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Avonex 30 Mcg 0.5 mL 4 Prefilled Syringe

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DESCRIPTION

AVONEX® (Interferon beta-1a) is a 166 amino acid glycoprotein with a predicted molecular weight of approximately 22,500 daltons. It is produced by recombinant DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human interferon beta gene has been introduced. The amino acid sequence of AVONEX® is identical to that of natural human interferon beta.

Using the World Health Organization (WHO) natural interferon beta standard, Second International Standard for Interferon, Human Fibroblast (Gb-23-902-531), AVONEX® has a specific activity of approximately 200 million international units (IU) of antiviral activity per mg of Interferon beta-1a determined specifically by an in vitro cytopathic effect bioassay using lung carcinoma cells (A549) and Encephalomyocarditis virus (ECM). AVONEX® 30 mcg contains approximately 6 million IU of antiviral activity using this method. The activity against other standards is not known. Comparison of the activity of AVONEX® with other Interferon betas is not appropriate, because of differences in the reference standards and assays used to measure activity.

30 mcg Lyophilized Powder Vial

A vial of AVONEX® is formulated as a sterile, white to off-white lyophilized powder for intramuscular injection after reconstitution with supplied diluent (Sterile Water for Injection, USP). Each vial of reconstituted AVONEX® contains 30 mcg of Interferon beta-1a; 15 mg Albumin (Human), USP; 5.8 mg Sodium Chloride, USP; 5.7 mg Dibasic Sodium Phosphate, USP; and 1.2 mg Monobasic Sodium Phosphate, USP, in 1.0 mL at a pH of approximately 7.3.

30 mcg Prefilled Syringe

A prefilled syringe of AVONEX® is formulated as a sterile liquid for intramuscular injection. Each 0.5 mL (30 mcg dose) of AVONEX® in a prefilled glass syringe contains 30 mcg of Interferon beta-1a, 0.79 mg Sodium Acetate Trihydrate, USP; 0.25 mg Glacial Acetic Acid, USP; 15.8 mg Arginine Hydrochloride, USP; and 0.025 mg Polysorbate 20 in Water for Injection, USP at a pH of approximately 4.8.

CLINICAL PHARMACOLOGY

General

Interferons are a family of naturally occurring proteins and glycoproteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferon beta, one member of this family, is produced by various cell types including fibroblasts and macrophages. Natural interferon beta and Interferon beta-1a are glycosylated, with each containing a single N-linked complex carbohydrate moiety. Glycosylation of other proteins is known to affect their stability, activity, aggregation, biodistribution, and half-life in blood. However, the effects of glycosylation of interferon beta on these properties have not been fully defined.

Biologic Activities

Interferons are cytokines that mediate antiviral, antiproliferative and immunomodulatory activities in response to viral infection and other biological inducers. Three major interferons have been distinguished: alpha, beta, and gamma. Interferons alpha and beta form the Type I class of interferons, and interferon gamma is a Type II interferon. These interferons have overlapping but clearly distinct biological activities.

Interferon beta exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers. These include 2', 5'-oligoadenylate synthetase, β2-microglobulin, and neopterin. These products have been measured in the serum and cellular fractions of blood collected from patients treated with AVONEX®.

The specific interferon-induced proteins and mechanisms by which AVONEX® exerts its effects in multiple sclerosis have not been fully defined. Clinical studies conducted in multiple sclerosis patients showed that interleukin 10 (IL-10) levels in cerebrospinal fluid were increased in patients treated with AVONEX® compared to placebo. Serum IL-10 levels were increased 48 hours after intramuscular (IM) injection of AVONEX® and remained elevated for 1 week. However, no relationship has been established between absolute levels of IL-10 and clinical outcome in multiple sclerosis.

Pharmacokinetics

Pharmacokinetics of AVONEX® in multiple sclerosis patients have not been evaluated. The pharmacokinetic and pharmacodynamic profiles of AVONEX® in healthy subjects following doses of 30 mcg through 75 mcg have been investigated. Serum levels of AVONEX® as measured by antiviral activity are slightly above detectable limits following a 30 mcg IM dose, and increase with higher doses.

After an IM dose, serum levels of AVONEX® typically peak between 3 and 15 hours and then decline at a rate consistent with a 10 hour elimination half-life. Serum levels of AVONEX® may be sustained after IM administration due to prolonged absorption from the IM site. Systemic exposure, as determined by AUC and Cmax values, is greater following IM than subcutaneous (SC) administration.

Subcutaneous administration of AVONEX® should not be substituted for intramuscular administration. Subcutaneous and intramuscular administration have been observed to have non-equivalent pharmacokinetic and pharmacodynamic parameters following administration to healthy volunteers.

Biological response markers (e.g., neopterin and β2-microglobulin) are induced by AVONEX® following parenteral doses of 15 mcg through 75 mcg in healthy subjects and treated patients. Biological response marker levels increase within 12 hours of dosing and remain elevated for at least 4 days. Peak biological response marker levels are typically observed 48 hours after dosing. The relationship of serum AVONEX® levels or levels of these induced biological response markers to the mechanisms by which AVONEX® exerts its effects in multiple sclerosis is unknown.

Clinical Studies

The clinical effects of AVONEX® in multiple sclerosis were studied in two randomized, multicenter, double-blind, placebo-controlled studies in patients with multiple sclerosis.1,2 Safety and efficacy of treatment with AVONEX® beyond 3 years is not known.

In Study 1, 301 patients received either 30 mcg of AVONEX® (n=158) or placebo (n=143) by IM injection once weekly. Patients were entered into the trial over a 2½ year period, received injections for up to 2 years, and continued to be followed until study completion. Two hundred eighty-two patients completed 1 year on study, and 172 patients completed 2 years on study. There were 144 patients treated with AVONEX® for more than 1 year, 115 patients for more than 18 months and 82 patients for 2 years.

All patients had a definite diagnosis of multiple sclerosis of at least 1 year duration and had at least 2 exacerbations in the 3 years prior to study entry (or 1 per year if the duration of disease was less than 3 years). At entry, study participants were without exacerbation during the prior 2 months and had Kurtzke Expanded Disability Status Scale (EDSS3) scores ranging from 1.0 to 3.5. Patients with chronic progressive multiple sclerosis were excluded from this study.

The primary outcome assessment was time to progression in disability, measured as an increase in the EDSS score of at least 1.0 point that was sustained for at least 6 months. An increase in EDSS score reflects accumulation of disability. This endpoint was used to ensure that progression reflected permanent increase in disability rather than a transient effect due to an exacerbation.

Secondary outcomes included exacerbation frequency and results of magnetic resonance imaging (MRI) scans including gadolinium (Gd)-enhanced lesion number and volume and T2-weighted (proton density) lesion volume. Additional secondary endpoints included 2 upper limb (tested in both arms) and 3 lower limb function tests.

Twenty-three of the 301 patients (8%) discontinued treatment prematurely. Of these, 1 patient treated with placebo (1%) and 6 patients treated with AVONEX® (4%) discontinued treatment due to adverse events. Thirteen of these 23 patients remained on study and were evaluated for clinical endpoints.

Figure 1

Figure 1 Onset of Sustained Disability Progression by Time on Study (Kaplan-Meier Methodology)

Time to onset of sustained progression in disability was significantly longer in patients treated with AVONEX® than in patients receiving placebo (p = 0.02). The Kaplan-Meier plots of these data are presented in Figure 1. The Kaplan-Meier estimate of the percentage of patients progressing by the end of 2 years was 34.9% for placebo-treated patients and 21.9% for AVONEX®-treated patients, indicating a slowing of the disease process. This represents a 37% relative reduction in the risk of accumulating disability in the AVONEX®-treated group compared to the placebo-treated group.

Figure 2

Figure 2 Confirmed EDSS Change from Study Entry to End of Study

The distribution of confirmed EDSS change from study entry (baseline) to the end of the study is shown in Figure 2. There was a statistically significant difference between treatment groups in confirmed change for patients with at least 2 scheduled visits (136 placebo-treated and 150 AVONEX®-treated patients; p = 0.006; see Table 1).

The rate and frequency of exacerbations were determined as secondary outcomes. For all patients included in the study, irrespective of time on study, the annual exacerbation rate was 0.67 per year in the AVONEX®-treated group and 0.82 per year in the placebo-treated group (p = 0.04).

AVONEX® treatment significantly decreased the frequency of exacerbations in the subset of patients who were enrolled in the study for at least 2 years (87 placebo-treated patients and 85 AVONEX®-treated patients; p = 0.03; see Table 1).

Gd-enhanced and T2-weighted (proton density) MRI scans of the brain were obtained in most patients at baseline and at the end of 1 and 2 years of treatment. Gd-enhancing lesions seen on brain MRI scans represent areas of breakdown of the blood brain barrier thought to be secondary to inflammation. Patients treated with AVONEX® demonstrated significantly lower Gd-enhanced lesion number after 1 and 2 years of treatment (p ≤ 0.05; see Table 1). The volume of Gd-enhanced lesions was also analyzed, and showed similar treatment effects (p ≤ 0.03). Percentage change in T2-weighted lesion volume from study entry to Year 1 was significantly lower in AVONEX®-treated than placebo-treated patients (p = 0.02). A significant difference in T2-weighted lesion volume change was not seen between study entry and Year 2.

The exact relationship between MRI findings and the clinical status of patients is unknown. The prognostic significance of MRI findings in these studies has not been evaluated.

Of the limb function tests, only 1 demonstrated a statistically significant difference between treatment groups (favoring AVONEX®). A summary of the effects of AVONEX® on the clinical and MRI endpoints of this study is presented in Table 1.

Table 1 Clinical and MRI Endpoints in Study 1

Note: (N: , ) denotes the number of evaluable placebo and AVONEX® patients, respectively.

1Patient data included in this analysis represent variable periods of time on study.

2Analyzed by Mantel-Cox (logrank) test.

3Analyzed by Mann-Whitney rank-sum test.

4Analyzed by Cochran-Mantel-Haenszel test.

5Analyzed by likelihood ratio test.

Endpoint

Placebo

AVONEX®

P-Value

PRIMARY ENDPOINT:

     


Time to sustained progression
in disability (N: 143, 158)1

--- See Figure 1 ---

0.022


Percentage of patients progressing in disability at 2 years (Kaplan-Meier estimate)1

34.9%

21.9%

 


SECONDARY ENDPOINTS :
DISABILITY

     


Mean confirmed change in EDSS from study entry to end of study (N: 136, 150)1

0.50

0.20

0.0063


EXACERBATIONS

     


Number of exacerbations in subset completing 2 years (N: 87, 85)

     

       0

26%

38%

0.033

       1

30%

31%

 

       2

11%

18%

 

       3

14%

7%

 

       ≥ 4

18%

7%

 


Percentage of patients exacerbation-free in subset completing 2 years (N: 87, 85)

26%

38%

0.104


Annual exacerbation rate (N: 143, 158)1

0.82

0.67

0.045


MRI

     


Number of Gd-enhanced lesions:

     

At study entry (N: 132, 141)

     

       Mean (Median)

2.3 (1.0)

3.2 (1.0)

 

       Range

0-23

0-56

 


Year 1 (N: 123, 134)

     

       Mean (Median)

1.6 (0)

1.0 (0)

0.023

       Range

0-22

0-28

 


Year 2 (N: 82, 83)

     

       Mean (Median)

1.6 (0)

0.8 (0)

0.053

       Range

0-34

0-13

 


T2 lesion volume:

     

Percentage change from study entry to Year 1 (N: 116, 123)

     

       Median

-3.3%

-13.1%

0.023


Percentage change from study entry to Year 2 (N: 83, 81)

     

       Median

-6.5%

-13.2%

0.363

In Study 2, 383 patients who had recently experienced an isolated demyelinating event involving the optic nerve, spinal cord, or brainstem/cerebellum, and who had lesions typical of multiple sclerosis on brain MRI, received either 30 mcg AVONEX® (n = 193) or placebo (n = 190) by IM injection once weekly. All patients received intravenous steroid treatment for the initiating clinical exacerbation. Patients were enrolled into the study over a two-year period and followed for up to three years or until they developed a second clinical exacerbation in an anatomically distinct region of the central nervous system. Sixteen percent of subjects on AVONEX® and 14% of subjects on placebo withdrew from the study for a reason other than the development of a second exacerbation2.

The primary outcome measure was time to development of a second exacerbation in an anatomically distinct region of the central nervous system. Secondary outcomes were brain MRI measures, including the cumulative increase in the number of new or enlarging T2 lesions, T2 lesion volume compared to baseline at 18 months, and the number of Gd-enhancing lesions at 6 months.

Time to development of a second exacerbation was significantly delayed in patients treated with AVONEX® compared to placebo (p = 0.002). The Kaplan-Meier estimates of the percentage of patients developing an exacerbation within 24 months were 38.6% in the placebo group and 21.1% in the AVONEX® group (Figure 3). The relative rate of developing a second exacerbation in the AVONEX® group was 0.56 of the rate in the placebo group (95% confidence interval 0.38 to 0.81). The brain MRI findings are described in Table 2.

Figure 3

Figure 3 Onset of Second Exacerbation by Time on Study (Kaplan-Meier Methodology)

Table 2 Brain MRI Data According to Treatment Group

1 P value <0.001

2 P value <0.03

* P value from a Mann-Whitney rank-sum test

 

AVONEX®

Placebo

CHANGE IN T2 VOLUME @18 MONTHS:

N = 119

N = 109

     

Actual Change (mm3)1* 
Median (25th%, 75th%)

28 (-576, 397)

313 (5, 1140)

Percentage Change1* 
Median (25th%, 75th%)

1 (-24, 29)

16 (0, 53)

 


NUMBER OF NEW OR ENLARGING T2 LESIONS @ 18 MONTHS1*:


N = 132
N (%)


N = 119
N (%)

 

0

62 (47)

22 (18)

1-3

41 (31)

47 (40)

≥4

29 (22)

50 (42)

Mean (SD)

2.13 (3.19)

4.97 (7.71)

 


NUMBER OF GD-ENHANCING LESIONS @ 6 MONTHS2*:


N = 165
N (%)


N = 152
N (%)

   

0

115 (70)

93 (61)

1

27 (16)

16 (11)

>1

23 (14)

43 (28)

Mean (SD)

0.87 (2.28)

1.49 (3.14)

INDICATIONS AND USAGE

AVONEX® (Interferon beta-1a) is indicated for the treatment of patients with relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations. Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. Safety and efficacy in patients with chronic progressive multiple sclerosis have not been established.

CONTRAINDICATIONS

AVONEX® is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, or any other component of the formulation.

The lyophilized vial formulation of AVONEX® is contraindicated in patients with a history of hypersensitivity to albumin (human).

WARNINGS

Depression and Suicide

AVONEX® should be used with caution in patients with depression or other mood disorders, conditions that are common with multiple sclerosis. Depression and suicide have been reported to occur with increased frequency in patients receiving interferon compounds, including AVONEX®. Patients treated with AVONEX® should be advised to report immediately any symptoms of depression and/or suicidal ideation to their prescribing physicians. If a patient develops depression or other severe psychiatric symptoms, cessation of AVONEX® therapy should be considered. In Study 2, AVONEX®-treated patients were more likely to experience depression than placebo-treated patients. An equal incidence of depression was seen in the placebo-treated and AVONEX®-treated patients in Study 1. Additionally, there have been post-marketing reports of depression, suicidal ideation and/or development of new or worsening of pre-existing other psychiatric disorders, including psychosis. Some of these patients improved upon cessation of AVONEX® dosing.

Anaphylaxis

Anaphylaxis has been reported as a rare complication of AVONEX® use. Other allergic reactions have included dyspnea, orolingual edema, skin rash and urticaria (see ADVERSE REACTIONS).

Decreased Peripheral Blood Counts

Decreased peripheral blood counts in all cell lines, including rare pancytopenia and thrombocytopenia, have been reported from post-marketing experience (see ADVERSE REACTIONS). Some cases of thrombocytopenia have had nadirs below 10,000/μL. Some cases reoccur with rechallenge (see ADVERSE REACTIONS). Patients should be monitored for signs of these disorders (see Precautions: Laboratory Tests).

Hepatic Injury

Severe hepatic injury, including cases of hepatic failure, has been reported rarely in patients taking AVONEX®. Asymptomatic elevation of hepatic transaminases has also been reported, and in some patients has recurred upon rechallenge with AVONEX®. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. The potential risk of AVONEX® used in combination with known hepatotoxic drugs or other products (e.g. alcohol) should be considered prior to AVONEX® administration, or when adding new agents to the regimen of patients already on AVONEX®. Patients should be monitored for signs of hepatic injury (see Precautions: Laboratory Tests).

Albumin (Human)

The lyophilized vial of AVONEX® contains 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 been identified for albumin. The prefilled syringe of AVONEX® does not contain albumin.

PRECAUTIONS

Seizures

Caution should be exercised when administering AVONEX® to patients with pre-existing seizure disorders. In the two placebo-controlled studies in multiple sclerosis, 4 patients receiving AVONEX® experienced seizures, while no seizures occurred in the placebo group. Three of these 4 patients had no prior history of seizure (see ADVERSE REACTIONS). It is not known whether these events were related to the effects of multiple sclerosis alone, to AVONEX®, or to a combination of both. The effect of AVONEX® administration on the medical management of patients with seizure disorder is unknown.

Cardiomyopathy and Congestive Heart Failure

Patients with cardiac disease, such as angina, congestive heart failure, or arrhythmia, should be closely monitored for worsening of their clinical condition during initiation and continued treatment with AVONEX®. While AVONEX® does not have any known direct-acting cardiac toxicity, during the post-marketing period infrequent cases of congestive heart failure, cardiomyopathy, and cardiomyopathy with congestive heart failure have been reported in patients without known predisposition to these events, and without other known etiologies being established. In rare cases, these events have been temporally related to the administration of AVONEX®. In some of these instances recurrence upon rechallenge was observed.

Autoimmune Disorders

Autoimmune disorders of multiple target organs have been reported post-marketing including idiopathic thrombocytopenia, hyper- and hypothyroidism, and rare cases of autoimmune hepatitis have also been reported. Patients should be monitored for signs of these disorders (see Precautions: Laboratory Tests) and appropriate treatment implemented when observed.

Information to Patients

All patients should be instructed to read the AVONEX® Medication Guide supplied to them. Patients should be cautioned not to change the dosage or the schedule of administration without medical consultation.

Patients should be informed of the most serious (see WARNINGS) and the most common adverse events associated with AVONEX® administration, including symptoms associated with flu syndrome (see ADVERSE REACTIONS). Symptoms of flu syndrome are most prominent at the initiation of therapy and decrease in frequency with continued treatment. Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms on treatment days.

Patients should be cautioned to report depression or suicidal ideation (see WARNINGS).

Patients should be advised about the abortifacient potential of AVONEX® (see Precautions: Pregnancy - Teratogenic Effects). If a woman becomes pregnant while taking AVONEX®, she should be advised to consider enrolling in the AVONEX® Pregnancy Registry by calling 1-800-456-2255.

When a physician determines that AVONEX® can be used outside of the physician's office, persons who will be administering AVONEX® should receive instruction in reconstitution and injection, including the review of the injection procedures. If a patient is to self-administer, the physical ability of that patient to self-inject intramuscularly should be assessed. The first injection should be performed under the supervision of a qualified health care professional. A puncture-resistant container for disposal of needles and syringes should be used. Patients should be instructed in the technique and importance of proper syringe and needle disposal and be cautioned against reuse of these items.

Laboratory Tests

In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and differential white blood cell counts, platelet counts, and blood chemistries, including liver function tests, are recommended during AVONEX® therapy (see WARNINGS: Decreased Peripheral Blood Counts and PRECAUTIONS: Cardiomyopathy and Congestive Heart Failure, and Autoimmune Disorders). During the placebo-controlled studies in multiple sclerosis, these tests were performed at least every 6 months. There were no significant differences between the placebo and AVONEX® groups in the incidence of liver enzyme elevation, leukopenia, or thrombocytopenia. However, these are known to be dose-related laboratory abnormalities associated with the use of interferons. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. Thyroid function should be monitored periodically. If patients have or develop symptoms of thyroid dysfunction (hypo- or hyperthyroidism), thyroid function tests should be performed according to standard medical practice.

Drug Interactions

No formal drug interaction studies have been conducted with AVONEX®. In the placebo-controlled studies in multiple sclerosis, corticosteroids or ACTH were administered for treatment of exacerbations in some patients concurrently receiving AVONEX®. In addition, some patients receiving AVONEX® were also treated with anti-depressant therapy and/or oral contraceptive therapy. No unexpected adverse events were associated with these concomitant therapies. However, the potential for hepatic injury should be considered when AVONEX® is used in combination with other products associated with hepatic injury, or when new agents are added to the regimen of patients already on AVONEX® (see WARNINGS: Hepatic Injury).

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis: No carcinogenicity data for AVONEX® are available in animals or humans.

Mutagenesis: AVONEX® was not mutagenic when tested in the Ames bacterial test and in an in vitro cytogenetic assay in human lymphocytes in the presence and absence of metabolic activation. These assays are designed to detect agents that interact directly with and cause damage to cel

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Avonex 30 Mcg 0.5 mL 4 Prefilled Syringe

  • Brand: Biogen
  • Product Code: 8699783950033
  • Availability: In Stock
  • $3thousand_point435.00

Tags: Avonex 30 Mcg 0.5 mL 4 Prefilled Syringe, Biogen, All Products