Version May 2024
Multiple sclerosis, relapsing: Note: Safety: In high-risk populations or in countries with high tuberculosis burden, screen for latent infections (eg, hepatitis, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other appropriate specialists (eg, liver specialists) regarding treatment options before initiating therapy (Ref). Premedication: 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.
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
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.
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.
Pulmonary arterial hypertension: Discontinue treatment with confirmed diagnosis.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%:
Gastrointestinal: Abdominal pain (Avonex: 8%; Rebif: 20% to 22%), nausea (Avonex: 23%)
Genitourinary: Urinary tract infection (Avonex: 17%)
Hematologic & oncologic: Leukopenia (Rebif: 28% to 36%), lymphadenopathy (Rebif: 11% to 12%)
Hepatic: Increased serum alanine aminotransferase (Rebif: 20% to 27%), increased serum aspartate aminotransferase (Rebif: 10% to 17%)
Immunologic: Antibody development (neutralizing; significance not known; Avonex: 5%; Rebif: 24% to 31%)
Local: Injection-site reaction (Avonex: 3% to 18%; Rebif: 89% to 92%)
Nervous system: Asthenia (Avonex: 24%), chills (Avonex: 19%), depression (Avonex: 18% to 20%), dizziness (Avonex: 14%), fatigue (Rebif: 41%), headache (58% to 70%), pain (Avonex: 23%), rigors (Rebif: 6% to 13%)
Neuromuscular & skeletal: Back pain (Rebif: 23% to 25%), myalgia (25% to 29%), skeletal pain (Rebif: 15%)
Ophthalmic: Visual disturbance (Rebif: 13%)
Respiratory: Flu-like symptoms (49% to 59%), sinusitis (Avonex: 14%), upper respiratory tract infection (Avonex: 14%)
Miscellaneous: Fever (20% to 28%)
1% to 10%:
Cardiovascular: Chest pain (5% to 8%), vasodilation (Avonex: 2%)
Dermatologic: Alopecia (Avonex: 4%), erythematous rash (Rebif: 5% to 7%), hyperhidrosis (Rebif: 4%), maculopapular rash (Rebif: 4% to 5%)
Endocrine & metabolic: Thyroid disease (Rebif: 4% to 6%)
Gastrointestinal: Toothache (Avonex: 3%), xerostomia (Rebif: 5%)
Genitourinary: Urinary frequency (Rebif: 7%), urinary incontinence (Rebif: 4%), urine abnormality (Avonex: 3%)
Hematologic & oncologic: Anemia (4% to 5%), thrombocytopenia (Rebif: 8%)
Hepatic: Hyperbilirubinemia (Rebif: 2% to 3%)
Infection: Infection (Avonex: 7%)
Local: Bruising at injection site (Avonex: 6%), inflammation at injection site (Avonex: 6%), pain at injection site (Avonex: 8%), tissue necrosis at injection site (Rebif: 1% to 3%)
Nervous system: Ataxia (Rebif: 4% to 5%), drowsiness (Rebif: 4% to 5%), hypertonia (Rebif: 6% to 7%), malaise (Rebif: 4% to 5%), migraine (Avonex: 5%), seizure (Avonex: 1%; Rebif: 4% to 5%), suicidal tendencies (Avonex: 4%)
Neuromuscular & skeletal: Arthralgia (Avonex: 9%)
Ophthalmic: Dry eye syndrome (Rebif: 1% to 3%), eye disease (Avonex: 4%)
Respiratory: Bronchitis (Avonex: 8%)
<1%: Local: Residual mass at injection site (Avonex)
Frequency not defined (all formulations):
Hematologic & oncologic: Pancytopenia
Local: Erythema at injection site
Postmarketing (all formulations):
Cardiovascular: Cardiomyopathy, heart failure
Dermatologic: Erythema multiforme, skin rash, Stevens-Johnson syndrome, urticaria, vesicular eruption
Endocrine & metabolic: Heavy menstrual bleeding, hyperthyroidism, hypothyroidism
Genitourinary: Uterine hemorrhage
Hematologic & oncologic: Hemolytic anemia, hemolytic-uremic syndrome, immune thrombocytopenia, thrombotic microangiopathy, thrombotic thrombocytopenic purpura
Hepatic: Autoimmune hepatitis, hepatic failure, hepatic injury, hepatotoxicity (idiosyncratic) (Chalasani 2021)
Hypersensitivity: Anaphylaxis, orolingual edema
Local: Abscess at injection site, cellulitis at injection site, swelling at injection site
Nervous system: Psychiatric disturbance (new or worsening, including psychosis), suicidal ideation
Neuromuscular & skeletal: Lupus erythematosus
Ophthalmic: Retinal artery occlusion, retinal cotton-wool spot, retinal vascular disease, retinal vein occlusion, retinopathy
Respiratory: Dyspnea, pulmonary hypertension (including pulmonary arterial hypertension) (McGovern 2015; Health Canada Nov. 2, 2016)
Hypersensitivity to natural or recombinant interferon beta, human albumin (albumin-containing formulations only), or any other component of the formulation.
Canadian labeling: Additional contraindications (not in US labeling): Rebif: Decompensated liver disease.
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 to 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.
• Infections: In high-risk populations or in countries with high tuberculosis burden, screen for latent infections (eg, hepatitis, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other specialists (eg, liver specialists) regarding treatment options before initiating therapy (AAN [Farez 2019]).
• Injection-site reactions: Severe injection-site reactions have occurred, including pain, bruising, erythema, edema, mass, 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. Do not inject into affected area until completely healed; if multiple lesions occur, discontinue use until they are fully healed.
• 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.
• Pulmonary effects: Pulmonary arterial hypertension (sometimes requiring hospitalization and one patient requiring a lung transplant) has occurred in patients without other risk factors taking interferon beta products; onset varies and may occur several years after initiation of treatment. Patients with unexplained symptoms (eg, dyspnea, new or worsening fatigue) should be evaluated for pulmonary arterial hypertension.
• 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 labeling 2020). 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 preexisting cardiovascular disease. Rare cases of new-onset cardiomyopathy and/or HF have been reported. In a scientific statement from the American Heart Association, interferon has been determined to be an agent that may either cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate/major) (AHA [Page 2016]).
• 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.
Other warnings/precautions:
• Immunizations: Avoid live-attenuated vaccines in patients who currently receive or have recently discontinued interferon beta-1a; consider using live-attenuated vaccines only if risk of infection is high and killed vaccines are unavailable (AAN [Farez 2019]).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
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; prefilled autoinjector]
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]
No
Auto-injector Kit (Avonex Pen Intramuscular)
30 mcg/0.5 mL (per each): $9,919.01
Prefilled Syringe Kit (Avonex Prefilled Intramuscular)
30 mcg/0.5 mL (per each): $9,919.01
Solution Auto-injector (Rebif Rebidose Subcutaneous)
22 mcg/0.5 mL (per 0.5 mL): $992.08
44 mcg/0.5 mL (per 0.5 mL): $992.08
Solution Auto-injector (Rebif Rebidose Titration Pack Subcutaneous)
6X8.8 & 6X22 mcg (per mL): $2,834.53
Solution Prefilled Syringe (Rebif Subcutaneous)
22 mcg/0.5 mL (per 0.5 mL): $992.08
44 mcg/0.5 mL (per 0.5 mL): $992.08
Solution Prefilled Syringe (Rebif Titration Pack Subcutaneous)
6X8.8 & 6X22 mcg (per mL): $2,834.53
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
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.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Avonex: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103628s5269lbl.pdf#page=22
Rebif: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103780s5214lbl.pdf#page=16
US labeling:
Multiple sclerosis, relapsing: Treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease
Canadian labeling:
Treatment of relapsing forms of 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
Avonex may be confused with Avelox
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Cladribine: May enhance the adverse/toxic effect of Interferons (Beta). Specifically, the risk for lymphopenia may be increased. Risk X: Avoid combination
Natalizumab: Interferon Beta-1a may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk for progressive multifocal leukoencephalopathy (PML) may be increased. Interferon Beta-1a may increase the serum concentration of Natalizumab. Management: Consider alternatives to this combination whenever possible. Combined use may increase the risk for progressive multifocal leukoencephalopathy (PML). Risk D: Consider therapy modification
Zidovudine: Interferons may enhance the adverse/toxic effect of Zidovudine. Interferons may decrease the metabolism of Zidovudine. Risk C: Monitor therapy
In general, disease-modifying therapies for multiple sclerosis (MS) are stopped prior to a planned pregnancy except in females at high risk of MS activity (AAN [Rae-Grant 2018]). When disease-modifying therapy is needed in females planning a pregnancy (eg, high risk of disease reactivation), interferon beta-1a may be considered until pregnancy is confirmed, and in select cases (eg, female with active disease), use may be continued during pregnancy. Delaying pregnancy is recommended for females with persistent high disease activity (ECTRIMS/EAN [Montalban 2018]).
Based on available data, an increased risk of adverse fetal events has not been observed when exposure occurs during pregnancy (Burkill 2019; Foulds 2010; Nguyen 2019; Richman 2012; Sandberg-Wollheim 2011; Tomczyk 2013).
In general, disease-modifying therapies for multiple sclerosis (MS) are not initiated during pregnancy, except in females at high risk of MS activity (AAN [Rae-Grant 2018]). When disease-modifying therapy is needed in females planning a pregnancy (eg, high risk of disease reactivation), interferon beta-1a may be considered until pregnancy is confirmed, and in select cases (eg, female with active disease), use may be continued during pregnancy (ECTRIMS/EAN [Montalban 2018]).
Interferon beta-1a is present in breast milk.
Milk samples were obtained from 6 lactating women (6 to 23 months postpartum) receiving Avonex 30 mcg IM once weekly; sampling occurred at intervals for 72 hours after the dose. The highest reported concentration was 179 pg/mL and the relative infant dose was calculated to be <1% of the maternal dose. Adverse events were not observed in the breastfed infant (Hale 2012). In addition, interferon beta does not have a systemic biologic effect if given orally (Fragoso 2018).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Based on its chemical properties, others consider interferon beta compatible with breastfeeding (Almas 2016; Dobson 2019; Fragoso 2018).
Thyroid function tests, CBC with differential, complete metabolic panel; symptoms of autoimmune disorders; signs/symptoms of psychiatric disorder (including depression and/or suicidal ideation); signs/symptoms of injection-site reactions; signs/symptoms of new onset/worsening cardiovascular disease; signs/symptoms of thrombotic microangiopathy (new-onset hypertension, thrombocytopenia, renal impairment); assess patients who develop unexplained symptoms (eg, dyspnea, new or worsening fatigue) for pulmonary arterial hypertension; latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline).
Avonex: Frequency of monitoring for patients receiving Avonex has not been specifically defined; in clinical trials, monitoring was at 6-month intervals.
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).
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)
Duration: Avonex: 4 days (based on biological response markers)
Half-life elimination: Avonex: ~19 hours (range: 8-54 hours); Rebif: 69 hours
Time to peak, serum: Avonex (IM): ~15 hours (range: 6-36 hours); Rebif (SubQ): 16 hours
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