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Interferon Beta-1a

Pronunciation

(in ter FEER on BAY ta won aye)

Index Terms

  • rIFN beta-1a

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution [preservative free]:

Avonex: 30 mcg [contains albumin (human), mouse (murine) and/or hamster protein; supplied with diluent]

Injection, solution:

Avonex: 30 mcg/0.5 mL (0.5 mL) [albumin free; contains mouse (murine) and/or hamster protein; prefilled syringe]

Avonex Pen: 30 mcg/0.5 mL (0.5 mL) [albumin free; contains mouse (murine) and/or hamster protein]

Injection, solution [preservative free]:

Rebif: 22 mcg/0.5 mL (0.5 mL), 44 mcg/0.5 mL (0.5 mL) [contains albumin (human), mouse (murine) and/or hamster protein; prefilled syringe]

Rebif Rebidose: 22 mcg/0.5 mL (0.5 mL), 44 mcg/0.5 mL (0.5 mL) [contains albumin (human), mouse (murine) and/or hamster protein; autoinjector]

Injection, solution [preservative free, combination package]:

Rebif Titration Pack: 8.8 mcg/0.2 mL (6s) and 22 mcg/0.5 mL (6s) [contains albumin (human), mouse (murine) and/or hamster protein; prefilled syringe]

Rebif Rebidose Titration Pack: 8.8 mcg/0.2 mL (6s) and 22 mcg/0.5 mL (6s) [contains albumin (human), mouse (murine) and/or hamster protein; autoinjector]

Brand Names: U.S.

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

Pharmacologic Category

  • Interferon

Pharmacology

Interferon beta differs from naturally occurring human protein by a single amino acid substitution and the lack of carbohydrate side chains; alters the expression and response to surface antigens and can enhance immune cell activities. Properties of interferon beta that modify biologic responses are mediated by cell surface receptor interactions; mechanism in the treatment of MS is unknown.

Onset of Action

Avonex: 12 hours (based on biological response markers)

Time to Peak

Serum: Avonex (IM): ~15 hours (range: 6-36 hours); Rebif (SubQ): 16 hours

Duration of Action

Avonex: 4 days (based on biological response markers)

Half-Life Elimination

Avonex: ~19 hours (range: 8-54 hours); Rebif: 69 hours

Use: Labeled Indications

US labeling: Treatment of relapsing forms of multiple sclerosis (MS) to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability

Canadian labeling:

Treatment of relapsing forms of multiple sclerosis (MS) to decrease the frequency of clinical exacerbations, delay the accumulation of physical disability, reduce the requirement for steroids, reduce the number of hospitalizations, and reduce disease burden

To decrease the number and volume of active brain lesions, decrease overall disease burden, and delay onset of clinically definite MS in patients who have experienced a single demyelinating event.

Contraindications

Hypersensitivity to natural or recombinant interferon beta, human albumin (albumin-containing formulations only), or any other component of the formulation

Documentation of allergenic cross-reactivity for interferons is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Rebif: Pregnancy; decompensated liver disease

Dosing: Adult

Multiple sclerosis (MS): Note: Analgesics and/or antipyretics may help decrease flu-like symptoms on treatment days:

IM (Avonex):

US labeling: 30 mcg once weekly; to decrease flu-like symptoms, may initiate once-weekly dosing with 7.5 mcg (week 1) then increase dose in increments of 7.5 mcg once weekly (weeks 2 to 4) up to recommended dose (30 mcg once weekly)

Canadian labeling: 30 mcg once weekly; to decrease flu-like symptoms, may initiate once-weekly dosing with 7.5 mcg (week 1) then increase dose in increments of 7.5 mcg once weekly (weeks 2 to 4) or once every 2 weeks (to week 7) up to recommended dose (30 mcg once weekly). In progressive relapsing MS or secondary progressive MS with recurrent neurologic dysfunction may consider increasing to 60 mcg once weekly.

SubQ (Rebif): Target dose is either 22 or 44 mcg 3 times weekly; doses should be separated by at least 48 hours:

Target dose 44 mcg 3 times weekly:

Initial: 8.8 mcg (20% of target dose) 3 times weekly for 2 weeks

Titration: 22 mcg (50% of target dose) 3 times weekly for 2 weeks

Target dose: 44 mcg 3 times weekly

Target dose 22 mcg 3 times weekly:

Initial: 4.4 mcg (20% of target dose) 3 times weekly for 2 weeks

Titration: 11 mcg (50% of target dose) 3 times weekly for 2 weeks

Target dose: 22 mcg 3 times weekly

Single demyelinating event (Canadian labeling [Rebif]; not in US labeling): SubQ:

Target dose 44 mcg 3 times weekly: Note: Analgesics and/or antipyretics prior to and for 24 hours after dosing may help decrease flu-like symptoms:

Initial: 8.8 mcg (20% of target dose) 3 times weekly for 2 weeks

Titration: 22 mcg (50% of target dose) 3 times weekly for 2 weeks

Target dose: 44 mcg 3 times weekly

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustment provided in the manufacturer’s labeling; use with caution in patients with active liver disease, alcohol abuse, ALT >2.5 x ULN, or a history of significant liver disease. Rebif Canadian labeling contraindicates use in decompensated liver disease.

Dosing: Adjustment for Toxicity

Autoimmune disorder development: Consider discontinuing treatment.

Depression or other severe psychiatric symptoms: Consider discontinuing treatment.

Hepatotoxicity:

ALT >5 x ULN: Temporarily discontinue therapy or consider dose reduction until ALT normalizes, then may consider retitration of dose.

Symptomatic (eg, jaundice): Discontinue immediately.

Leukopenia: May require temporary discontinuation or dose reduction until resolution.

Reconstitution

Avonex: Reconstitute with 1.1 mL of diluent (SWFI) and swirl gently to dissolve. Do not shake. The reconstituted product contains no preservative and is for single-use only; discard unused portion.

Administration

The first injection should be administered under the supervision of a health care professional.

Avonex: Administer IM; rotate injection site; do not inject into area where skin is irritated, red, bruised, scarred, or infected. Two hours after injection, examine site for redness, swelling, or tenderness. Discard any unused portion.

Rebif: Administer SubQ at the same time of day on the same 3 days each week (eg, Mon, Wed, Fri), preferably in the late afternoon or evening; doses should be at least 48 hours apart; rotate injection site; do not inject into area where skin is irritated, red, bruised, or scarred. Discard any unused portion.

Storage

Avonex:

Prefilled syringe or pen: Store at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Allow to warm to room temperature prior to use (do not use external heat source). If refrigeration is not available, product may be stored at ≤25°C (77°F) for up to 7 days.

Vial: Store unreconstituted vial at 2°C to 8°C (36°F to 46°F). If refrigeration is not available, may be stored at 25°C (77°F) for up to 30 days; do not freeze. Protect from light. Following reconstitution, use immediately, but may be stored up to 6 hours at 2°C to 8°C (36°F to 46°F); do not freeze.

Rebif: Store at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from heat and light. Allow to warm to room temperature prior to use (do not use external heat source). Refrigeration is preferred; however, if needed, may be stored at 2°C to 25°C (36°F to 77°F) for up to 30 days.

Drug Interactions

Theophylline Derivatives: Interferons may decrease the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

Zidovudine: Interferons may enhance the adverse/toxic effect of Zidovudine. Interferons may decrease the metabolism of Zidovudine. Monitor therapy

Adverse Reactions

Adverse reactions reported as a composite of both commercially-available products. Spectrum and incidence of reactions is generally similar between products, but consult individual product labels for specific incidence.

>10%:

Central nervous system: Headache (58% to 70%), fatigue (33% to 41%), depression (18% to 25%), pain (23%), chills (19%), dizziness (14%)

Gastrointestinal: Nausea (23%), abdominal pain (8% to 22%)

Genitourinary: Urinary tract infection (17%)

Hematologic & oncologic: Leukopenia (28% to 36%), lymphadenopathy (11% to 12%)

Hepatic: Increased serum ALT (20% to 27%), increased serum AST (10% to 17%)

Immunologic: Antibody development (neutralizing; significance not known; Rebif: 24% to 31%; Avonex: 5%)

Local: Injection site reaction (3% to 92%)

Neuromuscular & skeletal: Myalgia (25% to 29%), back pain (23% to 25%), weakness (24%), skeletal pain (10% to 15%), rigors (6% to 13%)

Ophthalmic: Visual disturbance (7% to 13%)

Respiratory: Flu-like symptoms (49% to 59%), sinusitis (14%), upper respiratory tract infection (14%)

Miscellaneous: Fever (20% to 28%)

1% to 10%:

Cardiovascular: Chest pain (5% to 8%), vasodilation (2%)

Central nervous system: Hypertonia (6% to 7%), migraine (5%), ataxia (4% to 5%), drowsiness (4% to 5%), malaise (4% to 5%), seizure (1% to 5%), suicidal tendencies (4%)

Dermatologic: Erythematous rash (5% to 7%), maculopapular rash (4% to 5%), alopecia (4%), hyperhidrosis (4%), urticaria

Endocrine & metabolic: Thyroid disease (4% to 6%)

Gastrointestinal: Xerostomia (1% to 5%), toothache (3%)

Genitourinary: Urinary frequency (2% to 7%), urinary incontinence (2% to 4%), urine abnormality (3%)

Hematologic & oncologic: Thrombocytopenia (2% to 8%), anemia (3% to 5%)

Hepatic: Hyperbilirubinemia (2% to 3%)

Infection: Infection (7%)

Local: Pain at injection site (8%), bruising at injection site (6%), inflammation at injection site (6%), tissue necrosis at injection site (1% to 3%)

Neuromuscular & skeletal: Arthralgia (9%)

Ophthalmic: Eye disease (4%), xerophthalmia (1% to 3%)

Respiratory: Bronchitis (8%)

<1% (Limited to important and life-threatening): Abnormal healing, abscess, abscess at injection site, amnesia, anaphylaxis, arteritis, arthritis, bloody stools, breast fibroadenosis, cardiac failure, cellulitis at injection site, conjunctivitis, depersonalization, dermal ulcer, diverticulitis, drug dependence, emphysema, epididymitis, erythema multiforme, facial paralysis, fibrosis at injection site, furunculosis, gallbladder disease, gastritis, gastrointestinal hemorrhage, gingivitis, gynecomastia, hemolytic-uremic syndrome, hemorrhage, hepatic failure, hepatic neoplasm, hepatitis, hepatomegaly, hepatotoxicity (idiosyncratic) (Chalasani 2014), hernia, hypersensitivity reaction at injection site, hyperthyroidism, hypoglycemia, hypokalemia, hypomagnesemia, hypotension, hypothyroidism, immune thrombocytopenia, intestinal obstruction, intestinal perforation, lipoma, lupus erythematosus, menopause, neoplasm, nephrolithiasis, neurological signs and symptoms (transient; may mimic multiple sclerosis exacerbations), nevus, orthostatic hypotension, osteonecrosis, pancytopenia, pelvic inflammatory disease, pericarditis, periodontitis, peripheral vascular disease, Peyronie's disease, pneumonia, postmenopausal bleeding, proctitis, psychiatric disorders (new or worsening; including suicidal ideation), psychoneurosis, pulmonary embolism, pyelonephritis, retinal vascular disease, sepsis, severe weakness (transient), skin photosensitivity, Stevens-Johnson syndrome, synovitis, tachycardia, telangiectasia, testicular disease, thromboembolism, thrombotic thrombocytopenic purpura, uterine fibroids, vaginal hemorrhage, vascular disease, vesicular eruption

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity reactions: Allergic reactions, including anaphylaxis, have been reported. Some reactions may occur after prolonged use. Discontinue therapy if anaphylaxis or other allergic reactions occur.

• Autoimmune disorders: Autoimmune disorders including idiopathic thrombocytopenia, hyper- and hypothyroidism and rarely autoimmune hepatitis have been reported. Consider discontinuation of treatment if patient develops a new autoimmune disorder.

• Bone marrow suppression: Pancytopenia (rare), leukopenia, and thrombocytopenia have been reported. Monitor blood counts at 1-, 3-, and 6 months post therapy initiation and periodically thereafter. Events may recur with rechallenge.

• Flu-like symptoms: Associated with a high incidence of flu-like adverse effects; use of analgesics and/or antipyretics on treatment days may be helpful.

• Hepatic effects: Rare cases of severe hepatic injury, including cases of hepatic failure requiring transplantation, have been reported in patients receiving interferon beta-1a; risk may be increased by ethanol use or concurrent therapy with hepatotoxic drugs. Some reports indicate symptoms began after 1-6 months of treatment. Transaminase elevations may be asymptomatic. Use with caution in patients with active or a history of liver disease, alcohol abuse, or increased serum ALT (>2.5 times ULN) at baseline. Obtain liver function tests at 1-, 3-, and 6 months post therapy initiation and periodically thereafter. Treatment should be suspended immediately if jaundice or symptoms of hepatic dysfunction occur. Consider dose reductions or temporary discontinuation if ALT >5 times ULN.

• Injection site reactions: Severe injection site reactions have occurred, including pain, erythema, edema, cellulitis, abscess, and necrosis. Necrosis may occur at single and multiple sites. Some reactions have occurred ≥2 years after initiation; reactions typically resolve with conservative treatment (antibiotics or surgical intervention may be required). Patient and/or caregiver competency in injection technique should be confirmed and periodically re-evaluated.

• Neuropsychiatric disorders: Interferons have been associated with psychiatric adverse events (psychosis, depression, suicidal behavior/ideation) in patients with and without previous psychiatric symptoms; use with caution in patients with depression. Patients exhibiting symptoms of depression or other severe psychiatric symptoms should be closely monitored and discontinuation of therapy should be considered.

• Thrombotic microangiopathy: Cases of thrombotic microangiopathy manifesting as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS) (some fatal) have been reported (Hunt 2014; Mahe 2013; Rebif Canadian product monograph 2014). Some cases may occur after several years of therapy. Monitor for new onset hypertension, thrombocytopenia, or impaired renal function; discontinuation of therapy and prompt treatment may be necessary if TTP/HUS are confirmed.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with pre-existing cardiovascular disease. Rare cases of new-onset cardiomyopathy and/or HF have been reported.

• Hepatic impairment: Use with caution in patients with hepatic impairment or in those who abuse alcohol.

• Seizure disorder: Use with caution in patients with a history of seizure disorder.

• Thyroid dysfunction: Thyroid abnormalities may develop with use; may worsen pre-existing thyroid conditions. Monitor thyroid function tests every 6 months or as clinically necessary.

Special populations:

• Chronic progressive MS: Safety and efficacy have not been established for this use.

Dosage form specific issues:

• Albumin: Some formulations contain albumin, which may carry a remote risk of transmitting Creutzfeldt-Jakob or other viral diseases. Interferon beta-1a formulations that contain albumin are contraindicated in albumin-sensitive patients.

• Latex: The packaging (prefilled syringe tip cap) may contain latex.

Monitoring Parameters

Thyroid function tests, CBC with differential, transaminase levels, blood chemistries, symptoms of autoimmune disorders, signs/symptoms of psychiatric disorder (including depression and/or suicidal ideation), signs/symptoms of new onset/worsening cardiovascular disease, signs/symptoms of thrombotic microangiopathy (new-onset hypertension, thrombocytopenia, renal impairment)

Avonex: Frequency of monitoring for patients receiving Avonex® has not been specifically defined; in clinical trials, monitoring was at 6-month intervals. Canadian labeling recommends liver function testing monthly for first 6 months, then every 6 months thereafter or as clinically indicated.

Rebif: CBC and liver function testing at 1-, 3-, and 6 months, then periodically thereafter. Thyroid function every 6 months (in patients with pre-existing abnormalities and/or clinical indications). Canadian labeling recommends liver function testing monthly for first 6 months, then every 6 months thereafter or as clinically indicated.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies; however, the possibility of adverse effects cannot be ruled out. Preliminary data from the Avonex pregnancy registry (published in abstract) do not show an increased risk of adverse fetal events when exposure occurs during pregnancy (Richman, 2012; Tomczyk, 2013); however, other studies have reported conflicting results. Until additional information is available, consideration should be given to discontinuing treatment if a woman becomes pregnant, or 1 month prior to becoming pregnant in women with mild disease (Coyle, 2012; Houtchens, 2013; Lu, 2013). Rebif Canadian product monograph contraindicates use in pregnant women.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flu-like symptoms, nausea, vomiting, abdominal pain, muscle pain, back pain, fatigue, or dry mouth. Have patient report immediately to prescriber signs of infection, signs of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (bruising or bleeding; feeling very tired or weak; dark urine or yellow skin or eyes; pale skin; change in the amount of urine passed; vision changes; change in strength on one side is greater than the other, trouble speaking or thinking, change in balance; or fever), signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine, black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of thyroid problems (change in weight without trying, feeling nervous and excitable, feeling restless, feeling very weak, hair thinning, low mood (depression), neck swelling, not able to focus, not able to handle heat or cold, period (menstrual) changes, shakiness, or sweating), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), severe injection site reaction, polyuria, shortness of breath, angina, tachycardia, seizures, severe dizziness, passing out, or severe edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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