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ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)]

DESCRIPTION
ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] is a sterile aqueous formulation of purified, natural, human interferon alpha proteins for use by injection. ALFERON N InjectionŽ consists of interferon alpha proteins comprising approximately 166 amino acids ranging in molecular weights from 16,000 to 27,000 daltons. The specific activity of Interferon alfa-n3 is approximately equal to, or greater than, 2 x 108 IU/mg of protein.

ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] is manufactured from pooled units of human leukocytes which have been induced by incomplete infection with a murine virus (Sendai virus) to produce Interferon alfa-n3. The manufacturing process includes immunoaffinity chromatography with a murine monoclonal antibody, acidification (pH 2) for 5 days at 4°C, and gel filtration chromatography.

Since ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] is manufactured using source leukocytes, human, donor screening is performed to minimize the risk that the leukocytes could contain infectious agents. In addition, the manufacturing process contains steps which have been shown to inactivate known viruses, and there has been no evidence of infection transmission to recipients in clinical trials (See WARNINGS).

The ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] manufacturing process was evaluated for quantitative removal or inactivation of model pathogenic viruses. The viruses were deliberately added to the leukocytes in amounts far exceeding those present in contaminated blood, i.e. greater than or equal to 109 infectious units per milliliter. The manufacturing process yielded a cumulative reduction of greater than or equal to 1014 of infectious HIV-1, i.e., greater than or equal to 106.5 removal by acid inactivation and greater than or equal to 107.9 removal by the purification process. In the validation studies, there was 108 reduction in the titer of hepatitis B virus as determined by HBsAg assay, and a 109 reduction in the infectious titer of herpes simplex virus-1 (HSV-1). Cultivation of ALFERON N InjectionŽ Purified Drug Concentrate with human indicator cells, i.e., MRC-5 cells, peripheral blood leukocytes in the presence of Cyclosporin A, and fetal cord blood cells, did not detect the presence of infectious viruses.
As part of a validation study, ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] was examined for the presence of the following viruses: Sendai virus (SV), HIV-1, HTLV-I, HBV, HSV-1, CMV, and EBV. ALFERON N InjectionŽ contained no detectable quantities of these viruses. In addition other studies, i.e., Polymerase Chain Reaction (PCR) and Dot Blot Hybridization (DBH), have shown no detectable genetic material from these viruses in ALFERON N InjectionŽ . The sensitivity of the PCR was 10 copies for HIV-1 (env gene probe) and 10 copies for HBV (S/P gene probe). The sensitivity of the DBH was 1 pg for EBV, less than 10 pg for CMV, less than 10 pg for HSV-1, and less than 2 pg for SV. Furthermore, sera from 105 patients treated with ALFERON N InjectionŽ (95 with condylomata acuminata and 10 with cancer) were tested for antibody to HIV-1 and HIV p24 antigen. There was no evidence to suggest transmission of HIV-1 by ALFERON N InjectionŽ . Sera from 135 patients with condylomata acuminata treated with ALFERON N InjectionŽ were tested to determine abnormal SGOT laboratory values. There was no evidence to suggest transmission of hepatitis by ALFERON N InjectionŽ based on both SGOT results and patient data collected during clinical trials.

ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] has been extensively purified using immunoaffinity chromatography with a murine monoclonal antibody, acidification (pH 2) for 5 days at 4°C, and gel filtration chromatography. ALFERON N InjectionŽ has been subjected to the acid treatment for five days during its manufacture in order to reduce the risk of viral transmission. Subsequent analyses of the ALFERON N InjectionŽ Purified Drug Concentrate confirm the absence of detectable infectious or non-infectious viral particles.

The leukocyte nutrient medium contains the antibiotic neomycin sulfate at a concentration of 35 mg/L; however, neomycin sulfate is not detectable in the final product, i.e., less than 0.64 ug/ml.

Murine immunoglobulin (IgG) is detected in the ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] Purified Drug Concentrate at levels below 0.15% of the Interferon alfa-n3 protein. This equates to levels less than 8 ng of murine IgG per million IU Interferon alfa-n3 (range of 0.9 to 5.6 ng typically found).

ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] is available in an injectable solution containing 5 million IU Interferon alfa-n3 per vial for intralesional injection. The solution is clear and colorless. Each milliliter (ml) contains five million IU of Interferon alfa-n3 in phosphate-buffered saline (8.0 mg sodium chloride, 1.74 mg sodium phosphate dibasic, 0.20 mg potassium phosphate monobasic, and 0.20 mg potassium chloride) containing 3.3 mg phenol as a preservative and 1 mg Albumin (Human) as a stabilizer.

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CLINICAL PHARMACOLOGY
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.

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Pharmacokinetics
In a study of intralesional use of ALFERON N InjectionŽ [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., less than or equal to 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).

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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 InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] in the treatment of condylomata acuminata.
In a multicenter randomized double-blind, placebo-controlled clinical trial, intralesional administration of ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] was an effective treatment for condylomata acuminata.1-4 One hundred fifty-six (156) patients were evaluable for efficacy (81 ALFERON N InjectionŽ 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 InjectionŽ per wart 2 times a week for up to 8 weeks.
Overall, 80% (65/81) of patients treated with ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] had a complete or partial resolution of warts compared with 44% (33/75) of placebo-treated patients (p < 0.001). ALFERON N InjectionŽ was significantly more effective than placebo in producing a complete resolution of warts (p < 0.001), as shown by Table 1:

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Percent of Patients with:

 

Complete
Resolution

Partial Resolution
(>=50% resolution)

Minor Resolution
(less than 50% resolution)

Progression/
No change

Alferon
(n=81)

54%

26%

15%

5%

Placebo
(n=75)

20%

24%

13%

43%

Table 1
Degree of Resolution as Measured By Total Wart Volume per Patient

Percent of Patients with:
Complete Resolution Partial Resolution (>=50% resolution) Minor Resolution (less than 50% resolution) Progression/ No change
Alferon(n=81) 54% 26% 15% 5%
Placebo(n=75) 20% 24% 13% 43%
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 InjectionŽ [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 InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] -treated warts, 73% (297/407) completely resolved, as compared to 35% (125/355) of the placebo-treated warts (p< 0.0001). ALFERON N InjectionŽ 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 InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] as compared to 43% (29/67) of placebo patients (p < 0.001). Fifty-four percent (38/71) of the evaluable ALFERON N InjectionŽ 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 InjectionŽ 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 InjectionŽ [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 InjectionŽ recipients and 8 placebo recipients), the difference between ALFERON N InjectionŽ and placebo treatment was not statistically significant. However, when the resolution of primary warts was examined, 75% (33/44) of the ALFERON N InjectionŽ -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 InjectionŽ [Interferon alfa-n3 (human leukocyte derived)]. 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 InjectionŽ [Interferon alfa-n3 (human leukocyte derived)], side effects were minor and transient. After 4 weeks of treatment, the frequency of adverse reactions was similar in ALFERON N InjectionŽ and placebo treatment groups. The most frequent side effects were myalgias, fever, and headache (See ADVERSE REACTIONS).

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Antigenicity

  1. ALFERON N InjectionŽ
    One hundred and five (105) patients treated with ALFERON N InjectionŽ [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 InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] have been observed. ALFERON N InjectionŽ uses a murine monoclonal antibody in one of the purification procedures. A possibility exists that patients treated with ALFERON N InjectionŽ may develop hypersensitivity to the mouse proteins. However, none of the patients receiving ALFERON N InjectionŽ during clinical trials developed antibodies or hypersensitivity to mouse proteins (See CONTRAINDICATIONS)
     
  3. Egg Protein
    The initial stage in the manufacture of ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] 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 InjectionŽ may develop hypersensitivity to egg protein (See CONTRAINDICATIONS).

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INDICATIONS AND USAGE
ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] is indicated for the intralesional treatment of refractory or recurring external condylomata acuminata in patients 18 years of age or older (See DOSAGE AND ADMINISTRATION).
The physician should select patients for treatment with ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] after consideration of a number of factors: the locations and sizes of the lesions, past treatment and response thereto, and the patient's ability to comply with the treatment regimen. ALFERON N InjectionŽ is particularly useful for patients who have not responded satisfactorily to other treatment modalities, e.g., podophyllin resin, surgery, laser or cryotherapy.
There have been no studies with this product in adolescents. This product is not recommended for use in patients less than 18 years of age.

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CONTRAINDICATIONS
ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] is contraindicated in patients with known hypersensitivity to human interferon alpha proteins or any component of the product. The product is also contraindicated in patients who have anaphylactic sensitivity to mouse immunoglobulin (IgG), egg protein or neomycin.

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WARNINGS
Because of the fever and other "flu-like" symptoms associated with ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] (See ADVERSE REACTIONS), it should be used cautiously in patients with debilitating medical conditions such as cardiovascular disease (e.g., unstable angina and uncontrolled congestive heart failure), severe pulmonary disease (e.g., chronic obstructive pulmonary disease), or diabetes mellitus with ketoacidosis.
ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] should be used cautiously in patients with coagulation disorders (e.g., thrombophlebitis, pulmonary embolism and hemophilia), severe myelosuppression, or seizure disorders. Acute, serious hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have not been observed in patients receiving ALFERON N InjectionŽ. However, if such reactions develop, drug administration should be discontinued immediately and appropriate medical therapy should be instituted.
Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

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PRECAUTIONS
General
Patients being treated with ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] 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.

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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 InjectionŽ [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.

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Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with ALFERON N InjectionŽ [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 levels.5
ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] should be used with caution in fertile men. Fertile women should be cautioned to use effective contraception while being treated with ALFERON N InjectionŽ.
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 InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] (120 times the maximum recommended dose), this recombinant interferon formulation produced menstrual cycle changes in the monkeys.
In human clinical trials with ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)], menstrual cycle data were reported by 51 patients (36 ALFERON N InjectionŽ and 15 placebo). There was no significant difference between ALFERON N InjectionŽ and placebo treatment groups with regard to menstrual cycle changes.

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PREGNANCY
Pregnancy Category C
Animal reproduction studies have not been conducted with ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)]. It is also not known whether ALFERON N InjectionŽ can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. ALFERON N InjectionŽ 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 InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] (360 times the maximum recommended dose).

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Nursing Mothers
It is not known whether ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] is excreted in human milk. Studies in mice have shown that mouse interferons are excreted in milk.7 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.

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Pediatric Use
Safety and effectiveness have not been established in patients below the age of 18 years.

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ADVERSE REACTIONS
Adverse reactions were evaluated in 202 patients with condylomata acuminata receiving ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] by intralesional administration and in 31 patients with cancer receiving ALFERON N InjectionŽ by systemic administration. In the double-blind efficacy trial for the treatment of condylomata acuminata, 104 patients were treated with doses of ALFERON N InjectionŽ of 0.05 million to 2.5 million IU per treatment session (average dose = 0.92 million IU per treatment session) by intralesional injection. In open trials, an additional 98 patients received a dose range of 0.05 to 4.6 million IU of ALFERON N InjectionŽ per treatment session (average dose = 1.12 million IU per treatment session). Patients with cancer were given doses of ALFERON N InjectionŽ of 3 million, 9 million, or 15 million IU per day for ten days by intramuscular injection.

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Adverse Reactions in Patients with Condylomata Acuminata
A total of 104 patients with condylomata acuminata was treated with ALFERON N InjectionŽ [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 InjectionŽ. 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 InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] so that the incidences due to ALFERON N InjectionŽ 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:

Table 2
Percent of Patients With Adverse Reactions

Adverse Reactions:

Alferon
(n=104)

Placebo
(n=85)

Autonomic Nervous System

 

 

Sweating

2%

1%

Vasovagal Reaction

2%

0%

Body as a Whole

 

 

Fever

40%

19%

Chills

14%

2%

Fatigue

14%

6%

Malaise

9%

9%

Skin

 

 

Generalized Pruritis

2%

0%

Central & Peripheral Nervous System

 

 

Dizziness

9%

4%

Insomnia

2%

1%

Gastrointestinal System

 

 

Nausea

4%

7%

Vomiting

3%

0%

Dyspepsia/

 

 

Heartburn

3%

1%

Diarrhea

2%

2%

Musculoskeletal System

 

 

Arthralgia

5%

1%

Back Pain

4%

1%

Myalgias

45%

15%

Headache

31%

15%

Psychiatric Disorders

 

 

Depression

2%

1%

Nasopharyngeal

 

 

Nose/sinus

 

 

Drainage

2%

2%

Most of the systemic adverse reactions were mild or moderate. Severe systemic adverse reactions were reported by 18% of ALFERON N InjectionŽ [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 InjectionŽ 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 InjectionŽ [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 InjectionŽ ; this seizure was judged to be unrelated to ALFERON N InjectionŽ administration.

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

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Laboratory Test Values
Abnormalities were seen with statistically equivalent frequencies in both the ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] and placebo groups. None of the laboratory abnormalities were considered clinically significant. The abnormalities in the ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)]-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 InjectionŽ-treated patients involved increases of only one WHO grade.

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Adverse Reactions in Patients with Cancer
Thirty-one (31) patients with cancer were treated with a maximum of ten intramuscular injections of ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] in doses of 3 million IU, 9 million IU, or 15 million IU per treatment session. The occurrence of adverse reactions was judged to be unrelated to the dose of ALFERON N InjectionŽ .
The following adverse reactions were reported at least once (the percentage of patients experiencing the reaction is indicated in parentheses): chills (87%), fever (81%), anorexia (68%), malaise (65%), nausea (48%), vomiting (29%), myalgias (16%), arthralgia (10%), chest pains (10%), soreness at injection site (10%), sleepiness (10%), headache (10%), diarrhea (6%), fatigue (6%), low blood pressure (6%), sore mouth/stomatitis (6%), and blurred vision (6%). Those adverse reactions which were each reported by only one patient treated with ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] include: stiff shoulders, flushed face, edema, dry mouth, mucositis, coughing, numbness, numbness in hands, numbness in fingers, pain on ocular rotation, shakes/shivers, ringing in ears, cramps, constipation, muscle soreness, confusion, light-headedness, depression, upset stomach, and sweating. The following adverse reactions were reported as severe by at least one patient (the percentage of patients experiencing the reaction is indicated in parentheses); fever (55%), malaise (54%), anorexia (45%), chills (45%), nausea (16%), myalgias (13%), vomiting (10%), fatigue (6%), low blood pressure (6%), chest pains (6%), sore mouth/stomatitis (6%), headache (3%), diarrhea (3%), sleepiness (3%), arthralgia (3%), blurred vision (3%), stiff shoulders (3%), numbness (3%), pain on ocular rotation (3%), muscle soreness (3%), confusion (3%), light-headedness (3%), depression (3%), and sweating (3%).

The number and percentage of patients with cancer who experienced a significant abnormal laboratory test value (values that changed from WHO Grades 0, 1, or 2 at baseline to WHO Grades 3 or 4 during or after treatment) at least once during the trials are shown in the following table:

Table 3
Abnormal Laboratory Test Values

 

Cancer
(n=31)

Hemoglobin Level

2(7%)

White Blood Cell Count

1(3%)

Platelet Count

1(3%)

GGT

1(6%)

SGOT

1(3%)

Alkaline Phosphatase

2(8%)

Total Bilirubin

1(4%)

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DOSAGE AND ADMINISTRATION
The recommended dose of ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] for the treatment of condylomata acuminata is 0.05 ml (250,000 IU) per wart. ALFERON N InjectionŽ should be administered twice weekly for up to 8 weeks. The maximum recommended dose per treatment session is 0.5 ml (2.5 million IU). ALFERON N InjectionŽ should be injected into the base of each wart, preferably using a 30 gauge needle. For large warts, ALFERON N InjectionŽ may be injected at several points around the periphery of the wart, using a total dose of 0.05 ml per wart.

The minimum effective dose of ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] for the treatment of condylomata acuminata has not been established. Moderate to severe adverse experiences may require modification of the dosage regimen or, in some cases, termination of therapy with ALFERON N InjectionŽ .

Genital warts usually begin to disappear after several weeks of treatment with ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)]. Treatment should continue for a maximum of 8 weeks. In clinical trials with ALFERON N InjectionŽ , many patients who had partial resolution of warts during treatment experienced further resolution of their warts after cessation of treatment. Of the patients who had complete resolution of warts due to treatment, half the patients had complete resolution of warts by the end of the treatment and half had complete resolution of warts during the 3 months after cessation of treatment. Thus, it is recommended that no further therapy (ALFERON N InjectionŽ or conventional therapy) be administered for 3 months after the initial 8-week course of treatment unless the warts enlarge or new warts appear. Studies to determine the safety and efficacy of a second course of treatment with ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] have not been conducted.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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HOW SUPPLIED
Injectable Solution: Each vial contains 1 ml of ALFERON N InjectionŽ. Each ml of ALFERON N InjectionŽ contains 5 million IU of Interferon alfa-n3, 3.3 mg of phenol, and 1 mg of Albumin (Human) in a pH 7.4 phosphate-buffered saline solution (8.0 mg/ml sodium chloride, 1.74 mg/ml sodium phosphate dibasic, 0.20 mg/ml potassium phosphate monobasic, and 0.20 mg/ml potassium chloride). One vial per box (NDC 54746-001-01).

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STORAGE
ALFERON N InjectionŽ [Interferon alfa-n3 (human leukocyte derived)] should be stored at 2° to 8°C (36° to 46°F). Do not freeze. Do not shake.
CAUTION: FEDERAL (U.S.A.) LAW PROHIBITS DISPENSING WITHOUT PRESCRIPTION.

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REFERENCES
1. Friedman-Kien, AE; Eron, LJ; Conant, M; et al., JAMA 1988; 259:533-538.
2. Kirby, P, (editorial comment), JAMA 1988; 259:570-572.
3. Friedman-Kien, AE; Plasse, TF; et al., Papilloma Viruses: Molecular and Clinical Aspects [Howley, PM, Broker, TR (eds)], New York, Alan R. Liss, Inc.; 1986; 217-233.
4. Geffen, JR; Klein, RJ; Friedman-Kien, AE, J. Infect. Dis.1984; 150:612-615.
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Information contained on the Hemispherx website other than historical information, should be considered forward-looking and is subject to various risk factors and uncertainties. For instance, the strategies and operations of Hemispherx involve risks of competition, changing market conditions, changes in laws and regulations affecting these industries and numerous other factors discussed on the Hemispherx website and in the Company's filings with the Securities and Exchange Commission. Accordingly, actual results may differ materially from those in any forward-looking statements. Additionally, all the referenced investigational drugs and associated technologies of the company are experimental in nature and as such are not designated safe and effective by a regulatory authority for general use and are legally available only through clinical trials with the referenced disorders. The forward-looking statements represent the Company's judgement as of the date of this website. The Company disclaims, however, any intent or obligation to update these forward-looking statements.