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Interferon, Beta-1a (Systemic)


VA CLASSIFICATION
Primary: CN900; IM409

Commonly used brand name(s): Avonex; Rebif.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Multiple sclerosis (MS) therapy agent {01}

Biological response modifier{04}

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Multiple sclerosis, relapsing-remitting (treatment)—Interferon beta-1a is indicated for treatment of relapsing forms of multiple sclerosis (MS) to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations {01}. The safety and efficacy in patients with chronic progressive MS have not been evaluated {01}.

[Condyloma acuminatum (treatment)]—Interferon beta-1a is indicated for treatment of condyloma acuminatum to promote shrinkage of lesions{04}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Synthetic. Interferon beta-1a is a 166 amino acid glycoprotein produced by recombinant DNA techniques {01}. It is produced by mammalian cells (Chinese hamster ovary cells) into which the human interferon beta gene has been introduced {01}. The amino acid sequence is identical to that of human interferon beta {01}.

Chemical group—
    Interferons are a family of naturally occurring proteins and glycoproteins produced by eukaryotic cells in response to viral infection and other biological inducers {01}. Interferon beta, one member of this family, is produced by various cell types including fibroblasts and macrophages {01}. Natural interferon beta and interferon beta-1a are glycosylated, with each containing a single N-linked complex carbohydrate moiety {01}. Glycosylation of other proteins is known to affect their stability, activity, biodistribution, and half-life in blood {01}. However, the effects of glycosylation of interferon beta on these properties have not been fully defined {01}.
Molecular weight—
    Approximately 22,500 daltons {01}{02}{03}{04}


pH
    7.3 (reconstituted injection) {01}.


Specific activity
    Avonex:200 million international units (IU) of antiviral activity per mg. The unit measurement is derived using the World Health Organization (WHO) natural interferon beta standard, Second International Standard for Interferon, Human Fibroblast (Gb-23-902-531) {01}{02}{03}
    Rebif:270 million IU of antiviral activity per mg. The unit measurement is derived using an in-house natural hIFN-β National Institutes of Health (NIH) standard that is obtained from human fibroblasts (BILS 11), which has been calibrated against the NIH natural hIFN-β standard (GB 23–902–531){04}.

Mechanism of action/Effect:

Interferons are cytokines that mediate antiviral, antiproliferative, and immunomodulatory activities in response to viral infection and other biological inducers {01}. Three major classes have been identified: alpha, beta, and gamma {01}. Interferons alpha and beta form the Type 1 class of interferons, and interferon gamma is a Type 2 interferon; these interferons have overlapping yet distinct biologic activities {01}.

Interferon beta-1a exerts its biological effects by binding to specific receptors on the surface of human cells {01}. This binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers including 2',5'-oligoadenylate synthetase, beta 2-microglobulin, and neopterin {01}. The specific interferon-induced proteins and mechanisms by which interferon beta-1a exerts its effects in MS have not been fully defined {01}.

Biological response markers (e.g., neopterin and beta 2-microglobulin) are induced by interferon beta-1a following parenteral doses of 15 to 75 mcg in both healthy subjects and treated patients {01}. Concentrations of these markers increase within 12 hours of dosing, and remain elevated for at least 4 days {01}. Peak biological response marker concentrations typically are observed 48 hours after dosing {01}. The relationship of serum interferon beta-1a concentrations or of the concentrations of these induced biological response markers to the mechanisms by which interferon beta-1a exerts its effects in MS is unknown {01}.

Pharmacokinetics

Pharmacokinetic information on patients with multiple sclerosis (MS) has not been evaluated {01}. Serum concentrations of interferon beta-1a, as measured by its antiviral activity, are only slightly above detectable limits following a 30 mcg intramuscular dose, but increase with higher doses {01}. Pharmacokinetic and pharmacodynamic profiles in healthy subjects following doses of 30 to 75 mcg have been determined {01}.

Half-life:


Elimination:

10 hours, following a 60-mcg dose administered intramuscularly {01}.

8.6 hours, following a 60-mcg dose administered subcutaneously {01}.


Time to peak concentration:

9.8 (range, 3 to 15) hours following a 60-mcg dose administered intramuscularly {01}.

7.8 hours (range, 3 to 18 hours) following a 60-mcg dose administered subcutaneously {01}.

Note: Serum concentrations of interferon beta-1a may be sustained after its intramuscular administration due to prolonged absorption from the injection site {01}.


Peak serum concentration:

45 international units (IU) per mL following a 60-mcg dose administered intramuscularly {01}.

30 IU per mL following a 60-mcg dose administered subcutaneously {01}.

Systemic exposure, as determined by peak serum concentrations and area under the serum concentration–time curve (AUC) values, is greater following intramuscular than following subcutaneous administration {01}.


Precautions to Consider

Carcinogenicity

No carcinogenicity data are available for interferon beta-1a in animals or humans {01}.

Mutagenicity

Interferon beta-1a was not mutagenic in the Ames bacterial test or in an in vitro cytogenetic assay in human lymphocytes in the presence and absence of metabolic activation {01}; these assays are designed to detect agents that interact directly with and cause damage to cellular DNA {01}. Interferon beta-1a is a glycosylated protein that does not directly bind to DNA {01}.

Pregnancy/Reproduction
Fertility—
No studies have been conducted in healthy women or women with MS {01}. It is not known if interferon beta-1a can affect human reproductive capacity {01}.

Menstrual irregularities were observed in monkeys receiving interferon beta at a dose 100 times the recommended weekly human dose, based upon a body surface area comparison {01}; anovulation and decreased serum progesterone concentrations also occurred transiently in some animals {01}. These effects were reversible upon discontinuation of interferon beta treatment {01}. Monkeys receiving interferon beta at a dose two times the recommended weekly human dose exhibited no changes in cycle duration or ovulation {01}. In the placebo-controlled premarketing clinical trial, 6% of patients receiving placebo and 5% of patients receiving interferon beta-1a reported menstrual disorders {01}. It is not known if, or for how long, menstrual irregularities will persist in women following treatment {01}.

Pregnancy—
Adequate and well-controlled studies have not been done in humans {01}.

Studies in pregnant monkeys receiving 100 times the recommended weekly human dose, based on a body surface comparison, revealed no teratogenic or other adverse effects on fetal development {01}; however, abortifacient activity was evident following administration of three to five doses {01}. No abortifacient activity was seen in monkeys receiving two times the recommended weekly human dose, based on a body surface comparison {01}. Although no teratogenic effects were demonstrated in these studies, it is not known if such effects would occur in humans {01}. If a woman becomes pregnant or plans to become pregnant, it is recommended that interferon beta-1a therapy be discontinued due to potential risks to the fetus {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether interferon beta-1a is distributed into human breast milk {01}. However, because of the potential for serious adverse reactions in nursing infants, discontinuation of interferon beta-1a or discontinuation of breast-feeding is recommended {01}.

Pediatrics

Appropriate studies on the relationship of age to the effects of interferon beta-1a have not been performed in children up to 18 years of age. Safety and efficacy have not been established {01}.


Geriatrics


No information is available on the relationship of age to the effects of interferon beta-1a in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Studies designed to evaluate drug interactions with interferon beta-1a have not been conducted {01}. However, treatment of exacerbations with corticosteroids or ACTH, and concomitant administration of antidepressants and/or oral contraceptives to some patients during the placebo-controlled premarketing clinical trial did not result in unexpected adverse effects {01}.
Other interferons have been shown to reduce cytochrome P450 oxidase-mediated drug metabolism {01}. Formal studies in humans have not been conducted, but hepatic microsomes isolated from interferon beta-1a–treated monkeys showed no influence on hepatic cytochrome P450 enzyme-mediated metabolic activity {01}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Myelosuppressive agents {01}    (as with all interferon products, the potential for additive myelosuppressant effects exists)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Aspartate aminotransferase (AST [SGOT]) values {01}    (during the placebo-controlled premarketing clinical trial, 3% of patients receiving interferon beta-1a had values greater than or equal to three times the upper limits of normal, as compared with 1% of the patients receiving placebo)


Eosinophil counts {01}    (during the placebo-controlled premarketing clinical trial, 5% of patients receiving interferon beta-1a had counts£ 10%, as compared with 4% of patients receiving placebo)


Hematocrit {01}    (during the placebo-controlled premarketing clinical trial, 3% of patients receiving interferon beta-1a had hematocrits £ 37% (males) and £ 32% (females), as compared with 1% of patients receiving placebo)


Serum neutralizing activity    (during the placebo-controlled premarketing clinical trial, 24% of patients treated with interferon beta-1a were found to have serum neutralizing activity at one or more time points tested; 15% of these patients tested positive for serum neutralizing activity at a level at which no placebo patient tested positive{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Cardiac disease {01} , such as:
Angina {01}
Arrhythmias {01}
Congestive heart failure {01}    (symptoms of influenza-like syndrome resulting from interferon beta-1a therapy may be stressful to patients with severe cardiac conditions {01})


» Depression, mental, especially with suicidal ideation {01}    (condition may be exacerbated; patients should be monitored carefully; causal relationship to medication is not proven)


» Seizure disorder {01}    (condition may be exacerbated, although causal relationship to medication is not proven)


Sensitivity to natural or recombinant interferon beta or human albumin {01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood chemistry values, including liver function tests {01}    (recommended at periodic intervals during treatment)


Depression, especially suicidal ideation{02}
Platelet counts {01} and
White blood cell counts, complete and differential {01}    (recommended at periodic intervals during treatment)


Note: Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.{02}




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Anemia {01} (unusual bleeding or bruising; unusual tiredness or weakness)
    
asthenia {01} (unusual tiredness or weakness)
    
diarrhea {01}
    
infection {01} (fever; chills)
    
influenza-like syndrome {01} including arthralgia {01} (joint pain), chills {01}
fever {01}
headache {01}
and myalgia {01} (muscle aches)
    
nausea {01}
    
pain {01}


Incidence less frequent
    
Abdominal pain {01}
    
ataxia {01} (clumsiness or unsteadiness)
    
chest pain {01}
    
decreased hearing {01}
    
dizziness {01}
    
dyspnea {01} (troubled breathing )
    
hypersensitivity reaction {01} (coughing; difficulty in swallowing ; hives or itching; swelling of face, lips, or eyelids; wheezing or difficulty in breathing)
    
injection-site reactions {01} (redness; swelling; tenderness)
    
mental depression, especially with suicidal ideation {01} ( mood changes, especially with thoughts of suicide)
    
muscle spasms {01}
    
nevi {01} (skin lesions)
    
ovarian cyst {01} ( pelvic discomfort, aching, or heaviness)
    
seizures {01}
    
speech problems {01}
    
syncope {01} ( fainting)
    
upper respiratory infection {01} (runny or stuffy nose; sneezing ; sore throat)
    
urticaria {01} (hives or itching)
    
vaginitis {01} (pain or discharge from the vagina)
    
vasodilation {01} (flushing)

Note: Most injection site reactions are mild to moderate{02}. Rare cases of skin ulceration and/or necrosis at the injection site have been reported with long term treatment{02}.


Incidence rare
    
Anorexia {01} (loss of appetite)
    
herpes simplex {01} ( painful cold sores or blisters on lips, nose, eyes, or genitals)
    
herpes zoster {01} (painful blisters on trunk of body)—also known as “shingles”
    
malaise {01} (general feeling of discomfort or illness)
    
otitis media (earache)
    
sinusitis {01} (headache; stuffy nose)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Dyspepsia (heartburn; acid indigestion ; sour stomach)
{01}
Incidence less frequent
    
Alopecia (hair loss)
{01}    
insomnia (trouble in sleeping)
{01}




Overdose
For information on the management of interferon beta-1a overdose, contact a Poison Control Center (see Poison Control Center Listing ).


Patient Consultation
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to natural or recombinant interferon beta or Albumin Human USP

Pregnancy—Potential abortifacient effects





Breast-feeding—Not recommended due to potential serious adverse effects in the nursing infant
Other medications, especially myelosuppressive agents and agents that are largely dependent on the hepatic cytochrome P450 system for clearance, such as anticonvulsants and some classes of antidepressants
Other medical problems, especially mental depression with suicidal ideation, and seizure disorder

Proper use of this medication
» Proper administration:

• Importance of aseptic technique {01}


• Importance of training patient or caregiver in administration of intramuscular injections {01}


• Importance of proper disposal of syringes and needles {01}


» Proper dosing
Missed dose: Using as soon as remembered; the next injection should be scheduled at least 48 hours later {01}

» Proper storage


Side/adverse effects
Signs of potential side effects, especially anemia; asthenia; diarrhea; infection; influenza-like syndrome, including arthralgia, chills, fever, headache, and myalgia; nausea; pain; abdominal pain; ataxia; chest pain; decreased hearing; dizziness; dyspnea; hypersensitivity reaction; injection site reactions; mental depression, especially with suicidal ideation; muscle spasms; nevi; ovarian cyst; seizures; speech problems; syncope; upper respiratory infection; urticaria; vaginitis; vasodilation; anorexia; herpes simplex; herpes zoster; malaise; otitis media; and sinusitis


General Dosing Information
For treatment of condyloma acuminatum, interferon beta-1a is best suited for patients with fewer than 9 lesions and who have failed other treatment{04}. In the case of patients with 9 or more lesions, if the first treatment is successful, the remaining lesions could be treated with a second course of therapy{04}. Interferon beta-1a should also be considered for patients for whom the side effects of other treatments (e.g., scarring) are of concern{04}.

If it is determined that interferon beta-1a can be used outside of the physician's office, the person who will be administering the injections should be instructed in proper aseptic technique for reconstitution and injection, and in proper disposal of syringes and needles {01}. If the patient is to self-administer interferon beta-1a, the physical ability of that patient to self-inject intramuscularly should be assessed {01}. The first injection should be performed under the supervision of a qualified health care professional {01}{04}.

For condyloma, all injections should be administered by a qualified health care professional{04}.

For treatment of adverse effects
Recommended treatment consists of the following:    • Systemic acetaminophen may lessen the impact of influenza-like symptoms {01}.
   • An anesthetic cream such as lidocaine-prilocaine may lessen the pain of intralesional injections for condyloma acuminata{04}



Parenteral Dosage Forms

INTERFERON BETA-1a FOR INJECTION

Usual adult dose
Multiple sclerosis, relapsing-remitting
Avonex: Intramuscular, 30 mcg once a week {01}{02}{03}.

Rebif: Subcutaneous, 22 mcg 3 times per week. Patients with an EDSS of 4 or higher may require a dose of 44 mcg 3 times per week.{04}

Condyloma acuminatum
Rebif:Intra- or peri-lesional, 3.67 mcg (1 million IU) per lesion 3 times per week for 3 weeks{04}


Usual pediatric dose
Safety and efficacy in children up to 18 years of age have not been established {01}.

Strength(s) usually available
U.S.—


33 mcg (6.6 million International Units [IU])per single-use vial (Rx) [Avonex (diluent: Sterile Water for Injection USP ) (Albumin Human USP 16.5 mg) ( Sodium Chloride USP 6.4 mg) (Dibasic Sodium Phosphate USP 6.3 mg) (Monobasic Sodium Phosphate USP 1.3 mg)]{01}{02}

Canada—


33 mcg (6.6 million International Units [IU]) per single-use vial (Rx) [Avonex (diluent: Sterile Water for Injection USP) ( albumin human USP) (dibasic sodium phosphate USP ) (monobasic sodium phosphate USP ) (sodium chloride USP)]{03}


11 mcg (3 million IU) (Rx) [Rebif (diluent: sodium chloride 0.9% in water) (albumin human) ( mannitol) (sodium acetate) ( sodium hydroxide)]{04}


44 mcg (12 million IU) (Rx) [Rebif (diluent: sodium chloride 0.9% in water) (albumin human) ( mannitol) (sodium acetate) ( sodium hydroxide)]{04}

Packaging and storage:
Store between 2 and 8 ºC (36 and 46 ºF) {01}. Protect from freezing {01}.

If refrigeration is not available, the vials may be stored at 25 ºC (77 ºF) for up to 30 days {01}.

Preparation of dosage form:


Relapsing-remitting multiple sclerosis:
Avonex,for intramuscular administration: The vials of drug and diluent should be allowed to come to room temperature before reconstitution {01}. Using aseptic technique, 1.1 mL of the supplied diluent is transferred into the lyophilized interferon beta-1a vial {01}. The vial should be swirled gently until the solid material is completely dissolved {01}. If particulate matter remains or the reconstituted product is discolored, the vial should be discarded before use {01}. Following reconstitution with the accompanying diluent, the resulting solution will contain 30 mcg of interferon beta-1a per mL {01}. After reconstitution, l mL of solution should be withdrawn into a sterile syringe to be injected intramuscularly {01}{02}{03}.

Rebif,for subcutaneous administration: To the 11–mcg vial, add 0.5 mL of diluent (sodium chloride 0.9% in water), for a final concentration of 22 mcg (6 million IU) per mL. To the 44–mcg vial, add 0.5 mL of diluent for a final concentration of 88 mcg (24 million IU) per mL{04}



Condyloma acuminatum:
Rebif,for intra- and peri-lesional administration: To the 11–mcg vial, add 0.3 mL of diluent (sodium chloride 0.9% in water) for a final concentration of 37 mcg (10 million IU) per mL. To the 44–mcg vial, add 1.2 mL of diluent for a final concentration of 37 mcg (10 million IU) per mL{04}.


Stability:
Interferon beta-1a contains no preservatives; after reconstitution, if not used immediately, it should be refrigerated and used within 6 hours {01}.

Auxiliary labeling:
   • Refrigerate.
   • Do not freeze.



Developed: 12/19/1997
Revised: 05/02/2000



References
  1. Avonex package insert (Biogen—US), Rev 5/96, Rec 6/13/97.
  1. Product Information: Avonex®, interferon beta-1a. Biogen, Cambridge, MA (PI revised 5/99) reviewed 4/2000.
  1. Product Information: Avonex®, interferon beta-1a. Biogen, Canada. In: Welbanks L (ed): Compendium of Pharmaceuticals and Specialties, 35th ed. Canadian Pharmaceutical Association, Ottawa, Ontario, Canada, 2000: p. 159–161.
  1. Product Information: Rebif™, interferon beta-1a. Serono, Canada. In: Welbanks L (ed): Compendium of Pharmaceuticals and Specialties, 35th ed. Canadian Pharmaceutical Association, Ottawa, Ontario, Canada, 2000: p. 1345–1348.
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