Betaseron

Common Side Effects of Betaseron

Tell your doctor if any of the following symptoms become severe or don't go away:

• Weakness
• Headache
• Muscle pain or muscle weakness
• Sleep problems
• Drowsiness
• Dizziness
• Mild stomach pain or nausea
• Indigestion, constipation, or diarrhea
• Mild skin rash
• Increased need to urinate
• Irregular menstrual periods or increased menstrual pain
• Flushing
• Hair loss

Serious Side Effects of Betaseron

Tell your doctor if you experience any of the symptoms listed in the Warning section, as well as the following serious side effects:

• Feeling hot or cold all the time
• Unexplained weight gain or weight loss
• Oozing, bruising, swelling, or skin changes at the injection site
• Irregular, fast, or pounding heartbeat
• Chest tightness or pain
• Sore throat, cough, fever, chills, or other signs of infection
• Hives, rash, or itching
• Trouble breathing or swallowing
• Swelling of the face, throat, tongue, lips, eyes, hands, arms, feet, ankles, or lower legs
• Seizures
• Excessive fatigue or lack of energy
• Hoarseness
• Pain or swelling the upper right part of the stomach
• Change in coordination
• Vaginal bleeding or spotting between menstrual periods
• Swollen lymph nodes

BETASERON
(bay-ta-seer-on) interferon beta-1b (in-ter-feer-on beta-one-be) Subcutaneous Injection

What is the most important information I should know about BETASERON?

BETASERON can cause serious side effects, including:

• liver problems including liver failure. Symptoms of liver problems may include:
  • yellowing of your eyes
  • itchy skin
  • nausea or vomiting
  • feeling very tired
  • flu-like symptoms
  • bruising easily or bleeding problems
    Your healthcare provider will do blood tests to check for these problems while you take BETASERON.
• serious allergic reactions. Serious allergic reactions can happen quickly and may happen after your first dose of BETASERON or after you have taken BETASERON many times. Symptoms may include difficulty breathing or swallowing, swelling of the mouth or tongue, rash, itching, or skin bumps.
• depression or suicidal thoughts. Call your healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you:
  • thoughts about suicide or dying
  • new or worse depression
  • new or worse anxiety
  • trouble sleeping (insomnia)
  • acting aggressive, being angry, or violent
  • acting on dangerous impulses
  • hallucinations
  • other unusual changes in behavior or mood

What is BETASERON?

BETASERON is a prescription medicine used to reduce the number of relapses in people with relapsing forms of multiple sclerosis (MS). This includes people who have had their first symptoms of multiple sclerosis and have an MRI consistent with multiple sclerosis. BETASERON is similar to certain interferon proteins that are produced in the body. It will not cure your MS but may decrease the number of flare-ups of the disease.

It is not known if BETASERON is safe and effective in children.

Who should not take BETASERON?

Do not take BETASERON if you are allergic to interferon beta-1b, to another interferon beta, to human albumin, or mannitol. See the end of this leaflet for a complete list of ingredients in BETASERON

What should I tell my healthcare provider before taking BETASERON?

Before you take BETASERON, tell your healthcare provider if you:

• have or have had depression (sinking feeling or sadness), anxiety (feeling uneasy, nervous, or fearful for no reason) or trouble sleeping
• have or have had liver problems
• have or have had blood problems such as bleeding or bruising easily, low red blood cells (anemia) or low white blood cells
• have or have had seizures
• have or have had heart problems
• are pregnant or plan to become pregnant. BETASERON can harm your unborn baby. BETASERON may cause you to lose your baby (miscarry). If you become pregnant while taking BETASERON call your healthcare provider right away. You and your healthcare provider should decide if you should continue to take BETASERON.
• are breastfeeding or plan to breastfeed. It is not known if BETASERON passes into your breast milk. You and your healthcare provider should decide if you will take BETASERON or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take BETASERON?

• See the Instructions for Use at the end of this Medication Guide for complete information on how to use BETASERON.
• BETASERON is given by injection under your skin (subcutaneous injection) every other day.
• Take BETASERON exactly as your healthcare provider tells you to take it.
• If your healthcare provider feels that you or someone else may give you the injections then you or the other person should be trained by your healthcare provider in how to give an injection.
• Do not try to give yourself or have another person give you injections until you or both of you understand and are comfortable with how to prepare your dose and give the injection.
• You may be started on a lower dose when you first start taking BETASERON. Your healthcare provider will tell you what dose of BETASERON to use.
• Your healthcare provider may change your dose of BETASERON. You should not change your dose without talking to your healthcare provider.
• If you miss a dose, you should take your next dose as soon as you remember or are able to take it. Your next injection should be taken about 48 hours (2 days) after that dose. Do not take BETASERON on 2 consecutive days. If you accidentally take more than your prescribed dose, or take it on 2 consecutive days, call your healthcare provider right away.
• Always use a new, unopened vial of BETASERON and pre-filled diluent syringe for each injection. Throw away any unused medicine. Do not re-use any vials, syringes, or needles.
• It is important for you to change your injection site each time you inject BETASERON. This will lessen the chance of you having a serious skin reaction at the site where you inject BETASERON. Avoid injecting BETASERON into an area of skin that is sore, reddened, infected or has other problems.

What are the possible side effects of BETASERON?

BETASERON may cause serious side effects. Call your healthcare provider right away if you have any of the serious side effects of BETASERON including:

• See “What is the most important information I should know about BETASERON?”
• heart problems. BETASERON may worsen heart problems including congestive heart failure. Symptoms of heart problems may include:
  • swollen ankles
  • shortness of breath
  • not being able to lay flat in bed
  • tightness in chest
  • decreased ability to exercise
  • fast heartbeat
  • increased need to urinate at night
• injection site problems. Serious skin reactions can happen in some people including areas of severe damage to skin and the tissue below the skin (necrosis). These reactions can happen anywhere you inject BETASERON. Symptoms of injection site problems may include swelling, redness, or pain at the injection site, fluid drainage from the injection site, and breaks in your skin or blue-black skin discoloration.
• flu-like symptoms. BETASERON can cause flu-like symptoms including:
  • fever
  • tiredness
  • sweating
  • chills
  • muscle aches when you first start to use it
    These symptoms may decrease over time. Taking medicines for fever and pain relief on the days you are using BETASERON may help decrease these symptoms.

• seizures. Some people have had seizures while taking BETASERON, including people who have never had seizures before. It is not known if the seizures were related to their MS, to BETASERON, or to a combination of both. If you have a seizure after taking BETASERON call your healthcare provider right away.

The most common side effects of BETASERON include:

• low white blood cell count
• increases in your liver enzymes
• problems sleeping
• headache
• increases in your muscle tension
• weakness
• pain
• rash
• stomach pain

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of BETASERON. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store BETASERON?

• Before mixing, store BETASERON at room temperature between 68°F to 77°F (20°C to 25°C).
• Before mixing, BETASERON may be stored for up to 3 months between 59°F to 86°F (15°C to 30°C).
• After mixing, you can refrigerate BETASERON for up to 3 hours before using. Your BETASERON must be used within 3 hours of mixing even if refrigerated.
• Do not freeze.

Keep BETASERON and all medicines out of the reach of children.

General information about the safe and effective use of BETASERON.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BETASERON for a condition for which it was not prescribed. Do not give BETASERON to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about BETASERON. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about BETASERON that is written for health professionals.

For more information, go to www.BETASERON.com or call BETAPLUS, the BETASERON patient support program, at 1-800- 788-1467.

What are the ingredients in BETASERON?

Active ingredient: interferon beta-1b

Inactive ingredients: albumin (human), mannitol

Diluent contains sodium chloride solution.

Instructions for Use

BETASERON
(bay-ta-seer-on)
interferon beta-1b (in-ter-feer-on beta-one-be)

Read the Instructions for Use that come with your BETASERON before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment. Before you use BETASERON for the first time, make sure your healthcare provider shows you the right way to use it.

Supplies needed for your BETASERON Injection (See Figure A).

• 1 single-use carton containing:
  • A vial of BETASERON
  • A pre-filled diluent syringe
  • A vial adapter with a 30-gauge needle attached (in the blister pack)
  • 2 alcohol prep pads

Figure A

Step 1: Preparing for Your BETASERON Injection

• Place the supplies you will need on a clean, flat surface in a well-lit area.
• Check the expiration date on the single-use carton to make sure that it has not expired. Do not use it if the medication has expired.
• Wash your hands thoroughly with soap and water.
• Open the single-use carton and take out all the contents. Make sure the blister pack containing the vial adapter is sealed. Check to make sure the plastic cap on the pre-filled diluent syringe is firmly attached.
• Remove the tray from the single-use carton and place it on a flat surface.
• Place the BETASERON vial in the well (vial holder) and place the pre-filled diluent syringe in the U-shaped trough (See Figure B).

Figure B

Step 2: Mixing BETASERON

• Remove the BETASERON vial from the well (vial holder) and take the cap off the vial.
• Place the vial back into the well (vial holder).
• Use an alcohol prep pad to clean the top of the vial. Move the alcohol prep pad in 1 direction. Leave the alcohol prep pad on top of the vial.
• Peel the label off the blister pack with the vial adapter in it. The vial adapter is sterile. Do not remove or touch the vial adapter.
• Remove the alcohol prep pad from the top of the BETASERON vial. Pick up the vial adapter in the blister pack. Turn over the blister pack keeping the vial adapter inside. Put the adapter on top of the BETASERON vial. Push down on the adapter until it pierces the rubber top of the BETASERON vial and snaps in place (See Figure C). Remove the blister packaging from the vial adapter.

Figure C

• Twist the plastic cap from the pre-filled diluent syringe. Throw away the plastic cap (See Figure D).

Figure D

• Keep the vial adapter attached to the vial and remove the vial from the well (vial holder). Be careful not to pull the vial adapter off the top of the vial.
• Connect the pre-filled diluent syringe to the vial adapter by turning clockwise until resistance is felt and the attachment is secure. This forms the syringe assembly (See Figure E).

Figure E

• Slowly push the plunger of the pre-filled diluent syringe all the way in. This will transfer all of the liquid from the syringe into the BETASERON vial (See Figure F). The plunger may return to its original position after you release it.

Figure F

• Gently swirl the vial to completely dissolve the white powder of BETASERON. Do not shake. Shaking and even gentle mixing can cause foaming of the medicine. If there is foam, let the vial sit until the foam settles before using it.
• After the powder dissolves, look closely at the solution in the vial. Do not use the solution if it is cloudy or contains particles. It should be clear and colorless.
• Do not use cracked or damaged BETASERON vials. If your vial is cracked or damaged, get a new single-use carton containing a BETASERON vial, pre-filled diluent syringe, vial adapter and 2 alcohol prep pads. Repeat the steps to prepare your BETASERON dose.
• Contact BETAPLUS, the BETASERON patient support program, at 1-800-788-1467 to obtain a replacement product.

Step 3: Preparing the Injection

You have completed the steps to prepare your BETASERON and are ready for the injection. The injection should be given immediately after mixing and allowing any foam in the solution to settle. If you must wait to give yourself the injection, you may refrigerate the solution and use within 3 hours of mixing your BETASERON. Do not freeze.

• Push the plunger in and hold it there; then turn the syringe assembly so that the syringe is horizontal and the vial is on top.
• Slowly pull the plunger back to withdraw all the liquid from the BETASERON vial into the syringe (See Figure G).

Figure G

• NOTE: The syringe barrel is marked with numbers from 0.25 mL to 1 mL (See Figure H). If the solution in the vial cannot be drawn up to the 1 mL mark, discard the vial and syringe and start over with a new single-use carton containing a BETASERON vial, pre-filled diluent syringe, vial adapter and alcohol prep pads.

Figure H

• Turn the syringe assembly so that the needle end is pointing up. Remove any air bubbles by tapping the outside of the syringe with your fingers. Slowly push the plunger to the 1 mL mark on the syringe or to the mark that matches the amount of BETASERON prescribed by your healthcare provider (See Figure H). If too much solution is pushed into the vial, repeat Step 3.
• Turn the syringe assembly so that the vial is at the bottom. Remove the vial adapter and the vial from the syringe by twisting the vial adapter. This will remove the vial adapter and the vial from the syringe, but will leave the needle on the syringe (See Figure I).

Figure I

Step 4: Choosing an Injection Site

• BETASERON (interferon beta-1b) is injected under the skin and into the fat layer between the skin and the muscles (subcutaneous tissue). The best areas for injection are where the skin is loose and soft and away from the joints, nerves, and bones. Do not use the area near your navel or waistline. If you are very thin, use only the thigh or outer surface of the arm for injection.
• Choose a different site each time you give yourself an injection. Figure J shows different areas for giving injections. Do not inject in the same area for 2 injections in a row. Keep a record of your injections to help make sure you change (rotate) your injection sites. You should decide where you will inject BETASERON before you prepare your medicine for injection. If there are any sites that are difficult for you to reach, you can ask someone who has been trained to give the injection to help you.

Figure J

• Do not inject BETASERON in a site where the skin is red, bruised, infected, or scabbed, has broken open, or has lumps, bumps, or pain. Tell your healthcare provider if you find skin conditions like the ones mentioned here or any other unusual looking areas where you have been given injections.

Step 5: Injecting BETASERON

• Using a circular motion, clean the injection site with an alcohol prep pad, starting at the injection site and moving outward. Let the skin area air dry.
• Remove the cap from the needle. Hold the syringe like a pencil or dart in 1 hand.
• Gently pinch the skin around the site with the thumb and forefinger of the other hand (See Figure K). Insert the needle straight up and down into your skin at a 90° angle with a quick, dart-like motion.

Figure K

• Slowly push the plunger all the way in until the syringe is empty (See Figure L).

Figure L

• Remove the needle from the skin. Place a dry cotton ball or gauze pad over the injection site. Gently massage the injection site for a few moments with the dry cotton ball or gauze pad. Throw away the syringe in your puncture-proof disposal container.
• Optional Use of BETACONNECT Autoinjector:
  You may also give BETASERON by using the BETACONNECT autoinjector. You should get help with training on the use of the BETACONNECT autoinjector from a healthcare provider before using it for the first time. The BETACONNECT autoinjector should only be used with the syringes that come in the BETASERON packaging. See the Instructions for Use that come with the BETACONNECT autoinjector. For more information, call BETAPLUS, the BETASERON patient support program, at 1-800-788-1467.

Step 6: Disposing of used syringes, needles, and vials

• To prevent needle-stick injury and spread of infection, do not try to re-cap the needle.
• Place used needles, syringes, and vials in a closeable, puncture-resistant container. You may use a sharps container (such as a red biohazard container), hard plastic container (such as a detergent bottle), or metal container (such as an empty coffee can). Do not use glass or clear plastic containers. Ask your healthcare provider for instructions on the right way to throw away (dispose of) the container. There may be state and local laws about how you should throw away used needles and syringes.
• Do not throw used needles, syringes, or vials in your household trash or recycle.
• Throw away any unused medicine. Do not save any unused BETASERON for a future dose.
• Keep the disposal container, needles, syringes, and vials of BETASERON out of the reach of children.

Instructions

Reconstitute with 1.2 mL of 0.54% NaCl diluent (provided); the removable diluent cap contains natural rubber latex

Rotate SC injection site between upper outer arm, thight, and abdomen

See prescribing information for detailed instructions for preparation

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Betaseron falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

In the U.S.

• Betaseron
• Extavia

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Immunological Agent

Pharmacologic Class: Interferon, Beta (class)

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Signs of low mood (depression), thoughts of killing yourself, nervousness, emotional ups and downs, thinking that is not normal, anxiety, or lack of interest in life.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Signs of lupus like a rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs.
• Very bad irritation where the shot was given.
• Swelling.
• Seizures.
• Change in balance.
• Very bad headache.
• Change in color of hands or feet from pale to blue or red.
• Numbness, pain, tingling, or cold feeling of the hands or feet.
• Any sores or wounds on the fingers or toes.

Betaseron is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, Albumin (Human), or any other component of the formulation.

Betaseron (interferon beta-1b) is a purified, sterile, lyophilized protein product produced by recombinant DNA techniques. Interferon beta-1b is manufactured by bacterial fermentation of a strain of Escherichia coli that bears a genetically engineered plasmid containing the gene for human interferon betaser17. The native gene was obtained from human fibroblasts and altered in a way that substitutes serine for the cysteine residue found at position 17. Interferon beta-1b has 165 amino acids and an approximate molecular weight of 18,500 daltons. It does not include the carbohydrate side chains found in the natural material.

The specific activity of Betaseron is approximately 32 million international units (IU)/mg interferon beta-1b. Each vial contains 0.3 mg of interferon beta-1b. The unit measurement is derived by comparing the antiviral activity of the product to the World Health Organization (WHO) reference standard of recombinant human interferon beta. Mannitol, USP and Albumin (Human), USP (15 mg each/vial) are added as stabilizers.

Lyophilized Betaseron is a sterile, white to off-white powder, for subcutaneous injection after reconstitution with the diluent supplied (Sodium Chloride, 0.54% Solution). Albumin (Human) USP and Mannitol, USP (15 mg each/vial) are added as stabilizers.

Mechanism of Action

The mechanism of action of Betaseron (interferon beta-1b) 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 1 (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 bioactivities 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-1b receptor binding induces the expression of proteins that are responsible for the pleiotropic bioactivities of interferon beta-1b. A number of these proteins (including neopterin, β2-microglobulin, MxA protein, and IL-10) have been measured in blood fractions from Betaseron-treated patients and Betaseron-treated healthy volunteers. Immunomodulatory effects of interferon beta-1b include the enhancement of suppressor T cell activity, reduction of pro-inflammatory cytokine production, down-regulation of antigen presentation, and inhibition of lymphocyte trafficking into the central nervous system. It is not known if these effects play an important role in the observed clinical activity of Betaseron in multiple sclerosis (MS).

Pharmacokinetics

Because serum concentrations of interferon beta-1b are low or not detectable following subcutaneous administration of 0.25 mg or less of Betaseron, pharmacokinetic information in patients with MS receiving the recommended dose of Betaseron is not available.

Following single and multiple daily subcutaneous administrations of 0.5 mg Betaseron to healthy volunteers (N=12), serum interferon beta-1b concentrations were generally below 100 IU/mL. Peak serum interferon beta-1b concentrations occurred between one to eight hours, with a mean peak serum interferon concentration of 40 IU/mL. Bioavailability, based on a total dose of 0.5 mg Betaseron given as two subcutaneous injections at different sites, was approximately 50%.

After intravenous administration of Betaseron (0.006 mg to 2 mg), similar pharmacokinetic profiles were obtained from healthy volunteers (N=12) and from patients with diseases other than MS (N=142). In patients receiving single intravenous doses up to 2 mg, increases in serum concentrations were dose proportional. Mean serum clearance values ranged from 9.4 mL/min•kg-1 to 28.9 mL/min•kg-1 and were independent of dose. Mean terminal elimination half-life values ranged from 8 minutes to 4.3 hours and mean steady-state volume of distribution values ranged from 0.25 L/kg to 2.88 L/kg. Three-times-a-week intravenous dosing for two weeks resulted in no accumulation of interferon beta-1b in sera of patients. Pharmacokinetic parameters after single and multiple intravenous doses of Betaseron were comparable.

Following every other day subcutaneous administration of 0.25 mg Betaseron in healthy volunteers, biologic response marker levels (neopterin, β2- microglobulin, MxA protein, and the immunosuppressive cytokine, IL-10) increased significantly above baseline six-twelve hours after the first Betaseron dose. Biologic response marker levels peaked between 40 and 124 hours and remained elevated above baseline throughout the seven-day (168-hour) study. The relationship between serum interferon beta-1b levels or induced biologic response marker levels and the clinical effects of interferon beta-1b in multiple sclerosis is unknown.

Drug Interaction Studies

No formal drug interaction studies have been conducted with Betaseron.

The following serious adverse reactions are discussed in more details in other sections of labeling:

• Hepatic Injury [see WARNINGS AND PRECAUTIONS]
• Anaphylaxis and Other Allergic Reactions [see WARNINGS AND PRECAUTIONS]
• Depression and Suicide [see WARNINGS AND PRECAUTIONS]
• Congestive Heart Failure [see WARNINGS AND PRECAUTIONS]
• Injection Site Necrosis and Reactions [see WARNINGS AND PRECAUTIONS]
• Leukopenia [see WARNINGS AND PRECAUTIONS]
• Thrombotic microangiopathy [see WARNINGS AND PRECAUTIONS]
• Flu-like Symptom Complex [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions and over varying lengths of time, adverse reaction rates observed in the clinical trials of BETASERON cannot be directly compared to rates in clinical trials of other drugs, and may not reflect the rates observed in practice.

Among 1407 patients with MS treated with BETASERON 0.25 mg every other day (including 1261 patients treated for greater than one year), the most commonly reported adverse reactions (at least 5% more frequent on BETASERON than on placebo) were injection site reaction, lymphopenia, flu-like symptoms, myalgia leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, and asthenia. The most frequently reported adverse reactions resulting in clinical intervention (for example, discontinuation of BETASERON, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) were depression, flu-like symptom complex, injection site reactions, leukopenia, increased liver enzymes, asthenia, hypertonia, and myasthenia.

Table 2 enumerates adverse reactions and laboratory abnormalities that occurred among patients treated with 0.25 mg of BETASERON every other day by subcutaneous injection in the pooled placebo-controlled trials (Study 1-4) at an incidence that was at least 2% more than that observed in the placebo-treated patients [see Clinical Studies].

Table 2: Adverse Reactions and Laboratory Abnormalities in Patients with MS in Pooled Studies 1, 2, 3, and 4

In addition to the Adverse Reactions listed in Table 2, the following adverse reactions occurred more frequently on BETASERON than on placebo, but with a difference smaller than 2%: alopecia, anxiety, arthralgia, constipation, diarrhea, dizziness, dyspepsia, dysmenorrhea, leg cramps, menorrhagia, myasthenia, nausea, nervousness, palpitations, peripheral vascular disorder, prostatic disorder, tachycardia, urinary frequency, vasodilatation, and weight increase.

In the four clinical trials (Studies 1, 2, 3, and 4), leukopenia was reported in 18% and 6% of patients in BETASERON and placebo-treated groups, respectively. No patients were withdrawn or dose reduced for neutropenia in Study 1. Three percent (3%) of patients in Studies 2 and 3 experienced leukopenia and were dose-reduced. Other abnormalities included increase of SGPT to greater than five times baseline value (12%), and increase of SGOT to greater than five times baseline value (4%). In Study 1, two patients were dose reduced for increased hepatic enzymes; one continued on treatment and one was ultimately withdrawn. In Studies 2 and 3, 1.5% of BETASERON patients were dose-reduced or interrupted treatment for increased hepatic enzymes. In Study 4, 1.7% of patients were withdrawn from treatment due to increased hepatic enzymes, two of them after a dose reduction. In Studies 1-4, nine (0.6%) patients were withdrawn from treatment with BETASERON for any laboratory abnormality, including four (0.3%) patients following dose reduction.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples were monitored for the development of antibodies to BETASERON during Study 1. In patients receiving 0.25 mg every other day 56/124 (45%) were found to have serum neutralizing activity at one or more of the time points tested. In Study 4, neutralizing activity was measured every 6 months and at end of study. At individual visits after start of therapy, activity was observed in 17% up to 25% of the BETASERON-treated patients. Such neutralizing activity was measured at least once in 75 (30%) out of 251 BETASERON patients who provided samples during treatment phase; of these, 17 (23%) converted to negative status later in the study. Based on all the available evidence, the relationship between antibody formation and clinical safety or efficacy is not known.

These data reflect the percentage of patients whose test results were considered positive for antibodies to BETASERON using a biological neutralization assay that measures the ability of immune sera to inhibit the production of the interferoninducible protein, MxA. Neutralization assays are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of neutralizing activity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to BETASERON with the incidence of antibodies to other products may be misleading.

Anaphylactic reactions have been reported with the use of BETASERON [see WARNINGS AND PRECAUTIONS].

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of BETASERON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: Anemia, Thrombocytopenia

Endocrine disorders: Hypothyroidism, Hyperthyroidism, Thyroid dysfunction

Metabolism and nutrition disorders: Triglyceride increased, Anorexia, Weight decrease, Weight increase

Psychiatric disorders: Anxiety, Confusion, Emotional lability

Nervous system disorders: Convulsion, Dizziness, Psychotic symptoms

Cardiac disorders: Cardiomyopathy, Palpitations, Tachycardia

Vascular disorders: Vasodilatation

Respiratory, thoracic and mediastinal disorders: Bronchospasm

Gastrointestinal disorders: Diarrhea, Nausea, Pancreatitis, Vomiting

Hepatobiliary disorders: Hepatitis, Gamma GT increased

Skin and subcutaneous tissue disorders: Alopecia, Pruritus, Skin discoloration, Urticaria

Musculoskeletal and connective tissue disorders: Arthralgia

Reproductive system and breast disorder: Menorrhagia

General disorders and administration site conditions: Fatal capillary leak syndrome*

*The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of this syndrome.

Read the entire FDA prescribing information for Betaseron (Interferon beta-1b)

Usual Adult Dose of Betaseron for Multiple Sclerosis:

Initial dose: 0.0625 mg subcutaneously every other day, and increased (in 25% increments) every 2 weeks, over a 6 week period, to maintenance dose
Maintenance dose: 0.25 mg subcutaneously every other day

Schedule for dose titration:
Weeks 1 and 2: 0.0625 mg subcutaneously every other day (25% of recommended dose)
Weeks 3 and 4: 0.125 mg subcutaneously every other day (50% of recommended dose)
Weeks 5 and 6: 0.1875 mg subcutaneously every other day (75% of recommended dose)
Week 7 and beyond: 0.25 mg subcutaneously every other day (100% of recommended dose)

Avoid injecting this medicine into skin that is sore, red, or infected.

Drinking alcohol with this medicine can cause serious side effects.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Other drugs may interact with interferon beta-1b, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.