survival or merely selects out patients with a better initial prognosis. Factors associated with higher rates of response to interferon alfa therapy include a low tumor burden with lung-predominant metastases (including mediastinum, pleural, and mediastinal node metastases), good performance status, prior nephrectomy, prolonged disease-free interval between nephrectomy and disease recurrence, relatively low nadir granulocyte counts, and perhaps in vitro sensitivity of the tumor to interferon alfa, as determined by clonogenic assay. Although reliable criteria for selecting patients most likely to benefit from cytokine therapy have not been established, prognostic factors have been identified that are associated with poor outcome despite treatment with interferon alfa and/or aldesleukin (e.g., multiple sites of metastasis, metastasis to the liver, metastasis within 1 year following diagnosis of primary tumor.

Except in rare cases, interferon alfa has not exhibited antitumor activity against unresected renal cell carcinoma or retroperitoneal, brain, or hepatic metastases. Patient selection appears to have considerable influence on outcome of therapy, and no single prognostic factor appears to correlate strongly with therapeutic response. Many patients with renal cell carcinoma who respond to interferon alfa therapy develop anti-interferon antibodies which, in some but not all studies, appear to have been associated with loss of response to therapy. However, many factors influence the frequency, magnitude, and importance of this antibody response, and further studies are needed to determine whether such antibody development affects outcome of therapy with interferon alfa in patients with renal cell carcinoma. (See Dermatologic, Local, Sensitivity, and Immunologic Reactions: Antibody Formation, in Cautions.)

Bladder Cancer

Intravesical therapy^† with interferon alfa has been used in the prophylaxis or treatment of superficial bladder cancer^†. Although intravesicular BCG generally is preferred for superficial bladder cancer, responses to intravesical interferon alfa have been noted in patients with disease that failed to respond to or is refractory to other intravesical agents (e.g., BCG).

Interferon alfa administered intravesically has been used alone or in combination therapy as adjuvant or prophylactic therapy to prevent the recurrence of superficial bladder cancer following transurethral resection (TUR). Interferon alfa used alone as an intravesical agent generally appears to be less effective but less toxic than intravesical therapy with BCG or chemotherapeutic agents for the prophylaxis of superficial bladder cancer. At a mean follow-up of 43 months, relapse rates were similar in patients with stage T1, grade 2 or 3 or relapsed grade 1, bladder cancer receiving TUR with or without adjuvant intravesical therapy with interferon alfa-2b 60 million units once weekly for 12 weeks and then once monthly for up to 1 year of treatment. In a comparative study, intravesical interferon alfa-2b was inferior to intravesical mitomycin for preventing tumor recurrence in patients with papillary bladder tumors. In a small randomized trial, interferon alfa-2a (no longer commercially available in the US) was inferior to BCG as intravesical therapy for recurrent stage T1, grade 1 to 3, superficial bladder cancer. In a large randomized trial using a single intravesical instillation immediately following TUR, interferon alfa-2b was inferior to epirubicin for preventing recurrence of stage Ta or T1 superficial bladder cancer.

Interferon alfa also has been used in combination therapy for the prophylaxis of superficial bladder cancer. In a few randomized studies with small numbers of patients, combination therapy with interferon alfa and epirubicin administered intravesically did not appear to be more effective than either agent alone in preventing or delaying the recurrence of superficial bladder cancer at low risk of recurrence. Further study is needed to evaluate the additive or synergistic effects of interferon alfa used in combination therapy with other intravesical agents (e.g., BCG) for the prophylaxis of superficial bladder cancer.

Limited evidence suggests that interferon alfa administered intravesically is an active agent in the treatment of superficial bladder cancer, both as primary therapy and as secondary therapy after intravesical administration of other agents has failed. The drug has produced objective response rates ranging from 30–60% when administered intravesically for the treatment of superficial cancer of the bladder. Complete responses to intravesical interferon alfa have been observed in some patients with noninvasive papillary tumors and/or carcinoma in situ, including patients with recurrent disease or disease refractory to intravesical therapy with BCG live or cytotoxic agents. Limited data suggest that high intravesical doses (e.g., 100 million units) of interferon alfa may be more effective, with minimal toxicity, than lower doses (e.g., 10 million units) in achieving complete responses in patients with carcinoma in situ.

Responses have been reported in small numbers of patients receiving intralesional administration (into the base of the tumor or surrounding tissue) of interferon alfa for papillary tumors of the bladder. In limited numbers of patients, little or no efficacy has been demonstrated for the use of interferon alfa administered IM for the prophylaxis or treatment of superficial bladder cancer. Continuous intra-arterial administration^† of interferon alfa showed no efficacy and considerable toxicity in 5 patients with advanced bladder cancer.

Intravesical administration of interferon has been associated with minimal toxicity; local symptoms rarely have been observed, and the most commonly observed systemic toxicity has consisted of mild to moderate flu-like symptoms. Comparative studies in larger numbers of patients are needed to determine the role of interferon alfa therapy in the prophylaxis and treatment of superficial bladder cancer.

Ovarian Cancer

Agents other than interferon alfa are preferred for the treatment of ovarian cancer. Interferon alfa has been administered intraperitoneally^† for the treatment of minimal residual epithelial ovarian cancer^† in a limited number of patients. Interferon alfa appears to be an active agent in ovarian cancer when administered intraperitoneally, particularly in patients with small-volume, platinum-sensitive disease. Further studies are needed to establish the role of interferon alfa administered intraperitoneally as a single agent or in combination with conventional antineoplastic agents to patients with minimal or no evidence of residual ovarian carcinoma.

Objective responses (mostly partial responses) have been reported in less than 20% of a small number of patients with advanced ovarian cancer receiving IV or IM administration of interferon alfa.

Multiple Myeloma

Interferon alfa has been used for the palliative treatment of multiple myeloma^† in patients whose disease has relapsed or become refractory to conventional antineoplastic therapy (e.g., melphalan plus prednisone); the drug also has been used as induction therapy in a limited number of patients with the disease. Although therapy with interferon alfa alone appears to produce objective responses in only 10–30% of patients with relapsed or refractory disease, limited data suggest that some of these patients may respond to reinstitution of antineoplastic therapy following treatment with interferon alfa. Responses to interferon alfa therapy may be more common in patients who have relapsed from previous therapy than in individuals with initially refractory disease. Limited data indicate that interferon alfa may prolong duration of response and survival when given as maintenance therapy to patients following successful induction therapy with antineoplastic agents. In one study in patients who achieved an objective response following multiple courses of induction chemotherapy (a regimen of melphalan and prednisone or a regimen of vincristine, melphalan, cyclophosphamide, and prednisone [VMCP] alternating with vincristine, carmustine, doxorubicin, and prednisone [VBAP]), the median duration of response for those who subsequently received interferon alfa maintenance therapy (3 million units/m² subcutaneously 3 times weekly) compared with those who did not was 26 versus 14 months and the median duration of survival was 52 versus 39 months; differences in survival between interferon alfa maintenance and no maintenance were particularly evident in the subset of patients who had achieved a substantial objective response to induction chemotherapy; Previously untreated patients receiving interferon alfa in a combined regimen with conventional antineoplastic therapy (i.e., melphalan and prednisone) may have at best a marginally improved response rate compared with those receiving antineoplastic therapy alone, although no substantial difference in overall survival was observed.

When used for induction of remission in a limited number of previously untreated patients with multiple myeloma, therapy with interferon alfa has been associated with response rates of up to 50–75%. Evidence suggests that patients most likely to benefit from interferon therapy are those who have received limited or no prior treatment, those with early-stage disease, and those who have a small tumor burden. Patients responding to interferon alfa therapy may have subjective improvement in bone pain, recalcification of osteolytic lesions, decreases in bone marrow plasma cells, decreased concentrations of monoclonal (M-component) immunoglobulins (e.g., myeloma or Bence-Jones proteins) in serum and/or urine, and an increase in performance status. IgM synthesis and decreased serum concentrations of IgG, IgA, and IgM reportedly normalize in patients who respond to interferon, which suggests that interferon alfa stimulates the recovery of normal immune function in these individuals; this restoration to normal of immunoglobulin concentrations is uncommon in patients who respond to therapy with antineoplastic agents alone. Preliminary results of studies in which multiple-drug regimens of antineoplastic agents (e.g., vincristine, carmustine, melphalan, cyclophosphamide, and prednisone) have been alternated with courses of interferon alfa suggest that such alternating therapy may increase the rate of response and duration of survival in patients with multiple myeloma, although combined therapy also may increase toxicity (e.g., neutropenia). Further long-term follow-up, and randomized studies comparing such alternating regimens with antineoplastic therapy alone, are needed to confirm these results.

Other Uses

Interferon alfa has been used for the management of various angiomatous (angiogenic) disorders^† in a limited number of patients. Although experience to date is limited, interferon alfa has been used with encouraging results in some such conditions that previously were fatal in most cases (e.g, pulmonary hemangiomatosis^†). Initiation of interferon alfa therapy in a 12-year-old boy with pulmonary hemangiomatosis resulted in substantial improvement in pulmonary function, pulmonary angiograms, exercise tolerance, and other manifestations (e.g., digital clubbing) of this disorder; the condition has remained in remission for at least 30 months with long-term interferon alfa maintenance therapy. Encouraging results also have been observed following initiation of interferon alfa therapy in several other patients with pulmonary hemangiomatosis or other angiomatous disorders, and in at least 2 infants with progressive hemangioendotheliomas^†. It has been suggested that interferons may inhibit angiogenesis in part by inhibiting proliferation of endothelial cells, smooth muscle cells, and fibroblasts that have been stimulated by fibroblast growth factor (FGF); decreasing collagen production; and increasing endothelial prostacyclin production. Other mechanisms also may be involved. Additional study and experience are needed to establish the role of interferon alfa in the management of these disorders and to determine the optimum dosage and duration of therapy. Some clinicians recommend that, pending further accumulation of data, interferon alfa therapy be reserved for consistently life-threatening or fatal angiomatous conditions for which effective alternative treatment is not available (e.g., pulmonary hemangiomatosis), patients with life-threatening complications of angiomatous disease that fail to respond adequately to conventional therapy or in whom such therapy is not tolerated (e.g., those developing excessive corticosteroid toxicity during the management of Kasabach-Merritt [ hemangioma-thrombocytopenia] syndrome^†), conditions that seriously compromise vital organs or structures, and conditions that result in disfigurement, disability, or potential amputation.

Interferon alfa also has been used in the treatment of metastatic small intestinal carcinoid tumors^†. The drug has reduced the frequency and/or severity of symptoms associated with the carcinoid syndrome and has produced substantial reductions in urinary 5-hydroxyindoleacetic acid concentrations, serum human chorionic gonadotropin concentrations, and serum pancreatic peptide tumor markers.

Interferon Alfa (Antineoplastic) Dosage and Administration

Reconstitution and Administration

Interferon alfa-2b is administered by IM, subcutaneous, or intralesional injection or by IV infusion.

Interferon alfa-2b may be self-administered if the clinician determines that the patient and/or their caregiver are competent to reconstitute and safely administered the drug after appropriate training and with medical follow-up as necessary. Patients and/or their caregivers who administer interferon alfa in a home setting should be cautioned against reuse of syringes and needles, supplied with a puncture-resistant container for the safe disposal of such equipment after use, and instructed on the proper disposal of full disposal containers.

Interferon alfa-2b is available in various strengths in single-dose vials containing a powder for injection that requires reconstitution prior to injection and in multiple-dose vials containing solution for injection. Not all dosage forms and strengths are appropriate for all indications.

Interferon alfa solutions should be inspected visually for discoloration and particulate matter prior to administration whenever solution and container permit.

Patients should be well hydrated during interferon alfa therapy, especially during initial stages of treatment.

Some adverse effects associated with interferon alfa therapy (e.g., flu-like syndrome) may be prevented or ameliorated by administering the drug in the evening or at bedtime. In addition, the incidence of adverse effects may be reduced by administration of acetaminophen or other nonopiate analgesic at the time the interferon alfa dose is given.

IV Administration

Melanoma

For use as an adjunct to surgery in the treatment of malignant melanoma, interferon alfa-2b is given initially by IV infusion (induction therapy) and then by subcutaneous injection (maintenance therapy). (See Melanoma under Reconstitution and Administration: Subcutaneous Injection, in Dosage and Administration.)

IV solutions should be prepared using single-dose vials of interferon alfa-2b powder for injection containing 10, 18, or 50 million units of the drug. Solutions of the drug commercially available in multiple-dose vials should not be used for IV administration.

Single-dose vials of interferon alfa-2b containing 10, 18, or 50 million units of the drug should be reconstituted by adding 1 mL of the sterile water for injection diluent provided by the manufacturer and gently swirling the vial; the resultant solution contains 10, 18, or 50 million units/mL, respectively.

The appropriate dose of reconstituted solution should be withdrawn from the vial and added to 100 mL of 0.9% sodium chloride injection. The final concentration of the IV solution should not be less than 10 million units/100 mL (100,000 units/mL).

IV solutions of interferon alfa-2b should be given by IV infusion over 20 minutes.

IM Injection

IM injections of interferon alfa-2b should be made into the anterolateral thigh, upper arm, or outer area of the buttocks.

Hairy Cell Leukemia

For IM injection for the treatment of hairy cell leukemia, single-dose vials of interferon alfa-2b powder for injection containing 10 million units of the drug should be reconstituted with 1 mL of the sterile water for injection diluent provided by the manufacturer and the vial gently swirled; the resultant solution contains 10 million units/mL. The appropriate dose of reconstituted solution should be administered IM undiluted.

Alternatively, the appropriate dose of interferon alfa-2b solution for injection from a multiple-dose vial containing 6 or 10 million units/mL can be administered IM undiluted.

Interferon alfa-2b should not be administered IM in patients with hairy cell leukemia and platelet counts less than 50,000/mm³.

AIDS-related Kaposi's Sarcoma

For IM injection for the treatment of AIDS-related Kaposi's sarcoma, single-dose vials of interferon alfa-2b powder for injection containing 50 million units should be reconstituted with 1 mL of the sterile water for injection diluent provided by the manufacturer and the vial gently swirled; the resultant solution contains 50 million units/mL. The appropriate dose of reconstituted solution should be administered IM undiluted.

Multiple-dose vials containing interferon alfa-2b solution for injection should not be used for treatment of AIDS-related Kaposi’s sarcoma.

Subcutaneous Injection

Subcutaneous injections of interferon alfa-2b should be made into the anterolateral thigh, upper arm, or abdomen (avoiding the navel). Subcutaneous injections should not be made into an area where the skin is irritated, red, bruised, infected, or has scars, stretch marks, or lumps.

Hairy Cell Leukemia

For subcutaneous injection for the treatment of hairy cell leukemia, single-dose vials of interferon alfa-2b powder for injection containing 10 million units of the drug should be reconstituted with 1 mL of the sterile water for injection provided by the manufacturer and the vial gently swirled; the resultant solution contains 10 million units/mL. The appropriate dose of reconstituted solution should be administered subcutaneously undiluted.

Alternatively, the appropriate dose of interferon alfa-2b solution for injection from a multiple-dose vial containing 6 or 10 million units/mL can be administered subcutaneously undiluted.

AIDS-related Kaposi's Sarcoma

For subcutaneous injection for the treatment of AIDS-related Kaposi's sarcoma, single-dose vials of interferon alfa-2b powder for injection containing 50 million units should be reconstituted with 1 mL of the sterile water for injection diluent provided by the manufacturer and the vial gently swirled; the resultant solution contains 50 million units/mL. The appropriate dose of reconstituted solution should be administered subcutaneously undiluted.

Multiple-dose vials containing interferon alfa-2b solution for injection should not be used for treatment of AIDS-related Kaposi’s sarcoma.

Follicular non-Hodgkin’s Lymphoma

For subcutaneous injection for the treatment of follicular non-Hodgkin's lymphoma, single-dose vials of interferon alfa-2b powder for injection containing 10 million units should be reconstituted with 1 mL of the sterile water for injection diluent provided by the manufacturer and the vial gently swirled; the resultant solution contains 10 million units/mL. The appropriate dose of reconstituted solution should be administered subcutaneously undiluted.

Alternatively, the appropriate dose of interferon alfa-2b solution for injection from a multiple-dose vial containing 6 or 10 million units/mL can be administered subcutaneously undiluted.

Melanoma

For use as an adjunct to surgery in the treatment of malignant melanoma, interferon alfa-2b is given initially by IV infusion (induction therapy) and then by subcutaneous injection (maintenance therapy). (See Melanoma under Reconstitution and Administration: IV Administration, in Dosage and Administration.)

For subcutaneous injection for maintenance therapy, single-dose vials of interferon alfa-2b powder for injection containing 10 or 18 million units of the drug should be reconstituted with 1 mL of the sterile water for injection diluent provided by the manufacturer and the vial gently swirled; the resultant solution contains 10 or 18 million units/mL, respectively. The appropriate dose of reconstituted solution should be administered subcutaneously undiluted.

Alternatively, the appropriate dose of interferon alfa-2b solution for injection from a multiple-dose vial containing 6 or 10 million units/mL can be administered subcutaneously undiluted.

Dosage

Hairy Cell Leukemia

The usual adult dosage of interferon alfa-2b for induction of remission in hairy cell leukemia is 2 million units/m² given by IM or subcutaneous injection 3 times weekly. The drug should be administered subcutaneously (not IM) in patients with platelet counts less than 50,000/mm³.

Improvement in one or more hematologic variables generally occurs within 2 months after initiation of interferon alfa therapy in patients with hairy cell leukemia; however, improvement in granulocyte and platelet counts may require up to 6 months or longer of interferon alfa therapy. The manufacturer states that interferon alfa-2b therapy should be continued for up to 6 months; patients who are responding may benefit from continued treatment, but the drug should be discontinued if disease progresses or fails to respond after 6 months of treatment. Some clinicians suggest that therapy with interferon alfa be continued for at least 12 months before discontinuance for nonresponse is considered, unless there is evidence of disease progression. The minimum effective dosage and optimum duration of therapy with interferon alfa for hairy cell leukemia have not been clearly established.

If severe adverse effects occur during interferon alfa-2b therapy, dosage should be decreased by 50% or the drug should be temporarily discontinued. If adverse effects abate, interferon alfa-2b therapy may be resumed using reduced dosage (1 million units/m² 3 times weekly). The drug should be permanently discontinued if severe adverse effects persist or if they recur when reduced dosage is used.

AIDS-Related Kaposi’s Sarcoma

For the treatment of AIDS-related Kaposi’s sarcoma, the manufacturer recommends that adults receive interferon alfa-2b in a dosage of 30 million units/m² 3 times weekly given by IM or subcutaneous injection. The manufacturer states that interferon alfa-2b should be continued until disease progression or maximal response has been achieved after 16 weeks of treatment. Response to interferon alfa is slow, and the maximum effect occurs after 6 or more months of treatment.

If severe adverse effects occur during interferon alfa-2b therapy, dosage should be decreased by 50% or the drug should be temporarily discontinued. If adverse effects abate, interferon alfa-2b therapy may be resumed using reduced dosage. The drug should be permanently discontinued if severe adverse effects persist or if they recur when reduced dosage is used.

Follicular non-Hodgkin’s Lymphoma

If interferon alfa-2b is used in conjunction with anthracycline-containing chemotherapy for the treatment of follicular lymphoma, the manufacturer recommends that adults receive interferon alfa-2b in a dosage of 5 million units given by subcutaneous injection 3 times weekly for up to 18 months.

When interferon alfa-2b is added to the chemotherapy regimen, myelosuppressive drug dosage has been reduced by 25% from full dose and the cycle length increased by 33% (e.g., from 21 to 28 days). The chemotherapy cycle should be delayed if neutrophil counts are less than 1500/mm³ or platelet counts are less than 75,000/mm³.

Interferon alfa-2b therapy should be withheld if neutrophil counts are less than 1000/mm³ or platelet counts are less than 50,000/mm³. Dosage of interferon alfa-2b should be decreased by 50% (2.5 million units 3 times weekly) if neutrophil counts are greater than 1000/mm³ but less than 1500/mm³. If hematologic toxicity resolves (absolute neutrophil count greater than 1500/mm³), interferon alfa-2b dosage may be reescalated to the initial starting dosage (5 million units 3 times weekly). Interferon alfa-2b therapy should be permanently discontinued if serum AST concentrations exceed 5 times the upper limit of normal or if serum creatinine concentrations exceed 2 mg/dL.

Melanoma

For use as an adjunct to surgery in the treatment malignant melanoma, interferon alfa-2b is given in 2 phases (induction therapy and maintenance therapy).

For induction therapy, the recommended adult dosage of interferon alfa-2b is 20 million units/m² daily given by IV infusion 5 consecutive days per week for 4 weeks. For maintenance therapy, the recommended adult dosage of interferon alfa-2b is 10 million units/m² given by subcutaneous injection 3 times weekly for 48 weeks.

If severe adverse effects occur during interferon alfa-2b therapy (e.g., granulocyte counts greater than 250/mm³ but less than 500/mm³, serum ALT and/or AST concentrations greater than 5–10 times the upper limit of normal), the drug should be withheld until adverse effects abate. Interferon alfa-2b therapy may then be resumed at 50% of the previous dosage. If toxicity does not abate when the drug is withheld, serious adverse effects recur with reduced dosage, or granulocyte counts decrease to less than 250/mm³ or serum ALT and/or AST concentrations increase to more than 10 times the upper limit of normal, interferon alfa-2b therapy should be permanently discontinued.

Cautions for Interferon Alfa (Antineoplastic)

Almost all patients experience adverse effects at some time during the course of interferon alfa therapy. However, evaluation of some adverse effects and establishment of a causal relationship to interferon alfa have been difficult since the drug has been used principally in patients with serious underlying diseases, such as acquired immunodeficiency syndrome (AIDS), various cancers, and/or viral hepatitis.

The incidence and severity of many adverse effects associated with interferon alfa therapy may be related to the underlying disease, type and dosage (including duration of therapy) of interferon alfa administered, route of administration (e.g., systemic versus local injection), and age and/or performance status of the patient. Patients receiving relatively low dosages and local administration of interferon alfa (e.g., in the management of exophytic genital warts) generally appear to have a lower incidence of adverse effects compared with patients receiving relatively high systemic dosages (e.g., in the management of AIDS-related Kaposi’s sarcoma), although most types of adverse effects reported with systemic administration of the drug also have been reported with local administration. When administered 2–3 times weekly, interferon alfa doses of 1–9 million units generally are well tolerated while doses of 18 million units or more usually produce moderate to severe adverse effects and those of 36 million units or more usually produce severe adverse effects. Intermittent doses of 50 million units or more rarely are tolerated for periods exceeding 8 weeks, and intermittent or daily doses of 100 million units or more rarely are tolerated for periods exceeding 4–8 or 1–2 weeks, respectively.

The most common adverse effect associated with interferon alfa therapy is a flu-like syndrome, which generally occurs within the first several hours to days and has been reported in up to 98% of patients receiving the drug.

Most of the adverse effects associated with interferon alfa therapy are mild to moderate in degree of severity and diminish in intensity and frequency with continued therapy. However, adverse effects may be severe enough to require discontinuance of the drug in about 3–11% of patients; the likelihood that intolerance will require dosage reduction and/or discontinuance increases with increasing doses. Noncompliance secondary to adverse effects also may increase with increasing doses. Some interferon alfa-induced adverse effects may be alleviated by dosage reduction or may subside despite continued therapy at the same dosage.

Flu-like Syndrome

A flu-like syndrome develops to some degree in almost all patients receiving 1 million units or more of interferon alfa but its severity appears to be dose related. The syndrome is characterized by the development of fever (in about 40–98% of patients), fatigue/malaise (in about 50–95% of patients), myalgia (in about 30–75% of patients), chills (in about 40–65% of patients), headache (in about 20–70% of patients), arthralgia (in about 5–24% of patients), rigors, tachycardia, anorexia, dry mouth, dysgeusia, back pain, sweating, and dizziness. Abdominal cramps and diarrhea also may be associated with the syndrome.

Fever frequently reaches 38–40°C within 6 hours of administration of interferon alfa, generally persists for 2–12 hours if untreated, and usually is preceded by chills, which can be severe. Pretreatment with a nonsteroidal anti-inflammatory agent (NSAIA) or acetaminophen may minimize the risk of developing fever and/or its severity. Such pretreatment also may attenuate some other effects (e.g., myalgia) associated with interferon alfa-induced flu-like syndrome. However, fever usually becomes self-limiting after the first several weeks of therapy, manifesting as a low-grade fever that does not require specific treatment. Therefore, subsequent development of high fever during prolonged interferon alfa therapy should prompt consideration of other possible causes (e.g., infection). The pyrogenic response to interferon alfa therapy may be mediated by a drug-induced increase of hypothalamic prostaglandin (PGE₂) production and/or release rather than by an increase in interleukin-1. This response does not appear to be secondary to an exogenous pyrogenic contaminant in interferon alfa preparations. Patients receiving high doses of interferon alfa (e.g., 50–120 million units) may experience a sharp febrile response accompanied by severe rigors and occasionally may develop peripheral cyanosis, vasoconstriction, nausea, vomiting, severe myalgias, intense headaches, and exhaustion. Transient hypotension and syncope also may occur in these patients, especially when the drug is administered IV.

There is considerable interindividual variation in the development of tolerance to interferon alfa-induced flu-like effects; however, tolerance of such effects appears to be optimized by employing relatively low (e.g., 10 million units or less 3–7 times weekly) dosages of interferon alfa, and such dosages usually permit continuous treatment for prolonged periods. In patients receiving daily interferon alfa therapy, fever and other flu-like symptoms usually diminish within a few days to weeks; malaise often recurs with each dose for the first few weeks of therapy. In patients receiving less frequent, intermittent therapy with the drug, flu-like symptoms may recur with each dose, particularly when the interval between doses exceeds 3 days or therapy is temporarily withheld and subsequently reinstituted.

A persistent and pervasive fatigue, which usually is preceded by fever and is characterized by weakness or tiredness, also can occur as a component of an interferon alfa-induced chronic flu-like syndrome; such patients frequently report a feeling of lassitude and/or lack of motivation to participate in normal activities (e.g., job absenteeism, social withdrawal), thus exhibiting decreased performance status. Fatigue/malaise may be the most prominent adverse effect associated with continued interferon alfa therapy and may include an increased need for sleep, anorexia and weight loss, myalgias, backache, headache, difficulty concentrating, chilliness, and low-grade fever. Although manifestations of this fatigue usually are intermittent, they can be severe enough to substantially impair physical activity and require interruption of therapy. Fatigue may be an important dose-limiting effect of interferon alfa therapy in patients receiving high dosages of the drug; dosage reduction or interruption of therapy with the drug usually is required in such patients but may only ameliorate rather than eliminate such symptoms. Tolerance to fatigue may be enhanced with intermittent dosing schedules, and some patients may better tolerate the drug when it is administered in the evening rather than in the morning. However, persistent and pervasive fatigue also has been reported in patients receiving relatively low dosages (e.g., 2–10 million units/m² three times weekly) of the drug.

It has been postulated that interferon alfa-induced fatigue may result from a neurotoxic effect of the drug preferentially manifesting as a frontal lobe or more generalized encephalopathy. Therefore, some clinicians have suggested that a distinct (from the flu-like syndrome), reversible neurasthenia syndrome may exist. However, the possibility that such manifestations may be secondary to the patient’s underlying condition cannot be excluded, and additional study is necessary. This neurasthenia syndrome has been described as a constant, pervasive, nonspecific symptom complex, manifested characteristically as a psychomotor retardation (i.e., sudden adynamic state with loss of cognitive, verbal, and motor spontaneity, incentive, and interest). While intellectual activity may be disturbed, formal intellect appears to be preserved (i.e., drive rather than ability is impaired). For additional information on these and other adverse nervous system effects, see Cautions: Nervous System Effects.

Musculoskeletal Effects

Myalgia and arthralgia, often associated with a flu-like syndrome, are the most frequent adverse musculoskeletal effects of interferon alfa, occurring in up to 70 and 24% of patients, respectively. These effects generally are transient, mild, and self-limiting. More severe myalgias, generally involving the lower extremities and associated with limitation of movement, have been observed in patients with chronic myelogenous leukemia receiving the drug. Such myalgias frequently require 1–2 weeks of bed rest and corticosteroid and/or analgesic (e.g., opiate) therapy for relief. These severe myalgias generally were not associated with an increase in serum muscle enzymes, and electromyograms have failed to reveal evidence of myositis. Skeletal pain, which frequently is one of the first adverse effects associated with interferon alfa therapy, has been reported in some patients with multiple myeloma who were receiving the drug; however, arthralgias were not observed in patients with metastatic osseous lesions associated with renal cell carcinoma or other malignancies.

Muscle (e.g., leg cramps) and bone disorders have been reported in less than 5% of patients receiving interferon alfa. Back pain, muscle pain, and stiffness of the shoulders have been reported in 1–4% of patients. Muscle weakness, arthrosis, polyarticular arthropathies, and arthritis have been reported in less than 1% of patients receiving the drug. Interferon alfa-associated arthropathies may be autoimmune in nature in some patients.

GI Effects

Anorexia has been reported in about 19–65% of patients with hairy cell leukemia or AIDS-related Kaposi’s sarcoma receiving interferon alfa. Anorexia and associated weight loss also are common in other patients during continued therapy with the drug. Anorexia, which usually occurs after continued dosing of the drug, also may be accompanied by flu-like symptoms and may require dosage reduction. Occasionally, associated weight loss may be striking and dose limiting, especially in patients who were underweight prior to initiating therapy with the drug.

Nausea, vomiting, diarrhea, dysgeusia (metallic or salty taste), and abdominal pain have been reported in about 17–50, 6–50, 20–45, 13–25, and 5–20% of patients, respectively, receiving interferon alfa therapy. Dysgeusia may be particularly likely during initiation of therapy and, at high dosages, may be accompanied by saburral (foulness resulting from accumulation of epithelial matter and debris) tongue and/or halitosis. Hypogeusia (especially for meat) also has been reported, and alterations in taste may be accompanied by alterations in smell. Diarrhea, which can be severe at high doses, generally is watery and usually is not accompanied by abdominal cramps or blood, mucus, or fat in the stools. Nausea rarely may require antiemetic therapy.

Dry mouth or gingivitis has been reported in up to 28 or 14% of patients, respectively, receiving interferon alfa. Stomatitis and eructation has been reported in up to 6% of patients. Dyspepsia, hypersalivation, thirst, GI hemorrhage melena, esophagitis, hyperesthesia of the tongue, discoloration of the GI mucosa, gastric ulcer, oral pain, bleeding gums, and hyperplasia of the gums have been reported rarely.

Nervous System Effects

Although interferon alfa distributes poorly into the CNS, adverse nervous system effects have been reported in patients receiving the drug and have ranged from mild mental disturbances (e.g., anxiety, irritability), fatigue, and headache to more severe delirium and global dysfunction with mental obtundation and stupor. In some cases, the patient’s underlying condition may have contributed to or caused the observed effect. Patients, especially geriatric patients, receiving relatively high systemic dosages of the drug and those with underlying CNS impairment appear to be particularly likely to develop adverse nervous system effects. However, nervous system effects also have been reported in patients receiving relatively low dosages (e.g., 2–10 million units/m² three times weekly) of the drug. Most adverse nervous system effects are mild and rapidly (e.g., within a few days) reversible following dosage reduction or interruption of interferon alfa therapy, although several (e.g., 2–4) weeks may be required for resolution, especially in severe cases.

Depression, suicidal behavior (e.g., suicidal ideation, suicide attempts), and suicides have been reported in association with the use of interferon alfa. If severe depression occurs, discontinuance of interferon alfa therapy generally is required.

The most common adverse nervous system effects associated with interferon alfa therapy are fatigue (usually as a component of a flu-like or neurasthenia syndrome) (see Cautions: Flu-like Syndrome), headache, malaise, and dizziness, which have been reported in up to 95, 10–50, 20–70, and 9–40% of patients, respectively. Headache also may be a component of a flu-like syndrome and, in some cases, was described as migraine. Depression (including exacerbation of underlying depression, which can be debilitating), circumoral and/or peripheral paresthesias (e.g., tingling of the extremities), unspecified pain, altered mental status, amnesia, and confusion have been reported in up to 28, up to 21, up to 17, up to 17, up to 14, and up to 12% of patients, respectively, receiving interferon alfa therapy. In some patients, especially geriatric patients, with malignancy receiving relatively high systemic dosages of the drug, alterations in mental status have been severe, manifesting as substantial mental obtundation and coma. In addition, paresthesia may be severe in some patients and may be more likely in patients previously exposed to vinca alkaloid therapy. (See Antineoplastic Agents: Vinca Alkaloids, in Drug Interactions.)

Somnolence, sleep disturbances (e.g., hypersomnia, insomnia), anxiety, hypoesthesia, nervousness, emotional lability, and vertigo have been reported in 5% or less of patients receiving interferon alfa. Lethargy, tremor, hallucinations, abnormal thinking, psychomotor retardation, stupor, coma, stroke, and transient ischemic attacks have been reported in less than 1% of patients receiving interferon alfa. Impaired coordination, extrapyramidal reactions, paralysis, bradykinesia, hypertonia, dysphasia, and aphasia also have been reported in less than 1% of patients receiving the drug.

Patients receiving interferon alfa also have developed decreased tendon reflexes, hyporeflexia, mild to marked motor loss, and slowing of motor and sensory conduction velocities. Such changes were suggestive of a mild sensory motor neuropathy; in some patients with preexisting neurologic dysfunction and/or receiving high dosages of the drug, severe neurotoxicity (e.g., polyradiculopathy) and neurogenic muscle atrophy (e.g., neuralgic amyotrophy) were reported. Exacerbation of neurologic manifestations also has been reported in some patients with multiple sclerosis following initiation of interferon alfa therapy. (See Cautions: Precautions and Contraindications.)

Reversible EEG abnormalities, which may be severe, have been reported in patients receiving interferon alfa and were characterized by progressive slowing of background activity, with a dominant slowing of alpha rhythm and appearance of diffuse slow waves (e.g., theta and delta), and mainly involved the frontal and temporal lobes. Other EEG abnormalities (e.g., paroxysmal bursts of moderate- to high-voltage frontal rhythmic delta waves) also have been reported. Seizures have been reported occasionally in patients receiving the drug. The risk of EEG abnormalities does not appear to correlate with serum interferon alfa concentrations, and the drug generally was undetectable in the CSF of these patients. However, the risk of such abnormalities may be increased with increasing dosages, and some patients may tolerate reduced interferon alfa dosages.

EEG abnormalities reported in patients receiving interferon alfa often have been associated with profound but selective CNS dysfunction (e.g., psychomotor retardation, marked somnolence, fatigue, confusion, disorientation, social withdrawal, general mental slowing, expressive dysphagia) that was characteristic of a frontal lobe neurasthenia syndrome. However, other clinicians have described the syndrome as a more complex and generalized encephalopathy. The syndrome also may mimic viral encephalitis. Patients with manifestations of this syndrome most notably exhibit a sudden adynamic state (psychomotor retardation) that includes loss of higher mental function such as cognitive, verbal, and motor spontaneity, incentive, expressions, gestures, and interest; such patients may exhibit moderate to severe behavioral changes. Loss of libido also may occur. The mechanism(s) for this possible neurotoxic reaction has not been elucidated, although alterations in central neurotransmitters may contribute, at least in part, since metoclopramide or methylphenidate occasionally have reversed neuropsychiatric effects associated with interferon alfa therapy.

Other neuropsychiatric effects associated with interferon alfa therapy have included phobias, obsessional thoughts and rituals, tearfulness, delirium (which may include clouding of consciousness, agitation, paranoia, and suicidal ideation), disruption of interpersonal relationships, irritability, and psychosis. In some cases, the patient’s underlying condition may have contributed to the observed effects. Difficulty in concentration, mental clouding, disorientation to time and space, visuospatial disorientation, numbness, and speech disorders also have been reported. Delirium appears to be the most severe adverse neuropsychiatric effect associated with interferon alfa therapy and appears to be a continuum of such effects since patients developing delirium usually are irritable, depressed, withdrawn, and agitated and occasionally suicidal, paranoid, and anxious. In patients receiving relatively low doses of the drug, delirium appears to occur only rarely and probably only in patients with underlying CNS dysfunction (e.g., those with a history of CNS insult or injury). Tearfulness that develops in some patients receiving interferon alfa usually is labile, often unpredictable and uncontrollable (e.g., characterized by excessive sentimentality), and out of proportion to the precipitating situation (e.g., gestures of kindness, viewing television news).

Patients with a history of brain injury, severe substance abuse, or brain dysfunction such as mild organic brain syndrome associated with early hepatic failure may be at increased risk of developing delirium. In addition, the risk of adverse neuropsychiatric effects appears to be increased with increasing dosages. However, even during long-term interferon alfa therapy at relatively low dosages, neuropsychiatric effects reportedly occur in up to 20% of patients, and they are some of the most frequent reasons for dosage reduction or discontinuance of the drug during prolonged therapy. Patients with a history of alcohol or substance abuse may be vulnerable to interferon alfa-induced neuropsychiatric effects during prolonged therapy, developing craving, fear of recidivism to abuse, or actual relapse; therefore, such patients should be advised of the possibility of this effect and offered counseling if necessary.

Because the goal of interferon alfa therapy generally is to continue therapy if possible until the optimum benefit is achieved, efforts aimed at detecting and managing adverse psychiatric effects often become important during prolonged therapy. It is important that patients and their partners and family members be apprised of the potential for such effects and encouraged to aid clinicians in early detection. They should be advised that the onset of these effects often is insidious, and they initially may manifest as irritability and resultant problems at work or with interpersonal relationships. Tolerance of interferon alfa-induced adverse neuropsychiatric effects can be increased by providing encouragement, counseling, and reassurance that the effects are drug related and generally resolve once therapy is complete; dosage adjustment and symptomatic management may be required. Simple reassurance that irritability and associated effects are caused by interferon alfa and will decrease with dosage adjustment often is sufficient to relieve anxiety and make the effects tolerable. When irritability and associated symptoms are severe, reassurance may be insufficient to enable the patient to function socially or control their mood and behavior; dosage reduction (e.g., by one half) in such cases may improve neuropsychiatric manifestations within a few days. There is limited evidence that methylphenidate or metoclopramide may provide relief in some patients, but controlled studies are needed to confirm this finding. Rarely, discontinuance of interferon alfa therapy may be necessary. If delirium or severe depression occurs, dosage reduction or interruption of interferon alfa therapy generally is required. Limited data suggest that fluoxetine may be useful in treating depression associated with interferon alfa therapy. Because of the potential severity of delirium, discontinuance of interferon alfa and close observation (e.g., in a hospital setting) has been recommended for patients who develop this effect.

Hematologic Effects

Adverse hematologic effects occur frequently in patients receiving interferon alfa but, unlike the marked myelosuppression that frequently occurs with conventional antineoplastic (cytotoxic) agents, interferon alfa generally is mildly myelosuppressive and produces hematologic toxicity that generally is well tolerated and transient. Hematologic toxicity occasionally may be apparent within a few hours of interferon alfa administration and may not be cumulative. The incidence of adverse hematologic effects appears to be decreased in patients with exophytic genital warts receiving local, low-dose therapy compared with patients with AIDS-related Kaposi’s sarcoma or other malignancies.

The predominant manifestations of interferon alfa-induced hematologic toxicity include leukopenia (mainly neutropenia), anemia, and thrombocytopenia, which occur in about 3–69, 5–69, and 3–42% of patients, respectively. Thrombocytopenia and anemia generally are well tolerated, although thrombocytopenia occasionally may be severe enough to require discontinuance of interferon alfa. Marked decreases in erythrocytes can occur in patients with preexisting anemia. Leukopenia (e.g., granulocytopenia) also occasionally may be severe enough to require discontinuance of the drug. Reductions in interferon alfa dosage can ameliorate decreased blood cell counts. Following discontinuance of interferon alfa therapy, recovery from leukopenia and/or thrombocytopenia generally are rapid (e.g., within a few days), while recovery from anemia generally is slow (e.g., within weeks to a few months). Despite these adverse hematologic effects associated with interferon alfa therapy, patients generally do not experience abnormal blood loss, evidence of hemolysis, or bleeding diathesis. However, transient myelosuppression occasionally may be severe enough to require red blood cell and/or platelet transfusions.

Leukopenia, which may occur within a few hours of administration of interferon alfa, usually is asymptomatic and dose-related, may be dose-limiting, and may result both from granulocytopenia and lymphocytopenia. Leukopenia may improve following conversion to intermittent (e.g., every 3 or more days) administration or interruption of interferon alfa therapy. Interferon alfa-induced leukopenia appears to result from reversibly impaired bone marrow release of mature cells and/or from depletion or sequestration of circulating leukocytes rather than from direct myelotoxicity (e.g., maturation arrest). However, there is in vitro evidence that interferons may inhibit myeloid and erythroid progenitor cells. In patients with normal pretreatment blood cell counts, the risk of infection may not be increased substantially by interferon alfa-induced leukopenia since the leukocytic response to infection does not appear to be impaired by the drug in such patients. However, leukopenia may be more frequent and severe in patients with multiple myeloma or lymphoma, and these and other patients with preexisting leukopenia may be at increased risk of infection during interferon therapy.

Decreased hemoglobin concentration have occurred in patients, receiving chronic interferon alfa therapy. Prolonged administration of the drug occasionally may result in a normochromic, normocytic anemia; recovery from anemia generally requires weeks to months following discontinuance of interferon alfa, suggesting that some interference with erythropoiesis may be involved. Positive direct antiglobulin (Coombs’) test results occasionally have been observed in patients receiving interferon alfa. Rarely, immunologically mediated hemolytic anemia has occurred, which generally improved following discontinuance of the drug and administration of corticosteroids; anemia recurred in several patients who were rechallenged with the drug.

Interferon alfa-induced thrombocytopenia usually is mild and asymptomatic and generally develops slowly over several weeks, and its incidence appears to be related to the patient’s underlying condition. Patients with chronic lymphocytic leukemia or multiple myeloma appear to be at increased risk of developing thrombocytopenia during therapy with drug compared with patients with solid tumors. Platelet counts usually reach a nadir within 2–4 weeks. In some patients (e.g., those with malignant erythrocytosis or thrombocytosis associated with renal cell carcinoma or chronic myelocytic leukemia), the anemic and thrombocytopenic effects of interferon alfa may be therapeutically beneficial. Immunologically mediated thrombocytopenia (e.g., as reflected by platelet-associated immunoglobulin) has been reported rarely and disappeared following discontinuance of the drug and administration of corticosteroids. In several patients, thrombocytopenia has recurred following rechallenge with interferon alfa, and in at least one such patient, the drug subsequently was tolerated following splenectomy. Occasionally, immunologically mediated thrombocytopenia may be severe and result in bleeding complications. In a patient with preexisting thrombocytopenic purpura, rapid deterioration of the purpura, which became unresponsive to corticosteroid and IV immune globulin therapy, occurred following initiation of interferon alfa therapy; the patient died several weeks later from intracerebral hemorrhage. Purpura and cyanosis have been reported in less than 1% of patients receiving interferon alfa therapy. Petechiae have been reported rarely, but a causal relationship to interferon alfa has not been established. In some patients with leukemia who were receiving interferon alfa therapy, prolongation of prothrombin and partial thromboplastin times occurred.

Hepatic Effects

Increased serum concentrations of AST (SGOT) and ALT (SGPT) have been reported in about 10–50% of patients receiving interferon alfa therapy, although such increases appear to be dose-related and have been reported in up to 80% of patients receiving relatively high dosages of the drug. In addition, increases in these enzymes generally are more marked in patients with preexisting elevations. Increased serum concentrations of LDH, alkaline phosphatase, and bilirubin also have been reported frequently in patients receiving the drug, although less commonly than increased aminotransferase (transaminase) concentrations. Changes in LDH and alkaline phosphatase concentrations occur principally in patients with preexisting abnormalities and do not necessarily correlate with aminotransferase changes. Increases in hepatic enzymes generally are mild to moderate and transient. (See Cautions: Precautions and Contraindications.) However, substantial increases occasionally may occur in patients receiving relatively high dosages of interferon alfa; such increases generally are reversible following dosage reduction or discontinuance of the drug. Elevations of serum aminotransferase concentrations generally return to normal within several days to a week following discontinuance of interferon alfa.

Respiratory Effects

Dyspnea, cough (which may be nonproductive), pharyngitis, sinusitis, and drying of the oropharynx have been reported in up to 34% of patients receiving interferon alfa and may be severe. Nasal congestion, rhinitis, and rhinorrhea have been reported in up to 2–10% of patients. Antihistamines reportedly may alleviate some of these symptoms. Pulmonary infiltrates, pneumonitis, and pneumonia have been reported rarely in patients treated with interferon alfa; fatalities reportedly have occurred. Such effects have been reported most frequently in patients with chronic hepatitis C virus (HCV) infection receiving interferon alfa, but they also have occurred in patients receiving the drug for oncologic diseases. The etiology of these adverse effects has not been established. Epistaxis, drainage of sinus secretions, throat tightness, wheezing, and bronchospasm have been reported less frequently. Pneumonia or respiratory disorder was reported in at least one patient receiving the drug. While a causal relationship has not been established, some clinicians suggest that immunomodulating effects of interferons could predispose to the development of pulmonary sarcoidosis during prolonged therapy.

Dermatologic, Sensitivity, and Immunologic Reactions

Dermatologic Reactions

The most common adverse dermatologic effects of interferon alfa are rash and transient alopecia or thinning of the hair, which occur in about 25% or less of patients.

Interferon alfa-induced rash, which may be maculopapular, papular, macular, or urticarial, generally is intermittent or transient, does not require dosage reduction, and does not progress to more serious manifestations. Rash occurs most frequently on the extremities and trunk and, occasionally, on the neck and may be accompanied by pruritus and erythema. In several patients with rash, skin testing failed to show evidence of a true hypersensitivity reaction, and limited evidence suggests that some local erythematous reactions may result in part from a direct interferon alfa-induced vasodilation. In at least one patient with repeated flare-ups of rash, skin biopsy revealed evidence of mild vasculitis. While it previously was believed that many adverse dermatologic effects associated with interferon alfa therapy resulted from impurities in early preparations of the drug rather than from the drug itself, experience with currently available purified preparations suggests otherwise.

Interferon alfa-induced alopecia usually has been associated with prolonged (e.g., 3 months or longer) therapy and is manifested as thinning and slight to mild hair loss, which occasionally becomes more marked when therapy with the drug is interrupted. Hair loss generally is reversible but often persists for 1–3 months after discontinuance of interferon alfa; occasionally, an irreversible androgenetic (male-pattern) alopecia has developed in patients receiving prolonged therapy. It has been suggested that alopecia and hair thinning may result from the cytotoxic activity of interferon alfa. In addition, hair loss in some patients may be a manifestation of hypothyroidism associated with interferon alfa therapy. (See Cautions: Endocrine Effects.) Excessive growth of eyelashes also has been reported, and abnormal hair texture has been reported rarely.

Dry skin and dermatitis have been reported in approximately 8–13% of patients receiving interferon alfa. Excessive sweating or night sweats have been reported in 2–8% of patients. Acne, nail disorder, epidermal necrolysis, photosensitivity, skin discoloration, and exfoliative dermatitis have been reported less frequently.

In some patients with psoriasis, interferon alfa exacerbated the disease within 2–4 weeks of initiation of therapy with the drug for other conditions. Endogenous interferons (e.g., gamma and possibly alfa) have been detected in psoriatic blister fluid from patients with the disease, suggesting that local production of interferons may contribute in part to the pathogenesis of this skin condition.

Cutaneous vascular lesions with punctate telangiectasis have developed in patients with malignant melanoma who were receiving interferon alfa. The lesions developed principally on the trunk and extremities, but not at the sites of injection, after 4–8 months of therapy and showed histologic evidence of increased production of epidermis and proliferation of mature dermal blood vessels; it was suggested that these effects may have resulted indirectly secondary to interferon alfa-induced effects on interleukin-1 and/or epidermal thymocyte activating factor.

Sensitivity Reactions and Autoimmune Disorders

Severe, acute hypersensitivity reactions, characterized by urticaria, angioedema, bronchoconstriction, or anaphylaxis, have been reported rarely with interferon alfa. If a severe hypersensitivity reaction occurs during interferon alfa therapy, the drug should be discontinued and the patient given appropriate therapy. Sensitivity to allergens, which may be severe, has been reported occasionally in patients receiving interferon alfa, and anaphylactic reactions have been reported rarely. Autoimmune diseases, which rarely were fatal, including thrombocytopenia, vasculitis, Raynaud’s phenomenon, rheumatoid arthritis, lupus erythematosus, and rhabdomyolysis, have occurred in patients receiving interferon alfa. The mechanism(s) of these effects has not been determined, and a direct causal relationship to interferon alfa has not been established. Patients who develop an autoimmune disease while receiving interferon alfa therapy should be monitored closely and the drug discontinued if necessary. In addition, a systemic lupus erythematous (SLE)-like syndrome, manifested as myalgia, low-grade arthritis, leukopenia, and a high titer of antinuclear (ANA) and anti-double-stranded DNA antibodies, was observed in at least one patient receiving interferon alfa and resolved following administration of a corticosteroid and discontinuance of the drug; the syndrome recurred following interferon alfa rechallenge. Antinuclear antibodies also have been reported in other patients receiving the drug, some of whom had positive titers prior to therapy. There is some evidence to suggest that interferons (particularly alfa) may be involved, at least in part, in the pathogenesis of SLE. Parotitis and epididymitis, which were described as allergic or autoimmune reactions and subsequently progressed to unilateral scrotal and bilateral facial parotid swelling, also have been reported in at least one patient receiving the drug; resolution occurred 1 week after discontinuance of interferon alfa therapy but manifestations returned following rechallenge. Other possibly autoimmune sequelae of interferon alfa therapy have included hemolytic anemia, thyroid abnormalities, and hepatitis.

Antibody Formation

Numerous studies have confirmed that interferon neutralizing antibodies, probably of the IgG class, develop occasionally in patients receiving natural, partially purified interferons as well as in those receiving highly purified recombinant interferons, but their clinical importance has not been fully established. Such antibodies also can be present in patients with no history of exposure to exogenous interferon preparations. The prevalence of interferon neutralizing antibodies has not been clearly elucidated, in part because of differences in detection methods, sampling times, and interest in monitoring. In studies in which antibodies were monitored, the reported prevalence of their development showed considerable variability, ranging from 0–30% in patients receiving interferon alfa--2b. There is some evidence to suggest that patients with renal cell carcinoma or Kaposi’s sarcoma may be at increased risk of developing neutralizing antibodies to interferon alfa. The reason for the increased risk of developing antibodies in these patients is not known, but it has been suggested that exogenously administered interferon alfa may induce phenotypic changes in these tumor cells and that newly exposed antigens may cross react with the interferon alfa molecule. Some, but not all, evidence suggests that the risk of developing neutralizing antibodies increases with increasing duration of interferon alfa therapy. In addition, other factors such as type of interferon preparation, dose, dosing regimen, and route of administration have been suggested to affect the risk of antibody development, but carefully designed, comparative studies using standardized assay techniques are needed to more fully elucidate the relative risk associated with various interferon preparations and regimens.

The presence of interferon alfa neutralizing antibodies does not appear to alter the spectrum, incidence, or severity of interferon alfa-associated adverse effects, and dosage adjustment or interruption of therapy usually is not necessary; however, some evidence suggests that certain adverse effects occasionally may abate once such antibodies develop. Patients with detectable levels of interferon alfa neutralizing antibodies do not appear to be at increased risk of developing adverse effects that might be attributable to immune complex formation (e.g., renal, lung, or articular disorders or collagen vascular disease), and no correlation appears to exist between the development of interferon alfa neutralizing antibodies and the development of interferon alfa-associated autoimmune factors (e.g., antinuclear or antithyroid antibodies, rheumatoid factor) or disorders.

While many patients who develop interferon neutralizing antibodies continue to respond to interferon alfa therapy, other patients, some of whom had previously responded to therapy with the drug, exhibit evidence of disease progression and decreased serum interferon concentrations as neutralizing antibodies develop. In patients who continue to respond to interferon alfa therapy despite the development of antibodies, data are conflicting regarding the effect of such antibodies on the duration of response; some evidence suggests that the duration of response may be adversely affected (i.e., shortened), while other evidence suggests that the time to onset and the duration of response, including survival rates, are not affected.

Anti-interferon antibodies elicited by recombinant DNA-derived preparations usually do not neutralize the natural, partially purified, multispecies human interferon alfa obtained from leukocytes but instead neutralize a restricted range of recombinant DNA-derived interferon alfa species. Preliminary evidence suggests that patients who develop anti-interferon antibodies and show evidence of disease progression while receiving recombinant interferon alfa therapy may respond to treatment with a preparation of natural interferon alfa (e.g., a purified preparation of natural leukocyte interferon). There also is evidence that antibodies to recombinant interferon alfa-2a (no longer commercially available in the US) or interferon alfa-2b can cross-react with some naturally occurring interferon alfa subtypes. In addition, limited evidence suggests that some neutralizing antibodies to interferon alfa-2a also can neutralize interferon alfa-2b. Therefore, substituting one recombinant interferon alfa preparation for another may not provide effective second-line therapy in patients who develop anti-interferon antibodies to a given interferon preparation and show evidence of disease progression.

Renal, Electrolyte, Fluid, and Genitourinary Effects

Proteinuria is the most common adverse renal effect associated with interferon alfa therapy and occurs in about 15–20% of patients. Proteinuria generally is mild, rarely exceeds 1 g daily, is not associated with a decrease in serum protein, and has not been clearly related to prior renal impairment or to dose of interferon alfa. Urinary excretion of leukocytes and erythrocytes have been reported in about 5–14% of patients. Increased BUN and serum creatinine concentrations have been reported in up to 10% of patients. The possibility that the patient’s underlying condition (e.g., multiple myeloma) may have contributed to the development of renal dysfunction should be considered. However, in some patients with multiple myeloma and preexisting light-chain proteinuria, interferon alfa was well tolerated and did not produce worsening of renal function.

Acute renal failure and nephrotic syndrome accompanied by interstitial nephritis and minimal change nephropathy have been reported rarely in patients receiving interferon alfa; manifestations in such patients have included peripheral edema, marked nonselective proteinuria, and decreased creatinine clearance. Renal function improved following discontinuance of interferon alfa, but adverse renal effects recurred upon rechallenge with the drug. Nephrotic syndrome, secondary to membranoproliferative glomerulonephritis and associated with hypertension and proteinuria, has been reported in at least one patient receiving long-term interferon alfa therapy. Although measurements of urinary albumin and β₂-microglobulin in a limited number of patients receiving short-term (up to 28 days) interferon alfa therapy did not reveal glomerular or tubular lesions, glomerulonephritis has been reported in animals receiving high doses of the drug, and the drug has produced nephrotoxic effects at the proximal renal tubule cell membrane (e.g., inhibition of glucose and alanine uptake) in animals similar to those produced by other low-molecular-weight proteins.

Dehydration has been reported in less than 1% of patients receiving interferon alfa, and may be secondary to fever, loss of appetite, and/or other factors. Some patients receiving high dosages of the drug have developed hyperkalemia and hypercalcemia. Hyponatremia, probably secondary to a syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and hypocalcemia also have been reported in some patients receiving high dosages.

Transient impotence has been reported in up to 6% of patients receiving interferon alfa. Micturition disorders, nocturia, dysuria, and polyuria occurred in 1% or less of patients receiving the drug. Menstrual irregularities also have been reported.

Ocular and Otic Effects

Visual disturbances have been reported in up to 7% of patients receiving interferon alfa. Ocular pain, including that associated with ocular rotation, blurred vision, and stye (hordeolum) formation have been reported in 1–6% of patients receiving the drug. Conjunctivitis, lacrimal gland disorder, photophobia, and abnormal vision have been reported in less than 1% of patients, and periorbital edema has been reported in at least one patient. Retinal hemorrhages, cotton-wool spots, and retinal artery or vein obstruction have been observed rarely in patients receiving interferon alfa, but the mechanism of these adverse effects has not been determined. Although most cases of interferon alfa-associated visual loss have been mild and nonprogressive, at least one patient receiving interferon alfa-2b as adjuvant therapy (following surgical resection of melanoma at high risk of recurrence) experienced permanent and irreversible loss of visual function. Adverse retinal effects develop most commonly after several months of therapy with the drug; however, such effects occasionally have developed in patients receiving interferon alfa for shorter periods. Therefore, patients who experience ocular disturbances or changes in visual acuity or in visual fields during interferon alfa therapy should have an ophthalmologic examination. Baseline ophthalmologic examinations are recommended prior to initiation of interferon alfa therapy. (See Cautions: Precautions and Contraindications.)

Hearing disorders have been reported in less than 5% of patients and earache and tinnitus in less than 1% of patients receiving interferon alfa therapy.

Endocrine and Metabolic Effects

Thyroid dysfunction (hypothyroidism or hyperthyroidism) has been reported occasionally in patients receiving interferon alfa and, in some patients, may not resolve spontaneously following discontinuance of the drug. Most such cases reported to date were in patients receiving the drug for the treatment of breast cancer, carcinoid tumors, or chronic HCV infection. However, the possibility that any patient receiving interferon alfa could develop thyroid abnormalities should be considered. In some patients, clinical manifestations as well as laboratory evidence of thyroid dysfunction were observed, and thyroidal therapy (thyroid replacement for hyperthyroidism, antithyroid agents for hyperthyroidism) was required. Although the mechanism by which interferon alfa may alter thyroid function has not been established, antibodies to thyroid microsomal antigen, thyroid receptors, and thyroglobulin have been observed in interferon-treated patients with thyroid dysfunction, suggesting an autoimmune mechanism (e.g., Graves’ disease, thyroiditis). While a causal relationship to interferon alfa has not been clearly established, and some evidence suggests that interferon gamma present as a contaminant in interferon alfa preparations may in part be responsible, thyroid dysfunction has been reported in patients receiving highly purified interferon alfa preparations and a temporal relationship has been observed. If manifestations of possible thyroid dysfunction develop in a patient receiving interferon alfa, the patient’s thyroid function should be evaluated and appropriate therapy instituted if needed. Interferon alfa therapy should be discontinued in patients whose serum thyrotropin concentrations cannot be maintained in the normal range with antithyroid therapy or hormone replacement therapy, depending on the thyroid dysfunction. However, thyroid dysfunction is not always reversible by discontinuance of the drug.

Increased concentrations of follicle-stimulating hormone (FSH, follitropin) and low concentrations of testosterone have been reported occasionally in patients receiving interferon alfa. Serum estradiol and progesterone concentrations were decreased in certain women and in at least one man receiving the drug. Inconsistent fluctuations of prolactin, somatotropin (growth hormone), thyrotropin (TSH), and insulin also were observed in some of these women. Gynecomastia and loss of libido have been reported in less than 5% and virilization in less than 1% of patients receiving interferon alfa. Increased serum concentrations of 11-hydroxycorticosteroids also have been reported.

Weight loss, which often is associated with anorexia (see Cautions: GI Effects) and may be severe, has been reported in up to 25% of patients receiving interferon alfa therapy. Cachexia has been reported in less than 1% of patients receiving interferon alfa. Interferon alfa has produced glycosuria in healthy adults.

Hypertriglyceridemia, which has been severe (e.g., serum triglyceride concentration exceeding 1000 mg/dL) in some cases but reversible upon drug discontinuance, has been reported in patients receiving interferon alfa. (See Cautions: Precautions and Contraindications.) Serum total and/or HDL-cholesterol concentrations have decreased or increased in patients and healthy individuals receiving the drug.

Cardiovascular Effects

The most common adverse cardiovascular effects of interferon alfa therapy include edema (e.g., facial, peripheral) and hypotension, which occur in up to 9% of patients. Certain adverse cardiovascular effects (e.g., tachycardia, vasoconstriction, distal cyanosis, hypotension) may be related to the febrile reaction that occurs frequently during initial therapy with interferon alfa, and substantial hemodynamic changes may occur in some patients. Hypotension may occur during administration of interferon alfa or up to 2 days after therapy and may be severe, requiring dosage reduction and/or supportive therapy such as fluid replacement to maintain intravascular volume; however, hypotension that develops gradually during interferon alfa therapy may not respond to volume repletion. The risk of hypotension appears to increase with age and increasing dosages. Chest pain, which may be severe, and vasodilation have been reported in less than 5% of patients receiving interferon alfa. Flushing also has been reported in less than 5% of patients receiving the drug, and vasovagal reactions, heat intolerance, and hot sensation at the bottom of the foot have been reported in 2% or less of patients.

Cardiac arrhythmias, which were mainly supraventricular (e.g., paroxysmal atrial tachycardia, sinus tachycardia, atrial fibrillation), have been reported in less than 3% of patients receiving interferon alfa therapy, although ventricular arrhythmias (e.g., ventricular premature complexes) also have been reported. Most individuals in whom cardiac arrhythmias occurred were geriatric patients and some had preexisting heart disease, a history of arrhythmias, or received a potentially cardiotoxic drug (e.g., doxorubicin). Rarely, arrhythmias associated with interferon alfa therapy may be life-threatening. Hypertension and palpitations have been reported in less than 3% of patients receiving interferon alfa.

Cardiomyopathy, which generally is reversible, has been reported in up to 2% of patients receiving interferon alfa. Cardiomyopathy has been reported in some patients without a history of heart disease. Frank manifestations of congestive heart failure (e.g., cardiomegaly, pulmonary congestion, pleural effusions, T-wave flattening, fluid retention, shortness of breath, dyspnea) can occur in these patients, and it has been suggested that patients with limited cardiac reserve may be at risk of developing congestive heart failure secondary to acute cardiovascular changes associated with severe febrile reactions induced by interferon alfa. A causal relationship to the drug has not been established, but a temporal relationship was observed in several case reports. In several patients with AIDS-related Kaposi’s sarcoma who developed cardiomyopathy during prolonged, high-dose therapy with the drug, it was suggested that a synergistic interaction between the HIV infection and interferon alfa may have been responsible in part for the observed myocardial depression. However, other mechanisms (e.g., interferon alfa-induced impairment of myocyte metabolic processes) also appear to be involved. The incidence of hypotension, arrhythmias, and cardiomyopathy in patients with preexisting heart disease is not known. These adverse cardiovascular effects may require dosage reduction, discontinuance of interferon alfa, or supportive therapy. In patients without preexisting cardiac dysfunction, return to normal function can occur following discontinuance of the drug.

Raynaud’s phenomenon, bradycardia, cardiac failure, peripheral ischemia, and syncope have been reported in less than 1% of patients receiving interferon alfa therapy. Sudden death and/or myocardial infarction also have been reported rarely (in less than 1% of patients); these adverse effects usually occurred in individuals with a prior history of heart disease, including previous myocardial infarction and ischemic heart disease (e.g., angina), and a causal relationship to interferon alfa has not been established. However, myocardial infarction also has been reported in some patients without a history of heart disease. Nonmalignant pericardial effusion has been reported in at least one patient with renal cell carcinoma who received interferon alfa, suggesting the possibility of an interferon-induced perimyocarditis.

Local Reactions

Adverse local effects associated with parenteral administration of interferon alfa generally have been mild to moderate and were reported in up to 12–20% of patients. Burning, pruritus, pain, edema, erythema, rash, and vesiculation may occur at the injection site. Aseptic skin necrosis was reported in a few patients after inadvertent intra-arterial injection of interferon alfa.

Infectious Complications

Infectious complications have been reported in patients receiving interferon alfa, possibly secondary in part to neutropenia induced by the drug. Patients with preexisting cirrhosis (hepatic decompensation) and those with multiple myeloma, lymphoma, or other preexisting leukopenia may be at increased risk of developing such complications during therapy with the drug. Serious bacterial infections (e.g., cellulitis, septicemia, peritonitis, pneumonia, lung abscess, brain abscess) appear to be particularly likely during interferon alfa therapy for viral hepatitis in patients with cirrhosis, being reported in 5 of 7 such patients in one study. Candidiasis (moniliasis) has been reported in up to 18% of patients with AIDS-related Kaposi’s sarcoma receiving relatively high doses of the drug; the infection has been reported less frequently in other patients receiving lower dosages. Exacerbation or reactivation of herpes simplex (e.g., herpes labialis) has been reported in 1–8% of patients receiving the drug. Abscess formation, furunculosis, viral or fungal infections, nonherpetic cold sores, and sepsis occurred in less than 1% of patients receiving the drug. Swollen lymph nodes and lymphadenopathy have been reported in 1% of patients, and mucositis has been reported in at least one patient.

Precautions and Contraindications

Interferon alfa-2b is contraindicated in patients with known hypersensitivity to interferon alfa or any ingredient in the preparation. If a severe hypersensitivity reaction occurs during interferon alfa therapy, the drug should be discontinued and the patient given appropriate therapy.

Interferon alfa-2b is contraindicated in patients with autoimmune hepatitis or decompensated liver disease.

Interferon alfa may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be closely monitored with periodic clinical and laboratory evaluations and the drug discontinued in those with persistently severe or worsening signs or symptoms of these disorders. In many, but not all cases, these disorders resolve after interferon alfa is discontinued.

The potential benefit to the patient must be carefully weighed against the possible risks involved, and the patient should be apprised of these risks. Patients should be instructed about the proper use of interferon alfa and should read the patient information and medication guide provided by the manufacturer.

Interferon alfa should be used with caution in patients with a history of preexisting psychiatric disorders, especially those with a history of depression. All patients receiving interferon alfa should be informed that depression and suicidal ideation may be adverse effects of treatment and should be advised to immediately report these effects to a clinician if they occur. All patients should be closely monitored for evidence of depression and other psychiatric symptoms. Patients who develop such symptoms should be carefully monitored during therapy and for 6 months after discontinuing therapy. If symptoms persist or worsen, or suicidal ideation or aggressive behavior toward others is identified, interferon alfa should be discontinued and the patient followed with appropriate psychiatric intervention. If severe depression and/or other psychiatric condition develops, interferon alfa therapy should be discontinued immediately and appropriate psychiatric intervention provided.

Use of interferons may be associated with exacerbation of psychiatric symptoms in patients with concomitant psychiatric and substance use disorders. When initiating treatment in patients with a history of psychiatric conditions or substance use disorders, clinicians should consider the need for drug screening and periodic clinical evaluation, including psychiatric symptom monitoring. Re-emergence or development of neuropsychiatric symptoms or substance use should prompt early intervention.

Because interferon therapy has been associated with fever and flu-like symptoms (see Cautions: Flu-like Syndrome), the drug should be used with caution in patients with debilitating diseases such as cardiac disease (e.g., unstable angina, uncontrolled congestive heart failure), pulmonary disease (chronic obstructive pulmonary disease), or diabetes mellitus (who may be prone to ketoacidosis). The acute and generally self-limiting manifestations associated with the flu-like syndrome may exacerbate these preexisting conditions. In addition, the drug also should be used with caution in patients with cardiac disease or a history of any cardiac condition since hypotension, arrhythmias, myocardial infarction, sudden death, and cardiomyopathy have been reported occasionally in patients receiving the drug. (See Cautions: Cardiovascular Effects.) Patients with a history of cardiac disease must be monitored carefully when receiving interferon alfa therapy. Electrocardiographic monitoring should be performed prior to initiating and periodically during interferon alfa therapy in patients with preexisting cardiac disease and/or advanced stages of cancer. Certain adverse cardiovascular effects, (e.g., tachycardia, vasoconstriction, distal cyanosis, hypotension) may be related to the febrile reaction that occurs frequently during initial therapy with interferon alfa, and the drug should be used with caution in individuals with limited cardiac reserve. Because patients with underlying massive hemangiomas also may be at increased risk of developing substantial hemodynamic changes during initiation of interferon alfa therapy, the hemodynamic status of such patients should be monitored closely when therapy with the drug is started and for several days thereafter; if such changes occur, dosage should be reduced or the drug discontinued, and supportive and symptomatic care should be initiated as necessary.

Pulmonary infiltrates, pneumonitis, and pneumonia have been reported rarely in patients treated with interferon alfa; fatalities have occurred. Baseline chest radiographs are suggested before interferon alfa therapy is initiated, and should be performed when clinically indicated in patients who develop fever, cough, dyspnea, or other respiratory symptoms. If there is evidence of pulmonary infiltrates or pulmonary function impairment, the patient should be closely monitored and, if appropriate, interferon alfa should be discontinued. Recurrence of respiratory failure has occurred with interferon rechallenge.

Although fever frequently occurs during initiation of interferon alfa therapy, any change in pattern of fever should be regarded as a possible sign of some underlying condition (e.g., infection) rather than assumed to be induced by the drug. In addition, the subsequent development of high fever during prolonged interferon alfa therapy should prompt consideration of such other possible causes. The possibility that patients with viral hepatitis and cirrhosis and those with multiple myeloma, lymphoma, or other preexisting leukopenia may be at increased risk of infection during interferon alfa therapy should be considered. (See Cautions: Hematologic Effects and Cautions: Infectious Complications.)

Increased serum concentrations of AST and/or ALT have been reported in patients receiving interferon alfa. (See Cautions: Hepatic Effects.) Therefore, the drug should be used with caution in patients with hepatic disease, and liver function tests should be performed prior to initiating interferon alfa therapy and periodically thereafter. In patients with melanoma, liver function tests should be monitored weekly during the induction phase and monthly during the maintenance phase of interferon alfa therapy.

Adverse renal effects and fluid and electrolyte abnormalities (e.g., dehydration) have been reported occasionally in patients receiving interferon alfa. (See Cautions: Renal, Electrolyte, Fluid, and Genitourinary Effects.) In addition, all patients should be well hydrated during interferon alfa therapy, especially during initial stages of therapy. Electrolytes should be evaluated prior to initiation of therapy with the drug and monitored periodically thereafter. Because of the risk of acute rejection episodes, interferon alfa should be used with caution in renal transplant recipients, particularly when relatively high doses are considered. (See Cautions: Renal, Electrolyte, Fluid, and Genitourinary Effects.)

Because of the risk of potential adverse nervous system effects associated with interferon alfa therapy (see Cautions: Nervous System Effects), the drug should be used with caution in patients with seizure disorders, brain metastases, and/or compromised CNS; the drug should only be used in these patients if the possible benefits of therapy outweigh the potential risks. Because of the risk for adverse CNS effects and possible symptomatic exacerbation of previously asymptomatic brain lesions, some clinicians state that consideration should be given to performing computerized tomography scans prior to initiation of interferon alfa therapy in patients with malignancies that have a high incidence of brain metastasis; if brain metastases are detected, the drug should be used with caution and high doses probably should be avoided. In addition, all patients receiving interferon alfa should be monitored periodically for the possible development of drug-related neuropsychiatric effects; efforts at early detection and intervention are important, since a possible association to interferon alfa therapy may be overlooked by the patient until their life has been severely affected. (See Cautions: Nervous System Effects.) Because partners or family members may be the first to observe such changes, they should be advised that the drug can induce changes in mood and personality that potentially can affect interpersonal relationships. Patients should be warned that interferon alfa may impair their ability to perform hazardous activities requiring mental alertness (e.g., operating machinery, driving a motor vehicle), especially at high doses, and that CNS depressants (e.g., opiates, sedatives) should be used concomitantly with caution. In addition, because the drug can cause mental clouding and impair concentration ability, especially at high doses, patients whose job or life-style requires unimpaired intellectual function should be advised that their mental abilities may be impaired during interferon alfa therapy.

Baseline ophthalmologic examinations should be performed in all patients prior to initiation of interferon alfa therapy. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive ophthalmologic examinations periodically during therapy. A prompt and complete ophthalmologic examination should be performed in any patient who develops ocular symptoms; the drug should be discontinued in patients who develop new or worsening ophthalmologic disorders .

Serum TSH concentrations should be determined prior to initiation of interferon alfa therapy since thyroid dysfunction (hypothyroidism or hyperthyroidism) has been reported occasionally in patients receiving interferon alfa. Patients with preexisting thyroid dysfunction whose serum thyrotropin concentrations cannot be maintained in the normal range with antithyroid therapy or hormone replacement therapy should not receive interferon alfa therapy. In addition, if manifestations of possible thyroid dysfunction develop in a patient receiving interferon alfa, the patient’s thyroid function should be evaluated and appropriate therapy instituted if needed. (See Cautions: Endocrine and Metabolic Effects.)

Patients with preexisting diabetes mellitus and those who develop diabetes mellitus during interferon alfa therapy may continue to receive interferon alfa as long as their diabetes can be controlled with drug therapy. Patients with diabetes that cannot be controlled with drug therapy should discontinue interferon alfa therapy.

The possibility that interferon alfa may precipitate or exacerbate manifestations of autoimmune disorders (e.g., arthropathies, systemic lupus erythematosus, psoriasis, hemolytic anemia, thrombocytopenia, hepatitis, sarcoidosis) should be considered in patients receiving the drug. (See Cautions: Hepatic Effects.) In addition, since potentially fatal autoimmune diseases have occurred in patients receiving interferon alfa (see Cautions: Sensitivity Reactions and Autoimmune Disorders), patients who develop an autoimmune disease while receiving interferon alfa therapy should be monitored closely and the drug discontinued if necessary.

Interferon alfa should be used with caution in patients with myelosuppression and in those receiving drugs that may be myelosuppressive. Complete blood cell counts, platelet counts, and appropriate blood chemistry tests should be performed before initiating interferon alfa therapy and periodically thereafter. In patients with melanoma, differential leukocyte counts should be monitored weekly during the induction phase and monthly during the maintenance phase of interferon alfa therapy. Interferon alfa should be used with caution in patients with coagulation disorders (e.g., thrombophlebitis, pulmonary embolism, hemophilia), preexisting leukopenia, or increased risk of infection.

Because substantial increases in serum triglyceride concentrations have been reported with interferon alfa therapy, some clinicians suggest that serum triglyceride concentrations be monitored during interferon alfa therapy. (See Cautions: Endocrine and Metabolic Effects.) Since hypertriglyceridemia may result in pancreatitis, discontinuance of interferon alfa therapy should be considered in patients with persistently elevated triglycerides (e.g., serum triglyceride concentration exceeding 1000 mg/dL) associated with symptoms of potential pancreatitis (e.g., abdominal pain, nausea, vomiting).

Pancreatitis, sometimes fatal, has occurred in patients receiving interferon. Interferon alfa should be suspended in patients with signs and symptoms of pancreatitis (e.g., abdominal pain, nausea, vomiting); the drug should be discontinued if a diagnosis of pancreatitis is established.

Pediatric Precautions

Safety and efficacy of interferon alfa-2b have not been established in pediatric patients for any indications other than treatment of chronic hepatitis B virus (HBV) and chronic HCV infection.

In general, adverse effects (e.g., fever, chills, GI effects, nervous system effects, hematologic effects, hepatic effects, local effects at the injection site) observed in adolescents and younger children appear to be dose related, generally reversible, and similar to those observed in adults, although children may be more likely than adults to develop alopecia or thinning of the hair during prolonged therapy. In addition, delay in weight and height increases compared with baseline have been reported in pediatric patients receiving interferon alfa for the treatment of chronic HBV or HCV infection.

Geriatric Precautions

Clinical studies of interferon alfa have not included sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults. In studies evaluating use of interferon alfa in conjunction with oral ribavirin, geriatric patients had a higher frequency of anemia (67%) than younger patients (28%). There also is some evidence that adverse cardiovascular effects and confusion are reported more frequently in geriatric patients than in younger adults. Alterations in mental status associated with interferon alfa therapy can be severe in geriatric patients; mental obtundation and coma have been reported. (See Cautions: Cardiovascular Effects and Cautions: Nervous System Effects.)

Interferon alfa should be used with caution in geriatric patients because of age-related decreases in hepatic, renal, bone marrow, and/or cardiac function and concomitant disease and drug therapy. Dosage reduction or interruption of interferon alfa therapy and/or initiation of appropriate supportive measures may be necessary.

Mutagenicity and Carcinogenicity

Studies using interferon alfa-2b (Intron A) have not shown evidence of mutagenicity. Studies to determine the carcinogenic potential of interferon alfa-2b have not been performed to date.

Pregnancy, Fertility, and Lactation

Pregnancy

Interferon alfa should be used during pregnancy only when potential benefits justify possible risks to the fetus. Women of childbearing potential should use an effective method of contraception during therapy with the drug.

Although there are no adequate and controlled studies to date in humans, interferon alfa-2b has exhibited abortifacient activity in rhesus monkeys when given in dosages of 15 and 30 million units/kg daily (estimated human equivalent of 5 and 10 million units/kg, respectively, based on body surface area adjusted for a 60-kg adult).

Fertility

Interferon alfa may impair fertility. Menstrual cycle abnormalities have been observed in nonhuman primates and menstrual cycle irregularities and decreased serum estrogen and progesterone concentrations have been reported in humans receiving interferon alfa. Impaired spermatogenesis and transient impotence have been reported occasionally. Interferon alfa-2b should be used with caution in fertile males.

Lactation

It is not known whether interferon alfa is distributed into milk, but murine interferons distribute into milk in mice. Because of the potential for serious adverse effects to interferon alfa in nursing infants if the drug were distributed into milk, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Antineoplastic Agents

Interferon alfa should be used with caution in patients receiving drugs that are potentially myelosuppressive.

The antineoplastic activity of interferon alfa and certain cytotoxic agents (e.g., cisplatin, cyclophosphamide, doxorubicin, eflornithine [difluoromethylornithine, DFMO], fluorouracil, mechlorethamine, melphalan, methotrexate, mitomycin, nitrosoureas, vinblastine, vincristine) may be additive or synergistic in vitro and in vivo against some tumors. However, animal and in vitro studies may not accurately predict human response, and results of preliminary clinical studies using various combinations of interferon alfa and conventional antineoplastic agents generally have been disappointing. The mechanism(s) of potential synergistic activity has not been fully elucidated, but it appears to be complex. In addition, the resultant activity appears to depend not only on the specific cytotoxic drug that is combined with interferon alfa, but also on the concentrations, relative amounts, and duration and sequence of exposure of the drugs. Further studies are needed to determine the potential interactions between interferon alfa and antineoplastic agents, and to establish the optimum regimens, including dosages and sequencing.

There is some evidence to suggest that combined therapy with interferon alfa and vinblastine or etoposide may produce greater systemic toxicity without enhanced therapeutic benefits in patients with AIDS-related Kaposi’s sarcoma. (See the discussions on Vinca Alkaloids and on Etoposide that follow.)

Interferon alfa combined with carmustine or eflornithine has produced additive or synergistic antineoplastic activity in vitro and in animal models. While the clinical importance of these experimental data remains to be determined, limited evidence from clinical trials suggests that combined therapy with interferon alfa and carmustine, dacarbazine, or eflornithine does not appear to produce unacceptable toxicity but may be beneficial in some advanced cancers. Further long-term, controlled studies are needed to establish the potential therapeutic benefits of these combinations.

Vinca Alkaloids

Limited data indicate that the antineoplastic activity of interferon alfa and vinblastine does not appear to be additive against renal cell carcinoma^† or AIDS-related Kaposi’s sarcoma. However, vinblastine may potentiate the toxicity of interferon alfa when these drugs are used concomitantly. In patients with metastatic renal cell carcinoma, increased incidence and/or severity of hepatic toxicity and hematologic toxicity were reported with the addition of vinblastine to interferon alfa. In a limited number of patients with AIDS-related Kaposi’s sarcoma, the incidence of nausea, vomiting, thrombocytopenia, hepatic dysfunction, and fever usually was comparable to that observed with interferon alfa alone, but granulocytopenia, neurotoxicity, and malaise occurred at a higher incidence and with a greater degree of severity in patients receiving vinblastine concomitantly with interferon alfa; 70% of the patients with AIDS-related Kaposi’s sarcoma experienced severe fatigue, chills, and asthenia.

Neurotoxicity (e.g., paresthesia, peripheral neuropathy) in patients receiving interferon alfa usually occurs more frequently in those who have previously received or are concomitantly receiving vinca alkaloids (e.g., vinblastine, vincristine). The mechanism of this additive neurotoxic effect is not known; however, mild sensorimotor neuropathy was observed in patients who underwent neurologic evaluation. Some clinicians suggest that high doses of interferon alfa may produce severe neuronal lesions and neurogenic muscle atrophy.

Etoposide

Response rates in patients with AIDS-related Kaposi’s sarcoma receiving combination chemotherapy with interferon alfa and etoposide suggest that the combination has no synergistic antineoplastic activity against this malignancy, and the incidence of toxicity (e.g., hematologic effects) is higher with the combination than with either drug alone.

Antiviral Agents

Antiretroviral Agents

Concomitant use of interferon alfa and zidovudine can increase the risk of hematologic (e.g., neutropenia, thrombocytopenia) and hepatic toxicity. The increased risk of such toxicity may be synergistic, although the mechanism of such potential synergy is not known. In a study in patients with AIDS-related Kaposi’s sarcoma in which tolerance to varying subcutaneous interferon alfa dosages of 5–35 million units daily and oral zidovudine dosages of 50–250 mg every 4 hours daily were evaluated, the incidence of neutropenia, thrombocytopenia, and hepatic toxicity was higher than expected (based on experience with either drug alone) in patients receiving a 100- or 250-mg regimen of zidovudine combined with interferon alfa. In addition, interferon alfa dosages of 15 units or more daily were not tolerated in any patient receiving the 100- or 250-mg zidovudine regimen. Life-threatening toxicity, consisting of acute respiratory decompensation that possibly was caused by intrapulmonary hemorrhage associated with severe thrombocytopenia, developed 5 days after initiation of interferon therapy and resolved in at least one patient within a week after discontinuance of therapy.

Potentially fatal hepatic decompensation has been reported in HIV-infected patients coinfected with hepatitis C virus (HCV) who received antiretroviral therapy concomitantly with interferon alfa with or without ribavirin. Patients receiving zidovudine with interferon alfa with or without ribavirin should be closely monitored for toxicities (e.g., hepatic decompensation, neutropenia, anemia). Discontinuance of zidovudine should be considered as medically appropriate. Dosage reduction or discontinuance of interferon alfa and/or ribavirin also should be considered if worsening clinical toxicities, including hepatic decompensation (e.g., Child-Pugh score exceeding 6), occur.

Although no major alterations in the pharmacokinetics of zidovudine or interferon alfa were apparent in HIV-infected patients with Kaposi's sarcoma receiving both drugs, a trend for increased area under the plasma concentration-time curve (AUC) and decreased clearance of zidovudine after 3 weeks of administration of interferon alfa was observed in some other patients.

HCV Antivirals

In vitro, interferon alfa-2b and boceprevir have had additive effects against HCV without evidence of antagonism.

In vitro, interferon alfa and simeprevir have had synergistic effects against HCV; there is no in vitro evidence of antagonism.

There is no in vitro evidence of antagonistic anti-HCV effects between interferon alfa and sofosbuvir or telaprevir.

Telbivudine

Peripheral neuropathy has been reported when alfa interferons were used concomitantly with telbivudine. In one study, increased risk and severity of peripheral neuropathy were observed in patients receiving conjugated interferon alfa (peginterferon alfa-2a) concomitantly with telbivudine compared with those receiving telbivudine alone. The safety and efficacy of concomitant use of telbivudine with any interferon for treatment of chronic hepatitis B virus (HBV) infection have not been established.

Biologic Response Modifiers

Aldesleukin

Hypersensitivity reactions, consisting of erythema, pruritus, and hypotension, have been reported in patients receiving combination regimens that included sequential administration of high-dose aldesleukin and antineoplastic agents, specifically, interferon alfa, dacarbazine, cisplatin, and tamoxifen. These hypersensitivity reactions occurred within hours of administration of chemotherapy, and medical intervention was required in some patients.

Interferon alfa used in combination with aldesleukin has been associated with the development or exacerbation of autoimmune disease and inflammatory disorders. Exacerbation or presentation of thyroiditis, inflammatory arthritis, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis, Stevens-Johnson syndrome, or bullous pemphigoid has been reported following concurrent use of interferon alfa and aldesleukin. In one patient who developed rapidly progressive renal failure following combination therapy with interferon alfa and aldesleukin for metastatic renal cell carcinoma, renal biopsy revealed crescentic glomerulonephritis.

The incidence of myocardial injury, including myocardial infarction, myocarditis, ventricular hypokinesia, and severe rhabdomyolysis, appears to be increased in patients receiving concurrent interferon alfa and aldesleukin.

Effects on Hepatic Clearance of Drugs

Interferon alfa has been shown to inhibit the metabolism of theophylline, possibly via the hepatic cytochrome P-450 (microsomal) enzyme system. (See Pharmacology: Effects on Cytochrome P-450 System.) It is not known whether interferon alfa itself interacts with the cytochrome P-450 enzyme system or the drug exerts this effect through an interaction with the immune system. Concomitant use of interferon alfa with theophylline in healthy adults or in patients with chronic active hepatitis B has prolonged the terminal elimination half-life and increased areas under the plasma concentration-time curves (AUCs) of theophylline by reducing hepatic clearance of the drug. Concomitant use of interferon alfa and theophylline has resulted in a 100% increase in serum theophylline concentrations. It appears that the reduction of hepatic clearance of theophylline was greatest in individuals who were the fast metabolizer phenotype.

Interferon alfa also may inhibit metabolism of barbiturates. Initiation of interferon alfa in a patient stabilized on phenobarbital resulted in increased serum phenobarbital concentrations and manifestations of toxicity (e.g., lethargy, fatigue). Although these adverse effects can be induced by interferon alone, associated serum phenobarbital concentrations of 54 mcg/mL suggested that they were manifestations of barbiturate toxicity. While the mechanism of this potential interaction was not determined, it was suggested that inhibition of barbiturate metabolism may have resulted from inhibition of the hepatic cytochrome P-450 enzyme system.

Further studies and experience are needed to establish the clinical importance of this potential drug interaction and to determine whether interferon alfa interacts with other drugs that are metabolized by the hepatic cytochrome P-450 (microsomal) enzyme system. It has been reported that interferon alfa also inhibits the metabolism of antipyrine.

Radiation Therapy

Interferon has been used as an adjunct to radiation therapy in patients with various neoplasms; however, severe toxicity has been reported in some patients receiving such combined therapy. Severe oral mucositis, manifested by ulceration, bleeding, soreness, or edema of the lips, tongue, oral mucosa, oropharynx, or esophagus, has been reported in a limited number of patients with AIDS-related Kaposi’s sarcoma receiving concomitant administration of interferon alfa and radiation therapy. Severe mucositis, accompanied by airway obstruction, respiratory distress, life-threatening hemorrhage, or oropharyngeal edema, also has been reported in some patients with chronic myelogenous leukemia receiving interferon alfa and total body irradiation prior to bone marrow transplantation. In some patients with small cell lung cancer, interferon alfa appeared to potentiate the effects of radiation therapy; an increased incidence of severe radiation pneumonitis and esophagitis has been observed in these patients. Interferons may have either radioprotective or radiosensitizing properties, depending on the tumor cell type and/or type of interferon; however, some other evidence suggests that the drugs may not affect cellular sensitivity to radiation.

Patients receiving interferon alfa with radiation therapy should be closely monitored. Further studies are needed to evaluate the exact nature of interaction between radiation and interferon alfa therapy and to determine the safety and efficacy of the concomitant administration of these therapies.

Acute Toxicity

Studies in mice, rats, and cynomolgus monkeys receiving parenteral recombinant interferon alfa-2b 0.1 or 1 million units daily; 4, 20, or 100 million units/kg daily; and 1.1 million units/kg daily or 0.25, 0.75, or 2.5 million units/kg daily, respectively, for up to 9 days, 3 months, and 1 month, respectively, have revealed no evidence of toxicity. However, in cynomolgus monkeys receiving parenteral recombinant interferon alfa-2b 4, 20, or 100 million units/kg daily for 3 months, toxicity was observed at the mid- and high doses and mortality was observed at the high dose. Because interferon alfa-induced effects generally are species specific, animal toxicity studies may not be predictive of human response.

Resistance

Cells that are sensitive to the antiviral and antiproliferative effects of interferon alfa possess specific high-affinity saturable interferon receptor sites on their cell surface; however, the presence of such receptors is not necessarily a sufficient criterion for ensuring cellular sensitivity to the drug. Tumor cells may be resistant to the antiproliferative effects of interferon alfa despite the presence of functional, specific high-affinity interferon receptors on their cell surface. Resistance to the antiproliferative effects of interferon alfa usually occurs at the cellular level; however, the precise mechanism responsible for resistance to the drugs may differ among cell populations.

An association has been observed between the presence of neutralizing anti-interferon antibody and clinical resistance to interferon alfa in some patients with hairy cell leukemia, suggesting that resistance to the drug may not always arise at the intracellular level. However, a causal relationship between the presence of antibodies and disease progression and/or resistance to interferon alfa therapy was not established, and some patients who developed neutralizing antibodies to interferon continued to respond to the drug. Therefore, the development of antibodies should not necessarily be interpreted as indicating resistance to the drug. For a more complete discussion of anti- interferon antibodies, see Dermatologic, Local, Sensitivity, and Immunologic Reactions: Antibody Formation, in Cautions.

Pharmacology

Mechanism of Action

Interferon alfa exists as at least 23 proteins and, occasionally, glycoproteins that possess complex antiviral, antineoplastic, and immunomodulating activities. Interferons, including interferon alfa, are biologic response modifiers. Endogenous interferon alpha is produced and secreted in response principally to viral (especially double-stranded RNA viruses) infection mainly by peripheral blood leukocytes (e.g., monocytes; macrophages; non-B, non-T lymphocytes, natural killer [NK] cells) and interferon beta by fibroblasts and epithelial cells, although certain other synthetic and biologic substances (e.g., certain bacteria and other microorganisms capable of intracellular growth, endotoxins, surface glycoproteins, lipopolysaccharides, polynucleotides) also can induce their production. In addition, other cells may produce and secrete these interferons. Interferons are produced endogenously according to information encoded by species of interferon genes, and exert virus-nonspecific antiviral activity, at least in homologous cells, through cellular metabolic processes involving synthesis of RNA and proteins.

The precise mechanisms of action of interferons have not been fully elucidated but appear to be complex, and the resultant activities appear to be substantially interrelated. Unlike classic antiviral and cytotoxic agents, the antiviral and antineoplastic properties of interferons appear to result from a complex cascade of biologic modulation and pharmacologic effects rather than from direct virucidal or cytocidal effects. The drugs affect many cell functions producing restoration, augmentation, and/or modulation of the host’s immune system; direct antiproliferative and antineoplastic activities; modulation of cell differentiation; and modulation of cellular transcription and translation, including a reduction in oncogene expression. Some or all of these effects may be interrelated and ultimately responsible for the antiviral and antineoplastic activity of interferons.

Interferons must bind to specific cell surface receptors in order to exert biologic and pharmacologic effects (e.g., antiviral activity); such binding appears to involve high-affinity sites. In addition, some evidence suggests that the principal effects of interferons result not from direct intracellular actions but rather from ligand-receptor complexes at the cell surface that can mediate and induce intracellular events. The biologic and pharmacologic effects of interferons are relatively species specific, and such specificity may reside at the receptor level. In addition, there is some evidence that while interferon alfa and interferon beta bind to and compete for the same receptors, interferon gamma appears to bind to other receptors and therefore potentially acts via different cellular pathways; synergistic antiviral and antineoplastic activities may result from combined use of interferon gamma with interferon alfa or beta.

The mechanism(s) by which interferons ultimately elicit various intracellular effects has not been fully elucidated, but binding at the cell surface appears to induce differential gene transcription and translation of cellular mRNA; this selective increase in gene expression results in modulation of RNA and protein synthesis. Interferons can either enhance or suppress transcription and translation, with resultant alteration in the synthesis of numerous cellular proteins. However, it is not clear whether intact interferon, interferon degradation products, interferon receptors, or receptor-ligand complexes must be incorporated within the cell to elicit cellular responses, or whether interferon-receptor complexes at the cell surface are capable of generating intracellular signals that mediate interferon modulation of gene expression. Likewise, the importance of a second messenger or other mediators (e.g., cyclic adenosine monophosphate [cAMP], cyclic guanosine monophosphate [cGMP], diacylglycerol, prostaglandins) in eliciting intracellular effects of interferons has not been determined. While changes in intracellular concentrations of cAMP and cGMP occur soon after interferons bind to cell surface receptors, the biologic and pharmacologic importance of these changes is uncertain since the antiviral and antineoplastic effects of interferons do not appear to depend on changes in intracellular concentrations of cyclic nucleotides. Receptor binding of interferons does not activate a protein kinase with tyrosine phosphorylating activity nor does interferon binding inhibit the epidermal growth factor (EGF)-induced increase in protein kinase activity. Inhibition of viral replication is merely one of the multiple biologic effects mediated by interferons that involve selective gene activation and the synthesis of newly induced mRNAs and proteins. The antiviral and antiproliferative effects of interferons depend both on de novo RNA and protein synthesis; however, there is no convincing evidence to suggest that the clinical antineoplastic effects of interferon are linked to the antiviral properties of the drug in humans. The antiviral activity of interferon alfa generally is evident at lower doses than are the antiproliferative effects of the drug.

Antiviral Effects

The antiviral effects of interferons are complex. In addition, the potential therapeutic effect of interferons against viral infections also is complex and appears to depend on the immunomodulating as well as antiviral effects of the drug. Interferons generally can prevent but not cure certain viral infections, although progression of the infection may occur in some cases secondary to adverse immunologic effects of the drugs. Administration of interferons does not directly improve signs and symptoms of viral infections; in fact, endogenous interferons have been implicated as mediating some of the manifestations (e.g., fever, malaise, myalgia) associated with such infections.

Interferon alfa exhibits a broad spectrum of antiviral activity against numerous viruses including human immunodeficiency virus (HIV), human papillomaviruses (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), herpes simplex virus (HSV) types 1 and 2, cytomegalovirus (CMV), varicella-zoster virus (VZV), poliovirus, vaccinia virus, rhinoviruses, coronaviruses, adenoviruses, encephalomyocarditis virus (a cardiovirus), and vesicular stomatitis virus (a vesiculovirus). The antiviral activity of interferons against a given virus appears to depend in part on the host cell and the ability of the interferon to induce an antiviral mechanism within that cell, the inoculum size, and the interferon type and subtype employed.

Interferons exhibit virus-nonspecific antiviral activity through cellular metabolic processes involving synthesis of RNA and proteins. Interferon-induced inhibition of viral replication appears to involve several mechanisms, and different mechanisms may apply to various types of viruses. The degree of viral inhibition may be determined in part by the replicative characteristics of the virus as well as the dose of interferon. Inhibition of viral replication involves several processes, and the replicative properties of the individual virus and the host cell-virus interaction may determine which steps of viral proliferation are affected by interferons. For most viruses, however, inhibition of viral protein synthesis appears to be the principal process involved.

The antiviral properties of interferons generally are only evident when cells are exposed to the drugs before viral exposure. Although interferons may inhibit viral penetration, the drugs generally do not prevent the virion or viral nucleic acid from entering the cell and do not directly produce cellular resistance to viral infection, but rather mediate transcription of mRNA with resultant formation of potent antiviral proteins; such changes in gene expression occur rapidly (e.g., within several hours) after exposure to the drugs. These proteins can inhibit viral replication by inhibiting viral protein synthesis or enhancing the degradation of viral nucleic acid. Interferon-mediated inhibition of mRNA methylation and the drug’s effects on viral uncoating, assembly, and release also may contribute to the antiviral activity.

The antiviral activity of interferons appears to depend in part on two enzymes, a 2′-5′-oligoadenylate synthetase (polymerase) and a protein kinase; synthesis of these enzymes is induced when cells are exposed to the drugs. The activity of these enzyme systems depends on the presence of double-stranded RNA (dsRNA) formed during viral replication, and it has been suggested that interferons may have an effect on dsRNA that contributes to their antiviral activity. Interferon-induced degradation of mRNA and resultant inhibition of protein synthesis, inactivation of transfer RNA (tRNA), and inhibition of post-transcriptional modifications of mRNA are mediated principally by the actions of 2′-5′-oligoadenylate synthetase, protein kinase, and a 2′-phosphodiesterase.

Interferons induce an endonuclease system that can cleave single-stranded RNA regions of the RNA-replicative intermediate of RNA viruses and host-cell single-stranded RNA. Induction of 2′-5′-oligoadenylate synthetase, a nucleotide polymerase and the first enzyme in this system, by interferons converts ATP to several 2′-5′-linked oligonucleotides (polyadenylic acids). In the presence of dsRNA, certain 2′-5′-linked oligonucleotides can activate a latent ribonuclease (endoribonuclease RNase L, RNase F) that cleaves the replicative intermediate of RNA viruses and host single-stranded RNA. The oligonucleotides (polyadenylic acids) also are potent inhibitors of mRNA-dependent protein synthesis and can enhance the degradation of mRNA. Activation of the ribonuclease by the oligonucleotides is reversible. While these effects appear to be involved in the antiviral activity of interferons against RNA viruses, it remains to be elucidated whether the action of interferons on these enzymes also is involved in antiviral activity against DNA viruses.

The presence of the 2′-5′-phosphodiester linkage in these oligoadenylates makes them resistant to most cellular nucleases; however, a 2′-5′-phosphodiesterase that can degrade the oligonucleotides has been detected in murine and human cells. This enzyme, which has greater affinity for 2′-5′- phosphodiester bonds than for 3′-5′ bonds present in DNA and RNA, can rapidly hydrolyze the oligoadenylates to ATP and AMP, can reportedly cleave the cytosine-cytosine-adenine (CCA) terminus from tRNA, and may be responsible for the reversible tRNA inhibition of translation in interferon-treated cells.

In addition to effects of the drugs on gene transcription, interferons reportedly decrease the extent of methylation of cap structures on mRNA transcripts. 5′-Terminal cap structures are present on most eukaryotic cellular and viral mRNA, and the extent of methylation on the cap may influence its stability and the efficacy of translation of proteins, including viral proteins.

Interferons also induce the synthesis of a protein kinase, which, when activated by dsRNA in the presence of ATP, phosphorylates and inactivates one of the proteins (eIF-2) necessary for initiation of elongation (protein synthesis), a ribosome-associated protein P-1, and possibly the enzyme itself. The inactive eIF-2 cannot participate in the initial stage of protein synthesis. The resultant inhibition of protein synthesis can prevent the formation of the viral coat protein and thereby inhibit the formation of viral progeny. While the protein kinase also is capable of phosphorylating other substrates, such as histones, in interferon-treated cells, it is not known whether such substrates are physiologic substrates for the enzyme. The action of the protein kinase can be antagonized by the presence of a phosphoprotein phosphatase that dephosphorylates the phosphorylated P-1 and the eIF-2.

Although the precise role of protein kinase in the antiviral activity of interferons remains to be more fully elucidated, the increase in protein kinase activity induced by interferons correlates well with the establishment of antiviral activity, at least in some virus cell systems, and is a function of the duration of drug exposure and the concentration of interferon. In murine cells, for example, the rate and extent of antiviral activity induced by the drugs have been shown to be correlated with their ability to induce the P-1/eIF-2 protein kinase, suggesting that induction of the enzyme and phosphorylation of eIF-2 may contribute substantially to the antiviral effects of interferons, at least in this cell line. Likewise, declines in antiviral and protein kinase activities have been shown to be correlated, and such activities can be reinduced with subsequent reexposure to interferons. Continuous exposure to interferons prevents the decline in protein kinase activity and prolongs the antiviral activity induced by the drugs. In other virus-cell systems, however, other mechanisms may be principally responsible for the antiviral activity of interferons.

The extent to which the oligoadenylate synthetase and protein kinase systems contribute to the antiviral activity of interferons remains to be more fully elucidated, but other mechanisms also appear to be involved. Viral replication probably can be inhibited at more than one stage of the viral replicative cycle presumably secondary to different mediators of interferon actions, and not all pathways may be functioning in a given interferon-exposed cell. Thus, even within the same cell line, interferons may inhibit the replication of certain viruses but not others.

The biochemical basis for the selectivity of interferons against virus-infected rather than uninfected host cells has not been established. The oligoadenylate synthetase system cannot adequately explain the selectivity of the drugs for viral replication since endoribonuclease RNase L cleaves viral and host mRNA nonselectively in vitro; in some in vivo systems, however, viral protein synthesis is inhibited preferentially with respect to host protein synthesis. It has been suggested that the dsRNA-induced RNase system works at a subcellular level, and that the close proximity of ribosomes, ribosomal RNA, ds-RNA, 2′-5′-oligonucleotide synthetase, polyadenylate, and 2′-phosphodiesterase to each other may contribute to interferon selectivity for virally infected cells. The protein kinase-mediated inhibition of protein synthesis that inhibits binding of tRNA to the ribosome may discriminate between cellular and viral RNA, and may exhibit some selectivity for viral nucleic acid.

Interferons also may inhibit viral replication by augmenting the response of immune effector cells involved in the recognition and killing of virally infected cells. However, interferon-induced inhibition of viral replication does not eliminate the infection; instead, the antiviral effect of the drugs minimizes the viral burden to the host’s immune system. Thus, the antiviral efficacy of interferons depends on the host’s immunologic status.

Antiproliferative Effects

Interferons exhibit antiproliferative (growth inhibitory) activity against normal and malignant cells with resultant antineoplastic effects in vitro and in vivo, and can alter both the structure and behavior of these cells. In addition, the drugs can inhibit the growth of primary tumors as well as metastatic foci. The mechanism(s) of this antiproliferative activity has not been fully elucidated but appears to be complex. The ability of interferons to inhibit or enhance the synthesis of specific proteins, to modify expression of cell surface antigens, and/or to induce modulation of the immune system may be involved. Although some evidence suggests that the antiviral and antiproliferative activities of interferons may share some common biochemical and physiologic pathways, the possible roles of the 2′-5′-oligoadenylate synthetase and protein kinase systems (see Mechanism of Action: Antiviral Effects, in Pharmacology) in mediating the antiproliferative effects of interferons have not been clearly established. It has been suggested that the oligoadenylate synthetase system may be involved in the regulation of cellular proliferation and may contribute to the antiproliferative effects of interferons, since levels of this enzyme decrease substantially in rapidly proliferating cells and increase when cell growth is inhibited. Other evidence also indicates that the oligoadenylate synthetase system may contribute to the antiproliferative effects of interferon. However, there also is evidence to suggest that no correlation exists between the antiproliferative activity of interferons and induction of these enzyme systems by the drugs, and, in some studies, the relative antiproliferative activity of various interferons actually was the reverse of the relative antiviral activity.

The antineoplastic activity of interferons may result from a direct antiproliferative effect on the tumor cell and/or the ability of the drugs to induce a host response to the tumor. However, the drugs generally do not appear to be directly cytocidal to tumor cells; instead, the cytostatic effects of interferons may decrease the rate of cell proliferation to a level incompatible with cell survival. Interferons also may alter the host-tumor relationship by affecting host humoral factors (e.g., growth factors) or by modulating the response of immune effector cells (e.g., natural killer [NK] cells, T and B cells). However, evidence from studies in immunocompromised mice suggests that inhibition of tumor growth by interferons can occur independently of certain cellular immunologic mechanisms of the host. The ability of the drugs to modify cell surface morphology and function may result in altered transport of substances necessary for cell survival and thus contribute to their antiproliferative activity. The biologic effects of interferons on the host also may contribute to their antineoplastic properties since interferon-induced inhibition of tumor growth has been observed with some malignant cell lines despite resistance of the cells to the antiproliferative properties of the drugs. In addition, interferons have exhibited antineoplastic activity against tumors that lacked receptors for the drug, suggesting that an indirect effect may have been responsible for the observed activity against some cells.

Inhibition of Cell Division

Interferon-induced prolongation of the cell cycle appears to be principally responsible for the antiproliferative effects of the drugs. Interferons inhibit or reduce the synthesis of RNA and protein during the G₁ (first “gap,” post-mitotic, or presynthesis) phase of the cell cycle that is required for cells to enter the S (DNA synthetic) phase of the cell cycle. Interferons also inhibit ornithine decarboxylase, the rate-limiting enzyme in the synthesis of polyamines, which are necessary for the assembly of DNA. Interferons prolong all phases of the cell cycle, induce cells to enter the nonproliferative G₀ (resting) phase, and delay cells at the G₀/G₁ border from entering the cell cycle; the antiproliferative effects of the drugs may be more pronounced in this latter subpopulation of cells. These antiproliferative effects are dose dependent and reversible, with normal growth rate being restored within 24–72 hours after removal from exposure to the drug. Continued treatment with interferons in vitro and in vivo results in a more prolonged inhibition of cell proliferation. The antiproliferative effects of interferons on normal hematopoietic stem and progenitor cells may be responsible for the reversible myelosuppression that may occur secondary to therapy with the drugs.

The cytostatic property of interferons is not differentially selective for transformed or malignant cell populations, and thus can affect normal cells. Optimum antiproliferative activity generally is attained when interferons are administered repeatedly and are in direct contact with the cells or tumor. Human cell lines reported to be sensitive to the drugs include a lymphoblastoid cell line, osteosarcoma, myeloid leukemia, colon carcinoma, , hepatoma, neuroblastoma, and normal, hyperplastic, and malignant breast tissue. Interferon alfa also inhibits colony formation of transplantable murine tumors and fresh biopsies of human tumors including melanoma, lung cancer, myeloma, ovarian carcinoma, sarcoma, adenocarcinoma of unknown primary origin, acute leukemia, and renal cell carcinoma.

Effect on Cell Phenotype and Oncogene Expression

Interferons can decrease the transcription and expression of several oncogenes (e.g., c-myc, c-mos, c-abl, c-Ha-ras, c-sis, c-src) and in growth factor receptors, and can inhibit the expression of a protein induced by platelet-derived growth factor (the formation of this factor depends on the c-sis oncogene). In some transformed cell lines, this decrease in transcription and expression of the oncogene product has been correlated with inhibition of tumor cell proliferation. Long-term exposure of some transformed cell lines to interferons can lead to a reversion of the cells to a more normal phenotype, characterized by more normal growth characteristics and cellular morphology. This phenotypic reversion has been associated with a specific decrease in oncogene expression and loss of tumorigenicity and oncogenic potential of the cells. The interferon-induced reduction in c-Ha-ras and c-myc RNA appears to be selective for the oncogene transcripts; however, despite this selective decrease in the levels of the oncogene mRNA and the expression of their gene products, interferons do not alter the quantity or distribution of the transfected DNA present in the cell. Interferons principally may act at the level of gene transcription and subsequent mRNA translation; however, some evidence suggests that this effect on oncogene expression may be mediated in part by interferon-induced decreases in the number of copies of viral genome.

It has been suggested that expression of the c-myc gene plays a major role in the malignant transformation of some cells. Therefore, although a causal relationship between modulation of oncogene expression by interferons and growth inhibition has not been established, it has been proposed that the decrease in expression of this and other oncogenes by the drugs may contribute to their antiproliferative activity. Interferon-mediated decreases in the expression of c-myc gene in a Burkitt’s lymphoma cell line has been proposed as a model for interferon-induced cellular differentiation. Decreased c-myc oncogene expression occurs relatively early during interferon exposure and does not appear to be mediated by the accumulation of cells at the₀/G₁ border of the cell cycle. Interferons disrupt DNA replication in these cells in several ways, including inhibiting the synthesis of Okazaki fragments (short segments of base pairs that are formed and subsequently joined during DNA replication) and decreasing the stability of these newly synthesized replicons. A cell line resistant to the antiproliferative effects of an interferon does not exhibit this drug-induced decrease in oncogene expression. Similar observations regarding changes in the expression of c-myc, c-mos, and c-ras genes generally have been noted in patients with hairy cell leukemia who have received interferon alfa therapy, and the gradual reduction in the percentage of cells in bone marrow expressing the Philadelphia chromosome associated with interferon alfa therapy in patients with chronic myelogenous leukemia also may reflect the tendency of the leukemic cells to progress from a malignant phenotype and genotype toward a more normal nonmalignant state.

Limited evidence suggests that oncogenes present in transformed cell lines may modulate cellular sensitivity to different types of interferons, resulting in some cell types that are resistant to the effects of one interferon type (e.g., gamma) while sensitive to another interferon type (e.g., alfa). Interferons can inhibit the growth of numerous cell lines, without altering the level of the c-myc mRNA transcript or distribution of cells in the cell cycle, and can block the platelet-derived growth factor (PGDF)-induced stimulation of cell proliferation without affecting the increased expression of c-myc that precedes this stimulation. However, other evidence indicates that the importance of modulation of oncogene expression and alterations in phenotypic expression and differentiation of malignant cells in the antineoplastic activity of interferons remains to be established.

Effect on Cell Differentiation

Interferons generally enhance cellular differentiation, but can inhibit the functional and morphologic differentiation of some cells (e.g., fibroblasts). Interferons can alter the phenotypic expression of pre-natural killer (NK) cells and lymphocytes (e.g., T cells) and can augment the expression of Fc receptors on the cell surface of immune effector cells that require these receptors for immunologic reactivity. These changes in phenotypic expression, interferon-mediated increases in phagocytosis by macrophages or monocytes, augmentation of antibody-dependent cell-mediated cytotoxicity by killer (K) cells, and enhancement of histamine release by basophils presumably are related to the ability of interferons to modulate cellular differentiation. Interferons also can enhance or inhibit the maturation of normal monocyte and macrophage precursors, activate monocytes and macrophages, and enhance the differentiation of a human leukemic cell line to macrophages and/or granulocytes. Evidence from studies in which interferons stimulated their own immunologic neutralization by augmenting the expression of certain cell surface antigens also indicates that the drugs enhance cell differentiation.

Other Antiproliferative Mechanisms

There is limited evidence that some of the biologic and pharmacologic effects, including antiproliferative effects, of interferons may be mediated in part by prostaglandins. Prostaglandins can modulate cell proliferation and function as immunomodulators, and interferons have been shown to stimulate prostaglandin biosynthesis. In addition, the absence of cyclooxygenase in some cells may explain the resistance of these cells to the antiviral and antiproliferative effects of interferons. However, prostaglandins also produce effects on the immune system that can oppose those induced by interferons. In addition, cyclooxygenase inhibitors and exogenous prostaglandins have complex effects on the biologic activity of interferons, and interferons do not appear to affect phospholipase or cyclooxygenase activities. Further study is needed to establish the role, if any, of the cyclooxygenase system and prostaglandins in the biologic effects mediated by interferons.

It also has been suggested that the biologic and pharmacologic effects of interferons may be related partly to their ability to alter intracellular concentrations of cyclic nucleotides (e.g., cAMP, cGMP). Cells exposed to cyclic nucleotide derivatives or agents that increase the intracellular concentration of cyclic nucleotides exhibit increased sensitivity to the antiviral and antiproliferative properties of interferons. Interferon-induced elevations in the concentration of cAMP and cGMP occur prior to or concomitantly with the development of the antiproliferative and antiviral effects of the drugs and do not occur in cells resistant to the effects of interferons. However, such increases in cAMP and cGMP apparently are not essential to the antiviral and antiproliferative actions of interferons, since blocking these increases does not reduce the activity of the drugs. In addition, because of the complex role of cyclic nucleotides in the regulation of cell proliferation, it remains to be determined whether these second messengers have an established role in mediating these effects of interferons.

Effects on Cell Plasma Membrane

Agents (e.g., amphotericin B, colchicine, vinblastine) that alter plasma membrane and cytoskeletal components can inhibit the antiviral effects of interferons, whereas agents (e.g., sodium butyrate) that increase synthesis of microfilaments and the number of cellular desmosomes may enhance the action of interferons. Interferons can alter the cell surface expression of gangliosides and other membrane components and can decrease the unsaturated fatty acid content of major phospholipids, which may lead to a more rigid lipid bilayer in the plasma membrane and a decrease in cell motility. The overall cellular net charge becomes more negative, as does the intramembranous charge.

Interferons can alter the ion flux across plasma membranes and can increase neuronal excitability, decrease the release of plasminogen activator from the plasma membrane, increase the size and number of actin filaments, alter the cell surface distribution of fibronectin, and increase cell volume and surface area. These changes in cell size and degree of arrangement, polymerization, and amount of actin generally correlate with a decrease in the rate of cell proliferation.

Interferons also can alter nucleoside transport and cell surface antigen and immunoglobulin expression and can produce a relative increase in histocompatibility antigens on lymphocytes. Expression of membrane receptors for Fc fragments of IgG and IgM can be increased and decreased, respectively, by interferons alfa or beta.

Immune System Effects

Interferons are cytokines that exhibit complex and variable immunologic activity, including both immunomodulating and immunosuppressive effects. The immunomodulating activity of interferons may have important effects on the immunologic relationship between tumors and the host. However, despite the wide range of regulatory actions of interferons on the immune system and the possibility that these actions may contribute at least in part to the antineoplastic activity of the drugs, there currently is little direct evidence to support the theory that the antineoplastic activity of interferons depends on their effects on the immune system. While interferons generally exhibit similar pharmacologic actions, including many actions involving the immune system, differences between interferon types appear to be greatest for immunologic effects, with interferon gamma appearing to be the most distinct, particularly in its macrophage (phagocyte)-activating properties.

Interferons can influence the proliferation of immune effector cells, such as those that are cytotoxic to tumor cells, and can also modulate antibody production and the release of other lymphokines (e.g., interleukin-2 [IL-2], MIF, LIF), which may be important in the host’s immune response to tumors. Interferons also may alter host response to tumors and other cells by modulating the expression of cell surface antigens, including major histocompatibility antigens (e.g., interferon alfa increases class I histocompatibility molecules on lymphocytes and interferon gamma increases both class I and II molecules) and tumor-associated antigens, which may alter the immunogenicity of tumor and other cells. Interferons also can enhance natural killer (NK) cell activity and macrophage activity, although there currently is no direct evidence that such enhancement of the cytotoxicity of immune effector cells is responsible for the therapeutic effects of interferons. While some evidence also suggests that the effect of interferons on the host immune system may be an important determinant of the antiproliferative activity of the drugs and that the antineoplastic activity of interferons may be mediated in part by their effects on the host’s immune system, other evidence suggests that the effects of the drugs on host response may be mediated by nonimmune mechanisms, such as depletion of growth factors and inhibition of angiogenesis and stroma development.

Interferons, principally interferon gamma but also interferon alfa, can modulate cellular and humoral immune responses and can enhance the cytotoxicity of immune effector cells and the phagocytic activity of macrophages. In addition, the secretion of interferons alfa and beta is increased in activated macrophages, and mature B cells express receptors for interferons that probably contribute as governing signals to the complex immune responses of these cells. Interferon gamma appears to be a particularly important macrophage-activating cytokine (lymphokine); this interferon type, but not alfa or beta, exhibits clinically important effects on the production of intracellular, superoxide radicals that are capable of mediating killing activity against certain microorganisms. There also is limited evidence that interferons can stimulate lymphocytic infiltration. Although interferons can enhance antibody production, the effect of the drugs on the production of antibody to tumor-associated antigens has not been clearly established.

Interferons also may augment cytotoxicity of cytotoxic T cells (CTL, killer T cells) and lymphokine-activated killer (LAK) cells by potentiating interleukin-2 (IL-2) release. While it has been suggested that interferon-mediated stimulation of LAK production may increase the host’s response against tumor cells, some in vitro evidence indicates that interferons can inhibit the proliferation of interleukin-2-stimulated lymphocytes and can inhibit the induction of LAK activity.

Effects on Natural Killer Cell and Killer Cell Activity

Interferons, including interferon alfa, augment natural killer (NK) cell activity, but there reportedly is substantial variation in the ability of the numerous subtypes of interferon alfa to enhance NK-cell activity. NK cells possess some surface characteristics of both the myeloid and lymphoid lineage, and are defined in part by their ability to lyse certain types of tumor cells and normal targets. In animal models, NK cells can inhibit the formation of metastatic foci in the host, and interferons reportedly can augment this antimetastatic effect of these immune effector cells. Interferons augment NK-cell cytotoxicity directly and do not require the presence of an accessory cell population. In vitro, human NK-cell activity may increase 16-fold in the presence of interferon alfa, although substantial individual variation exists in response to interferon enhancement of NK-cell activity.

Interferons enhance NK-cell activity by increasing the proportion of NK cells that become cytotoxic and by decreasing both their cell cycle time and the time required for the cells to lyse their targets. An acceleration in lytic kinetics results, and the increased recyclability of NK cells allows the same effector cell to lyse more than one target. Interferons also can recruit cytotoxic cells from a non-cytotoxic pre-NK cell population that is capable of binding but not lysing target cells and can enhance NK-cell binding to less sensitive targets. Limited data suggest that the recruitment of pre-NK cells may be the principal mechanism by which interferons enhance NK-cell activity. Interferons are only capable of activating pre-NK cells and NK cells when present before these effector cells bind their target cells, and NK cells are activated only while in the presence of interferon. The drugs can enhance NK-cell activity against fresh or freshly frozen tumor cells of diverse origin; however, they consistently have failed to enhance the activity of the same effector cells against autologous tumor cells.

Interferons also may have effects on NK-cell activity that could negatively affect host responses. For example, interferons are capable of protecting malignant cells from NK cell-mediated lysis. Interferons also can inhibit the host’s immune response by decreasing NK-cell activity and by inducing increased resistance to NK cell-mediated lysis. This inhibition of NK cell activity may serve to protect from NK cell-mediated lysis any target cell population that expresses interferon receptors. Some evidence suggests that this protection of target cells from NK cell-mediated lysis may provide a mechanism whereby interferons could activate NK cells to lyse tumor cells preferentially while ensuring that normal cells were protected; however, other evidence indicates that certain malignant cells that possess interferon receptors also can be protected from NK cell-mediated cytotoxicity by preexposure to an interferon. This interferon-induced target cell protection from NK-cell lysis requires de novo RNA and protein synthesis, is specific for NK cell-mediated lysis, and is not accompanied by a decrease in antibody-dependent cellular cytotoxicity. It has been suggested that interferon-induced protection from NK cell-mediated cytolysis actually may result in a slight enhancement of immune-mediated target-cell killing secondary to increased expression of histocompatibility antigens and a stimulation of the alloimmune response from cytotoxic T cells (CTL, killer T cells).

The dose, schedule, and route of interferon administration can have profound effects on NK-cell activity. The optimum dose of interferons required for immune stimulation has not been established, but for interferon alfa, some evidence suggests that lower doses achieve higher NK-cell activity when the drug is administered for sustained periods and that NK-cell activity actually is depressed with continued administration of the drug. Other studies, however, have shown either consistent increases or decreases in NK-cell activity, or have shown individual variation and no consistent changes in such activity. Therefore, it has been suggested that a threshold dose of interferon exists, above which there is a negative influence on NK cells. The long-term effects of interferon alfa on NK-cell activity also have varied, with reports of increases or decreases in such activity. In one study, low-dose interferon alfa produced an increase in NK-cell activity within 48 hours, but this increase was not sustained despite repeated administration of the drug. High-dose interferon alfa gave a more sustained increase of NK-cell activity but did not produce the same initial increase observed with the low dose. In a study in which interferon alfa was administered on an intermittent schedule, the drug produced a dose-related decrease in NK-cell activity over a 6-week period, following an initial stimulatory effect. In addition, the route and schedule of administration appear to influence the effect of interferons on NK-cell activity. In general, no clearly defined relationship exists between stimulation of NK-cell activity by interferons and the clinical antineoplastic activity of these drugs.

Interferons generally enhance antibody-dependent cell-mediated cytotoxicity (ADCC) against a variety of antibody-coated target cells. While the mechanism of this enhancement in ADCC is not known, killer (K) cells, the subpopulation of lymphocytes that mediates ADCC, may be involved since these cells have Fc receptors to IgG, and interferons are known to enhance expression of these receptors.

Effects on Macrophage and Monocyte Activity

Interferon-induced activation of macrophages and monocytes results in morphologic changes in these cells, increased phagocytic activity, and nonspecific cytotoxicity against tumor cells and other target cells. Interferons enhance the number of phagocytic cells and the degree of phagocytosis of individual cells. Interferons also enhance Fc receptor-mediated phagocytosis. Activated macrophages can recognize cell-surface properties characteristic of transformed cells and can selectively destroy these malignant cells.

Interferon-mediated enhancement in macrophage phagocytosis can be neutralized by anti-interferon globulin. In addition, such enhancement of macrophage killing of leukemic cells can be suppressed when these effector cells are incubated with PGE₁, PGE₂, or hydrocortisone after interferon treatment, although the prostaglandins have no effect on unstimulated macrophages. This effect of prostaglandins may be mediated by increased intracellular concentrations of cAMP. (See Other Antiproliferative Mechanisms, under Mechanism of Action: Antiproliferative Effects, in Pharmacology.)

Effects on T Cells

Interferons have varied effects on T cells, a cell population that may influence tumor growth in several ways. T cells may interact directly with tumor cells or indirectly through regulatory influences on other immune effector cell types. The effects of the drugs on T cells most likely reflect the diverse functional activities of various T-cell subsets. While there is some in vitro and in vivo evidence that the drug either has no effect on or actually decreases (secondary to the drug’s antiproliferative activity) CTL-mediated killing, other evidence indicates that interferon alfa can enhance killing by CTL cells despite decreases in T-Cell proliferation. Therefore, interferon alfa may produce a selective increase in a specific population of cytotoxic T cells.

Interferon alfa also can affect delayed-type hypersensitivity responses, but the nature of the drug’s effect depends on the timing of interferon administration. Interferon alfa inhibits delayed hypersensitivity reactions when the drug is administered prior to sensitization or secondary challenge with antigen but enhances the response when it is administered a few hours after sensitization. Antigen-specific leukocyte-induced inhibition of granulocyte migration and leukocyte migration inhibition reactions resulting from exposure of lymphocytes to phytohemagglutin can be partially or totally suppressed by interferon alfa. Interferons also can modulate lymphokine release from mitogen-stimulated lymphocytes. Relatively low concentrations of interferon alfa reportedly can decrease or increase production by mitogen (concanavalin A)-stimulated lymphocytes of the lymphokines—leukocyte inhibitory factor (LIF) and macrophage inhibitory factor (MIF, migration inhibiting factor), while higher concentrations of the drug reportedly inhibit production of these migration inhibitory factors.

Limited data suggest that interferons may augment suppressor T-cell activity. Antigen-specific suppressor T cells may play a particularly crucial role in suppressing the host’s immune response to tumors; however, it has not been established how interferons may affect this subset of suppressor T cells.

Interferon alfa can modulate the expression of cell surface receptors on T cells (see Pharmacology: Effect on Cell Surface Antigens) and can increase the expression of IgG Fc receptors. Interferon alfa’s effect on CTL-cell activity in mixed lymphocyte culture (MLC) appears to depend on the duration of exposure of the lymphocytes to interferon.

Effects on B Cells

Interferons can either enhance or suppress B-cell responses depending on dose and sequence of administration relative to antigenic stimulation. Low or high doses of interferon alfa followed by antigen stimulation can increase or decrease antibody production, respectively. Interferons enhance the B-cell responses when added during late stages (48–72 hours after antigen) of the response, presumably secondary to a modulatory effect on T cells. Exposure to interferon prior to or immediately after exposure to antigen generally suppresses antibody response. In animal studies, B-cell antibody production and the proper functioning of memory cells generally was inhibited by interferons when the drugs were given prior to antigen exposure. More generally, in vivo administration of interferons 48–72 hours after antigen results in a twofold to sixfold enhancement of the antibody response.

Interferon-induced suppression of antibody responses affects both IgM and IgG antibodies. Interferon alfa also can modulate IgE production and action, and the drug has depressed the ability of spleen cells to elicit an anaphylactic response, probably by inhibiting IgE synthesis or release. However, exogenous addition of antibody enhances interferon alfa-mediated histamine release from human basophils in vitro via a mechanism that requires de novo RNA synthesis.

Effect on Cell Surface Antigens

Interferons also may affect immune responses by modulating cell surface antigen expression and by enhancing expression of transplantation antigens and alloantigens. In addition, interferon alfa has enhanced the expression of a major histocompatibility complex (MHC) class I antigen on hepatocytes infected with hepatitis B virus, thereby resulting in a more efficient induction of cytotoxic T-cell (CTL, killer T-cell) activity against viral antigens, and elimination of the infected cells from the liver. A similar immune-mediated mechanism has been suggested for tumor cells, since interferons are known to increase the expression of MHC antigens and tumor associated antigens on melanoma and other tumor cells.

Effect on Hepatic Cytochrome P-450 System

Interferons, including interferon alfa, and various agents that induce their production and/or secretion (e.g., viruses, quinacrine, tilorone, polyribonucleotides, endotoxin) have been shown to depress to varying degrees the hepatic cytochrome P-450 (microsomal) enzyme system, and the ability of interferon-inducing agents to depress this oxidative (monooxygenase) enzyme system may be mediated by interferons rather than by a direct effect of the agents. Depression of the cytochrome P-450 system has been manifested as reductions in the amount of hepatic microsomal protein, including the cytochrome P-450 and b ₅ hemoproteins, and in the activities of several cytochrome P-450-dependent enzymes.

It remains to be established whether interferon-induced depression of the cytochrome P-450 enzyme system results from increased degradation, suppressed synthesis, or inhibition of cytochrome P-450. Evidence mainly from studies with interferon inducers suggests that increased degradation of hepatic hemoproteins rather than suppressed synthesis may be principally involved; however, other evidence from such studies suggests that decreased synthesis of the apoprotein of cytochrome P-450, probably secondary to disturbances in heme turnover, is an important mechanism. A second mediator (e.g., interleukin-1), in addition to interferons, also has been suggested. The importance of the effects of interferons on the cytochrome P-450 enzyme system remains to be established, but interferon alfa can inhibit the metabolism of certain drugs (e.g., theophylline) (see Drug Interactions: Effects on Hepatic Clearance of Drugs), possibly secondary to depression of this enzyme system. In addition, the extent of effect on the cytochrome P-450 system depends in part on the type and subtype of interferon employed.

Other Effects

Interferons appear to be intrinsically pyrogenic. The pyrogenic response associated with administration of interferon alfa may be mediated by a drug-induced increase in the production and/or release of prostaglandin (PGE₂) in the hypothalamus rather than by an increase in interleukin-1. The response does not appear to be secondary to an exogenous pyrogenic contaminant in interferon alfa preparations.

Interferon Alfa (Antineoplastic) Pharmacokinetics

Few, if any, studies in humans are available that directly compare the pharmacokinetics of recombinant DNA-derived (e.g., interferon alfa-2a [no longer commercially available in the US], interferon alfa-2b) and mixtures of naturally occurring human interferons. Some data suggest that the overall disposition of these preparations is similar and that these interferons produce comparable serum concentration-time profiles in humans and several species of animals following IM administration. Although substantial interindividual variability in serum interferon concentrations has been observed after administration of recombinant interferon alfa-2a in healthy individuals and patients with disseminated cancer, the overall disposition of the drug was similar following IM or IV dosing in these individuals and in patients with amyotrophic lateral sclerosis (ALS), except for the possibility of a higher clearance in patients with ALS. Observed differences in interferon pharmacokinetics among patient populations may be related to differences in disease states, dosing schedules, or inherent interindividual variability.

In most studies of the pharmacokinetics of recombinant and mixtures of naturally occurring human interferons, interferon concentration or activity in serum, urine, or CSF was determined using hemadsorption inhibition tests with ⁵¹Cr-labeled erythrocytes, bioassays, radioimmunoassays, or enzyme-linked immunosorbent assays (ELISA). In patients with normal renal function, both ELISA and a bioassay based on inhibition of viral cytopathic effect give comparable results for serum concentrations of interferon alfa-2a; bioassay results with interferon alfa-2b reportedly also correlate well with those of radioimmunoassay.

Absorption

For systemic effects, interferon alfa is administered parenterally because the drug is susceptible to degradation by proteolytic enzymes in the GI tract. Interferon alfa is well absorbed following IM or subcutaneous injection; the apparent fraction of the dose absorbed after IM or subcutaneous injection exceeds 80%. Peak serum interferon alfa concentrations following IV administration of the drug generally occur within 15–60 minutes and are substantially greater than those attained after IM or subcutaneous administration. However, serum interferon alfa concentrations following IM or subcutaneous administration generally are maintained for longer periods of time than those produced by rapid IV injection or rapid (e.g., 40 minutes or less) IV infusion. Following a 36 million-unit dose of interferon alfa administered by IV infusion or by IM or subcutaneous injection, peak serum interferon alfa concentrations averaged approximately 2320, 340, or 290 units/mL, respectively; 24 hours after administration, concentrations of interferon alfa administered by all of these routes were less than 17 units/mL. Depending on the administered dose, serum interferon concentrations generally are detectable for approximately 4–8 hours after rapid IV injection or infusion or for approximately 16–30 hours after IM or subcutaneous injection.

Following IM administration of interferon alfa in doses of 1 million to 198 million units, peak serum interferon alfa concentrations ranged from 18–1000 units/mL 1–8 hours (range: 2–12 hours) after the injection. Dose-proportional increases in serum interferon alfa concentration were observed following IM doses of up to 198 million units; AUC also increased with increasing doses of interferon alfa, although route of administration did not have a consistent effect on this value. Limited data suggest that the time required to achieve peak serum drug concentrations following IM administration of interferon alfa may increase slightly with increasing doses up to 72 million units; however, this has not been a consistent finding. Following IM administration of recombinant interferon alfa-2a (no longer commercially available in the US) in patients with various solid and hematologic malignancies, serum interferon alfa concentrations achieved at 3, 4, and 8 hours were 14, 12, and 16 units/mL after 3-million-unit doses; 37, 38, and 46 units/mL with 9-million-unit doses; or 62, 108, and 182 units/mL with 18-million-unit doses. In patients with chronic lymphocytic leukemia or advanced non-Hodgkin’s lymphoma, peak serum interferon alfa concentrations 4–8 hours after IM administration of 5 million or 50 million units of recombinant interferon alfa-2a ranged from 91–542 or from 1009–3725 units/mL, respectively.

The serum concentration-time profile of interferon alfa following subcutaneous administration appears to be comparable to that following IM administration, although peak serum drug concentrations after subcutaneous injection are attained somewhat later. Following subcutaneous injection of recombinant interferon alfa-2a (no longer commercially available in the US) or alfa-2b in doses ranging from 1 million to 36 million units, mean peak serum interferon alfa concentrations ranged from 18–346 units/mL and were generally achieved in 6–8 hours (range: 3–12 hours).

Following intralesional injection of interferon alfa-n3 into anogenital warts, systemic plasma concentrations of the drug were undetectable (detection limit of 3 units/mL); however, some systemic absorption apparently occurs since adverse systemic effects have been reported in patients receiving intralesional therapy. Following intralesional injection of 3 million units of interferon alfa-2b weekly per wart for 4 weeks, serum concentrations of the drug ranged from 5–40 units/mL. The drug also was absorbed systemically following intralesional injection of interferon alfa-2b or a mixture of naturally occurring human interferon alfa at dosages of 18–30 million units weekly in patients with malignant melanoma; peak serum concentrations of the drug occurred 6 hours after injection, achieving a median of 95 units/mL. Some percutaneous absorption of interferon alfa also appears to occur following topical application of the drug, since adverse systemic effects have been reported rarely.

Interferon alfa can achieve high and sustained CSF concentrations following intrathecal^† or intraventricular^† administration. (See Pharmacokinetics: Distribution.) Following intraperitoneal^† administration, interferon alfa reportedly is absorbed systemically, resulting in high, sustained serum concentrations after several weeks of therapy; interferon alfa was still detectable in serum 5 days following intraperitoneal administration, but intraperitoneal concentrations were 30–1000 times those achieved in serum.

Following topical application to the eye (into the lower conjunctival sac) of 0.25, 0.75, 2.5, or 5 million units of a buffered solution of interferon alfa, concentrations of the drug in the nasal cavity at 1 hour were 602, 1461, 1197, or 4360 units/mL, respectively; detectable concentrations were present for at least 8 hours following administration. The extent of intraocular penetration of interferon alfa following topical application of the eye currently is not known.

Distribution

Limited data on the tissue distribution of interferon in animals suggest that mixtures of naturally occurring human or animal interferons are widely and rapidly distributed into body tissues after parenteral administration, with the highest concentrations occurring in spleen, kidney, liver, and lung. Limited evidence also indicates interferon uptake and/or binding by other types of tissue or tumors. Although a similar pattern of tissue distribution was noted in animals given certain recombinant DNA-derived interferons (human interferon alfa-2c), animal studies in which recombinant interferon alfa-2a (no longer commercially available in the US) or alfa-2b were used suggest that the these interferons are not concentrated in any organ or that only the kidney, which appears to be the principal site of interferon metabolism, demonstrates substantial uptake of the drugs. (See Pharmacokinetics: Elimination.) Studies with radiolabeled recombinant interferon alfa-2a in patients with osteosarcoma indicate uptake of the drug by the liver and by tumor tissue; differences in peak plasma concentrations following administration of human leukocyte interferon suggest that interferon alfa binds to a greater degree to tumors of the lymph nodes and bone marrow than to breast tumors. Following IM or subcutaneous injection of human recombinant interferon alfa-2a into the shank muscle of animals, interferon alfa readily distributes into lymph tissue.

Differences in volume of distribution and in other pharmacokinetic values among various recombinant interferons have been demonstrated in a few studies; however, the overall disposition of recombinant interferon alfa-2a in mice, dogs, monkeys, and humans appears to be similar (i.e., species independent). The volume of distribution of interferon alfa in humans reportedly approximates 20–60% of body weight; in healthy individuals who received 36 million units of recombinant interferon alfa-2a IV over 40 minutes, the volume of distribution at steady state (V_ss) ranged from 0.23–0.75 L/kg (mean: 0.4 L/kg).

Interferon alfa does not readily distribute into CSF following systemic administration of mixtures of naturally occurring human or recombinant interferons in animals or humans, although low concentrations have been detected in CSF following administration of large systemic doses. Following IM injection of a mixture of naturally occurring human leukocyte interferon, no interferon activity was detectable (i.e., concentration less than 20 units/mL) in CSF at 4 hours after a dose of 3 million units in an infant or at 6 and 8 hours after a dose of 30 million units in a 12-year-old boy. Using a radioimmunoassay (detection limit 2.5 units/mL), CSF interferon alfa concentrations of 3.1–3.8 units/mL were noted from 0.5–8 hours following a dose of recombinant interferon alfa-2b in a woman with disseminated breast cancer receiving 27 million units daily as a 30-minute IV infusion for 5 successive days every 3 weeks; corresponding serum interferon alfa concentrations ranged from 22–3065 units/mL. In a limited number of patients with amyotrophic lateral sclerosis, interferon alfa concentrations in CSF were undetectable (i.e., less than 2.6 units/mL) following IV infusion of a single 18-million units dose of recombinant interferon alfa-2a but ranged from 2.9–11.9 units/mL (550- to 1100-fold less than corresponding serum concentrations) following a dose of 50 million units; CSF concentrations were detectable after 1 hour and, in 2 patients, for at least 24 hours after the dose. In both animals and man, higher CSF concentrations of interferon alfa can be achieved by intrathecal^† or intraventricular^† administration. Distribution of interferon alfa into serum following injection into CSF occurs slowly; a stable serum concentration was maintained for 12–24 hours following intrathecal injection of 10 million units of human leukocyte interferon in monkeys. Intrathecal administration of interferon alfa in animals produced CSF interferon concentrations that were approximately 16- to 30-fold greater than corresponding serum concentrations. In a neonate who received 600,000 units of a mixture of naturally occurring human interferon alfa intrathecally once or twice daily for disseminated herpes simplex infection, CSF interferon alfa concentrations measured 12 or 24 hours after the dose ranged from 800–8000 units/mL. The presence of interferon alfa in CSF does not ensure penetration of the drug into parenchymal brain tissue; virus has been recovered postmortem from the brain tissue of a patient with disseminated herpes simplex infection in whom relatively high CSF concentrations of interferon alfa were attained following intrathecal injection of the drug. However, survival was substantially greater in monkeys infected with rabies virus and treated with intrathecally administered human leukocyte interferon than in those not treated, suggesting that interferon does reach grey and white matter of the brain.

It is not known whether interferon crosses the placenta in humans. Studies in mice indicate that murine interferon is distributed into milk; it is not known whether interferon is distributed into human milk.

Elimination

Interferon alfa is rapidly cleared from plasma following rapid IV injection or IV infusion in animals or humans, while more prolonged concentrations are observed following IM or subcutaneous administration. In healthy individuals and patients with normal renal function, plasma concentrations of interferon alfa appear to decline in a biphasic manner. Limited data from studies in humans receiving recombinant interferon alfa-2a (no longer commercially available in the US) or recombinant interferon alfa-2b suggest that variability in the reported elimination half-life of interferon alfa may be related to route or method of administration, interindividual variability in drug disposition, and/or presence of disease. However, the serum concentrations and clearance of partially purified human leukocyte interferon or recombinant interferon alfa-2a was not appreciably altered in several patients with chronic renal failure.

Following a brief IV infusion, the terminal elimination half-life of recombinant interferon alfa-2a averaged 5.1 hours (range 3.7–8.5 hours) in healthy individuals and ranged from approximately 0.75–2 hours in a limited number of patients with disseminated cancer. Elimination half-life of recombinant interferon alfa-2a was more prolonged following continuous IV infusion for 14 days in a few patients with leukemia, ranging from 4.6–9.8 hours. In healthy individuals who received a 30-minute IV infusion of recombinant interferon alfa-2b, elimination half-life averaged approximately 2 hours (range: 0.5–2.9 hours). Elimination half-life of recombinant interferon alfa-2a or alfa-2b averaged approximately 2–3.5 hours following IM or subcutaneous administration in healthy individuals and approximately 2.6–11.5 hours following IM administration in patients with disseminated cancer.

In a study using isolated, perfused rabbit kidneys, the plasma disappearance rate of recombinant interferon alfa was greater than that of a mixture of naturally occurring interferon alfa. Following a single, rapid IV injection or a 14-day continuous IV infusion of interferon alfa-2a, total body clearance of the drug from plasma was 1.9–3.6 or 0.6–1.4 mL/minute per kg, respectively. Although conflicting data have been reported, accumulation of interferon alfa appears to occur with multiple IM dosing.

The metabolism of recombinant interferon alfa appears to be similar to that of mixtures of naturally occurring human interferon alfa in general. Interferon alfa appears to be metabolized principally in the kidney. Interferon alfa generally is undetectable or present only in trace quantities in urine, and the drug reappears in systemic circulation in negligible concentrations following its passage through the kidney; studies in which interferons have been detected in urine reported no correlation between urine and serum concentrations of the drug. In animals and humans, the total body clearance of recombinant interferon alfa exceeds the creatinine clearance, which also suggests that renal tubular secretion, extrarenal elimination, and/or renal and/or extrarenal catabolism contribute to elimination of the drug. Studies in isolated, perfused kidney preparations demonstrate that interferon alfa is freely filtered through the glomeruli. Approximately 90–96% of the drug is absorbed by the renal tubule, where it undergoes rapid proteolytic degradation at the brush border or in the lysosomes of the tubular epithelium. Studies of human leukocyte or recombinant interferons in isolated liver perfusate systems suggest that hepatic metabolism and subsequent biliary excretion is a minor pathway of elimination for interferon alfa.

In a limited number of patients with chronic renal failure who received single, low doses (i.e., 3 million units) of partially purified or recombinant interferon alfa, the serum concentrations and clearance of the drugs were not substantially altered; however, it has been suggested that interferon alfa may accumulate in body fluids of patients with markedly depressed glomerular filtration rate (GFR) and creatinine clearance. Limited evidence in patients receiving recombinant interferon alfa-2a suggests that hemodialysis is not effective in removing interferon alfa from the body.

Chemistry and Stability

Chemistry

Interferon alfa is a family of highly homologous, species-specific proteins and, occasionally, glycoproteins that possess complex antiviral, antineoplastic, and immunomodulating activities. Because of the relative species-specific activity of interferons, interferons intended for human use are of human origin (e.g., prepared using donor-provided human cells such as leukocytes, using cultured human cell lines such as lymphoblastoid cells, or using recombinant techniques that employ human genes). At least 23 structurally similar subtypes of human interferon alfa (e.g., interferon alfa-2a, interferon alfa-2b) have been identified.

Interferon alfa is commercially available in the US as interferon alfa-2b and interferon alfa-n3. Interferon alfa-2b is of recombinant DNA origin and interferon alfa-n3 is derived from human leukocytes.

Interferons are produced and secreted principally by peripheral blood leukocytes, fibroblasts, and epithelial cells in response to viral infection or certain other synthetic and biologic inducers (e.g., double-stranded RNA, certain bacteria and other microorganisms, endotoxin, surface glycoproteins). By definition, interferons exist as proteins or glycoproteins, are produced endogenously according to information encoded by species of interferon genes, and exert virus-nonspecific antiviral activity, at least in homologous cells, through cellular metabolic processes involving synthesis of RNA and proteins. In addition to interferon alfa, interferon beta and interferon gamma have been identified and are classified according to antigenic specificity and/or biologic properties. Interferon alfa and interferon beta have been referred to as type I interferons in part because of their general acid stability, and interferon gamma has been referred to as a type II interferon in part because of its general acid lability; however, some subtypes may not possess the acid stability profile indicated by this classification. Although interferon alfa, interferon beta, and interferon gamma also have been referred to as leukocyte or lymphoblastoid interferon, fibroblast interferon, and lymphocyte or immune interferon, respectively, these descriptions are considered misnomers since interferons alfa and beta can both be produced by leukocytes and fibroblasts, and production of interferon gamma can be induced by mitogen-stimulated mechanisms.

Human interferon alfa proteins generally contain 165 or 166 amino acids and have molecular weights ranging from 16,000–28,000 daltons, with most subtypes containing 166 amino acids and having molecular weights of 18,000–20,000. While the precise subtype composition of interferon alfa-n3 (α-interferons, leukocyte interferon, HuIFN-α (Le)) currently is not known, interferon alfa proteins present in the mixture consist of approximately 166 amino acids each and have molecular weights ranging from 16,000–27,000 daltons. The precise subtype composition of interferon alfa-n1 (α-interferons, lymphoblastoid interferon, HuIFN-α (Ly); not commercially available in the US), which is a mixture of at least 8 interferon alfa proteins but is derived from lymphoblastoid cells rather than from leukocytes, also currently is not known. Interferon alfa-2a (HuIFN-αA, Ro 22-8181; no longer commercially available in the US) and interferon alfa-2b (Sch 38500) are biosynthetic (recombinant DNA origin) forms of interferon alfa (rHuIFN-α) that consist of 165 amino acids. Interferons alfa-2a and alfa-2b have molecular weights of approximately 19,000 daltons and differ at position 23 in the amino acid sequence, with alfa-2a possessing a lysine group and alfa-2b an arginine group at this position. The importance, if any, of this single amino acid difference has not been established, and it remains to be elucidated whether clinically important differences in therapeutic and/or toxicologic profiles exist. Compared with other interferon alfa subtypes, interferon alfa-2a and interferon alfa-2b both have a deletion at position 44 in the amino acid sequence. In addition, although 2 large molecular segments are identical in various interferon alfa subtypes, the amino acid sequences of the subtypes differ from one another by several amino acids and are 70–90% homologous. Interferon alfa-2c (not commercially available in the US) differs structurally from interferon alfa-2b by the presence of an arginine group rather than a histidine group at position 34 in the amino acid sequence. The structure-activity relationships for interferons have not been clearly established. While both the amino and carboxy terminal regions of the molecules may be involved in eliciting antiviral activity, studies to determine which region(s) of the molecules confers various degrees of activity have yielded conflicting results. In addition, some evidence indicates that different regions may be involved in eliciting various activities of the drug.

Interferon Alfa-2b

Interferon alfa-2b is prepared from cultures of genetically modified Escherichia coli using recombinant DNA technology. The bacteria is modified by the addition of a plasmid that incorporates an interferon alfa-2b gene from human leukocytes for human interferon alfa synthesis. Because a single gene is used for the preparation, single molecular species (i.e., 2b) rather than a mixture of interferon alfa subtypes is present in commercially available preparations of interferon alfa-2b. Trace amounts of residual E. coli protein may be produced during fermentation. Although tetracycline hydrochloride is included in the nutrient medium used during the fermentation process, it is undetectable in the final preparation of interferon alfa-2b.

Potency of interferon alfa-2b is expressed in International Units (IU) as tested against the activity of specific international reference preparations of interferons established by the World Health Organization (WHO). Interferon alfa-2b (recombinant DNA origin) commercially available in the US has a specific activity that is approximately 2.6 million units/mg of protein as measured by high performance liquid chromatography (HPLC) assay.

Interferon alfa-2b is commercially available in the US as a sterile powder for injection in single-dose vials or as a sterile solution in multiple-dose vials. The powder for injection occurs as a white to cream-colored lyophilized powder and contains dibasic and monobasic sodium phosphate as a buffer, glycine, and albumin human. Following reconstitution with the sterile water for injection diluent provided by the manufacturer, the injection occurs as a clear and colorless to light yellow solution. Commercially available solutions of interferon alfa-2b are clear and colorless and contain dibasic and monobasic sodium phosphate, edetate disodium, and polysorbate 80; m-cresol is added as a preservative.

Stability

Commercially available interferon alfa-2b powder for injection in single-dose vials should be stored in a refrigerator at 2–8°C. Following reconstitution of the powder for injection with the sterile water for injection diluent provided by the manufacturer, the solution should be used immediately, but may be stored at 2–8°C for up to 24 hours.

Commercially available interferon alfa-2b solution for injection in multiple-dose vials should be stored at 2–8°C and should not be frozen or exposed to heat. After the initial dose is administered, any solution remaining in the vial should be discarded after 1 month.

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web]

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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