Avonex

Name: Avonex

Indications

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.

Clinical pharmacology

Mechanism Of Action

The mechanism of action by which AVONEX exerts its effects in patients with multiple sclerosis is unknown.

Pharmacodynamics

Interferons (IFNs) are a family of naturally occurring proteins, produced by eukaryotic cells in response to viral infection and other biologic agents. Three major types of interferons have been defined: type I (IFN-alpha, beta, epsilon, kappa and omega), type II (IFN–gamma) and type III

(IFN-lambda). Interferon-beta is a member of the type I subset of interferons. The type I interferons have considerably overlapping but also distinct biologic activities. The bioactivities of all IFNs, including IFN-beta, are induced via their binding to specific receptors on the membranes of human cells. Differences in the bioactivites induced by the three major subtypes of IFNs likely reflect differences in the signal transduction pathways induced by signaling through their cognate receptors.

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.

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 maximally were increased by 48 hours after intramuscular 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 micrograms through 75 micrograms have been investigated. Serum levels of AVONEX as measured by antiviral activity are slightly above detectable limits following a 30 microgram intramuscular dose, and increase with higher doses.

After an intramuscular dose, serum levels of AVONEX generally peak at 15 hours post-dose (range: 6-36 hours) and then decline at a rate consistent with a 19 (range: 8-54) hour elimination half-life.

Subcutaneous administration of AVONEX should not be substituted for intramuscular administration as there is no data establishing that subcutaneous and intramuscular administration of AVONEX result in equivalent pharmacokinetic and pharmacodynamic parameters.

Biological response markers (e.g., neopterin and β2-microglobulin) are induced by AVONEX following parenteral doses of 15 micrograms through 75 micrograms 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 patients with relapsing forms of multiple sclerosis (MS) were studied in two randomized, multicenter, double-blind, placebo-controlled studies in patients with MS (Studies 1 and 2). Safety and efficacy of treatment with AVONEX beyond 3 years is not known.

In Study 1, 301 patients received either 30 micrograms of AVONEX (n=158) or placebo (n=143) by intramuscular injection once weekly. Patients 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. The EDSS is a scale that quantifies disability in patients with MS and ranges from 0 (normal neurologic exam) to 10 (death due to MS). Patients with chronic progressive multiple sclerosis were excluded from this study.

Disability

The primary outcome assessment was time to progression in disability, measured as an increase in the EDSS score of at least 1 point that was sustained for at least 6 months. An increase in EDSS score reflects accumulation of disability. This endpoint was used to help distinguish permanent increase in disability from a transient increase due to an exacerbation.

As shown in Figure 1, the time to onset of sustained progression in disability was significantly longer in AVONEX-treated patients than in placebo-treated patients in Study 1 (p = 0.02). The percentage of patients progressing by the end of 2 years was 35% for placebo-treated patients and 22% for AVONEX-treated patients. This represents a 37% relative reduction in the risk of accumulating disability in the AVONEX-treated group compared to the placebo-treated group.

1Kaplan-Meier Methodology; Disability progression was defined as at least a 1 point increase in EDSS score sustained for at least 6 months.

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 the AVONEX and placebo groups in confirmed change for patients with at least 2 scheduled visits (p = 0.006).

Figure 2: Confirmed Change in EDSS from Study Entry to End of Study 1

Exacerbations

The rate and frequency of MS exacerbations were 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 3).

MRI Results

Gadolinium (Gd)-enhanced and T2-weighted magnetic resonance imaging (MRI) scans of the brain were obtained in most patients at baseline and at the end of 1 and 2 years of treatment. Secondary outcomes included Gd-enhanced lesion number and volume, and T2-weighted lesion volume. Gd-enhancing lesions seen on brain MRI scans represent areas of breakdown of the blood brain barrier thought to be secondary to inflammation. AVONEX-treated patients demonstrated significantly lower Gd-enhanced lesion number after 1 and 2 years of treatment than placebo-treated patients (p ≤ 0.05; see Table 3). The volume of Gd-enhanced lesions showed similar treatment effects in the AVONEX and placebo groups (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 in the AVONEX and placebo groups.

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

Summary Of Effects Of Clinical And MRI Endpoints In Study 1

A summary of the effects of AVONEX on the clinical and MRI endpoints of this study is presented in Table 3.

Table 3: Clinical and MRI Endpoints in Patients with MS in Study 1

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 35% 22%
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) (0) .6 1.0 (0) 0.023
  Range 2 2 - 0 0-28  
Year 2 (N: 82, 83)
  Mean (Median) O CD 0.8 (0) 0.053
  Range ' 6 3 .1 0 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
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.

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 micrograms of AVONEX (n = 193) or placebo (n = 190) by intramuscular injection once weekly. Patients were enrolled into the study over a twoyear 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.

Exacerbations

In Study 2, the primary outcome measure was time to development of a second exacerbation in an anatomically distinct region of the central nervous system. Time to development of a second exacerbation was significantly delayed in AVONEX-treated compared to placebo-treated patients (p = 0.002). The Kaplan-Meier estimates of the percentage of patients developing an exacerbation within 24 months were 39% in the placebo group and 21% in the AVONEX group (see 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).

Figure 3: Time to onset of a Second Exacerbation in Study 21

1 Kaplan-Meier Methodology

MRI Findings

Secondary outcomes were brain MRI measures, including the cumulative increase in the number of new or enlarging T2 lesions, T2 lesion volume at baseline compared to results at 18 months, and the number of Gd-enhancing lesions at 6 months. See Table 4 for the MRI results.

Table 4: Brain MRI Results in Study 2

  AVONEX Placebo
CHANGE FROM BASELINE IN T2 VOLUME OF LESIONS AT 18 MONTHS: N = 119 N = 109
Actual Change (mm³)1* Median (25*%, 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 AT 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 (3.2) 4.97 (7.7)
NUMBER OF GD-ENHANCING LESIONS AT 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 (2.3) 1.49 (3.1)
1 P value < 0.001
2 P value < 0.03
* P value from a Mann-Whitney rank-sum test

Avonex Overview

Avonex is a prescription medication that is used to treat multiple sclerosis. Avonex belongs to a group of drugs called immunomodulators, which are thought to help limit the destruction of the protective myelin coating of nerve fibers.

Avonex comes as a liquid in prefilled syringes or single-use vials that come with sterile water to be mixed. It is to be injected directly into muscle (IM) once a week, or just under the skin (subcutaneous or sub-Q) 3 times a week, depending on the form you receive. Common side effects of Avonex include headache, flu-like symptoms, and fever.

Avonex Precautions

Potential serious side effects include:

  • Depression - Some people treated with interferons, including Avonex, have become depressed (feeling sad, feeling low or feeling bad about oneself). Some people have thought about killing themselves and a few have committed suicide. Depression is common in people with MS. If you are noticeably sadder or feeling more hopeless, you should tell a family member or friend right away and call your doctor as soon as possible. You should tell the doctor if you have ever had any mental illness, including depression, and if you take any medicines for depression.
  • Liver problems - Your liver may be affected by using Avonex and a few patients have developed severe liver injury. Your healthcare provider may ask you to have regular blood tests to make sure that your liver is working properly. If your skin or the whites of your eyes become yellow or if you are bruising easily you should call your doctor immediately.
  • Risk to pregnancy - If you become pregnant while using Avonex, you should stop using Avonex immediately and call your doctor. Avonex may cause you to lose your baby (miscarry) or may cause harm to your unborn child. You and your doctor will need to decide whether the potential benefit of taking Avonex is greater than the risks are to your unborn child.
  • Allergic reactions - Some patients using Avonex have had severe allergic reactions leading to difficulty breathing. Allergic reactions can happen after your first dose or may not happen until after you have used Avonex many times. Less severe allergic reactions such as rash, itching, skin bumps or swelling of the mouth and tongue can also happen. If you think you are having an allergic reaction, stop using Avonex immediately and call your doctor.
  • Blood problems - You may have a drop in the levels of infection-fighting blood cells, red blood cells or cells that help to form blood clots. If the drop in levels are severe, they can lessen your ability to fight infections, make you feel tired or sluggish or cause you to bruise or bleed easily.
  • Seizures - Some patients have had seizures while using Avonex, including some patients who have never had seizures before. It is not known whether the seizures were related to the effects of their MS, to Avonex, or to a combination of both. If you have a seizure while using Avonex, you should stop using Avonex and call your doctor right away.
  • Heart problems - While Avonex is not known to have direct effects on the heart, a few patients who did not have a history of heart problems developed heart muscle problems or congestive heart failure after using Avonex. Some of the symptoms of heart problems are swollen ankles, shortness of breath, decreased ability to exercise, fast heartbeat, tightness in chest, increased need to urinate at night, and not being able to lay flat in bed. If you develop these symptoms or any heart problems while using Avonex, you should call your doctor right away.

Do not use Avonex if you have had an allergic reaction to Avonex. (Allergic reactions include difficulty breathing, itching, flushing or skin bumps spread widely over the body). Do not use the vial formulation of Avonex if you have a history of hypersensitivity to albumin (human).

Avonex Dosage

Use Avonex exactly as your doctor prescribes it.

Intramuscular Form - The usual dose is 30 mcg injected intramuscularly (into the muscle) once a week. Do not change your dose unless your doctor tells you to.

Subcutaneous Form - Dosages are started low and gradually increased to 22 mcg or 44 mcg injected subcutaneously (under the skin) three times per week.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What other drugs will affect interferon beta-1a?

Interferon beta-1a can harm your liver. This effect is increased when you also use other medicines harmful to the liver. Many other drugs (including some over-the-counter medicines) can be harmful to the liver, and not all are listed here:

  • acetaminophen (Tylenol), aspirin, gout or arthritis medication (including gold injections); an NSAID (nonsteroidal anti-inflammatory drug)--ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others;

  • an antibiotic, antifungal medicine, or sulfa drug; tuberculosis medicine; antiviral or HIV/AIDS medication; medicine to treat mental illness; seizure medication--carbamazepine, phenytoin, valproic acid, and others;

  • birth control pills or hormone replacement therapy; anabolic steroids--methyltestosterone, "performance-enhancing drugs"; cancer medication; or

  • cholesterol-lowering medication--Crestor, Lipitor, Vytorin, Zocor, and others; heart or blood pressure medication.

This list is not complete. Other drugs may interact with interferon beta-1a, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Commonly used brand name(s)

In the U.S.

  • Avonex
  • Avonex Pen
  • Rebif
  • Rebif Rebidose
  • Rebif Rebidose Titration Pack

Available Dosage Forms:

  • Solution
  • Kit

Therapeutic Class: Immunological Agent

Pharmacologic Class: Interferon, Beta (class)

Proper Use of interferon beta-1a

This section provides information on the proper use of a number of products that contain interferon beta-1a. It may not be specific to Avonex. Please read with care.

A nurse or other trained health professional will give you this medicine. You may also be taught how to give your medicine at home. This medicine is given as a shot under your skin or into a muscle.

If you are injecting interferon beta-1a yourself, use it exactly as directed by your doctor. Do not change your dose or dosing schedule without checking first with your doctor. The exact amount of medicine you need has been carefully worked out. Using too much will increase the risk for side effects, while using too little may not improve your condition.

You will be shown the body areas where this shot can be given. Use a different body area each time you give yourself a shot. Keep track of where you give each shot to make sure you rotate body areas.

Use only the brand of this medicine that your doctor prescribed. Different brands may not work the same way.

Rebif® comes as an autoinjector or a prefilled syringe. It works best if you use it at the same time (usually in the late afternoon or evening) on the same 3 days (eg, Monday, Wednesday, and Friday) at least 48 hours apart each week.

Avonex® comes as a prefilled autoinjector pen, a prefilled syringe, or a powder. The powder must be mixed with sterile water before it is given. Do not shake the vial after you add the water. Gently swirl the water and medicine together to mix. The mixture should be clear or slightly yellow. Do not use the mixture if you see particles in it. Use the medicine as soon as possible after mixing. If you cannot give your shot right away, you can keep the syringe in the refrigerator for up to 6 hours. After 6 hours, throw the medicine away and mix another dose.

Use a new needle, unopened vial, or syringe each time you inject your medicine. Do not use any other needle for the prefilled autoinjector pen.

Each package of medicine contains a Medication Guide and a sheet called Instructions for Use. Read this information carefully and make sure you understand:

  • How to prepare the injection.
  • How to use disposable syringes or autoinjectors.
  • How to store the syringes or autoinjectors.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For injection dosage form:
    • For multiple sclerosis:
      • Adults—
        • Avonex®: At first, 7.5 micrograms (mcg) injected into a muscle once a week on the same day (eg, every Monday at bedtime). Your doctor will increase your dose by 7.5 mcg each week for the next 3 weeks until you reach 30 mcg weekly.
        • Rebif®: At first, 4.4 or 8.8 mcg injected under the skin 3 times a week. Your doctor will adjust your dose as needed.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Avonex®: If you miss a dose, give it as soon as you can. Go back to your regular schedule the following week. Do not use this medicine 2 days in a row.

Rebif®: If you miss a dose, give it as soon as you can. Skip the next day and give your regular dose 48 hours later. Go back to your regular schedule the following week. Do not use this medicine 2 days in a row.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store prefilled autoinjector pens, prefilled syringes, or vials in the refrigerator. Do not freeze. If refrigeration is not available, Rebif® prefilled syringes and Avonex® powder vials may be kept for up to 30 days at room temperature, away from heat (temperatures above 77 degrees F) and direct light. Avonex® prefilled autoinjector pens and prefilled syringes may be stored for up to 7 days at room temperature, away from heat (temperatures above 77 degrees F) and direct light. Allow Avonex® prefilled autoinjector pens and prefilled syringes to warm to room temperature before injection by removing from the refrigerator for about 30 minutes. Do not heat them in a microwave oven or in hot water.

Put the used needles into a hard, closed container that the needles cannot poke through. Keep this container away from children and pets.

Important information

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Avonex may be harmful to an unborn baby, or may cause a miscarriage. Do not use Avonex if you are pregnant. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

Before using Avonex, tell your doctor if you are allergic to any drugs, or if you have liver disease, a thyroid disorder, epilepsy or other seizure disorder, heart disease, chest pain (angina), congestive heart failure, a heart rhythm disorder, or a history of depression or suicidal behavior.

What other drugs will affect Avonex?

Avonex can harm your liver. This effect is increased when you also use other medicines harmful to the liver. Many other drugs (including some over-the-counter medicines) can be harmful to the liver, and not all are listed here:

  • acetaminophen (Tylenol), aspirin, gout or arthritis medication (including gold injections); an NSAID (nonsteroidal anti-inflammatory drug) - ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others;

  • an antibiotic, antifungal medicine, or sulfa drug; tuberculosis medicine; antiviral or HIV/AIDS medication; medicine to treat mental illness; seizure medication - carbamazepine, phenytoin, valproic acid, and others;

  • birth control pills or hormone replacement therapy; anabolic steroids - methyltestosterone, "performance-enhancing drugs"; cancer medication; or

  • cholesterol-lowering medication - Crestor, Lipitor, Vytorin, Zocor, and others; heart or blood pressure medication.

This list is not complete. Other drugs may interact with interferon beta-1a, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

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