Intron A (Interferon alfa-2b, recombinant) - 7 indications

Scroll down for information on each indication:

• hairy cell leukemia; approved June 1986
• genital warts; approved June of 1988
• AIDS-related Kaposi’s Sarcoma; approved November 1988
• hepatitis C; approved 1991
• chronic hepatitis B infection; approved 1992
• adjuvant treatment to surgery in malignant melanoma patients at high risk for systemic recurrence; approved January 1996
• for use in conjunction with anthracycline-containing combination chemotherapy for the initial treatment of patients with clinically aggressive follicular non-Hodgkin's lymphoma; approved November 1997

General Information

Intron A (Interferon alfa-2b, recombinant) is a recombinant version of a naturally occurring alpha interferon, with both antiviral and immunomodulatory effects.

Intron A is specifically indicated for the following conditions:

• the treatment of patients 18 years of age or older with hairy cell leukemia
• as adjuvant to surgical treatment in patients 18 years of age or older with malignant melanoma who are free of disease but at high risk for systemic recurrence, within 56 days of surgery
• for the initial treatment of clinically aggressive follicular Non-Hodgkin’s Lymphoma in conjunction with anthracycline-containing combination chemotherapy in patients 18 years of age or older
• for intralesional treatment of selected patients 18 years of age or older with condylomata acuminata involving external surfaces of the genital and perianal areas
• for the treatment of selected patients 18 years of age or older with AIDS-Related Kaposi's Sarcoma
• for the treatment of chronic hepatitis C in patients 18 years of age or older with compensated liver disease who have a history of blood or blood-product exposure and/or are HCV antibody positive
• for the treatment of chronic hepatitis B in patients 1 year of age or older with compensated liver disease

Intron A is supplied as a solution for intramuscular, intralesional or subcutaneous injection. Scroll down to see recommended dosing/administration for each indication.

Mechanism of Action

The exact mechanism of action is unknown. Intron A has been shown to have intracellular, antiviral immunomodulatory, and antiproliferative effects, in-vitro and in-vivo. These include effects on intracellular oncogene expression, stimulation of natural killer and cytotoxic T-cells, microphage activation, and induction of cytokine production. Antiproliferative effects shown include slowing of cell division and reversion of tumor cells to a normal phenotype.

Side Effects

Adverse effects associated with the use of Intron A for all indications may include, but are not limited to, the following:

• flu-like symptoms (asthenia, fever and headache)
• vomiting
• nausea
• anorexia
• abdominal pain
• diarrhea
• alopecia

The Intron A drug label comes with the following Black Box Warning: Alpha interferons, including Intron A, cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping Intron A therapy.

Indication 1 - hairy cell leukemia

approved June 1986

Dosage/Administration

The recommended dose for the treatment of hairy cell leukemia is 2 million IU/m2 administered intramuscularly or subcutaneously 3 times a week for up to 6 months. Patients with platelet counts of less than 50,000/mm3 should not be administered Intron A intramuscularly, but instead by subcutaneous administration. Patients who are responding to therapy may benefit from continued treatment.

Clinical Trial Results

In clinical trials in patients with hairy cell leukemia, there was depression of hematopoiesis during the first 1 to 2 months of Intron A treatment, resulting in reduced numbers of circulating red and white blood cells, and platelets. Subsequently, both splenectomized and nonsplenectomized patients achieved substantial and sustained improvements in granulocytes, platelets, and hemoglobin levels in 75% of treated patients and at least some improvement (minor responses) occurred in 90%. Intron A treatment resulted in a decrease in bone marrow hypercellularity and hairy cell infiltrates. The hairy cell index (HCI), which represents the percent of bone marrow cellularity times the percent of hairy cell infiltrate, was greater than or equal to 50% at the beginning of the study in 87% of patients. The percentage of patients with such an HCI decreased to 25% after 6 months and to 14% after 1 year.

Indication 2 - genital warts

approved June of 1988

Dosage/Administration

The recommended dose is 1.0 million IU per lesion in a maximum of 5 lesions in a single course. The lesions should be injected three times weekly on alternate days for 3 weeks. An additional course may be administered at 12 to 16 weeks.

Clinical Trial Results

Three clinical trials were conducted. Of 192 Intron A-treated patients and 206 placebo treated patients who were evaluable for efficacy at the time of best response during the course of the study, 42% of Intron A patients versus 17% of placebo patients experienced clearing of all treated lesions. Likewise, 24% of Intron A patients versus 8% of placebo patients experienced marked (75% to less than 100%) reduction in lesion size, 18% versus 9% experienced moderate (50% to 75%) reduction in lesion size, 10% versus 42% had a slight (less than 50%) reduction in lesion size, 5% versus 24% had no change in lesion size, and 0% versus 1% experienced exacerbation. In one of these studies, 43% (54/125) of patients in whom multiple (less than or equal to 3) lesions were treated experienced complete clearing of all treated lesions during the course of the study. Of these patients, 81% remained cleared 16 weeks after treatment was initiated. Patients who did not achieve total clearing of all their treated lesions had these same lesions treated with a second course of therapy. During this second course of treatment, 38% to 67% of patients had clearing of all treated lesions. The overall percentage of patients who had cleared all their treated lesions after two courses of treatment ranged from 57% to 85%. Intron A-treated lesions showed improvement within 2 to 4 weeks after the start of treatment in the above study; maximal response to Intron A therapy was noted 4 to 8 weeks after initiation of treatment.

Indication 3 - AIDS-related Kaposi’s Sarcoma

approved November 1988

Dosage/Administration

The recommended dose of Intron A for Kaposi’s Sarcoma is 30 million IU/m2/dose administered subcutaneously or intramuscularly three times a week until disease progression or maximal response has been achieved after 16 weeks of treatment. Dose reduction is frequently required.

Clinical Trial Results

Intron A was evaluated in clinical trials in 144 patients. In one study, Intron A doses of 30 million IU/m2 were administered subcutaneously three times per week (TIW) to patients with AIDS-Related KS. Doses were adjusted for patient tolerance. The average weekly dose delivered in the first 4 weeks was 150 million IU; at the end of 12 weeks this averaged 110 million IU/week; and by 24 weeks averaged 75 million IU/week. Forty-four percent of asymptomatic patients responded versus 7% of symptomatic patients. The median time to response was approximately 2 months and 1 month, respectively, for asymptomatic and symptomatic patients. The median duration of response was approximately 3 months and 1 month, respectively, for the asymptomatic and symptomatic patients. Baseline T4/T8 ratios were 0.46 for responders versus 0.33 for non-responders. In another study, Intron A doses of 35 million IU were administered subcutaneously, daily (QD), for 12 weeks. Maintenance treatment, with every other day dosing (QOD), was continued for up to 1 year in patients achieving antitumor and antiviral responses. The median time to response was 2 months and the median duration of response was 5 months in the asymptomatic patients. In all studies, the likelihood of response was greatest in patients with relatively intact immune systems as assessed by baseline CD4 counts (interchangeable with T4 counts). 

In the 30 million IU study group, 7% (5/72) of patients were complete responders and 22% (16/72) of the patients were partial responders. The 35 million IU study had 13% (3/23 patients) complete responders and 17% (4/23) partial responders. For patients who received 30 million IU TIW, the median survival time was longer in patients with CD4 greater than 200 (30.7 months) than in patients with CD4 less than or equal to 200 (8.9 months). Among responders, the median survival time was 22.6 months versus 9.7 months in non-responders.

Indication 4 - hepatitis C

approved 1991

Dosage/Administration

The recommended dose of Intron A for the treatment of chronic hepatitis C is 3 million IU three times a week (TIW) administered subcutaneously or intramuscularly. In patients tolerating therapy with normalization of ALT at 16 weeks of treatment, Intron A therapy should be extended to 18 to 24 months (72 to 96 weeks) at 3 million IU TIW to improve the sustained response rate. Patients who do not normalize their ALTs or have persistently high levels of HCV RNA after 16 weeks of therapy rarely achieve a sustained response with extension of treatment. Consideration should be given to discontinuing these patients from therapy.

Clinical Trial Results

Two independent clinical studies were used to support the submission for 18-24 months therapy duration: In study No. 1, patients received 3 million international units (MIU), three times a week (TIW) of Intron A for a period of 18 months. In study No. 2, patients received 3 MIU, TIW for a period of 24 months. In both studies, the extended duration arms were compared to the previously indicted six month course of therapy.

The combined results from the multicenter trials demonstrated that 24 percent of all patients treated for 18-24 months achieved a durable sustained response (6 months post-therapy) compared with 12.5 percent for those treated for six months.

Similarly, improvement in liver cell inflammation and death (necroinflammatory activity) -- another measure of response to treatment -- was seen in significantly more patients who received Intron A for 18-24 months compared to those who received six months of therapy (58 percent versus 38 percent respectively).

Indication 5 - chronic hepatitis B infection

approved 1992

Dosage/Administration

• Adults: The recommended dose of Intron A for the treatment of chronic hepatitis B is 30 to 35 million IU per week, administered subcutaneously or intramuscularly, either as 5 million IU daily (QD) or as 10 million IU three times a week (TIW) for 16 weeks.
• Pediatrics: The recommended dose of Intron A for the treatment of chronic hepatitis B is 3 million IU/m2 three times a week (TIW) for the first week of therapy followed by dose escalation to 6 million IU/m2 TIW (maximum of 10 million IU TIW) administered subcutaneously for a total duration of 16 to 24 weeks.

Clinical Trial Results

Intron A in the treatment of chronic hepatitis B were evaluated in three clinical trials in which Intron A doses of 30 to 35 million IU per week were administered subcutaneously (SC), as either 5 million IU daily (QD), or 10 million IU three times a week (TIW) for 16 weeks versus no treatment. Virologic response to treatment was defined in these studies as a loss of serum markers of HBV replication (HBeAg and HBV DNA). Secondary parameters of response included loss of serum HBsAg, decreases in serum ALT, and improvement in liver histology. In each of two randomized controlled studies, a significantly greater proportion of Intron A-treated patients exhibited a virologic response compared with untreated control patients. In a third study without a concurrent control group, a similar response rate to Intron A therapy was observed.

Indication 6 - malignant melanoma patients at high risk for systemic recurrence

approved January 1996

Dosage/Administration

Intron A adjuvant treatment of malignant melanoma is given in two phases, induction and maintenance.

• Induction Recommended Dose: The recommended daily dose of Intron A in induction is 20 million IU/m2 as an intravenous infusion, over 20 minutes, 5 consecutive days per week, for 4 weeks. 
• Maintenance Recommended Dose: The recommended dose of Intron A for maintenance is 10 million IU/m2 as a subcutaneous injection three times per week for 48 weeks.

Clinical Trial Results

In 1985, a large, randomized, controlled phase III clinical trial conducted at 29 centers by the Eastern Cooperative Oncology Group, in conjunction with the National Cancer Institute, 280 malignant melanoma subjects were randomized to either treatment with Intron A or observation post surgery. The primary study objectives were to determine the effectiveness of Intron A in prolonging relapse-free and overall survival. A marked improvement in each of these categories was demonstrated. In the clinical study, the addition of Intron A after surgical removal of the tumor increased median overall survival of malignant melanoma subjects by more than 12 months and median relapse-free survival by 9 months. A 24% improvement in the five-year survival rate was demonstrated. A 42% improvement in the five-year relapse-free survival rate was demonstrated for subjects receiving Intron A therapy.

Indication 7 - follicular non-Hodgkin's lymphoma

approved November 1997

Dosage/Administration

The recommended dose of Intron A for the treatment of follicular lymphoma is 5 million IU subcutaneously three times per week for up to 18 months in conjunction with anthracycline-containing chemotherapy regimen and following completion of the chemotherapy regimen.

Clinical Trial Results

Intron A was evaluated in the GELF study, a large, randomized, Phase III clinical study in 273 patients conducted in 31 medical centers between 1986 and 1991. In this study, patients were randomized between chemotherapy alone (cyclophosphamide, doxorubicin, teniposide and prednisone) or chemotherapy with Intron A. The dosage regimen with Intron A was 5 MIU administered three times weekly for 18 months. The primary study objective was to determine the effect of Intron A on progression-free survival in a homogenous population of patients with clinically aggressive follicular non-Hodgkin's lymphoma. the addition of Intron A to chemotherapy increased median progression-free survival from 1.5 years in patients with chemotherapy alone to 2.9 years in patients in the chemotherapy plus Intron A group. Moreover, patients in the chemotherapy plus Intron A group experienced a significant prolongation of overall survival as compared to patients in the chemotherapy alone group (median not yet reached versus 5.6 years.)