General—Interferons are naturally occurring proteins with antiviral, antiproliferative, and immunoregulatory properties. They are produced and secreted in response to viral infections and to a variety of other synthetic and biological inducers. Four major families of interferons have been identified: alpha, beta, gamma, and omega. The interferon alpha family contains 13 different non-allelic molecular species. Their molecular weights range from 16,000 to 27,000 daltons.

Interferons bind to specific membrane receptors on cell surfaces. Interferon alfa-n3 has been shown to bind to the same receptors as Interferon alfa-2b. The receptors have a high degree of selectivity for the binding of human but not mouse interferon. This correlates with the high species specificity found in laboratory studies.

Binding of interferon to membrane receptors initiates a series of events including induction of protein synthesis. These actions are followed by a variety of cellular responses, including inhibition of virus replication and suppression of cell proliferation. Immunomodulation, including enhancement of phagocytosis by macrophages, augmentation of the cytotoxicity of lymphocytes and enhancement of human leukocyte antigen expression occurs in response to exposure to interferons. One or more of these activities may contribute to the therapeutic effect of interferon.

Pharmacokinetics—In a study of intralesional use of Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] for the treatment of condylomata acuminata, plasma concentrations of interferon were below the detection limit of the assay, i.e., ≤ 3 IU/ml. Minor systemic effects (e.g., myalgias, fever, and headaches) were noted, indicating that some of the injected interferon entered the systemic circulation (See ADVERSE REACTIONS).

Condylomata Acuminata—Condylomata acuminata (venereal or genital warts) are associated with infections of human papilloma virus (HPV), especially HPV type-6 and possibly type-11. Given the antiviral and antiproliferative activities of interferons and the viral etiology of condylomata, a placebo-controlled clinical trial was conducted to evaluate the safety and efficacy of intralesional injection of Alferon N Injection® in the treatment of condylomata acuminata.

In a multicenter, randomized, double-blind, placebo-controlled, clinical trial, intralesional administration of Alferon N Injection® was an effective treatment for condylomata acuminata.1–4 One hundred fifty-six (156) patients were evaluable for efficacy (81 Alferon N Injection® patients and 75 placebo patients). Patients had a mean of five warts (range was 2-14) and all warts were treated. Patients were injected intralesionally with a mean of 225,000 IU of Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] per wart 2 times a week for up to 8 weeks.

Overall, 80% (65/81) of patients treated with Alferon N Injection® had a complete or partial resolution of warts compared with 44% (33/75) of placebo-treated patients (p < 0.001). Alferon N Injection® was significantly more effective than placebo in producing a complete resolution of warts (p < 0.001), as shown by Table 1.

Of the patients who had a complete resolution of warts, approximately half (21/44) the patients had complete resolution of warts by the end of treatment, and half (23/44) had complete resolution of warts during the three months after the cessation of treatment. Patients with complete resolution of warts were followed for a median of 48 weeks. Overall, 76% (31/41) of Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)]-treated patients who achieved complete resolution of warts remained clear of all treated lesions during follow-up, while 79% (11/14) of the placebo-treated patients remained clear of all treated lesions during follow-up.

A total of 762 evaluable warts were injected in this trial. Of the 407 Alferon N Injection®-treated warts, 73% (297/407) completely resolved, as compared to 35% (125/355) of the placebo-treated warts (p < 0.0001). Alferon N Injection® was effective in treating lesions of all sizes, and there was no difference in resolution for perianal, penile, or vulvar lesions.

There was no difference in resolution for patients who had received prior treatment of their warts and for those who had not. Among patients with recalcitrant warts (i.e., warts that were refractory to previous treatment or recurring), 82% (58/71) of the evaluable patients had complete or partial resolution of warts due to intralesional administration of Alferon N Injection® as compared to 43% (29/67) of placebo patients (p <0.001). Fifty-four percent (38/71) of the evaluable Alferon N Injection® patients had complete resolution of warts as compared to 18% (12/67) of placebo patients (p < 0.001). Patients with primary occurrence of genital warts (i.e., no prior treatment of warts) had a similar resolution rate compared to the patients with recalcitrant warts: 70% (7/10) had complete or partial resolution of warts due to Alferon N Injection® treatment and 60% (6/10) had complete resolution of warts, as compared to 50% (4/8) of placebo recipients who had complete or partial resolution of warts and 38% (3/8) who had complete resolution. Overall, 83% (5/6) of Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)]-treated patients with primary occurrence, who achieved complete resolution of warts, remained clear of all treated lesions during a median follow-up of 52 weeks. Because the number of patients with primary occurrence of warts was small (10 Alferon N Injection® recipients and 8 placebo recipients), the difference between Alferon N Injection® and placebo treatment was not statistically significant. However, when the resolution of primary warts was examined, 75% (33/44) of the Alferon N Injection®-treated primary warts resolved completely as compared to 39% (11/28) of the placebo-treated primary warts (p = 0.003).

In an open clinical trial using a once-a-week treatment schedule for up to 16 weeks, 28 patients were evaluable for efficacy. Eighty-nine percent (25/28) of patients had a complete or partial resolution of warts following treatment with Alferon N Injection®. The condylomata acuminata resolved completely in 46% (13/28) of the patients. Of the 154 warts treated, 77% (118/154) resolved completely.

After injections of Alferon N Injection®, side effects were minor and transient. After 4 weeks of treatment, the frequency of adverse reactions was similar in Alferon N Injection® and placebo treatment groups. The most frequent side effects were myalgias, fever, and headache (See ADVERSE REACTIONS).

Antigenicity

1. Alferon N Injection®

   One hundred five (105) patients treated with Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] during clinical trials were tested for the presence of anti-interferon antibodies using three different antibody assays: Immunoradiometric Assay (IRMA), Enzyme Linked Immunosorbent Assay (ELISA), and neutralization by the Cytopathic Effect Assay (CPE). To date, no antibodies to Interferon alfa-n3 have been detected in any of the patients.

2. Mouse Proteins

   No hypersensitivity reactions to the components in Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] have been observed. Alferon N Injection® uses a murine monoclonal antibody in one of the purification procedures. A possibility exists that patients treated with Alferon N Injection® may develop hypersensitivity to the mouse proteins. However, none of the patients receiving Alferon N Injection® during clinical trials developed antibodies or hypersensitivity to mouse proteins (See CONTRAINDICATIONS).

3. Egg Protein

   The initial stage in the manufacture of Alferon N Injection® uses Sendai virus which was grown in chicken-embryonated eggs as the specific Interferon alfa-n3 inducer. Although no egg protein (ovalbumin) has been detected in the initial stage of interferon manufacture using an ELISA (sensitivity of 16 ng/ml), a possibility exists that patients treated with Alferon N Injection® may develop hypersensitivity to egg protein (See CONTRAINDICATIONS).

4. INDICATIONS AND USAGE

General—Patients being treated with Alferon N Injection® should be informed of the benefits and risks associated with the treatment. Because the manufacturing process, strength, and type of interferon (e.g., natural, human leukocyte interferon versus single-species recombinant interferon) may vary for different interferon formulations, changing brands may require a change in dosage. Therefore, physicians are cautioned not to change from one interferon product to another without considering these factors.

The physician should select patients for treatment with Alferon N Injection® after consideration of the locations and sizes of the lesions, response to previous treatment, and the patient’s ability to comply with the treatment regimen. Data on Alferon N Injection® as initial treatment are limited. There are no data on a second course of Alferon N Injection® treatment. The mean number of warts treated in one treatment cycle was five.

Information for Patients—Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis, and should be advised to contact their physician if these symptoms occur.

Patients being treated with Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] should be informed of benefits and risks associated with treatment.

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

Carcinogenesis, Mutagenesis, Impairment of Fertility—Studies with Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] have not been performed to determine carcinogenicity, mutagenicity, or the effect on fertility. In studies with adult females, interferon alpha has been shown to affect the menstrual cycle and decrease serum estradiol and progesterone levels5.

Alferon N Injection® should be used with caution in fertile men. Fertile women should be cautioned to use effective contraception while being treated with Alferon N Injection®.

Changes in the menstrual cycle and abortions have been reported to occur in non-human primates given extremely high doses of recombinant interferon alpha6. In these studies, Macaca mulatta (rhesus monkeys) were given interferon daily by intramuscular injection. When given at daily intramuscular doses 326 times the average intralesional dose of Alferon N Injection® (120 times the maximum recommended dose), this recombinant interferon formulation produced menstrual cycle changes in the monkeys.

In human clinical trials with Alferon N Injection®, menstrual cycle data were reported by 51 patients (36 Alferon N Injection® and 15 placebo). There was no significant difference between Alferon N Injection® and placebo treatment groups with regard to menstrual cycle changes.

PREGNANCY Pregnancy Category C—Animal reproduction studies have not been conducted with Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)]. It is also not known whether Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Alferon N Injection® should be given to a pregnant woman only if clearly needed.

Changes in the menstrual cycle and abortions have been reported to occur in non-human primates given extremely high doses of recombinant interferon alpha. In these studies, Macaca mulatta (rhesus monkeys) were given interferon daily by intramuscular injection. Abortifacient effects were noted when the recombinant interferon alpha was given daily during early to mid-gestation at intramuscular doses of 978 times the average intralesional dose of Alferon N Injection® (360 times the maximum recommended dose).

Nursing Mothers—It is not known whether Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] is excreted in human milk. Studies in mice have shown that mouse interferons are excreted in milk7. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to not initiate drug treatment, taking into account the importance of the drug to the mother and the potential risks to the infant.

Pediatric Use—There have been no studies with this product in adolescents.

ADVERSE REACTIONS

Adverse Reactions in Patients with Condylomata Acuminata—A total of 104 patients with condylomata acuminata was treated with Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] during the double-blind clinical trial. Adverse reactions were reported to be likely, unlikely, or not known to be related to Alferon N Injection®. Adverse reactions consisted primarily of “flu-like” symptoms (myalgias, fever, and/or headache) which were in most cases mild or moderate, and transient, and did not interfere with treatment.

The “flu-like” adverse reactions, consisting of fever, myalgias, and/or headache, occurred primarily after the first treatment session and were reported by 30% of the patients. The frequency of “flu-like” adverse reactions abated with repeated dosing of Alferon N Injection® so that the incidences due to Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] and placebo were similar after three to four weeks of treatment (after six to eight treatment sessions). “Flu-like” symptoms were relieved by administration of acetaminophen.

Adverse reactions were reported at least once during the course of treatment in the following percentages of patients in each treatment group:

Most of the systemic adverse reactions were mild or moderate. Severe systemic adverse reactions were reported by 18% of Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)]-treated patients and 13% of placebo-treated patients (not a statistically significant difference). Most of the severe systemic adverse reactions reported were “flu-like”. Other severe systemic adverse reactions included back pain, insomnia, and sensitivity to allergens. Those adverse reactions which were reported by 1% of patients treated with Alferon N Injection® in the double-blind trial include: left groin lymph node swelling, tongue hyperaesthesia, thirst, tingling of legs/feet, hot sensation on bottom of feet, strange taste in mouth, increased salivation, heat intolerance, visual disturbances, pharyngitis, sensitivity to allergens, muscle cramps, nosebleed, throat tightness, and papular rash on neck. Additional adverse reactions which were reported by 1% of patients treated with placebo include: pharyngitis, oral pain, penile discharge, cold, knuckle stiffness, herpes outbreak, cough, disorientation, and weight/appetite loss.

Additional adverse reactions which occurred only in open clinical trials of intralesional use of Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] for treatment of condylomata acuminata were herpes labialis, hot flashes, nervousness, decrease in concentration, dysuria, photosensitivity, and swollen lymph nodes. These reactions occurred in 1% of the patients. One patient with a history of epilepsy, who was not taking anticonvulsant medication, had a grand mal seizure while being treated with Alferon N Injection®; this seizure was judged to be unrelated to Alferon N Injection® administration.

Application Site Disorders—The frequency of application site disorders (such as itching and pain) for patients treated with Alferon N Injection® was significantly less than that reported with placebo (12% versus 26%). No severe application site disorders were reported by patients treated with Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)], while 7% of placebo-treated patients reported severe disorders.

Laboratory Test Values—Abnormalities were seen with statistically equivalent frequencies in both the Alferon N Injection® and placebo groups. None of the laboratory abnormalities were considered clinically significant. The abnormalities in the Alferon N Injection®-treated patients consisted primarily of decreased WBC (11%). Decreases also occurred in 4% of the placebo patients (not a statistically significant difference). The abnormalities in Alferon N Injection®-treated patients involved increases of only one WHO grade.