INTRON A Interferon alfa-2b, recombinant for intramuscular, subcutaneous, intralesional, or intravenous Injection is a purified sterile recombinant interferon product.

Interferon alfa-2b, recombinant for Injection has been classified as an alfa interferon and is a water-soluble protein with a molecular weight of 19,271 daltons produced by recombinant DNA techniques. It is obtained from the bacterial fermentation of a strain of Escherichia coli bearing a genetically engineered plasmid containing an interferon alfa-2b gene from human leukocytes. The fermentation is carried out in a defined nutrient medium containing the antibiotic tetracycline hydrochloride at a concentration of 5 to 10 mg/L; the presence of this antibiotic is not detectable in the final product. The specific activity of Interferon alfa-2b, recombinant is approximately 2.6 × 10 8 IU/mg protein as measured by the HPLC assay.

Powder for Injection
Vial Strength mL Diluent Final Concentration after Reconstitution million
IU/mL *
mg INTRON A ** Interferon alfa-2b, recombinant Route of Administration
3 MIU 1  3 0.012 IM, SC, IV
5 MIU 1  5 0.019 IM, SC, IV
10 MIU 2  5 0.038 IM, SC, IV, IL ++
18 MIU 1 18 0.069 IM, SC, IV
25 MIU 5  5 0.096 IM, SC, IV
50 MIU 1 50 0.192 IM, SC, IV
*Each mL also contains 20 mg glycine, 2.3 mg sodium phosphate dibasic, 0.55 mg sodium phosphate monobasic, and 1.0 mg human albumin.
**/* Based on the specific activity of approximately 2.6 × 10 8 IU/mg protein, as measured by HPLC assay.
++ The 10 MIU vial for intralesional use should be reconstituted with 1 mL of the provided diluent.

Prior to administration, the INTRON A Powder for Injection is to be reconstituted with the provided Diluent for INTRON A Interferon alfa-2b, recombinant for Injection (bacteriostatic water for injection) containing 0.9% benzyl alcohol as a preservative. (See DOSAGE AND ADMINISTRATION .) INTRON A Powder for Injection is a white to cream-colored powder.

Solution Vials for Injection
Vial Strength Final Concentration *

mg INTRON A **
Interferon alfa-2b, recombinant

Route of Administration
 3 MIU  3 million IU/0.5 mL 0.012 IM, SC
 5 MIU  5 million IU/0.5 mL 0.019 IM, SC, IL
10 MIU 10 million IU/1.0 mL 0.038 IM, SC, IL
18 *** MIU multidose  3 million IU/0.5 mL 0.088 IM, SC
25 MIU multidose  5 million IU/0.5 mL 0.123 IM, SC, IL
* Each mL contains 7.5 mg sodium chloride, 1.8 mg sodium phosphate dibasic, 1.3 mg sodium phosphate monobasic, 0.1 mg edetate disodium, 0.1 mg polysorbate 80, and 1.5 mg m-cresol as a preservative.
** Based on the specific activity of approximately 2.6 × 10 8 IU/mg protein as measured by HPLC assay.
*** This is a multidose vial which contains a total of 22.8 million IU of interferon alfa-2b, recombinant per 3.8 mL in order to provide the delivery of six 0.5-mL doses, each containing 3 million IU of INTRON A Interferon alfa-2b, recombinant for Injection (for a label strength of 18 million IU).
This is a multidose vial which contains a total of 32.0 million IU of interferon alfa-2b, recombinant per 3.2 mL in order to provide the delivery of five 0.5-mL doses, each containing 5 million IU of INTRON A Interferon alfa-2b, recombinant for Injection (for a label strength of 25 million IU).

Solution in Multidose Pens for Injection
Pen
Strength
Final
Concentration *
INTRON A Dose
Delivered
(6 doses, 0.2 mL each)
mg INTRON A ** Route of
Administration
18 MIU 22.5 MIU/1.5 mL  3 MIU/dose 0.087 SC
30 MIU 37.5 MIU/1.5 mL  5 MIU/dose 0.144 SC
60 MIU 75 MIU/1.5 mL 10 MIU/dose 0.288 SC
* Each mL also contains 7.5 mg sodium chloride, 1.8 mg sodium phosphate dibasic, 1.3 mg sodium phosphate monobasic, 0.1 mg edetate disodium, 0.1 mg polysorbate 80, and 1.5 mg m-cresol as a preservative.
** Based on the specific activity of approximately 2.6 × 10 8 IU/mg protein as measured by HPLC assay.
These packages do not require reconstitution prior to administration. (See DOSAGE AND ADMINISTRATION .) INTRON A Solution for Injection is a clear, colorless solution.

General   The interferons are a family of naturally occurring small proteins and glycoproteins with molecular weights of approximately 15,000 to 2 7 ,600 daltons produced and secreted by cells in response to viral infections and to synthetic or biological inducers.

Preclinical Pharmacology   Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Once bound to the cell membrane, interferons initiate a complex sequence of intracellular events. In vitro studies demonstrated that these include the induction of certain enzymes, suppression of cell proliferation, immunomodulating activities such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, and inhibition of virus replication in virus-infected cells.

In a study using human hepatoblastoma cell line, HB 611, the in vitro antiviral activity of alfa interferon was demonstrated by its inhibition of hepatitis B virus (HBV) replication.

The correlation between these in vitro data and the clinical results is unknown. Any of these activities might contribute to interferon' therapeutic effects.

  The pharmacokinetics of INTRON A Interferon alfa-2b, recombinant for Injection were studied in 12 healthy male volunteers following single doses of 5 million IU/m 2 administered intramuscularly, subcutaneously, and as a 30-minute intravenous infusion in a crossover design.

The mean serum INTRON A concentrations following intramuscular and subcutaneous injections were comparable. The maximum serum concentrations obtained via these routes were approximately 18 to 116 IU/mL and occurred 3 to 12 hours after administration. The elimination half-life of INTRON A Interferon alfa-2b, recombinant for Injection following both intramuscular and subcutaneous injections was approximately 2 to 3 hours. Serum concentrations were undetectable by 16 hours after the injections.

After intravenous administration, serum INTRON A concentrations peaked (135 to 273 IU/mL) by the end of the 30-minute infusion, then declined at a slightly more rapid rate than after intramuscular or subcutaneous drug administration, becoming undetectable 4 hours after the infusion. The elimination half-life was approximately 2 hours.

Urine INTRON A concentrations following a single dose (5 million IU/m 2 ) were not detectable after any of the parenteral routes of administration. This result was expected since preliminary studies with isolated and perfused rabbit kidneys have shown that the kidney may be the main site of interferon catabolism.

There are no pharmacokinetic data available for the intralesional route of administration.

Serum Neutralizing Antibodies   In INTRON A treated patients tested for antibody activity in clinical trials, serum anti-interferon neutralizing antibodies were detected in 0% (0/90) of patients with hairy cell leukemia, 0.8% (2/260) of patients treated intralesionally for condylomata acuminata, and 4% (1/24) of patients with AIDS-Related Kaposi' Sarcoma. Serum neutralizing antibodies have been detected in <3% of patients treated with higher INTRON A doses in malignancies other than hairy cell leukemia or AIDS-Related Kaposi' Sarcoma. The clinical significance of the appearance of serum anti-interferon neutralizing activity in these indications is not known.

Serum anti-interferon neutralizing antibodies were detected in 7% (12/168) of patients either during treatment or after completing 12 to 48 weeks of treatment with 3 million IU TIW of INTRON A therapy for chronic hepatitis C and in 13% (6/48) of patients who received INTRON A therapy for chronic hepatitis B at 5 million IU QD for 4 months, and in 3% (1/33) of patients treated at 10 million IU TIW. Serum anti-interferon neutralizing antibodies were detected in 9% (5/53) of pediatric patients who received INTRON A therapy for chronic hepatitis B at 6 million IU/m 2 TIW. Among all chronic hepatitis B or C patients, pediatric and adults with detectable serum neutralizing antibodies, the titers detected were low (22/24 with titers </=1:40 and 2/24 with titers </=1:160). The appearance of serum anti-interferon neutralizing activity did not appear to affect safety or efficacy.

Hairy Cell Leukemia   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 (HCl), which represents the percent of bone marrow cellularity times the percent of hairy cell infiltrate, was >/=50% at the beginning of the study in 87% of patients. The percentage of patients with such an HCl decreased to 25% after 6 months and to 14% after 1 year. These results indicate that even though hematologic improvement had occurred earlier, prolonged INTRON A treatment may be required to obtain maximal reduction in tumor cell infiltrates in the bone marrow.

The percentage of patients with hairy cell leukemia who required red blood cell or platelet transfusions decreased significantly during treatment and the percentage of patients with confirmed and serious infections declined as granulocyte counts improved. Reversal of splenomegaly and of clinically significant hypersplenism was demonstrated in some patients.

A study was conducted to assess the effects of extended INTRON A treatment on duration of response for patients who responded to initial therapy. In this study, 126 responding patients were randomized to receive additional INTRON A treatment for 6 months or observation for a comparable period, after 12 months of initial INTRON A therapy. During this 6-month period, 3% (2/66) of INTRON A treated patients relapsed compared with 18% (11/60) who were not treated. This represents a significant difference in time to relapse in favor of continued INTRON A treatment (p=0.006/0.01, Log Rank/ Wilcoxon). Since a small proportion of the total population had relapsed, median time to relapse could not be estimated in either group. A similar pattern in relapses was seen when all randomized treatment, including that beyond 6 months, and available follow-up data were assessed. The 15% (10/66) relapses among INTRON A patients occurred over a significantly longer period of time than the 40% (24/60) with observation (p=0.0002/0.0001, Log Rank/Wilcoxon). Median time to relapse was estimated, using the Kaplan-Meier method, to be 6.8 months in the observation group but could not be estimated in the INTRON A group.

Subsequent follow-up with a median time of approximately 40 months demonstrated an overall survival of 87.8%. In a comparable historical control group followed for 24 months, overall median survival was approximately 40%.

Malignant Melanoma   The safety and efficacy of INTRON A Interferon alfa-2b, recombinant for Injection was evaluated as adjuvant to surgical treatment in patients with melanoma who were free of disease (postsurgery) but at high risk for systemic recurrence. These included patients with lesions of Breslow thickness >4 mm, or patients with lesions of any Breslow thickness with primary or recurrent nodal involvement. In a randomized, controlled trial in 280 patients, 143 patients received INTRON A therapy at 20 million IU/m 2 intravenously five times per week for 4 weeks (induction phase) followed by 10 million IU/m 2 subcutaneously three times per week for 48 weeks (maintenance phase). INTRON A therapy was begun </=56 days after surgical resection. The remaining 137 patients were observed.

INTRON A therapy produced a significant increase in relapse-free and overall survival. Median time to relapse for the INTRON A treated patients vs observation patients was 1.72 years vs 0.98 years (p<0.01, stratified Log Rank). The estimated 5-year relapse-free survival rate, using the Kaplan-Meier method, was 37% for INTRON A treated patients vs 26% for observation patients. Median overall survival time for INTRON A treated patients vs observation patients was 3.82 years vs 2.78 years (p=0.047, stratified Log Rank). The estimated 5-year overall survival rate, using the Kaplan-Meier method, was 46% for INTRON A treated patients vs 37% for observation patients.

Follicular Lymphoma   The safety and efficacy of INTRON A in conjunction with CHVP, a combination chemotherapy regimen, was evaluated as initial treatment in patients with clinically aggressive, large tumor burden, Stage III/IV follicular Non-Hodgkin' Lymphoma. Large tumor burden was defined by the presence of any one of the following: a nodal or extranodal tumor mass with a diameter of >7 cm; involvement of at least three nodal sites (each with a diameter of >3 cm); systemic symptoms; splenomegaly; serious effusion, orbital or epidural involvement; ureteral compression; or leukemia.

In a randomized, controlled trial, 130 patients received CHVP therapy and 135 patients received CHVP therapy plus INTRON A therapy at 5 million IU subcutaneously three times weekly for the duration of 18 months. CHVP chemotherapy consisted of cyclophosphamide 600 mg/m 2 , doxorubicin 25 mg/m 2 , and teniposide (VM-26) 60 mg/m 2 , administered intravenously on Day 1 and prednisone at a daily dose of 40 mg/m 2 given orally on Days 1 to 5. Treatment consisted of six CHVP cycles administered monthly, followed by an additional six 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 the combination of INTRON A therapy plus CHVP had a significantly longer progression-free survival (2.9 years vs 1.5 years, p=0.0001, Log Rank test). 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 plus INTRON A therapy had not been reached (p=0.004, Log Rank test). In three additional published, randomized, controlled studies of the addition of interferon alfa to anthracycline-containing combination chemotherapy regimens, 1-3 the addition of interferon alfa was associated with significantly prolonged progression-free survival. Differences in overall survival were not consistently observed.

Condylomata Acuminata   Condylomata acuminata (venereal or genital warts) are associated with infections of the human papilloma virus (HPV). The safety and efficacy of INTRON A Interferon alfa-2b, recombinant for Injection in the treatment of condylomata acuminata were evaluated in three controlled double-blind clinical trials. In these studies, INTRON A doses of 1 million IU per lesion were administered intralesionally three times a week (TIW), in </=5 lesions per patient for 3 weeks. The patients were observed for up to 16 weeks after completion of the full treatment course.

INTRON A treatment of condylomata was significantly more effective than placebo, as measured by disappearance of lesions, decreases in lesion size, and by an overall change in disease status. 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 vs 17% of placebo patients experienced clearing of all treated lesions. Likewise, 24% of INTRON A patients vs 8% of placebo patients experienced marked (>/=75% to <100%) reduction in lesion size. 18% vs 9% experienced moderate (>/=50% to </=75%) reduction in lesion size, 10% vs 42% had a slight (<50%) reduction in lesion size, 5% vs 24% had no change in lesion size, and 0% vs 1% experienced exacerbation (p<0.001).

In one of these studies, 43% (54/125) of patients in whom multiple (</=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.

The response to INTRON A therapy was better in patients who had condylomata for shorter durations than in patients with lesions for a longer duration.

Another study involved 97 patients in whom three lesions were treated with either an intralesional injection of 1.5 million IU of INTRON A Interferon alfa-2b, recombinant for Injection per lesion followed by a topical application of 25% podophyllin, or a topical application of 25% podophyllin alone. Treatment was given once a week for 3 weeks. The combined treatment of INTRON A Interferon alfa-2b, recombinant for Injection and podophyllin was shown to be significantly more effective than podophyllin alone, as determined by the number of patients whose lesions cleared. This significant difference in response was evident after the second treatment (Week 3) and continued through 8 weeks posttreatment. At the time of the patient' best response, 67% (33/49) of the INTRON A Interferon alfa-2b, recombinant for Injection and podophyllin treated patients had all three treated lesions clear while 42% (20/48) of the podophyllin treated patients had all three clear (p=0.003).

AIDS-Related Kaposi' Sarcoma   The safety and efficacy of INTRON A Interferon alfa-2b, recombinant for Injection in the treatment of Kaposi' Sarcoma (KS), a common manifestation of the Acquired Immune Deficiency Syndrome (AIDS), were evaluated in clinical trials in 144 patients.

In one study, INTRON A doses of 30 million IU/m 2 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 vs 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 vs 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). Results at doses of 30 million IU/m 2 TIW and 35 million IU/QD were subcutaneously similar and are provided together in TABLE 1. This table demonstrates the relationship of response to baseline CD4 count in both asymptomatic and symptomatic patients in the 30 million IU/m 2 TIW and the 35 million IU/QD treatment groups.

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 >200 (30.7 months) than in patients with CD4 </=200 (8.9 months). Among responders, the median survival time was 22.6 months vs 9.7 months in nonresponders.

Chronic Hepatitis C   The safety and efficacy of INTRON A Interferon alfa-2b, recombinant for Injection in the treatment of chronic hepatitis C was evaluated in 5 randomized clinical studies in which an INTRON A dose of 3 million IU three times a week (TIW) was assessed. The initial three studies were placebo-controlled trials that evaluated a 6-month (24 week) course of therapy. In each of the three studies, INTRON A therapy resulted in a reduction in serum alanine aminotransferase (ALT) in a greater proportion of patients vs control patients at the end of 6 months of dosing. During the 6 months of follow-up, approximately 50% of the patients who responded maintained their ALT response. A combined analysis comparing pretreatment and posttreatment liver biopsies revealed histological improvement in a statistically significantly greater proportion of INTRON A treated patients compared to controls.

Two additional studies have investigated longer treatment durations (up to 24 months). 5,6 Patients in the two studies to evaluate longer duration of treatment had hepatitis with or without cirrhosis in the absence of decompensated liver disease. Complete response to treatment was defined as normalization of the final two serum ALT levels during the treatment period. A sustained response was defined as a complete response at the end of the treatment period with sustained normal ALT values lasting at least 6 months following discontinuation of therapy.

In Study 1, all patients were initially treated with INTRON-A 3 million IU TIW subcutaneously for 24 weeks (run-in-period). Patients who completed the initial 24-week treatment period were then randomly assigned to receive no further treatment, or to receive 3 million IU TIW for an additional 48 weeks. In Study 2, patients who met the entry criteria were randomly assigned to receive INTRON A 3 million IU TIW subcutaneously for 24 weeks or to receive INTRON A 3 million IU TIW subcutaneously for 96 weeks. In both studies, patient follow-up was variable and some data collection was retrospective.

Results show that longer durations of INTRON A therapy improved the sustained response rate (see TABLE 2). In patients with complete responses (CR) to INTRON A therapy after 6 months of treatment (149/352 [42%]), responses were less often sustained if drug was discontinued (21/70 [30%]) than if it was continued for 18 to 24 months (44/79 [56%]). Of all patients randomized, the sustained response rate in the patients receiving 18 or 24 months of therapy was 22% and 26%, respectively, in the two trials. In patients who did not have a CR by 6 months, additional therapy did not result in significantly more responses, since almost all patients who responded to therapy did so within the first 16 weeks of treatment.

A subset (<50%) of patients from the combined extended dosing studies had liver biopsies performed both before and after INTRON A treatment. Improvement in necroinflammatory activity as assessed retrospectively by the Knodell (Study 1) and Scheuer (Study 2) Histology Activity Indices was observed in both studies. A higher number of patients (58%, 45/78) improved with extended therapy than with shorter (6 months) therapy (38%, 34/89) in this subset.

REBETRON™ Combination Therapy containing INTRON A and REBETOL® (ribavirin, USP) Capsules has been shown to provide a significant reduction in virologic load and improved histologic response in patients with compensated liver disease who have relapsed following therapy with alfa interferon alone and in patients previously untreated with alfa interferon. See REBETRON Combination Therapy package insert for additional information.

Chronic Hepatitis B Adults   The safety and efficacy of INTRON A Interferon alfa-2b, recombinant for Injection 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 vs no treatment. All patients were 18 years of age or older with compensated liver disease, and had chronic hepatitis B virus (HBV) infection (serum HBsAg positive for at least 6 months) and HBV replication (serum HBeAg positive). Patients were also serum HBV-DNA positive, an additional indicator of HBV replication, as measured by a research assay. 7,8 All patients had elevated serum alanine aminotransferase (ALT) and liver biopsy findings compatible with the diagnosis of chronic hepatitis. Patients with the presence of antibody to human immunodeficiency virus (anti-HIV) or antibody to hepatitis delta virus (anti-HDV) in the serum were excluded from the studies.

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 (see TABLE 3). In a third study without a concurrent control group, a similar response rate to INTRON A therapy was observed. Pretreatment with prednisone, evaluated in two of the studies, did not improve the response rate and provided no additional benefit.

The response to INTRON A therapy was durable. No patient responding to INTRON A therapy at a dose of 5 million IU QD or 10 million IU, TIW, relapsed during the follow-up period which ranged from 2 to 6 months after treatment ended. The loss of serum HBeAg and HBV DNA was maintained in 100% of 19 responding patients followed for 3.5 to 36 months after the end of therapy.

In a proportion of responding patients, loss of HBeAg was followed by the loss of HBsAg. HBsAg was lost in 27% (4/15) of patients who responded to INTRON A therapy at a dose of 5 million IU QD, and 35% (8/23) of patients who responded to 10 million IU TIW. No untreated control patient lost HBsAg in these studies.

In an ongoing study to assess the long-term durability of virologic response, 64 patients responding to INTRON A therapy have been followed for 1.1 to 6.6 years after treatment; 95% (61/64) remain serum HBeAg negative and 49% (30/61) have lost serum HBsAg.

INTRON A therapy resulted in normalization of serum ALT in a significantly greater proportion of treated patients compared to untreated patients in each of two controlled studies (see TABLE 4). In a third study without a concurrent control group, normalization of serum ALT was observed in 50% (12/24) of patients receiving INTRON A therapy.

Virologic response was associated with a reduction in serum ALT to normal or near normal (</=1.5 × the upper limit of normal) in 87% (13/15) of patients responding to INTRON A therapy at 5 million IU QD, and 100% (23/23) of patients responding to 10 million IU TIW.

Improvement in liver histology was evaluated in Studies 1 and 3 by comparison of pretreatment and 6-month posttreatment liver biopsies using the semiquantitative Knodell Histology Activity Index. 9 No statistically significant difference in liver histology was observed in treated patients compared to control patients in Study 1. Although statistically significant histological improvement from baseline was observed in treated patients in Study 3 (p</=0.01), there was no control group for comparison. Of those patients exhibiting a virologic response following treatment with 5 million IU QD or 10 million IU TIW, histological improvement was observed in 85% (17/20) compared to 36% (9/25) of patients who were not virologic responders. The histological improvement was due primarily to decreases in severity of necrosis, degeneration, and inflammation in the periportal, lobular, and portal regions of the liver (Knodell Categories I + II + III). Continued histological improvement was observed in four responding patients who lost serum HBsAg and were followed 2 to 4 years after the end of INTRON A therapy. 10

Pediatrics   The safety and efficacy of INTRON A Interferon alfa-2b, recombinant for Injection in the treatment of chronic hepatitis B was evaluated in one randomized controlled trial of 149 patients ranging from 1 year to 17 years of age. Seventy-two patients were treated with 3 million IU/m 2 of INTRON A therapy administered subcutaneously three times a week (TIW) for 1 week; the dose was then escalated to 6 million IU/m 2 TIW for a minimum of 16 weeks up to 24 weeks. The maximum weekly dosage was 10 million IU TIW. Seventy-seven patients were untreated controls. Study entry and response criteria were identical to those described in the adult patient population.

Patients treated with INTRON A therapy had a better response (loss of HBV DNA and HBeAg at 24 weeks of follow up) compared to the untreated controls (24% [17/72] vs 10% [8/77] p=0.05). Sixteen of the 17 responders treated with INTRON A therapy remained HBV DNA and HBeAg negative and had a normal serum ALT 12 to 24 months after completion of treatment. Serum HBsAg became negative in 7 out of 17 patients who responded to INTRON A therapy. None of the control patients who had an HBV DNA and HBeAg response became HBsAg negative. At 24 weeks of follow up, normalization of serum ALT was similar in patients treated with INTRON A therapy (17%, 12/72) and in untreated control patients (16%, 12/77). Patients with a baseline HBV DNA <100 pg/mL were more likely to respond to INTRON A therapy than were patients with a baseline HBV DNA >100 pg/mL (35% vs 9%, respectively). Patients who contracted hepatitis B through maternal vertical transmission had lower response rates than those who contracted the disease by other means (5% vs 31%, respectively). There was no evidence that the effects of HBV DNA and HBeAg were limited to specific subpopulations based on age, gender, or race.

TABLE 1
RESPONSE BY BASELINE CD4 COUNT *
IN AIDS-RELATED KS PATIENTS
30 million IU/m 2
TIW, SC and 35 million IU QD, SC
 
Asymptomatic   Symptomatic
CD4<200
4/14 (29%)   0/19 (0%)
200</=CD4</=400
6/12 (50%)   0/5  (0%)
 
    } 58%    
CD4>400
5/7  (71%)   0/0  (0%)
* Data for CD4, and asymptomatic and symptomatic classification were not available for all patients.

TABLE 2
SUSTAINED ALT RESPONSE RATE VS DURATION OF THERAPY
IN
CHRONIC HEPATITIS C PATIENTS
INTRON A 3 Million IU TIW
Treatment Group * --Number of Patients (%)
Study Number INTRON A 3 million IU
24 weeks of treatment
INTRON A 3 million IU
72 or 96 weeks of
treatment **
Difference
(Extended - 24 weeks)
(95% CI) ***
  ALT response at the end of follow-up    
1 12/101 (12%) 23/104 (22%) 10% (-3, 24)
2 9/67 (13%) 21/80 (26%) 13% (-4, 30)
Combined Studies 21/168 (12.5%) 44/184 (24%) 11.4% (2, 21)
  ALT response at the end of treatment    
1 40/101 (40%) 51/104 (49%) --  
2 32/67 (48%) 35/80 (44%) --  
* Intent to treat groups.
** Study 1: 72 weeks of treatment; Study 2: 96 weeks of treatment.
*** Confidence intervals adjusted for multiple comparisons due to 3 treatment arms in the study.

TABLE 3
VIROLOGIC RESPONSE *
IN
CHRONIC HEPATITIS B PATIENTS
Treatment Group ** --Number of Patients (%)
Study Number INTRON A
5 million IU QD
INTRON A
10 million IU TIW
Untreated Controls p *** Value
1 7 15/38 (39%) --   -- 3/42 (7%) 0.0009
--   -- 10/24 (42%) 1/22 (5%) 0.005 
3 8 --   -- 13/24 § (54%) 2/27 (7%) § NA §   
All Studies 15/38 (39%) 23/48 (48%) 6/91 (7%) --
* Loss of HBeAg and HBV DNA by 6 months posttherapy.
** Patients pretreated with prednisone not shown.
*** INTRON A treatment group vs untreated control.
§ Untreated control patients evaluated after 24-week observation period. A subgroup subsequently received INTRON A therapy. A direct comparison is not applicable (NA).

TABLE 4
ALT RESPONSES *
IN
CHRONIC HEPATITIS B PATIENTS
Treatment Group--Number of Patients (%)
Study Number INTRON A
5 million IU QD
INTRON A
10 million IU TIW
Untreated Controls P ** Value
1 16/38 (42%) --   -- 8/42 (19%) 0.03  
2 --   -- 10/24  (42%) 1/22 (5%) 0.0034
3 --   -- 12/24 *** (50%) 2/27 (7%) *** NA ***  
All Studies 16/38 (42%) 22/48 (46%) 11/91 (12%) --
* Reduction in serum ALT to normal by 6 months posttherapy.
** INTRON A treatment group vs untreated control.
*** Untreated control patients evaluated after 24-week observation period. A subgroup subsequently received INTRON A therapy. A direct comparison is not applicable (NA).

Hair Cell Leukemia

INTRON A Interferon alfa-2b, recombinant for Injection is indicated for the treatment of patients 18 years of age or older with hairy cell leukemia.

Malignant Melanoma

INTRON A Interferon alfa-2b, recombinant for Injection is indicated 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.

Follicular Lymphoma

INTRON A Interferon alfa-2b, recombinant for Injection is indicated for the initial treatment of clinically aggressive (see Clinical Experience ) follicular Non-Hodgkin' Lymphoma in conjunction with anthracycline-containing combination chemotherapy in patients 18 years of age or older. Efficacy of INTRON A in patients with low-grade, low-tumor burden follicular Non-Hodgkin' Lymphoma has not been demonstrated.

Condylomata Acuminata

INTRON A Interferon alfa-2b, recombinant for Injection is indicated for intralesional treatment of selected patients 18 years of age or older with condylomata acuminata involving external surfaces of the genital and perianal areas (see DOSAGE AND ADMINISTRATION ).

The use of this product in adolescents has not been studied.

AIDS-Related Kaposi' Sarcoma   INTRON A Interferon alfa-2b, recombinant for Injection is indicated for the treatment of selected patients 18 years of age or older with AIDS-Related Kaposi' Sarcoma. The likelihood of response to INTRON A therapy is greater in patients who are without systemic symptoms, who have limited lymphadenopathy and who have a relatively intact immune system as indicated by total CD4 count.

Chronic Hepatitis C   INTRON A Interferon alfa-2b, recombinant for Injection is indicated 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. Studies in these patients demonstrated that INTRON A therapy can produce meaningful effects on this disease, manifested by normalization of serum alanine aminotransferase (ALT) and reduction in liver necrosis and degeneration.

A liver biopsy should be performed to establish the diagnosis of chronic hepatitis. Patients should be tested for the presence of antibody to HCV. Patients with other causes of chronic hepatitis, including autoimmune hepatitis, should be excluded. Prior to initiation of INTRON A therapy, the physician should establish that the patient has compensated liver disease. The following patient entrance criteria for compensated liver disease were used in the clinical studies and should be considered before INTRON A treatment of patients with chronic hepatitis C:

Serum creatinine should be normal or near normal.

Prior to initiation of INTRON A therapy, CBC and platelet counts should be evaluated in order to establish baselines for monitoring potential toxicity. These tests should be repeated at weeks 1 and 2 following initiation of INTRON A therapy, and monthly thereafter. Serum ALT should be evaluated at approximately 3-month intervals to assess response to treatment (see DOSAGE AND ADMINISTRATION ).

Patients with preexisting thyroid abnormalities may be treated if thyroid-stimulating hormone (TSH) levels can be maintained in the normal range by medication. TSH levels must be within normal limits upon initiation of INTRON A treatment and TSH testing should be repeated at 3 and 6 months (see PRECAUTIONS - Laboratory Tests ).

INTRON A in combination with REBETOL (ribavirin, USP) Capsules is indicated for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alfa interferon therapy or who have relapsed following alfa interferon therapy. See REBETRON Combination Therapy package insert for additional information.

Chronic Hepatitis B   INTRON A Interferon alfa-2b, recombinant for Injection is indicated for the treatment of chronic hepatitis B in patients 1 year of age or older with compensated liver disease. Patients who have been serum HBsAg positive for at least 6 months and have evidence of HBV replication (serum HBeAg positive) with elevated serum ALT are candidates for treatment. Studies in these patients demonstrated that INTRON A therapy can produce virologic remission of this disease (loss of serum HBeAg), and normalization of serum aminotransferases. INTRON A therapy resulted in the loss of serum HBsAg in some responding patients.

Prior to initiation of INTRON A therapy, it is recommended that a liver biopsy be performed to establish the presence of chronic hepatitis and the extent of liver damage. The physician should establish that the patient has compensated liver disease. The following patient entrance criteria for compensated liver disease were used in the clinical studies and should be considered before INTRON A treatment of patients with chronic hepatitis B:

Patients with causes of chronic hepatitis other than chronic hepatitis B or chronic hepatitis C should be treated with INTRON A Interferon alfa-2b, recombinant for Injection. CBC and platelet counts should be evaluated prior to initiation of INTRON A therapy in order to establish baselines for monitoring potential toxicity. These tests should be repeated at treatment weeks 1, 2, 4, 8, 12, and 16. Liver function tests, including serum ALT, albumin, and bilirubin, should be evaluated at treatment weeks 1, 2, 4, 8, 12, and 16. HBeAg, HBsAg, and ALT should be evaluated at the end of therapy, as well as 3- and 6-months posttherapy, since patients may become virologic responders during the 6-month period following the end of treatment. In clinical studies in adults, 39% (15/38) of responding patients lost HBeAg 1 to 6 months following the end of INTRON A therapy. Of responding patients who lost HBsAg, 58% (7/12) did so 1- to 6-months posttreatment.

A transient increase in ALT >/=2 × baseline value (flare) can occur during INTRON A therapy for chronic hepatitis B. In clinical trials in adults and pediatrics, this flare generally occurred 8 to 12 weeks after initiation of therapy and was more frequent in INTRON A responders ( adults 63%, 24/38; pediatrics 59%, 10/17) than in nonresponders ( adults 27%, 13/48; pediatrics 35%, 19/55). However, in adults and pediatrics, elevations in bilirubin >/=3 mg/dL (>/=2 times ULN) occurred infrequently ( adults 2%, 2/86; pediatrics 3%, 2/72) during therapy. When ALT flare occurs, in general, INTRON A therapy should be continued unless signs and symptoms of liver failure are observed. During ALT flare, clinical symptomatology and liver function tests including ALT, prothrombin time, alkaline phosphatase, albumin, and bilirubin, should be monitored at approximately 2-week intervals (see ).

DOSAGE AND ADMINISTRATION

IMPORTANT:  INTRON A Interferon alfa-2b, recombinant for Injection dosing regimens are different for each of the following indications described in this section of the product information sheet. INTRON A Solution for Injection multidose pen contains a prefilled, multidose cartridge for subcutaneous administration. It is designed to deliver doses as required using a simple dial mechanism. The needles provided in the packaging should be used for the INTRON A Solution for Injection multidose pen only. A new needle is to be used each time as dose is delivered using the pen. Each INTRON A Solution for Injection multidose pen is for individual patient use only.

Hairy Cell Leukemia   The recommended dosage of INTRON A Interferon alfa-2b, recombinant for Injection for the treatment of hairy cell leukemia is 2 million IU/m 2 administered intramuscularly (see ) or subcutaneously 3 times a week for up to 6 months. The 50 million IU strength of the INTRON A Powder for Injection is not to be used for the treatment of hairy cell leukemia. Higher doses are not recommended. Responding patients may benefit from continued treatment.

If severe adverse reactions develop, the dosage should be modified (50% reduction) or therapy should be temporarily discontinued until the adverse reactions abate. If persistent or recurrent intolerance develops following adequate dosage adjustment, or disease progresses, INTRON A treatment should be discontinued. The minimum effective INTRON A dose has not been established.

Malignant Melanoma   The recommended INTRON A treatment regimen includes induction treatment 5 consecutive days per week for 4 weeks as an intravenous (IV) infusion at a dose of 20 million IU/m 2 , followed by maintenance treatment three times per week for 48 weeks as a subcutaneous (SC) injection, at a dose of 10 million IU/m 2 .

In the clinical trial, the median daily INTRON A doses administered to patients were 19.1 million IU/m 2 during the induction phase and 9.1 million IU/m 2 during the maintenance phase.

Regular laboratory testing should be performed to monitor laboratory abnormalities for the purposes of dose modification (see PRECAUTIONS - Laboratory Tests ). If adverse reactions develop during INTRON A treatment, particularly if granulocytes decrease to <500/mm 3 or SGPT/SGOT rises to >5 × upper limit of normal, treatment should be temporarily discontinued until the adverse reactions abate. INTRON A treatment should be restarted at 50% of the previous dose. If intolerance persists after dose adjustments or if granulocytes decrease to <250/mm 3 or SGPT/SGOT rises to > 10 × upper limit of normal, INTRON A therapy should be discontinued.

Follicular Lymphoma   The recommended dosage of INTRON A Interferon alfa-2b, recombinant for Injection is 5 million IU subcutaneously three times per week for up to 18 months in conjunction with an anthracycline-containing chemotherapy regimen.

In published reports, the doses of myelosuppressive drugs were reduced by 25% from those utilized in a full-dose CHOP regimen, and cycle length increased by 33% (eg, from 21 to 28 days) when an alfa interferon was added to the regimen. 1,4 The dosing regimen should be modified for evidence of serious toxicity. The following dose modification guidelines for hematologic toxicity were used in the clinical trial: the chemotherapy regimen was delayed if either the neutrophil count was <1500/mm 3 or the platelet count was <75,000/mm 3 . Administration of INTRON A was temporarily interrupted for a neutrophil count <1000/mm 3 , or a platelet count <50,000/mm 3 , or reduced by 50% to 2.5 MIU TIW for a neutrophil count >1000/mm 3 but <1500/mm 3 .

Reinstitution of the initial INTRON A dose (5 million IU TIW) was tolerated after resolution of hematologic toxicity (>/=1500/mm 3 ).

INTRON A therapy should be discontinued if SGOT exceeds >5 × the upper limit of normal or serum creatinine >2.0 mg/dL. (See .)

Condylomata Acuminata   The 10 million IU vial of INTRON A Powder for Injection must be reconstituted with 1 mL of Diluent for INTRON A Interferon alfa-2b, recombinant for Injection (bacteriostatic water for injection). Do not reconstitute the 10 million IU vial of INTRON A Powder for Injection with more than 1 mL of diluent since the injection would be subpotent. Do not use the 3 million, 5 million, 18 million, 25 million, or 50 million IU vials of INTRON A Powder for Injection for the treatment of condylomata acuminata since the resulting reconstituted solution would be either hypertonic or an inappropriate concentration. Do not use the 3 million IU vial or the 18 million IU multidose vial of INTRON A Solution for Injection for the intralesional treatment of condylomata acuminata since the concentrations are inappropriate for such use.

Inject 1.0 million IU of INTRON A Interferon alfa-2b, recombinant for Injection (either 0.1 mL of reconstituted 10 million IU INTRON A Powder for Injection or 0.1 mL of the 5 million IU, 10 million IU, or 25 million IU strengths of INTRON A Solution for Injection, each having a final concentration of 10 million IU/mL) into each lesion three times per week on alternate days, for 3 weeks. The injection should be administered intralesionally using a Tuberculin or similar syringe and a 25- to 30-gauge needle. The needle should be directed at the center of the base of the wart and at an angle almost parallel to the plane of the skin (approximating that in the commonly used PPD test). This will deliver the interferon to the dermal core of the lesion, infiltrating the lesion and causing a small wheal. Care should be taken not to go beneath the lesion too deeply; subcutaneous injection should be avoided, since this area is below the base of the lesion. Do not inject too superficially since this will result in possible leakage, infiltrating only the keratinized layer, and not the dermal core. As many as five lesions can be treated at one time. To reduce side effects, INTRON A injections may be administered in the evening, when possible. Additionally, acetaminophen may be administered may be administered at the time of injection to alleviate some of the potential side effects.

The maximum response usually occurs 4 to 8 weeks after initiation of the first treatment course. If results at 12 to 16 weeks after the initial treatment course has concluded are not satisfactory, a second course of treatment using the above dosage schedule may be instituted providing that clinical symptoms and signs, or changes in laboratory parameters (liver function tests, WBC, and platelets) do not preclude such a course of action.

Patients with 6 to 10 condylomata may receive a second (sequential) course of treatment at the above dosage schedule, to treat up to five additional condylomata per course of treatment. Patients with greater than 10 condylomata may receive additional sequences depending on how large a number of condylomata are present.

AIDS-Related Kaposi' Sarcoma   The recommended INTRON A dosage is 30 million IU/m 2 three times a week administered subcutaneously or intramuscularly. The 18 million and 25 million IU multidose strengths of the INTRON A Solution for Injection should not be used for the treatment of AIDS-Related Kaposi' Sarcoma since the concentrations are inappropriate.

The selected dosage regimen should be maintained unless the disease progresses rapidly or severe intolerance is manifested. If severe adverse reactions develop, the dosage should be modified (50% reduction) or therapy should be temporarily discontinued until the adverse reactions abate. When patients initiate therapy at 30 million IU/m 2 TW, the average dose tolerated at the end of 12 weeks of therapy is 110 million IU/week and 75 million IU/week at the end of 24 weeks of therapy.

When disease stabilization or a response to treatment occurs, treatment should continue until there is no further evidence of tumor or until discontinuation is required by evidence of a severe opportunistic infection or adverse effect.

Chronic Hepatitis C   The recommended dosage of INTRON A Interferon alfa-2b, recombinant for Injection 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 (see CLINICAL PHARMACOLOGY - Chronic Hepatitis C ). Patients who do not normalize their ALTs after 16 weeks of therapy rarely achieve a sustained response with extension of treatment. Consideration should be given to discontinuing these patients from therapy.

If severe adverse reactions develop during INTRON A treatment, the dose should be modified (50% reduction) or therapy should be temporarily discontinued until the adverse reactions abate. If intolerance persists after dose adjustment, INTRON A therapy should be discontinued.

See REBETRON Combination Therapy package insert for dosing when used in combination with REBETOL (ribavirin, USP) Capsules.

Chronic Hepatitis B Adults   The recommended dosage of INTRON A Interferon alfa-2b, recombinant for Injection 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 dosage of INTRON A Interferon alfa-2b, recombinant for Injection for the treatment of chronic hepatitis B is 3 million IU/m 2 three times a week (TIW) for the first week of therapy followed by dose escalation to 6 million IU/m 2 TIW (maximum of 10 million IU TIW) administered subcutaneously for a total therapy duration of 16 to 24 weeks.

If severe adverse reactions or laboratory abnormalities develop during INTRON A therapy, the dose should be modified (50% reduction), or discontinued if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, INTRON A therapy should be discontinued.

For patients with decreases in white blood cell, granulocyte, or platelet counts, the following guidelines for dose modification should be followed:

INTRON A Dose White Blood Cell Count Granulocyte Count Platelet Count
Reduce 50%
<1.5 × 10 9 /L <0.75 × 10 9 /L <50 × 10 9 /L
Permanently Discontinue
<1.0 × 10 9 /L <0.5 × 10 9 /L <25 × 10 9 /L

INTRON A therapy was resumed at up to 100% of the initial dose when white blood cell, granulocyte, and/or platelet counts returned to normal or baseline values.

At the discretion of the physician, the patient may self-administer the medication. (See illustrated PATIENT INFORMATION SHEET for instructions.)

Preparation and Administration of INTRON A Interferon alfa-2b, recombinant Powder for Injection for Intramuscular, Subcutaneous, or Intralesional Administration

Reconstitution of INTRON A Powder for Injection   Inject the amount of Diluent for INTRON A Interferon alfa-2b, recombinant for Injection (bacteriostatic water for injection) stated in the chart below (diluent is supplied in either a vial or syringe, see HOW SUPPLIED below), into the INTRON A vial. Swirl gently to hasten complete dissolution of the powder. The appropriate INTRON A dose should then be withdrawn and injected intramuscularly, subcutaneously, or intralesionally. (See PATIENT INFORMATION SHEET for detailed instructions.) After preparation and administration of the INTRON A injection, it is essential to follow the procedure for proper disposal of syringes and needles. (See PATIENT INFORMATION SHEET for detailed instructions.)

INTRON A Powder for Injection is not indicated for use in infants and should not be used in pediatric patients in this age group because when reconstituted with the provided diluent it contains benzyl alcohol. (See : Chronic Hepatitis B .)

Preparation and Administration of INTRON A Interferon alfa-2b, recombinant Powder for Injection for Intravenous Injection

The infusion solution should be prepared immediately prior to use. Based on the desired dose, the appropriate vial strength(s) of INTRON A Interferon alfa-2b, recombinant Powder for Injection should be reconstituted with the diluent provided. The appropriate INTRON A dose should then be withdrawn and injected into a 100-mL bag of 0.9% Sodium Chloride Injection, USP. The final concentration of INTRON A Interferon alfa-2b, recombinant for Injection should be not less than 10 million IU/100 mL. The prepared solution should be infused over a 20-minute period.

INTRON A Interferon alfa-2b, recombinant Powder for Injection
 
3 million IU 5 million IU 10 million IU 18 million IU 25 million IU 50 million IU &
  1 mL 1 mL      
1 mL          
1 mL 1 mL 2 mL   5 mL  
AIDS-Related Kaposi' Sarcoma
          1 mL
Condylomata Acuminata
    1 mL **      
Malignant Melanoma induction phase #
1 mL * 1 mL 1 mL 1 mL 5 mL 1 mL
1 mL * 1 mL 1 mL 1 mL   1 mL
1 mL 1 mL 1 mL   5 mL  
 * Use only for dose reduction.
** IMPORTANT: For patients with condylomata acuminata, reconstitute the 10 million IU vial with only 1 mL of the diluent provided to reach a final concentration of 10 million IU/mL to be administered intralesionally.
  # Based on the desired dose, the appropriate vial strengths should be reconstituted and administered intravenously.
  & This vial strength should be used only for the treatment of patients with AIDS-Related Kaposi' Sarcoma or malignant melanoma since the concentration is inappropriate for all other indications.

Stability   INTRON A Interferon alfa-2b, recombinant Powder for Injection provided in vials ranging from 3 to 50 million IU per vial, is stable at 45°C (113°F) for up to 7 days. After reconstitution with Diluent for INTRON A Interferon alfa-2b, recombinant for Injection (bacteriostatic water for injection) the solution is stable for 1 month at 2° to 8°C (36° to 46°F). The reconstituted solution is clear and colorless to light yellow.

Preparation and Administration of INTRON A Interferon alfa-2b, recombinant Solution for Injection

The 3 million IU, 5 million IU, and 10 million IU vials, and the 18 million and 25 million IU multidose vials of INTRON A Solution for Injection do not require reconstitution prior to administration. The solution is clear and colorless. The appropriate INTRON A dose should be withdrawn from the vial and injected intramuscularly, subcutaneously, or intralesionally (5 million IU and 10 million IU vials, and 25 million IU multidose vials only). After administration of INTRON A Solution for Injection, it is essential to follow the procedure for proper disposal of syringes and needles. (See PATIENT INFORMATION SHEET for detailed instructions.)

INTRON A Interferon alfa-2b, recombinant Solution for Injection
 
3 million IU 5 million IU 10 million IU 18 million IU multidose * 25 million IU multidose **
  \/ \/   \/ §
\/     \/  
\/ \/ \/ \/ \/
Condylomata Acuminata
  \/ \/   \/
\/ *** \/ \/ \/ *** \/
  \/     \/
* This is a multidose vial which contains a total of 22.8 million IU of interferon alfa-2b, recombinant per 3.8 mL in order to provide the delivery of six 0.5-mL doses, each containing 3 million IU of INTRON A Interferon alfa-2b, recombinant for Injection (for a label strength of 18 million IU).
** This is a multidose vial which contains a total of 32 million IU of interferon alfa-2b, recombinant per 3.2 mL in order to provide the delivery of five 0.5-mL doses, each containing 5 million IU of INTRON A Interferon alfa-2b, recombinant for Injection (for a label strength of 25 million IU).
*** Use only for dose reduction.
§ Use only for the 5 MIU daily regimen.
Use only for maintenance treatment.

INTRON A Interferon alfa-2b, recombinant Solution
in Multidose Pens
  
3 million IU/0.2 mL * 5 million IU/0.2 mL ** 10 million IU/0.2 mL ***
  \/ \/
\/    
\/ \/  
    \/
  \/  
  *The 3 million IU multidose pen contains a total of 22.5 million IU of interferon alfa-2b, recombinant per 1.5 mL in order to provide delivery of six 0.2-mL doses each containing 3 million IU of interferon alfa-2b, recombinant Solution for Injection (for a label strength of 18 million IU).
 **The 5 million IU multidose pen contains a total of 37.5 million IU of interferon alfa-2b, recombinant per 1.5 mL in order to provide delivery of six 0.2-mL doses each containing 5 million IU of interferon alfa-2b, recombinant Solution for Injection (for a label strength of 30 million IU).
***The 10 million IU multidose pen contains a total of 75 million IU of interferon alfa-2b, recombinant per 1.5 mL in order to provide delivery of six 0.2-mL doses each containing 10 million IU of interferon alfa-2b, recombinant Solution for Injection (for a label strength of 60 million IU).

IMPORTANT:   The 3 million IU vial and the 18 million IU multidose vial of INTRON A Solution for Injection are not to be used for chronic hepatitis B or condylomata acuminata. The multidose pen should not be used for condylomata acuminata. The 10 million IU vial of INTRON A Solution for Injection should not be used for chronic hepatitis C. INTRON A Solution for Injection should not be used for AIDS-Related Kaposi's Sarcoma since the concentrations are inappropriate. INTRON A Solution for Injection is not recommended for intravenous administration and should not be used for the induction phase of malignant melanoma. (See DOSAGE AND ADMINISTRATION - Condylomata Acuminata ; DOSAGE AND ADMINISTRATION - AIDS-Related Kaposi' Sarcoma .)

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. INTRON A Interferon alfa-2b, recombinant for Injection may be administered using either sterilized glass or plastic disposable syringes.

Stability   INTRON A Interferon alfa-2b, recombinant Solution for Injection multidose pens provided in strengths ranging from 18 to 60 million IU per pen is stable at 30°C (86°F) for up to 2 days. INTRON A Interferon alfa-2b, recombinant Solution for Injection provided in vials ranging from 3 to 25 million IU per vial, is stable at 35°C (95°F) for up to 7 days and at 30°C (86°F) for up to 14 days. The solution is clear and colorless.

INTRON A SOLUTION FOR INJECTION IS NOT RECOMMENDED FOR INTRAVENOUS ADMINISTRATION.

CONTRAINDICATIONS

INTRON A Interferon alfa-2b, recombinant for Injection is contraindicated in patients with a history of hypersensitivity to interferon alfa or any component of the injection. REBETRON Combination Therapy containing INTRON A and REBETOL (ribavirin, USP) Capsules must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of patients taking combination INTRON A/REBETOL therapy. Patients with autoimmune hepatitis must not be treated with combination INTRON A/REBETOL therapy. See REBETRON Combination Therapy package insert for additional information.

General   Moderate to severe adverse experiences may require modification of the patient' dosage regimen, or in some cases termination of INTRON A therapy. Because of the fever and other "flu-like" symptoms associated with INTRON A administration, it should be used cautiously in patients with debilitating medical conditions, such as those with a history of pulmonary disease (eg, chronic obstructive pulmonary disease), or diabetes mellitus prone to ketoacidosis. Caution should also be observed in patients with coagulation disorders (eg, thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Patients with platelet counts of less than 50,000/mm 3 should not be administered INTRON A Interferon alfa-2b, recombinant for Injection intramuscularly, but instead by subcutaneous administration.

INTRON A therapy should be used cautiously in patients with a history of cardiovascular disease. Those patients with a history of myocardial infarction and/or previous or current arrhythmic disorder who require INTRON A therapy should be closely monitored (see Laboratory Tests ). Cardiovascular adverse experiences, which include hypotension, arrhythmia, or tachycardia of 150 beats per minute or greater, and rarely, cardiomyopathy and myocardial infarction have been observed in some INTRON A treated patients. Some patients with these adverse events had no history of cardiovascular disease. Transient cardiomyopathy was reported in approximately 2% of the AIDS-Related Kaposi' Sarcoma patients treated with INTRON A Interferon alfa-2b, recombinant for Injection. Hypotension may occur during INTRON A administration, or up to 2 days posttherapy, and may require supportive therapy including fluid replacement to maintain intravascular volume.

Supraventricular arrhythmias occurred rarely and appeared to be correlated with preexisting conditions and prior therapy with cardiotoxic agents. These adverse experiences were controlled by modifying the dose or discontinuing treatment, but may require specific additional therapy.

DEPRESSION AND SUICIDAL BEHAVIOR INCLUDING SUICIDAL IDEATION, SUICIDAL ATTEMPTS, AND COMPLETED SUICIDES HAVE BEEN REPORTED IN ASSOCIATION WITH TREATMENT WITH ALFA INTERFERONS, INCLUDING INTRON A THERAPY. Patients with a preexisting psychiatric condition, especially depression, or a history of severe psychiatric disorder should not be treated with INTRON A Interferon alfa-2b, recombinant for Injection. 11 INTRON A therapy should be discontinued for any patient developing severe depression or other psychiatric disorder during treatment. Obtundation and coma have also been observed in some patients, usually elderly, treated at higher doses. While these effects are usually rapidly reversible upon discontinuation of therapy, full resolution of symptoms has taken up to 3 weeks in a few severe episodes. Narcotics, hypnotics, or sedatives may be used concurrently with caution and patients should be closely monitored until the adverse effects have resolved.

Infrequently, patients receiving INTRON A therapy developed thyroid abnormalities, either hypothyroid of hyperthyroid. The mechanism by which INTRON A Interferon alfa-2b, recombinant for Injection may alter thyroid status is unknown. Patients with preexisting thyroid abnormalities whose thyroid function cannot be maintained in the normal range by medication should not be treated with INTRON A Interferon alfa-2b, recombinant for Injection. Prior to initiation of INTRON A therapy, serum TSH should be evaluated. Patients developing symptoms consistent with possible thyroid dysfunction during the course of INTRON A therapy should have their thyroid function evaluated and appropriate treatment instituted. Therapy should be discontinued for patients developing thyroid abnormalities during treatment whose thyroid function cannot be normalized by medication. Discontinuation of INTRON A therapy has not always reversed thyroid dysfunction occurring during treatment.

Hepatotoxicity, including fatality, has been observed in interferon alfa treated patients, including those treated with INTRON A Interferon alfa-2b, recombinant for Injection. Any patient developing liver function abnormalities during treatment should be monitored closely and if appropriate, treatment should be discontinued.

Pulmonary infiltrates, pneumonitis and pneumonia, including fatality, have been observed in interferon alfa treated patients, including those treated with INTRON A Interferon alfa-2b, recombinant for Injection. The etiologic explanation for these pulmonary findings has yet to be established. Any patient developing fever, cough, dyspnea, or other respiratory symptoms should have a chest x-ray taken. If the chest x-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient should be closely monitored, and, if appropriate, interferon alfa treatment should be discontinued. While this has been reported more often in patients with chronic hepatitis C treated with interferon alfa, it has also been reported in patients with oncologic diseases treated with interferon alfa.

Retinal hemorrhages, cotton-wool spots, and retinal artery or vein obstruction have been observed rarely in patients treated with interferon alfa, including those treated with INTRON A Interferon alfa-2b, recombinant for Injection. The etiologic explanation for these findings has not yet been established. These events appear to occur after use of the drug for several months, but also have been reported after shorter treatment periods. Diabetes mellitus or hypertension have been present in some patients. Any patient complaining of changes in visual acuity or visual fields, or reporting other ophthalmologic symptoms during treatment with INTRON A Interferon alfa-2b, recombinant for Injection, should have an eye examination. Because the retinal events may have to be differentiated from those seen with diabetic or hypertensive retinopathy, a baseline ocular examination is recommended prior to treatment with interferon in patients with diabetes mellitus or hypertension.

Rare cases of autoimmune diseases including thrombocytopenia, vasculitis, Raynaud' phenomenon, rheumatoid arthritis, lupus erythematosus, and rhabdomyolysis have been observed in patients treated with alfa interferons, including patients treated with INTRON A Interferon alfa-2b, recombinant for Injection. In very rare cases the event resulted in fatality. The mechanisms by which these events develop and their relationship to interferon alfa therapy is not clear. Any patient developing an autoimmune disorder during treatment should be closely monitored and, if appropriate, treatment should be discontinued.

Diabetes mellitus and hyperglycemia have been observed rarely in patients treated with INTRON A Interferon alfa-2b, recombinant for Injection. Symptomatic patients should have their blood glucose measured and followed up accordingly. Patients with diabetes mellitus may require adjustment of their antidiabetic regimen.

The 50 million IU strength of the INTRON A Powder for Injection is not to be used for the treatment of hairy cell leukemia, condylomata acuminata, follicular lymphoma, chronic hepatitis C, or chronic hepatitis B. The 3 million, 5 million, 18 million, and 25 million IU strengths of the INTRON A Powder for Injection are not to be used for the intralesional treatment of condylomata acuminata since the dilution required for the intralesional use would result in a hypertonic solution.

The INTRON A multidose pens, the 3 million IU vial, and the 18 million IU multidose vial of INTRON A Solution for Injection are not to be used for the treatment of condylomata acuminata. The INTRON A multidose pens and the 18 million and 25 million IU multidose vials of INTRON A Solution for Injection are not to be used for the treatment of AIDS-Related Kaposi' Sarcoma. INTRON A Solution for Injection is not recommended for the intravenous treatment of malignant melanoma.

The powder formulations of this product contain albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

AIDS-Related Kaposi' Sarcoma   INTRON A therapy should not be used for patients with rapidly progressive visceral disease (see CLINICAL PHARMACOLOGY ). Also of note, there may be synergistic adverse effects between INTRON A Interferon alfa-2b, recombinant for Injection and zidovudine. Patients receiving concomitant zidovudine have had a higher incidence of neutropenia than that expected with zidovudine alone. Careful monitoring of the WBC count is indicated in all patients who are myelosuppressed and in all patients receiving other myelosuppressive medications. The effects of INTRON A Interferon alfa-2b, recombinant for Injection when combined with other drugs used in the treatment of AIDS-Related disease are unknown.

Chronic Hepatitis C and Chronic Hepatitis B   Patients with decompensated liver disease, autoimmune hepatitis or a history of autoimmune disease, and patients who are immunosuppressed transplant recipients should not be treated with INTRO A Interferon alfa-2b, recombinant for Injection. There are reports of worsening liver disease, including jaundice, hepatic encephalopathy, hepatic failure, and death following INTRON A therapy in such patients. Therapy should be discontinued for any patient developing signs and symptoms of liver failure.

Chronic hepatitis B patients with evidence of decreasing hepatic synthetic functions, such as decreasing albumin levels or prolongation of prothrombin time, who nevertheless meet the entry criteria to start therapy, may be at increased risk of clinical decompensation if a flare of aminotransferases occurs during INTRON A treatment. In such patients, if increases in ALT occur during INTRON A therapy for chronic hepatitis B, they should be followed carefully including close monitoring of clinical symptomatology and liver function tests, including ALT, prothrombin time, alkaline phosphatase, albumin, and bilirubin. In considering these patients for INTRON A therapy, the potential risks must be evaluated against the potential benefits of treatment.

INTRON A Interferon alfa-2b, recombinant Powder for Injection when reconstituted with the provided Diluent for INTRON A Interferon alfa-2b, recombinant for Injection (bacteriostatic water for injection) contains benzyl alcohol. There have been rare reports of death in infants associated with excessive exposure to benzyl alcohol. The amount of benzyl alcohol at which toxicity or adverse effects may occur in infants is not known. INTRON A Powder for Injection is not indicated for use in infants and should not be used in pediatric patients in this age group.

REBETRON Combination Therapy containing INTRON A and REBETOL (ribavirin, USP) Capsules was associated with hemolytic anemia. Hemoglobin <10 g/dL was observed in approximately 10% of patients in clinical trials. Anemia occurred within 1 to 2 weeks of initiation of ribavirin therapy. REBETRON Combination Therapy containing INTRON A and REBETOL is not recommended in patients with severe renal impairment and should be used with caution in patients with moderate renal impairment. See REBETRON Combination Therapy package insert for additional information.

PRECAUTIONS

General   Acute serious hypersensitivity reactions (eg, urticaria, angioedema, bronchoconstriction, anaphylaxis) have been demonstrated rarely in INTRON A treated patients; if such an acute reaction develops, the drug should be discontinued immediately and appropriate medical therapy instituted. Transient rashes have occurred in some patients following injection, but have not necessitated treatment interruption.

While fever may be related to the flu-like syndrome reported commonly in patients treated with interferon, other causes of persistent fever should be ruled out.

There have been reports of interferon, including INTRON A Interferon alfa-2b, recombinant for Injection, exacerbating preexisting psoriasis; therefore, INTRON A therapy should be used in these patients only if the potential benefit justifies the potential risk.

Variations in dosage, routes of administration, and adverse reactions exist among different brands of interferon. Therefore, do not use different brands of interferon in any single treatment regimen.

Drug Interactions   Interactions between INTRON A Interferon alfa-2b, recombinant for Injection and other drugs have not been fully evaluated. Caution should be exercised when administering INTRON A therapy in combination with other potentially myelosuppressive agents such as zidovudine. Concomitant use of alfa interferon and theophylline decreases theophylline clearance, resulting in a 100% increase in serum theophylline levels.

Information for Patients   Patients receiving INTRON A treatment should be directed in its appropriate use, informed of benefits and risks associated with treatment, and referred to the PATIENT INFORMATION SHEET . This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

If home use is prescribed, a puncture-resistant container for the disposal of used syringes and needles should be supplied to the patient. Patients should be thoroughly instructed on the importance of proper disposal and cautioned against any reuse of needles and syringes. The full container should be disposed of according to the directions provided by the physician (see PATIENT INFORMATION SHEET ).

Patients should be cautioned not to change brands of interferon without medical consultation as a change in dosage may result.

Patients receiving high INTRON A doses should be cautioned against performing tasks that would require complete mental alertness, such as operating machinery or driving a motor vehicle.

The most common adverse experiences occurring with INTRON A therapy are "flu-like" symptoms, such as fever, headache, fatigue, anorexia, nausea, or vomiting (see ADVERSE REACTIONS ) and appear to decrease in severity as treatment continues. Some of these "flu-like" symptoms may be minimized by bedtime administration. Antipyretics may be used to prevent or partially alleviate the fever and headache. Another common adverse experience is thinning of the hair.

It is advised that patients be well hydrated, especially during the initial stages of treatment.

INTRON A in combination with REBETOL (ribavirin, USP) Capsules therapy must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of patients taking INTRON A/REBETOL therapy. Combination INTRON A/REBETOL therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. See REBETRON Combination Therapy package insert for additional information.

Laboratory Tests   In addition to those tests normally required for monitoring patients, the following laboratory tests are recommended for all patients on INTRON A therapy, prior to beginning treatment and then periodically thereafter.

Those patients who have preexisting cardiac abnormalities and/or are in advanced stages of cancer should have electrocardiograms taken prior to and during the course of treatment.

Mild-to-moderate leukopenia and elevated serum liver enzyme (SGOT) levels have been reported with intralesional administration of INTRON A Interferon alfa-2b, recombinant for Injection (see ADVERSE REACTIONS ); therefore, the monitoring of these laboratory parameters should be considered.

Baseline chest x-rays are suggested and should be repeated if clinically indicated.

For malignant melanoma patients, differential WBC count and liver function tests should be monitored weekly during the induction phase of therapy and monthly during the maintenance phase of therapy.

For specific recommendations in chronic hepatitis C and chronic hepatitis B, see .

Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with INTRON A Interferon alfa-2b, recombinant for Injection have not been performed to determine carcinogenicity.

Interferon may impair fertility. In studies of interferon administration in nonhuman primates, menstrual cycle abnormalities have been observed. Decreases in serum estradiol and progesterone concentrations have been reported in women treated with human leukocyte interferon. 12 Therefore, fertile women should not receive INTRON A therapy unless they are using effective contraception during the therapy period. INTRON A therapy should be used with caution in fertile men.

Mutagenicity studies have demonstrated that INTRON A Interferon alfa-2b, recombinant for Injection is not mutagenic.

Studies in mice (0.1, 1.0 million IU/day), rats (4, 20, 100 million IU/kg/day), and cynomolgus monkeys (1.1 million IU/kg/day; 0.25, 0.75, 2.5 million IU/kg/day) injected with INTRON A Interferon alfa-2b, recombinant for Injection for up to 9 days, 3 months, and 1 month, respectively, have revealed no evidence of toxicity. However, if cynomolgus monkeys (4, 20, 100 million IU/kg/day) injected daily for 3 months with INTRON A Interferon alfa-2b, recombinant for Injection toxicity was observed at the mid and high doses and mortality was observed at the high dose.

However, due to the known species-specificity of interferon, the effects in animals are unlikely to be predictive of those in man.

INTRON A in combination with REBETOL (ribavirin, USP) Capsules should be used with caution in fertile men. See the REBETRON Combination Therapy package insert for additional information.

Pregnancy Category C   INTRON A Interferon alfa-2b, recombinant for Injection has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 7.5, 15, and 30 million IU/kg (90, 180, and 360 times the intramuscular or subcutaneous dose of 2 million IU/m 2 ). Although abortion was observed in all dose groups, it was only statistically significant at the mid- and high-dose groups. There are no adequate and well-controlled studies in pregnant women. INTRON A therapy should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

REBETRON Combination Therapy containing INTRON A and REBETOL (ribavirin, USP) Capsules   

Pregnancy Category X   applies to the REBETRON Combination Therapy containing Intron A and Rebetol (ribavirin, USP) (see CONTRAINDICATIONS ). See Rebetron Combination Therapy package insert for additional information.

Nursing Mothers   It is not known whether this drug is excreted in human milk. However, studies in mice have shown that mouse interferons are excreted into the milk. Because of the potential for serious adverse reactions from the drug to nursing infants, a decision should be made whether to discontinue nursing or to discontinue INTRON A therapy, taking into account the importance of the drug to the mother.

Pediatric Use General   Safety and effectiveness in pediatric patients below the age of 18 years have not been established for indications other than chronic hepatitis B.

Chronic hepatitis B   Safety and effectiveness in pediatric patients ranging in age from 1 to 17 years have been established based upon one controlled clinical trial (see CLINICAL PHARMACOLOGY , , DOSAGE AND ADMINISTRATION ; Chronic Hepatitis B ). Safety and effectiveness in pediatric patients below the age of 1 year have not been established.

INTRON A Interferon alfa-2b, recombinant Powder for Injection when reconstituted with the provided Diluent for INTRON A Interferon alfa-2b, recombinant for Injection (bacteriostatic water for injection) contains benzyl alcohol and is not indicated for use in infants. There have been rare reports of death in infants associated with excessive exposure to benzyl alcohol. The amount of benzyl alcohol at which toxicity or adverse effects may occur in infants is not known. (See : Chronic Hepatitis B .)

ADVERSE REACTIONS

General   The adverse experiences listed below were reported to be possibly or probably related to INTRON A therapy during clinical trials. Most of these adverse reactions were mild to moderate in severity and were manageable. Some were transient and most diminished with continued therapy.

The most frequently reported adverse reactions were "flu-like" symptoms, particularly fever, headache, chills, myalgia, and fatigue. More severe toxicities are observed generally at higher doses and may be difficult for patients to tolerate.

In addition, the following spontaneous adverse experiences have been reported during the marketing surveillance of INTRON A Interferon alfa-2b, recombinant for Injection: nephrotic syndrome, pancreatitis, psychosis, including hallucinations, renal failure, and renal insufficiency.

TREATMENT-RELATED ADVERSE EXPERIENCES BY INDICATION
Dosing Regimens
Percentage (%) of Patients *
MALIGNANT
MELANOMA
FOLLICULAR
LYMPHOMA
HAIRY CELL
LEUKEMIA
CONDYLOMATA
ACUMINATA
AIDS-RELATED
KAPOSI'S SARCOMA
CHRONIC
HEPATITIS C ^
CHRONIC
HEPATITIS B
 
20 MIU/m 2
Induction (IV)
10 MIU/m 2
Maintenance (SC)
5 MIU
TIW/SC
2 MIU/m 2
TIW/SC
1 MIU
lesion
30 MIU/m 2
TIW/SC
35 MIU
QD/SC
3 MIU
TIW
Adults Pediatrics
5 MIU
QD
10 MIU
TIW
6 MIU/m 2
TIW
ADVERSE EXPERIENCE
N=143 N=135 N=145 N=352 N=74 N=29 N=183 N=101 N=78 N=116
Application-Site Disorders
20  
 injection site  inflammation
-- 1 -- -- -- -- 5 3 -- --
 other (</=5%)
Blood Disorders (<5%)
anemia, anemia hypochromic, granulocytopenia, hemolytic anemia, leukopenia, lymphocytosis, neutropenia (9% in chronic hepatitis C, 14% in chronic hepatitis B pediatrics), thrombocytopenia (10% in chronic hepatitis C) (bleeding 8% in malignant melanoma), thrombocytopenic purpura
Body as a Whole
 facial edema
-- 1 -- <1 -- 10 <1 3 1 <1
 weight decrease
3 13 <1 <1 5 3 10 2 5 3
 other (</=5%)
Cardiovascular System Disorders (<5%)
Endocrine System Disorders (<5%)
Flu-like Symptoms
 fever
81 56 68 56 47 55 34 66 86 94
 headache
62 21 39 47 36 21 43 61 44 57
 chills
54 -- 46 45 --  --  -- -- -- --
 myalgia
75 16 39 44 34 28 43 59 40 27
 fatigue
96 8 61 18 84 48 23 75 69 71
 increased sweating
6 13 8 2 4 21 4 1 1 3
 asthenia
-- 63 7  -- 11  -- 40 5 15 5
 rigors
2 7  --  -- 30 14 16 38 42 30
 arthralgia
6 8 8 9 -- 3 16 19 8 15
 dizziness
23 -- 12 9 7 24 9 13 10 8
 influenza-like symptoms
10 18 37  -- 45 79 26 5 -- <1
 back pain
-- 15 19 6 1 3  -- -- -- --
 dry mouth
1 2 19  -- 22 28 5 6 5 --
 chest pain
2 8 <1 <1 1 28 4 4 -- --
 malaise
6 --  -- 14 5  -- 13 9 6 3
 pain (unspecified)
15 9 18 3 3 3  -- -- -- --
 other (<5%)
 diarrhea
35 19 18 2 18 45 13 19 8 12
 anorexia
69 21 19 1 38 41 14 43 53 43
 nausea
66 24 21 17 28 21 19 50 33 18
 taste alteration
24 2 13 <1 5 7 2 10 -- --
 abdominal pain
2 20 <5 1 5 21 16 5 4 23
 loose stools
 --  1  -- <1 -- 10 2 2 -- 2
 vomiting
# 32 6 2 11 14 8 7 10 27
 constipation
 1 14 <1  -- 1 10 4 5 -- 2
 gingivitis
  2 &   7 &  --  -- -- 14  -- 1 -- --
 dyspepsia
--   2 -- 2 4 -- 7 3 8 3
 other (<5%)
Liver and Biliary System
Disorders (<5%)
abnormal hepatic function tests, biliary pain, bilirubinemia, hepatitis, increased lactate dehydrogenase, increased transaminases (SGOT/SGPT) (elevated SGOT 63% in malignant melanoma and 24% in follicular lymphoma), jaundice, right upper quadrant pain (15% in chronic hepatitis C), and very rarely, hepatic encephalopathy, hepatic failure, and death
 musculoskeletal pain
-- 18 -- -- -- -- 21 9 1 10
 other (<5%)
Nervous System and Psychiatric Disorders
 depression
40 9 6 3 9 28 19 17 6 4
 paresthesia
13 13 6 1 3 21 5 6 3 <1
 impaired concentration
-- 1 -- <1 3 14 3 8 5 3
 amnesia
§ 1 <5 -- -- 14 -- -- -- --
 confusion
8 2 <5 4 12 10 1 -- -- 2
 hypoesthesia
-- 1 <5 1 -- 10 -- -- -- --
 irritability
1 1 -- -- -- -- 13 16 12 22
 somnolence
1 2 <5 3 3 --   33 14 9 5
 anxiety
1 9 5 <1 1 3 5 2 -- 3
 insomnia
5 4 -- <1 3 3 12 11 6 8
 nervousness
1 1 -- 1 -- 3 2 3 -- 3
 decreased libido
1 1 <5 -- -- -- 1 5 1 --
 other (<5%)
abnormal coordination, abnormal dreaming, abnormal gait, abnormal thinking, aggravated depression, aggressive reaction, agitation (7% in chronic hepatitis B pediatrics) alcohol intolerance, apathy, aphasia, ataxia, Bell' palsy, CNS dysfunction, coma, convulsions, delirium, dysphonia, emotional lability, extrapyramidal disorder, feeling of ebriety, flushing, hearing disorder, hearing impairment, hot flashes, hyperesthesia, hyperkinesia, hypertonia, hypokinesia, impaired consciousness, labyrinthine disorder, loss of consciousness, manic depression, manic reaction, migraine, neuralgia, neuritis, neuropathy, neurosis, paresis, paroniria, parosmia, personality disorder, polyneuropathy, psychosis, speech disorder, stroke, suicidal ideation, suicide attempt, syncope, tinnitus, tremor, twitching, vertigo (8% in follicular lymphoma)
Reproduction System Disorders (<5%)
Resistance Mechanism Disorders
 moniliasis
-- 1 -- <1 -- 17 -- -- -- --
 herpes simplex
1 2 -- 1 -- 3 1 5 -- --
 other (<5%)
Respiratory System Disorders
 dyspnea
15 14 <1 -- 1 34 3 5 -- --
 coughing
6 13 <1 -- -- 31 1 4 -- 5
 pharyngitis
2 8 <5 1 1 31 3 7 1 7
 sinusitis
1 4 -- -- -- 21 2 -- -- --
 nonproductive coughing
2 7 -- -- -- 14 0 1 -- --
 nasal congestion
1 7 -- 1 -- 10 <1 4 -- --
 other (</=5%)
Skin and Appendages Disorders
 dermatitis
1 -- 8 -- -- -- 2 1 -- --
 alopecia
29 23 8 -- 12 31 28 26 38 17
 pruritus
-- 10 11 1 7 -- 9 6 4 3
 rash
19 13 25 -- 9 10 5 8 1 5
 dry skin
1 3 9 -- 9 10 4 3 -- <1
 other (<5%)
Urinary System Disorders (<5%)
Vision Disorders (<5%)
abnormal vision, blurred vision, diplopia, dry eyes, eye pain, nystagmus, photophobia
* Dash (--) indicates not reported
# Vomiting was reported with nausea as a single term
& Includes stomatitis/mucositis
§ Amnesia was reported with confusion as a single term
^ Percentages based upon a summary of all adverse events during 18 to 24 months of treatment
Predominantly lethargy

Hairy Cell Leukemia   The adverse reactions most frequently reported during clinical trials in 145 patients with hairy cell leukemia were the "flu-like" symptoms of fever (68%), fatigue (61%), and chills (46%).

Malignant Melanoma   The INTRON A dose was modified because of adverse events in 65% (n=93) of the patients. INTRON A therapy was discontinued because of adverse events in 8% of the patients during induction and 18% of the patients during maintenance. The most frequently reported adverse reaction was fatigue which was observed in 96% of patients. Other adverse reactions that were recorded in >20% of INTRON A treated patients included neutropenia (92%), fever (81%), myalgia (75%), anorexia (69%), vomiting/nausea (66%), increased SGOT (63%), headache (62%), chills (54%), depression (40%), diarrhea (35%), alopecia (29%), altered taste sensation (24%), dizziness/vertigo (23%), and anemia (22%).

Adverse reactions classified as severe or life threatening (ECOG Toxicity Criteria grade 3 or 4) were recorded in 66% and 14% of INTRON A treated patients, respectively. Severe adverse reactions recorded in >10% of INTRON A treated patients included neutropenia/leukopenia (26%), fatigue (23%), fever (18%), myalgia (17%), headache (17%), chills (16%), and increased SGOT (14%). Grade 4 fatigue was recorded in 4% and grade 4 depression was recorded in 2% of INTRON A treated patients. No other grade 4 AE was reported in more than 2 INTRON A treated patients. Lethal hepatotoxicity occurred in 2 INTRON A treated patients early in the clinical trial. No subsequent lethal hepatotoxicities were observed with adequate monitoring of liver function tests (see PRECAUTIONS - Laboratory Tests ).

Follicular Lymphoma   Ninety-six percent of patients treated with CHVP plus INTRON A therapy and 91% of patients treated with CHVP alone reported an adverse event of any severity. Asthenia, fever, neutropenia, increased hepatic enzymes, alopecia, headache, anorexia, "flu-like" symptoms, myalgia, dyspnea, thrombocytopenia, paresthesia, and polyuria occurred more frequently in the CHVP plus INTRON A treated patients than in patients treated with CHVP alone. Adverse reactions classified as severe or life threatening (World Health Organization grade 3 or 4) recorded in >5% of CHVP plus INTRON A treated patients included neutropenia (34%), asthenia (10%), and vomiting (10%). The incidence of neutropenic infection was 6% in CHVP plus INTRON A vs 2% in CHVP alone. One patient in each treatment group required hospitalization.

Twenty-eight percent of CHVP plus INTRON A treated patients had a temporary modification/interruption of their INTRON A therapy, but only 13 patients (10%) permanently stopped INTRON A therapy because of toxicity. There were four deaths on study; two patients committed suicide in the CHVP plus INTRON A arm and two patients in the CHVP arm had unwitnessed sudden death. Three patients with hepatitis B (one of whom also had alcoholic cirrhosis) developed hepatoxicity leading to discontinuation of INTRON A. Other reasons for discontinuation included intolerable asthenia (5/135), severe flu symptoms (2/135), and one patient each with exacerbation of anklyosing spondylitis, psychosis, and decreased ejection fraction.

Condylomata Acuminata   Eighty-eight percent (311/352) of patients treated with INTRON A Interferon alfa-2b, recombinant for Injection for condylomata acuminata who were evaluable for safety, reported an adverse reaction during treatment. The incidence of the adverse reactions reported increased when the number of treated lesions increased from one to five. All 40 patients who had five warts treated, reported some type of adverse reaction during treatment.

Adverse reactions and abnormal laboratory test values reported by patients who were untreated were qualitatively and quantitatively similar to those reported during the initial INTRON A treatment period.

AIDS-Related Kaposi' Sarcoma   In patients with AIDS-Related Kaposi' Sarcoma, some type of adverse reaction occurred in 100% of the 74 patients treated with 30 million IU/m 2 three times a week and in 97% of the 29 patients treated with 35 million IU per day.

Of these adverse reactions, those classified as severe (World Health Organization grade 3 or 4) were reported in 27% to 55% of patients. Severe adverse reactions in the 30 million IU/m 2 TIW study included: fatigue (20%), influenza-like symptoms (15%), anorexia (12%), dry mouth (4%), headache (4%), confusion (3%), fever (3%), myalgia (3%), and nausea and vomiting (1% each). Severe adverse reactions for patients who received the 35 million IU QD included: fever (24%), fatigue (17%), influenza-like symptoms (14%), dyspnea (14%), headache (10%), pharyngitis (7%), and ataxia, confusion, dysphagia, GI hemorrhage, abnormal hepatic function, increased SGOT, myalgia, cardiomyopathy, face edema, depression, emotional lability, suicide attempt, chest pain, and coughing (1 patient each). Overall the incidence of severe toxicity was higher among patients who received the 35 million IU per day dose.

Chronic Hepatitis C   Two studies of extended treatment (18 to 24 months) with INTRON A Interferon alfa-2b, recombinant for Injection show that approximately 95% of all patients treated experience some type of adverse event and that patients treated for extended duration continue to experience adverse events throughout treatment. Most adverse events reported are mild to moderate in severity. However, 29/152 (19%) of patients treated for 18 to 24 months experienced a serious adverse event compared to 11/163 (7%) of those treated for 6 months. Adverse events which occur or persist during extended treatment are similar in type and severity to those occurring during short-course therapy.

Of the patients achieving a complete response after 6 months of therapy, 12/79 (15%) subsequently discontinued INTRON A treatment during extended therapy because of adverse events, and 23/79 (29%) experienced severe adverse events (WHO grade 3 or 4) during extended therapy.

In patients using REBETRON Combination Therapy containing INTRON A and REBETOL (ribavirin, USP) Capsules, the primary toxicity observed was hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of therapy. Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients treated with INTRON A/REBETOL therapy. See REBETRON Combination Therapy package insert for additional information.

Chronic Hepatitis B Adults   In patients with chronic hepatitis B, some type of adverse reaction occurred in 98% of the 101 patients treated at 5 million IU QD and 90% of the 78 patients treated at 10 million IU TIW. Most of these adverse reactions were mild to moderate in severity, were manageable, and were reversible following the end of therapy.

Adverse reactions classified as severe (causing a significant interference with normal daily activities or clinical state) were reported in 21% to 44% of patients. The severe adverse reactions reported most frequently were the "flu-like" symptoms of fever (28%), fatigue (15%), headache (5%), myalgia (4%), rigors (4%), and other severe "flu-like" symptoms which occurred in 1% to 3% of patients. Other severe adverse reactions occurring in more than one patient were alopecia (8%), anorexia (6%), depression (3%), nausea (3%), and vomiting (2%).

To manage side effects, the dose was reduced, or INTRON A therapy was interrupted in 25% to 38% of patients. Five percent of patients discontinued treatment due to adverse experiences.

Pediatrics   In pediatric patients, the most frequently reported adverse events were those commonly associated with interferon treatment; flu-like symptoms (100%), gastrointestinal system disorders (46%), and nausea and vomiting (40%). Neutropenia (13%) and thrombocytopenia (3%) were also reported. None of the adverse events were life threatening. The majority were moderate to severe and resolved upon dose reduction or drug discontinuation.

ABNORMAL LABORATORY TEST VALUES BY INDICATION
Dosing Regimens
Percentage (%) of Patients
 
MALIGNANT MELANOMA FOLLICULAR LYMPHOMA HAIRY CELL LEUKEMIA CONDYLOMATA ACUMINATA AIDS-RELATED
KAPOSI'S SARCOMA
CHRONIC HEPATITIS C CHRONIC
HEPATITIS B
 
20 MIU/m 2 Induction (IV)
10 MIU/m 2
Maintenance (SC)
5 MIU
TIW/SC
2 MIU/m 2
TIW/SC
1 MIU/lesion 30 MIU/m 2
TIW/SC
35 MIU
QD/SC
3 MIU TIW Adults Pediatrics
5 MIU QD 10 MIU TIW 6 MIU/m 2
TIW
Laboratory Tests
N=143 N=135 N=145 N=352 N=69-73 N=26-28 N=140-171 N=96-101 N=75-103 N=113-115
22  8 NA --  1 15 26 32 * 23 * 17 **
White Blood Cell Count
^ -- NA 17 10 22 26 # 68 # 34 #  9 #
15 13 NA --  0  8 15 & 12 &   5 &  1 &
 3  2  0 -- -- --  6  3  0  3
13 --  4 -- -- -- --  8  4  0
 1 --  0 -- -- -- -- -- -- --
12  4  0 -- -- -- --  2  0  2
63 24  4 12 11 41 -- --   --
 2 -- 13 -- 10 15 -- --   --
·Total
92 36 NA -- 31 39 45 § 75 § 61 § 70 §
·1000-<1500/mm 3
66 -- -- -- -- -- 32 30 32 43
·750-<1000/mm 3
-- 21 -- -- -- -- 10 24 18 18
·500-<750/mm 3
25 -- -- -- -- --  1 17  9  7
·<500/mm 3
 1 13 -- -- -- --  2  4  2  2
NA -- Not Applicable - Patients' initial hematologic laboratory test values were abnormal due to their condition.
* Decrease of >/=2 g/dL
** Decrease of >/=2 g/dL; 14% 2-<3 g/dL; 3% >/=3g/dL
# Decrease to <3000/mm 3
& Decrease to <70,000/mm 3
§ Neutrophils plus bands
^ White Blood Cell Count was reported as neutropenia
Decrease of >/=2 g/dL; 20% 2-<3 g/dL; 6% >/=3 g/dL

HOW SUPPLIED

INTRON A Interferon alfa-2b, recombinant Powder for Injection   INTRON A Interferon alfa-2b, recombinant Powder for Injection INTRON A, Pak-3, containing 6 INTRON A vials, 3 million IU per vial; 6 syringes of Diluent for INTRON A Interferon alfa-2b, recombinant for Injection (bacteriostatic water for injection) 1 mL per syringe for chronic hepatitis C; and 6 alcohol swabs (NDC 0085-0647-05).

INTRON A Interferon alfa-2b, recombinant Powder for Injection, 5 million IU per vial and Diluent for INTRON A Interferon alfa-2b, recombinant for Injection (bacteriostatic water for injection) 1 mL per vial; boxes containing INTRON A vial and 1 vial of INTRON A Diluent (NDC 0085-0120-02).

INTRON A Interferon alfa-2b, recombinant Powder for Injection, 10 million IU per vial and Diluent for INTRON A Interferon alfa-2b, recombinant for Injection (bacteriostatic water for injection) 2 mL per vial; boxes containing 1 INTRON A vial and 1 vial of INTRON A Diluent (NDC 0085-0571-02).

INTRON A Interferon alfa-2b, recombinant Powder for Injection, 18 million IU per vial and Diluent for INTRON A Interferon alfa-2b, recombinant for Injection (bacteriostatic water for injection) 1 mL per vial; boxes containing 1 vial of INTRON A and 1 vial of INTRON A Diluent (NDC 0085-1110-01).

INTRON A Interferon alfa-2b, recombinant Powder for Injection, 25 million IU per vial and Diluent for INTRON A Interferon alfa-2b, recombinant for Injection (bacteriostatic water for injection) 5 mL per vial; boxes containing 1 INTRON A vial and 1 vial of INTRON A Diluent (NDC 0085-0285-02).

INTRON A Interferon alfa-2b, recombinant Powder for Injection, 50 million IU per vial and Diluent for INTRON A Interferon alfa-2b, recombinant for Injection (bacteriostatic water for injection) 1 mL per vial; boxes containing 1 INTRON A vial and 1 vial of INTRON A Diluent (NDC 0085-0539-01).

Store INTRON A Interferon alfa-2b, recombinant Powder for Injection both before and after reconstitution between 2° and 8°C (36° and 46°F).

INTRON A Interferon alfa-2b, recombinant Solution for Injection   INTRON A Interferon alfa-2b, recombinant Solution for Injection, 6 doses of 3 million IU (18 million IU) multidose pen (22.5 million IU per 1.5 mL per pen); boxes containing 1 INTRON A multidose pen, six disposable needles and alcohol swabs (NDC 0085-1242-01).

INTRON A Interferon alfa-2b, recombinant Solution for Injection, 6 doses of 5 million IU (30 million IU) multidose pen (37.5 million IU per 1.5 mL per pen); boxes containing 1 INTRON A multidose pen, six disposable needles and alcohol swabs (NDC 0085-1235-01).

INTRON A Interferon alfa-2b, recombinant Solution for Injection, 6 doses of 10 million IU (60 million IU) multidose pen (75 million IU per 1.5 mL per pen); boxes containing 1 INTRON A multidose pen, six disposable needles and alcohol swabs (NDC 0085-1254-01).

INTRON A Interferon alfa-2b, recombinant Solution for Injection INTRON A, Pak-3, containing 6 INTRON A vials, 3 million IU per vial; 6 syringes; and 6 alcohol swabs (NDC 0085-1184-02).

INTRON A Interferon alfa-2b, recombinant Solution for Injection INTRON A, Pak-5, containing 6 INTRON A vials, 5 million IU per vial; 6 syringes; and 6 alcohol swabs (NDC 0085-1191-02).

INTRON A Interferon alfa-2b, recombinant Solution for Injection INTRON A, Pak-10, containing 6 INTRON A vials, 10 million IU per vial; 6 syringes; and 6 alcohol swabs (NDC 0085-1179-02).

INTRON A Interferon alfa-2b, recombinant Solution for Injection, 18 million IU multidose vial (22.8 million IU per 3.8 mL per vial); boxes containing 1 vial of INTRON A Solution for Injection (NDC 0085-1168-01).

INTRON A Interferon alfa-2b, recombinant Solution for Injection, 25 million IU multidose vial (32 million IU per 3.2 mL per vial); boxes containing 1 vial of INTRON A Solution for Injection (NDC 0085-1133-01).

Store INTRON A Interferon alfa-2b, recombinant Solution for Injection between 2° and 8°C (36° and 46°F).

Schering Corporation   18766183

Kenilworth, NJ 07033 USA

Rev. 8/99

U.S. Patents 4,530,901 & 4,496,537

Copyright © 1986, 1999, Schering Corporation. All rights reserved.

REFERENCES

  1. Smalley R, et al. N Engl J Med. 1992;327:1336-1341.
  2. Aviles A, et al. Leukemia and Lymphoma. 1996;20:495-499.
  3. Unterhalt M, et al. Blood 1996;88 (10Suppl 1):1744A.
  4. Schiller J, et al. J Biol Response Mod. 1989;8:252-261.
  5. Poynard T, et al. N Engl J Med. 1995;332:(22)1457-1462.
  6. Lin R, et al. J Hepatol. 1995;23:487-496.
  7. Perrillo R, et al. N Engl J Med. 1990;323;295-301.
  8. Perez V, et al. J Hepatol. 1990;11S113-S117.
  9. Knodell R, et al. Hepatology 1981;1:431-435.
  10. Perrillo R, et al. Ann Intern Med. 1991;115:113-115.
  11. Renault P, et al. Arch Intern Med. 1987;147:1577-1580.
  12. Kauppila A, et al. Int J Cancer. 1982;29:291-294.