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Interferon Beta

Class: Immunomodulatory Agents
- Cytokines
- Biologic Response Modifiers
VA Class: IM900
Chemical Name: Interferon β1 (human fibroblast protein moiety)
Molecular Formula: C908H1406N246O252S7C908H1406N246O252S5
CAS Number: 145258-61-3
Brands: Avonex, Betaseron, Extavia, Rebif

Introduction

Biologic response modifier; biosynthetic (recombinant DNA origin) form of endogenous human interferon beta. Available as interferon beta-1a and interferon beta-1b. Interferon beta-1a also is available covalently bound to polyethylene glycol (PEG) (i.e., peginterferon beta-1a).

Uses for Interferon Beta

Multiple Sclerosis (MS)

Management of relapsing forms of MS (e.g., relapsing-remitting MS [RRMS]).

Has been shown to reduce frequency of clinical exacerbations and slow accumulation of physical disability in adults with RRMS; also shown to delay time to clinically definite MS in patients who have experienced an isolated demyelinating event and have magnetic resonance imaging (MRI) features consistent with MS.

Interferon beta is one of several disease-modifying therapies used in the management of RRMS. Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing MRI lesions, and disability progression.

The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with RRMS who have had recent relapses and/or MRI activity. Clinicians should consider adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate therapy.

Has been used with equivocal results in the management of secondary progressive MS.

Also has been used for primary progressive MS; although beneficial effects on MRI measures of disease activity observed, no effect on disease progression.

Interferon Beta Dosage and Administration

General

  • Intended for use under the guidance and supervision of a clinician; however, may be self-administered if clinician determines that the patient or caregiver is competent to prepare and safely administer the drug.

  • If home use is prescribed, carefully instruct patients and/or their caregivers on appropriate use; provide a puncture-resistant container for proper, safe disposal of used syringes and needles. Perform initial injection under the supervision of a qualified clinician.

  • Patients may feel worse or experience a temporary worsening of MS symptoms immediately following initiation of interferon beta therapy; these effects often abate with continued therapy and should not be interpreted as an indication of treatment failure.

  • To minimize flu-like symptoms, may premedicate patient with analgesics and/or antipyretics on treatment days; administration of interferon beta in the evening also may improve tolerability.

Administration

Administer by IM or sub-Q injection.

Interferon beta-1a is commercially available as a once-weekly IM injection (Avonex) or a 3-times-weekly sub-Q injection (Rebif). Interferon beta-1b is commercially available as a sub-Q alternate-day injection (Betaseron, Extavia); the 2 currently available interferon beta-1b preparations are identical except for some packaging components (e.g., needle size).

Sub-Q administration associated with higher rates of injection site reactions than IM administration.

IM Administration of Interferon Beta-1a (Avonex)

Administer once weekly by IM injection into thigh or upper arm. Rotate injection sites and avoid injecting into sites that appear irritated, reddened, bruised, infected, or scarred. Inspect injection site for any redness, swelling, or tenderness 2 hours after administration.

Commercially available as a single-dose vial containing lyophilized powder, prefilled syringe, or prefilled auto-injector (i.e., Avonex Pen).

The lyophilized powder and prefilled syringes are packaged with a 23-gauge, 1¼-inch needle supplied by the manufacturer; a 25-gauge, 1-inch needle for IM injection may be substituted by the clinician if appropriate. The prefilled auto-injector must be used with the supplied 25-gauge, 5/8-inch needle; do not substitute with any other needle.

Remove prefilled syringes and auto-injectors from refrigerator about 30 minutes prior to use to allow solution to reach room temperature; do not use external heat sources (e.g., hot water) to warm solution. Prefilled syringes and auto-injectors are for single use only; do not re-use.

The needle cap of the prefilled syringe contains natural rubber latex, which may cause allergic reactions in individuals who are sensitive to latex. (See Latex Sensitivity under Cautions.)

Reconstitution of Avonex Lyophilized Powder

Reconstitute vial containing 33 mcg of interferon beta-1a (Avonex) lyophilized powder by adding 1.1 mL of sterile water for injection (supplied by manufacturer) to provide a solution containing 30 mcg of interferon beta-1a per mL.

Gently swirl vial to ensure complete dissolution; do not shake.

Reconstituted solutions contain no preservatives; solutions preferably should be prepared immediately before use. (See Storage under Stability.) Vials are for single use only; discard any residual solution.

Sub-Q Administration of Interferon Beta-1a (Rebif)

Administer 3 times weekly by sub-Q injection into the abdomen (avoiding waistline or areas within 2 inches of navel), thigh, upper arm, or buttock. Administer on the same 3 days (e.g., Monday, Wednesday, and Friday) at least 48 hours apart each week and at the same time (preferably in the late afternoon or evening) each day.

Rotate injection sites and avoid injecting into sites that appear irritated, reddened, bruised, infected, or abnormal in any way.

Removing the drug from refrigerator 30 minutes prior to use may reduce incidence of injection site pain.

Commercially available as a prefilled syringe or prefilled auto-injector (i.e., Rebidose). Prefilled syringes and auto-injectors are for single use only; do not re-use.

Sub-Q Administration of Interferon Beta-1b (Betaseron, Extavia)

Administer by sub-Q injection every other day into the abdomen (except areas near the waistline and navel), thigh, upper arm, or buttocks.

Rotate injection sites and avoid injecting into sites that appear reddened, bruised, infected, or abnormal in any way.

Available as a lyophilized powder that must be reconstituted prior to use. An optional auto-injector (Betaconnect) is commercially available and may be obtained through the manufacturer's patient support program by calling 1-800-788-1467.

Reconstitution of Betaseron and Extavia Lyophilized Powder

Reconstitute vial containing 0.3 mg of interferon-beta-1b (Betaseron, Extavia) lyophilized powder by attaching the manufacturer-supplied prefilled syringe containing 1.2 mL of 0.54% sodium chloride to the vial; slowly inject entire contents of syringe to provide a solution containing 0.25 mg of interferon beta-1b per mL. The needle cap of the prefilled diluent syringe supplied with Extavia contains dry natural rubber (latex) and should not be handled by individuals sensitive to latex. (See Latex Sensitivity under Cautions.)

Gently swirl vial to ensure complete dissolution; do not shake.

Reconstituted solutions contain no preservatives; solutions preferably should be prepared immediately before use. (See Storage under Stability.) Vials are for single use only; discard any residual solution.

Dosage

Available as interferon beta-1a or interferon beta-1b; dosage expressed in terms of mg.

Potency of interferon beta also has been expressed in terms of international units. Each mg of interferon beta-1a is equivalent to approximately 200 million units (for Avonex) and 270 million units (for Rebif); each mg of interferon beta-1b is equivalent to approximately 32 million units (for Betaseron and Extavia).

Adults

Relapsing Forms of MS
Interferon beta-1a (Avonex)
IM

30 mcg once weekly. To reduce incidence and severity of flu-like symptoms, initiate at a low dosage of 7.5 mcg once weekly, and then increase by 7.5 mcg each week for the next 3 weeks up to recommended dosage.

If a dose is missed, administer as soon as possible and resume regular weekly schedule. Do not administer on 2 consecutive days.

Safety and efficacy of Avonex therapy beyond 3 years not established.

Interferon beta-1a (Rebif)
Sub-Q

Gradually titrate dosage over a 4-week period to 22 or 44 mcg 3 times weekly using the schedule in Table 1. When titrating to the 22-mcg dose, use only the prefilled syringes (not auto-injectors).

Table 1. Rebif Dosage Titration Schedule20

Week

Percentage of Target Dose

Rebif 22 mcg Target Dose

Rebif 44 mcg Target Dose

Weeks 1–2

20%

4.4 mcg (use ½ of 8.8-mcg syringe)

8.8 mcg (use full 8.8-mcg syringe or auto-injector)

Weeks 3–4

50%

11 mcg (use ½ of 22-mcg syringe)

22 mcg (use full 22-mcg syringe or auto-injector)

Weeks 5+

100%

22 mcg (use full 22-mcg syringe or auto-injector)

44 mcg (use full 44-mcg syringe or auto-injector)

Safety and efficacy of Rebif therapy beyond 2 years not established.

Interferon beta-1b (Betaseron, Extavia)
Sub-Q

Gradually titrate dosage over a 6-week period to 0.25 mg every other day using the schedule in Table 2.

Table 2. Betaseron and Extavia Dosage Titration Schedule161

Week

Percentage of Target Dose

Betaseron and Extavia Dose

Weeks 1–2

25%

0.0625 mg

Weeks 3–4

50%

0.125 mg

Weeks 5–6

75%

0.1875 mg

Weeks 7+

100%

0.25 mg

If a dose is missed, administer as soon as possible; administer next scheduled dose approximately 48 hours later. Do not administer on 2 consecutive days.

Safety and efficacy of interferon beta-1b therapy beyond 3 years not established.

Special Populations

Hepatic Impairment

Manufacturer of Rebif states to consider dosage reduction if serum ALT concentrations increase to >5 times ULN. May gradually re-escalate dosage when serum ALT concentrations have returned to normal.

Geriatric Patients

No specific dosage adjustments required; however, select dosage with caution, usually initiating therapy at the low end of the dosage range due to possible age-related decreases in hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.

Cautions for Interferon Beta

Contraindications

  • Known hypersensitivity to natural or recombinant interferon beta or any other component of the formulations.

  • Administration of preparations containing albumin human in patients with known hypersensitivity to albumin. (See Albumin Sensitivity under Cautions.)

Warnings/Precautions

Depression and Suicide

Possible depression, suicidal ideation, and suicide.

Some manufacturers state to use with caution in patients with depression or other mood disorders. Monitor patients closely for evidence of depression or other psychiatric symptoms; consider discontinuance of therapy if any such symptoms occur.

Because of a high prevalence of mood disorders in patients with MS, a history of depression is not an absolute contraindication to use of interferon beta. It may be difficult to separate neuropsychiatric symptoms related to interferon beta therapy from those related to MS.

Hepatotoxicity

Serious hepatic injury including autoimmune hepatitis and possibly severe, fulminant hepatic failure requiring liver transplantation reported.

Asymptomatic elevations in serum aminotransferase concentrations (particularly ALT) reported commonly with interferon beta therapy.

Use with caution in patients with active liver disease, alcohol abuse, increased serum ALT concentrations (>2.5 times ULN), or history of clinically important liver disease.

Consider potential risks in patients receiving concomitant therapy with other drugs associated with hepatic injury, including alcohol; use caution when other drugs are added to an existing interferon beta treatment regimen.

Monitor for manifestations of hepatic injury. Perform liver function tests at regular intervals (e.g., 1, 3, and 6 months) following initiation of therapy and then periodically thereafter in the absence of clinical symptoms.

Some manufacturers recommend discontinuance of therapy if substantial elevations in serum aminotransferase concentrations or clinical manifestations of liver dysfunction (e.g., jaundice) occur.

Sensitivity Reactions

Hypersensitivity Reactions

Possible anaphylaxis or anaphylactoid reactions.

If acute, serious hypersensitivity reactions occur, discontinue immediately and initiate appropriate therapy.

Latex Sensitivity

Some packaging components of certain formulations (e.g., Avonex prefilled syringe cap, Extavia prefilled diluent syringe cap) contain natural rubber latex; individuals sensitive to latex should not handle these packaging components. Safety of Extavia reconstituted using the prefilled diluent syringe in latex-sensitive individuals not evaluated.

Albumin Sensitivity

Some formulations (e.g., Avonex powder for injection, Betaseron, Extavia, Rebif) contain albumin human; contraindicated in sensitive patients.

Immunogenicity

Potential for immunogenicity. Possible development of binding or neutralizing antibodies to interferon beta following long-term therapy.

The presence of neutralizing antibodies, particularly in persistently high titers, associated with reductions in radiographic and clinical efficacy of interferon beta therapy. Neutralizing antibodies generally develop 6–24 months after initiation of therapy, after which the risk is low.

Risk of antibody development may vary based on preparation, dosing frequency, total dose, and route of administration.

Cardiovascular Effects

Cardiomyopathy with or without CHF reported in patients without known predisposition or other known etiologies; temporal relationship to administration of interferon beta observed. In some cases, recurred upon rechallenge

Monitor patients with preexisting CHF for clinical worsening during therapy. Some manufacturers state to consider discontinuance of therapy if worsening CHF occurs without any other etiology.

Injection Site Necrosis

Severe injection site necrosis reported following sub-Q administration, sometimes requiring dermal debridement or skin grafting. Has not been reported to date following IM administration.

Periodically re-evaluate patient’s understanding and use of aseptic technique and proper procedures for self-administration. Whether to discontinue therapy following a single site of necrosis depends on the extent of necrosis; if therapy is continued, avoid further injections into affected area until fully healed. If multiple sites of necrosis occur, discontinue therapy until healing occurs. (See Advice to Patients.)

Hematologic Effects

Decreased peripheral blood cell counts in all cell lines, including rare pancytopenia, leukopenia, thrombocytopenia, reported.

Monitor patients for signs and symptoms of decreased blood counts. Perform CBCs, platelet counts, and appropriate blood chemistry tests prior to initiation of therapy and periodically thereafter. Patients with myelosuppression may require more intensive monitoring.

Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA), including sometimes fatal thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, reported. Occurred several weeks to years after starting interferon beta therapy.

If clinical manifestations and/or laboratory findings consistent with TMA occur, discontinue therapy and manage patient as clinically indicated.

Flu-like Syndrome

Flu-like syndrome occurs commonly. Although there is considerable interindividual variation, symptoms occur most frequently during initiation of therapy (e.g., within hours or days after injection) and usually subside within a few months.

Consider premedication with analgesic and/or antipyretic agents. (See General under Dosage and Administration.)

Seizures

Possible seizures, including in patients with no history of seizure; not known whether related to preexisting seizure disorder, effects of MS alone, use of interferon beta, or other potential risk factors (e.g., fever). Use with caution in patients with preexisting seizure disorders.

If patients with no seizure history develop seizures during therapy, establish an etiologic basis and institute appropriate anticonvulsant therapy prior to considering resumption of therapy.

Autoimmune Disorders

Autoimmune disorders, including idiopathic thrombocytopenia, hyperthyroidism, hypothyroidism, and autoimmune hepatitis, reported; consider discontinuance of therapy if a new autoimmune disorder develops.

Drug-induced lupus erythematosus reported. Discontinue therapy if manifestations (e.g., rash, serositis, polyarthritis, nephritis, Raynaud phenomenon) develop.

Specific Populations

Pregnancy

Category C.

No adequate and well-controlled studies in pregnant women; spontaneous abortions reported rarely in pregnant women who received interferon beta in clinical studies. Use during pregnancy only if potential benefits justify potential risks.

In animal studies, teratogenicity not demonstrated; however, increased embryolethality and abortion observed.

Lactation

Not known whether interferon beta is distributed into milk; discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Consider dosage reduction in patients with increased serum ALT concentrations. (See Hepatic Impairment under Dosage and Administration.)

Common Adverse Effects

Flu-like symptoms, local effects at the injection site.

Interactions for Interferon Beta

No formal drug interaction studies to date.

Because of the potential for hepatic injury, use caution when administering concomitantly with hepatotoxic agents. (See Hepatotoxicity under Cautions.)

Has been used concomitantly with corticosteroids, corticotropin (ACTH), antidepressants, and/or oral contraceptives in clinical studies without unusual adverse effects.

Interferon Beta Pharmacokinetics

Absorption

Bioavailability

Bioavailability of interferon beta-1b (Betaseron, Extavia) following sub-Q administration is approximately 50%.

Elimination

Half-life

Elimination half-life of interferon beta-1a (Avonex) following a single IM dose is 19 hours.

Plasma half-life of interferon beta-1a (Rebif) following a single sub-Q dose is approximately 69 hours.

Elimination half-life of interferon beta-1b ranges from 8 minutes to 4.3 hours in healthy individuals.

Stability

Storage

Parenteral

Injection

Interferon beta-1a (Avonex) prefilled syringes or auto-injectors: 2–8°C (may be stored at ≤25°C for up to 7 days). Protect from heat and light; do not freeze. Discard if exposed to >25°C or to conditions other than those recommended.

Interferon beta-1a (Rebif) prefilled syringes or auto-injectors: 2–8°C (may be stored at ≤25°C for up to 30 days). Protect from heat and light; do not freeze.

Powder for Injection

Interferon beta-1a (Avonex) lyophilized powder: 2–8°C (may be stored at 25°C for up to 30 days). Following reconstitution, store for up to 6 hours at 2–8°C. Protect from heat and light; do not freeze.

Interferon beta-1b (Betaseron, Extavia) lyophilized powder: 20–25°C (may be exposed to 15–30°C for up to 3 months). Following reconstitution, store at 2–8°C and use within 3 hours. Do not freeze.

Actions

  • Has complex antiviral, antineoplastic, and immunomodulating activities.

  • Mechanisms of action in the treatment of MS have not been fully elucidated, but may involve immunomodulating effects, including anti-inflammatory effects.

  • Potency of interferon beta has been expressed in international units (IU, units) of antiviral activity using reference standards established by WHO. Avonex has a specific activity of approximately 200 million units of antiviral activity per mg. Rebif has a specific activity of approximately 270 million units of antiviral activity per mg. Betaseron and Extavia have a specific action of approximately 32 million units of antiviral activity per mg.

Advice to Patients

  • Importance of patients reading the manufacturer's patient information (medication guide) and instructions for use before initiating treatment and each time the prescription is refilled.

  • Importance of taking interferon beta exactly as prescribed. Advise patients not to change interferon beta preparations during a single regimen of therapy without consulting their clinician.

  • Importance of instructing patients and/or caregivers regarding proper methods of preparation and administration, including the use of aseptic technique. Importance of rotating injection sites. Importance of providing instructions on the appropriate use, storage, and disposal of syringes and needles.

  • Risk of developing depression, suicidal ideation, or psychotic disorders. Importance of patients notifying their clinician immediately if symptoms of depression or other psychiatric effects occur.

  • Potential for temporary worsening of symptoms immediately following initiation of therapy; advise patients that these symptoms often abate with continued therapy and should not be interpreted as an indication of treatment failure.

  • Risk of hepatotoxicity; importance of advising patients to immediately inform their clinician if they experience any symptoms of liver injury (e.g., jaundice, nausea, loss of appetite, fatigue, unusual bleeding, confusion, somnolence, dark-colored urine, pale stools).

  • Risk of hypersensitivity reactions, including anaphylaxis. Importance of advising patients to seek immediate medical attention if any symptoms of hypersensitivity occur.

  • Importance of informing patients that flu-like symptoms (e.g., fever, muscle aches, chills, fatigue) are common following initiation of interferon beta therapy, and that pretreatment with analgesics and/or antipyretics may minimize these symptoms.

  • Risk of seizures. Importance of patients immediately informing their clinician if a seizure occurs during therapy.

  • Risk of injection site reactions, including necrosis, particularly with sub-Q administration. Importance of patients immediately informing their clinician if any blue-black discoloration, swelling, or fluid drainage occurs in conjunction with skin breakage at the injection site.

  • Risk of decreased peripheral blood counts, which may increase the risk of infections, anemia, or bleeding.

  • Importance of informing patients that worsening CHF has been reported with interferon beta therapy. Importance of informing patients of the symptoms of worsening heart failure and to immediately report any such symptoms to their clinician.

  • Some packaging components may contain natural rubber latex; importance of advising patients to inform their clinician if they have an allergy to latex. (See Latex Sensitivity under Cautions.)

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Interferon Beta-1a

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IM use

30 mcg

Avonex (with sterile water for injection diluent, syringe, 23-gauge needle, and vial adapter)

Biogen

Injection, for IM use

30 mcg per 0.5 mL

Avonex (available as prefilled syringes and prefilled auto-injectors [Avonex Pen])

Biogen

Injection, for subcutaneous use

8.8 mcg per 0.2 mL

Rebif (available as prefilled syringes and prefilled auto-injectors [Rebidose])

EMD Serono

22 mcg per 0.5 mL

Rebif (available as prefilled syringes and prefilled auto-injectors [Rebidose])

EMD Serono

44 mcg per 0.5 mL

Rebif (available as prefilled syringes and prefilled auto-injectors [Rebidose])

EMD Serono

Interferon Beta-1b

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for subcutaneous use

0.3 mg

Betaseron (with prefilled syringe containing 0.54% sodium chloride diluent, 30-gauge needle, vial adapter, and alcohol swabs)

Bayer

Extavia (with prefilled syringe containing 0.54% sodium chloride diluent, 27-gauge needle, vial adapter, and alcohol swabs)

Novartis

AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 25, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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