Interferon beta, a biosynthetic (recombinant DNA origin) form of endogenous human interferon beta,1 has immunomodulatory and disease-modifying activity in multiple sclerosis (MS).1, 4, 8, 9, 19, 20, 26 Interferon beta is available as interferon beta-1a19, 20 and interferon beta-1b.1, 70
Interferon beta (beta-1a, beta-1b) is used for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome (CIS), relapsing-remitting disease, and active secondary-progressive disease, in adults.1, 19, 20, 70 Interferon beta appears to reduce the frequency of neurologic disturbances (also known as attacks or relapses) and produces a beneficial effect on several magnetic resonance imaging (MRI) measures of disease activity in patients with MS.6, 7, 26, 27, 28, 30, 32, 53
Interferon beta-1a is commercially available as a once-weekly IM injection (Avonex®) or a 3-times-weekly subcutaneous injection (Rebif®).19, 20 Interferon beta-1b is commercially available as a subcutaneous alternate-day injection (Betaseron®, Extavia®);1, 70 the 2 currently available interferon beta-1b preparations are identical except for some packaging components (e.g., needle size).1, 70
Important differences in beneficial effects (clinical, MRI measures of response) between the different types of interferon beta in the management of MS have not been reported and the existence of such differences is as yet unknown.16, 61 Clinical interpretation of head-to-head comparative studies involving various interferon beta preparations is limited by methodologic problems (e.g., short duration, open--label studies, nonstandardized dosages and/or routes of administration).16, 60
Interferon Beta-1b (Betaseron®)
Efficacy and safety of interferon beta-1b (Betaseron®) for the management of relapsing-remitting MS were established in a randomized, double-blind, multicenter, placebo-controlled study (Study 1).1 The study included ambulatory patients 18-50 years of age (Expanded Disability Status Scale [EDSS] score of 0-5.5) who exhibited a relapsing-remitting clinical course and had experienced at least 2 exacerbations over the previous 2 years without any exacerbations within the previous month.1 Patients were randomized to receive interferon beta-1b (0.05 mg or 0.25 mg) or placebo by subcutaneous injection every other day.1 Both dosages of interferon beta-1b were significantly more effective at reducing the frequency of annual exacerbations than placebo; patients who received the higher dosage of interferon beta-1b (0.25 mg) experienced reduced clinical relapse rates and lessened new MRI activity compared with those who received the lower dosage (0.05 mg).1, 6, 7, 62 The effect of interferon beta treatment on measures of disease severity (i.e., MRI measures of disease burden, disability progression) was less impressive.6, 7, 62 There was a robust effect of treatment on the MRI T2 disease burden, but no substantial effects on the measure of confirmed 1-point EDSS progression (i.e., a change of one or more EDSS point sustained on 2 consecutive assessments performed 3 months apart), which was the primary end point of the trial.6, 7, 62
Efficacy of interferon beta-1b (Betaseron®) in patients with secondary progressive MS was established in 2 randomized, double-blind, placebo-controlled studies (Study 2 and Study 3).1, 48, 72 Both studies enrolled patients with MS in the secondary progressive phase who had disability progression or 2 relapses within the previous 2 years.1 Patients had a baseline EDSS score of 3-6.5.1, 48, 72 Patients were randomized in Study 2 to receive interferon beta-1b (0.25 mg) or placebo by subcutaneous injection every other day for up to 3 years.48 In Study 3, patients were randomized to interferon beta-1b (0.25 mg or 0.16 mg/m2 based on body surface area [BSA]) or placebo by subcutaneous injection every other day for 3 years.72 In Study 2, there was a significant difference in time to confirmed progression in disability (as determined by a 1-point increase on the EDSS or a 0.5-point increase if baseline EDSS was 6-6.5) in favor of interferon beta-1b therapy.1, 48 In this study, interferon beta-1b reduced confirmed disease progression by 22% compared to placebo.48, 61 In addition, clinical and MRI attack rates, and volume of white matter disease on MRI were all reduced in patients who received interferon beta-1b in Study 2 compared with those who received placebo.48, 62 In Study 3, the rate of clinical progression did not differ significantly between treatment groups with either dosage of interferon beta-1b compared with placebo.1, 72 However, a significant benefit in the annual relapse rate was demonstrated with interferon beta-1b in the 0.25-mg treatment group, but not for the 0.16-mg/m2 treatment group.72 The mean annual relapse rates were 0.16, 0.2, and 0.28 in the interferon beta-1b 0.25 mg, interferon beta-1b 0.16 mg/m2, and placebo groups, respectively.1 MRI endpoints in both Study 2 and Study 3 showed smaller increases in T2 MRI lesion area and decreased number of active MRI lesions in patients who received interferon beta-1b compared with those who received placebo.1, 72
Efficacy of interferon beta-1b (Betaseron®) in patients with clinically isolated syndrome was evaluated in the BENEFIT study, which was a multicenter, randomized, placebo-controlled trial conducted over a 2 year period.1, 75 Patients who were enrolled had a recent (within 60 days) first demyelinating event with lesions typical of MS on brain MRI.1, 75 After 2 years, time to development of a second exacerbation was significantly delayed in patients treated with interferon beta-1b compared to patients treated with placebo.1, 75 The risk for developing a second exacerbation in patients receiving interferon beta-1b was 53% of the risk in the placebo group.75
Efficacy of the Extavia® preparation of interferon beta-1b in the management of relapsing forms of MS is based on the four efficacy studies conducted with Betaseron®.1, 6, 48, 72
Efficacy of interferon beta-1a (Avonex®) in relapsing forms of MS was established in 2 multicenter, placebo-controlled studies, one in patients with CIS, and one in relapsing-remitting MS.19, 27, 38 The relapsing-remitting MS study included patients 18-55 years of age (EDSS scores up to 3.5) who had at least 2 documented relapses in the prior 3 years, and no relapses for 2 months prior to study entry.19, 27 Patients were randomized to interferon beta-1a 30 mcg IM or placebo once weekly for 2 years.19, 27 A decrease in confirmed 1-point EDSS progression was the primary end point.19, 27 At baseline, there were no differences in EDSS scores across groups, and by week 78, substantial differences in disability were observed between groups.27 By week 130, average EDSS scores were substantially lower in the interferon beta group versus placebo.27 Secondary outcomes of clinical relapse rate and the neurologic attack rate as measured by the median number of gadolinium-enhanced lesions noted on MRI were reduced in patients receiving interferon beta-1a compared with those receiving placebo.19, 27, 28, 60 The total volume of T2 disease burden present on MRI also was reduced compared with placebo, but this difference was not significant.19, 28, 60
The CIS study with interferon beta-1a (Avonex®) included patients who had recently experienced an isolated demyelinating event involving the optic nerve, spinal cord, or brainstem/cerebellum, and who had lesions typical of MS on brain MRI.19 Patients received corticosteroid treatment for their first clinical episode, and were then randomized to interferon beta-1a (Avonex®) 30 mcg IM once weekly or placebo for 3 years.19, 38 Time to development of a second exacerbation was significantly delayed in interferon beta-1a-treated patients compared to placebo-treated patients.19 The relative rate of developing a second exacerbation in the interferon beta-1a group was 56% of the rate in the placebo group.19, 38 Interferon beta-1a treatment also demonstrated a significant relative reduction in brain lesions, new or enlarging lesions, and gadolinium-enhancing lesions at 6, 12, and 18 months compared to placebo.19, 38
Efficacy of interferon beta-1a (Rebif®) in the management of relapsing-remitting MS was established in 2 multicenter studies.20 The Evidence for Interferon Dose Effect: European-North American Comparative Efficacy (EVIDENCE) trial was a randomized, open-label, evaluator-blinded, comparative study that included patients with relapsing-remitting MS with EDSS scores ranging from 0 to 5.5, and at least 2 exacerbations in the previous 2 years.20 Results of the study indicated that the relative risk of experiencing a relapse at any time during the initial 24-week treatment period was approximately 32-37% lower in patients who received the higher dose (44 mcg), more frequent (3 times weekly) subcutaneous administration of Rebif® than in those who received the lower dose (30 mcg), less frequent (once weekly) IM administration of Avonex®.20, 29, 62 The number of active combined unique lesions on MRI scans (defined as active lesions on T2 or T1 post-gadolinium sequences) also was substantially reduced in patients treated with Rebif® compared with those treated with Avonex®.20, 29 These results are consistent with those of the Independent Comparison of Interferon (INCOMIN) trial, in which a greater clinical benefit over a 2-year treatment period was shown in patients who received higher dose (0.25 mg subcutaneously), more frequently administered (every other day) Betaseron®, both on clinical outcomes (i.e., relapse-free status and sustained progression) and on MRI outcomes (i.e., new T2 lesions or gadolinium-enhanced lesions), compared with those who received the lower dose (30 mcg IM), less frequently administered (once weekly) Avonex®.34, 60
The efficacy of interferon beta-1a (Rebif®) was also evaluated in a multicenter, double-blind, placebo controlled study in relapsing-remitting MS patients with EDSS scores ranging from 0-5, and with at least 2 exacerbations within the previous 2 years (the PRISMS [Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis] study).20, 30 Patients were randomized to interferon beta-1a 22 mcg, 44 mcg, or placebo by subcutaneous injection 3 times weekly for 2 years.30 The mean number of exacerbations per patient over 2 years was 29% and 32% lower with interferon beta-1a 22 mcg and 44 mcg, respectively, compared with placebo.20 Time to disease progression, defined as an increase of 1 or more points on the EDSS for at least 3 months, was significantly prolonged with interferon beta-1a 22 mcg and 44 mcg compared to placebo.30 Median time to first relapse was delayed by 3 months with interferon beta-1a 22 mcg and by 5 months with interferon beta-1a 44 mcg.30 Disease burden on MRI, assessed using T2 weighted lesions, demonstrated a progressive decrease with interferon beta-1a compared with placebo.30
Interferon beta is one of several disease-modifying therapies used in the management of relapsing forms of MS.36, 76, 77 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.76, 78 The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with relapsing forms of MS who have had recent relapses and/or MRI activity; these experts state that the benefits versus risks (e.g., adverse effects or burden of taking a long-term medication) of treatment in patients who have not had relapses in 2 or more years and do not have active new MRI lesions are not known.76 Because CNS damage occurs early and continues throughout the course of MS, other clinicians recommend that disease-modifying therapy be initiated as soon as possible following diagnosis and continued indefinitely unless there is a clear lack of benefit, adverse effects are intolerable, the patient is unable to adhere to the recommended treatment regimen, or a more appropriate treatment becomes available.77 Clinicians should consider the adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate disease-modifying therapy.76, 77
Interferon beta has been investigated for use in the management of primary progressive MS (PPMS) †, a type of MS that affects approximately 10-15% of patients diagnosed with MS.13, 18 Patients with PPMS experience a progressive, uninterrupted accumulation of neurologic deficit (without clinical attacks) from disease onset that usually results in a worse prognosis for ultimate disability compared with that of patients with RRMS.11, 13, 18, 62 Because PPMS appears to have less of an inflammatory component than relapsing courses of MS, many clinicians believe that patients with PPMS may be less likely to respond to immunomodulators such as interferon beta.13, 18, 62 Results of 2 randomized, double-blind, placebo-controlled studies showed no clinical benefits of interferon beta therapy in a limited number of patients with PPMS.13, 18
Results of preliminary trials with interferon beta in the treatment of amyotrophic lateral sclerosis (ALS)†, 35 as an adjunct to tamoxifen for the treatment of metastatic breast cancer†, 15 or as an adjunct to radiation therapy for the treatment of patients with locally advanced, non-small cell lung cancer†14 have shown no clear treatment benefit with use of interferon beta.14, 15, 35 Use of interferon beta has resulted, however, in greater rates of both acute and late treatment-related toxicity in patients with locally advanced non-small cell lung cancer receiving concomitant radiation therapy.14
Dispensing and Administration Precautions
Administer by IM, or subcutaneous injection depending on the specific preparation.1, 19, 20, 70
Interferon beta-1a is commercially available as a once-weekly IM injection (Avonex®) or a 3-times-weekly subcutaneous injection (Rebif®).19, 20 Interferon beta-1b is commercially available as a subcutaneous alternate-day injection (Betaseron®, Extavia®);1, 70 the 2 currently available interferon beta-1b preparations are identical except for some packaging components (e.g., needle size).69
Subcutaneous administration of interferon beta is associated with higher rates of injection site reactions than IM administration.1, 19, 20, 29 Interferon beta prefilled syringes and auto-injectors are for single use only; do not re-use.1, 19, 20, 70
Interferon beta-1a for IM injection (Avonex®) is commercially available as a single-use prefilled syringe and a single-use prefilled auto-injector (i.e., Avonex Pen®).19 IM injections should be administered into the thigh or upper arm.19 Injections with Avonex Pen® should be made into the upper outer thigh.19 Injection sites should be rotated and free from any skin irritation, redness, bruising, infection, or scarring prior to injection.19 Injection sites should be inspected for any redness, swelling, or tenderness 2 hours after the drug is administered.19
Avonex® prefilled syringes and auto-injectors should be removed from the refrigerator and allowed to reach room temperature (about 30 minutes) prior to administration; external heat sources (e.g., hot water) should not be used to warm the solution.19 Prefilled syringes are packaged with a 23-gauge, 1¼-inch needle supplied by the manufacturer; the manufacturer states that a 25-gauge, 1-inch needle for IM injection may be substituted by the clinician if appropriate.19 The prefilled auto-injector (Avonex Pen®) should be used only with the 25-gauge, (5/8)-inch needle supplied by the manufacturer; no other needles may be substituted.19
The prefilled syringes and auto-injectors containing Avonex® solution for IM injection should be stored at 2-8°C, but may be exposed to temperatures up to 25°C for no more than 7 days.19 The prefilled syringes and auto-injectors should be protected from light and should not be frozen or exposed to high temperatures; the drug should be discarded if exposed to temperatures exceeding 25°C or to conditions other than those recommended.19
Interferon beta-1a for subcutaneous injection (Rebif®) is commercially available as a single-use prefilled syringe and a single-use prefilled auto-injector.20 Injections should be administered, if possible, at the same time (preferably in the late afternoon or evening) on the same 3 days (e.g., Monday, Wednesday, and Friday) at least 48 hours apart each week.20 Subcutaneous injections of interferon beta-1a (Rebif®) should be administered into the abdomen, thigh, upper arm, or buttocks; injections near the waistline or within 2 inches of the navel should be avoided.20 Injection sites should be rotated to minimize the risk of injection site reactions (e.g., infection, necrosis).20 Injections should not be made into areas where the skin is irritated, reddened, bruised, infected, or abnormal in any way.20 Remove the drug from the refrigerator 30 minutes prior to use.20 Do not heat or microwave the medication.20
Rebif® solution for subcutaneous injection in prefilled syringes or auto-injectors should be stored at 2-8°C, but may be stored at temperatures up to 25°C for up to 30 days.20 The prefilled syringes and auto-injectors should be protected from heat and light, and should not be frozen.20
Interferon Beta-1b (Betaseron®, Extavia®)
Interferon beta-1b powder for subcutaneous injection (Betaseron®, Extavia®) is commercially available as a white to off-white, lyophilized powder.1, 70 An optional interferon beta-1b auto-injector (Betaconnect®) is available and may be obtained through the manufacturer's patient support program by calling 1-800-788-1467.1 The manufacturer's instructions for use should be consulted for specific information regarding use of the Betaconnect® auto-injector.1 Subcutaneous injections of interferon beta-1b should be administered every other day into the abdomen, thigh, upper arm, or buttocks; injections near the waistline or navel should be avoided.1, 70 Injection sites should be rotated to minimize the risk of injection site reactions (e.g., infection, necrosis).1, 70 Injections should not be made into areas where the skin is reddened, bruised, infected, or abnormal in any way.1, 70
Interferon beta-1b lyophilized powder is reconstituted by slowly adding 1.2 mL of the 0.54% sodium chloride diluent from the prefilled diluent syringe supplied by the manufacturer to a vial labeled as containing 0.3 mg of the drug.1, 70 After adding the diluent, the vial should be swirled gently but should not be shaken to avoid foaming.1, 70 The resultant solution has a concentration of 0.25 mg of interferon beta-1b per 1 mL.1, 70 The reconstituted solution should be inspected visually for particulate matter and discoloration and discarded if either is present.1, 70 The drug should be used immediately after reconstitution or may be refrigerated at 2-8°C for up to 3 hours.1, 70 Any residual solution remaining after withdrawal of a dose should be discarded since the drug contains no preservatives and is intended for single use only.1, 70
Extavia® lyophilized powder for subcutaneous injection should be stored at 20-25°C, but excursions are permitted to temperatures of 15-30°C for up to 3 months.70 Betaseron® lyophilized powder should be stored at 2-30°C.1 Following reconstitution with the 0.54% sodium chloride diluent provided by the manufacturer, Betaseron® and Extavia® solutions should be used immediately, but may be refrigerated at 2-8°C for up to 3 hours.1, 70 Both lyophilized drug and reconstituted solutions should not be frozen.1, 70
Dosage of interferon beta is expressed in terms of mg.1, 19, 20, 70 Potency of interferon beta also has been expressed in terms of international units;1, 19, 20, 70 each mg of interferon beta-1a is equivalent to approximately 200 million units of antiviral activity for Avonex® and 270 million units for Rebif®19, 20 and each mg of interferon beta-1b is equivalent to approximately 32 million units for Betaseron® and Extavia®.1, 70 Although commercially available preparations of interferon beta-1a (Avonex®, Rebif®) generally have similar specific activities on a mcg-for-mcg basis when tested using the same assay system, dosages of these interferon beta-1a preparations and interferon beta-1b expressed in terms of units or mcg are not directly comparable.33 Some experts state that the conversion of interferon beta-1a doses to interferon beta-1b doses can be calculated using published data, with the result that 6 million units (30 mcg) of Avonex® is approximately equivalent to 7-9 million units (220-280 mcg) of Betaseron®.21 However, commercially available interferon beta preparations should not be switched in the middle of a treatment regimen,60, 62 except for safety reasons, and patients should be cautioned not to change the dosage or schedule of administration of interferon beta except at the advice of their clinician.1, 19, 20, 70
For the management of relapsing forms of multiple sclerosis (MS), the recommended adult dosage of interferon beta-1a (Avonex®) is 30 mcg once weekly administered by IM injection.19 To reduce the incidence and severity of flu-like symptoms, therapy may be initiated at a dosage of 7.5 mcg once weekly, and then increased by increments of 7.5 mcg each week for the next 3 weeks to the recommended dosage of 30 mcg once weekly.19 A kit containing 3 titration devices is available to be used only with Avonex® prefilled syringes.19
For the management of relapsing forms of MS, the recommended adult dosage of interferon beta-1a (Rebif®) is 22 or 44 mcg 3 times weekly administered by subcutaneous injection.20 Injections should be administered, if possible, at the same time (preferably in the late afternoon or evening) on the same 3 days (e.g., Monday, Wednesday, and Friday) at least 48 hours apart each week.20 Treatment generally should be initiated at 20% of the prescribed dosage, and then gradually increased over a 4-week period to the target dosage of 22 or 44 mcg 3 times weekly using the schedule in Table 1.20 When titrating to the 22-mcg dose, only prefilled syringes (not auto-injectors) should be used.20
| Rebif® 22 mcg Target Dose | Rebif® 44 mcg Target Dose |
|---|---|---|
Weeks 1-2 | 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 | 11 mcg (use ½ of 22-mcg syringe) | 22 mcg (use full 22-mcg syringe or auto-injector) |
Weeks 5+ | 22 mcg (use full 22-mcg syringe or auto-injector) | 44 mcg (use full 44-mcg syringe or auto-injector) |
Interferon Beta-1b (Betaseron®, Extavia®)
For the management of relapsing forms of MS, the recommended adult dosage of interferon beta-1b (e.g., Betaseron®, Extavia®) is 0.25 mg every other day administered by subcutaneous injection.1, 61, 70 The manufacturer recommends that therapy be initiated at a dosage of 0.0625 mg, and then increased gradually over a 6-week period to the recommended dosage using the schedule in Table 2.1, 70
| Percentage of Target Dose | Betaseron® and Extavia® Dose | Volume |
|---|---|---|---|
Weeks 1-2 | 25% | 0.0625 mg | 0.25 mL |
Weeks 3-4 | 50% | 0.125 mg | 0.5 mL |
Weeks 5-6 | 75% | 0.1875 mg | 0.75 mL |
Weeks 7+ | 100% | 0.25 mg | 1 mL |
If a dose of interferon beta-1b (Betaseron®, Extavia®) is missed, the missed dose should be administered as soon as possible and the next scheduled dose should be administered approximately 48 hours later.1, 70 The drug should not be administered on 2 consecutive days.1, 70 If two doses are administered on consecutive days, or more than the prescribed dose is administered, the prescriber should be contacted immediately.1, 70
Asymptomatic elevations of hepatic transaminases are common with interferon therapy.20 The manufacturer of Rebif® recommends that dosage reduction be considered if serum ALT concentrations increase above 5 times the upper limit of normal; dosage may be gradually re-escalated when serum ALT concentrations return to normal.20
The manufacturers make no specific dosage recommendations for patients with renal impairment.1, 19, 20, 70
Clinical studies of interferon beta did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1, 19, 20, 70 In general, dosage of interferon beta should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.20 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.20
Severe hepatic injury, including autoimmune hepatitis and hepatic failure requiring liver transplantation, has been reported rarely in patients receiving interferon beta.1, 19, 20, 60, 62, 70 The drug should be initiated with caution in patients with active liver disease, alcohol abuse, increased serum ALT concentrations (exceeding 2.5 times the upper limit of normal), or a history of clinically important liver disease.20 In addition, the potential risks should be considered when interferon beta is used concomitantly with other drugs associated with hepatic injury (including alcohol) or when other drugs are added to an existing interferon beta treatment regimen.1, 19, 20, 70
Asymptomatic elevations in serum aminotransferase concentrations (particularly ALT) are reported commonly with interferon beta therapy.1, 19, 20, 70 Patients receiving interferon beta should be monitored for manifestations of hepatic injury.1, 19, 70 Liver function tests should be performed at regular intervals (e.g., 1, 3, and 6 months) following initiation of therapy and then periodically thereafter in the absence of clinical symptoms.1, 19, 20, 70 Some manufacturers recommend discontinuance of therapy if substantial elevations in serum aminotransferase concentrations or clinical manifestations of liver dysfunction (e.g., jaundice) occur.1, 19, 20, 70 The manufacturer of Rebif® recommends that dosage reduction be considered if serum ALT concentrations increase above 5 times the upper limit of normal; dosage may be gradually re-escalated when serum ALT concentrations return to normal.20
Some packaging components of certain formulations (e.g., Avonex® prefilled syringe cap, Extavia® prefilled diluent syringe and pen cap) contain natural rubber latex;19, 70 individuals sensitive to latex should not handle these packaging components.124, 125, 126 Safety of Extavia® reconstituted using the prefilled diluent syringe in latex-sensitive individuals has not been evaluated.70
Anaphylaxis or anaphylactoid reactions have been reported rarely in patients receiving interferon beta-1a or beta-1b.1, 19, 20, 70 Discontinue if anaphylaxis occurs.1, 19, 20, 70 Other sensitivity reactions reported in patients receiving interferon beta include dyspnea,1, 19 bronchospasm,1 orolingual edema,1, 19 mild to severe skin rash (maculopapular, erythematous, vesicular),1, 19, 20 and urticaria.1, 19, 20 Although a clear relationship to dose or duration of interferon beta therapy remains to be established, allergic reactions, some of which have been severe, have occurred after prolonged interferon beta therapy.20
Depression, suicidal ideation, and suicide attempts have been reported with increased frequency in patients receiving type I interferons (interferon alfa, interferon beta).1, 19, 20, 70 In addition, development of new or worsening of other preexisting psychiatric disorders, including psychosis, has been reported during postmarketing surveillance.19, 60 Depression, suicides, and suicide attempts have been reported during clinical studies evaluating interferon beta-1b (Betaseron®) and there have been postmarketing reports of suicide in patients receiving interferon beta-1a (Rebif®).1, 20 It is not known whether these neuropsychiatric symptoms are related to the underlying neurologic basis of MS, to interferon beta therapy, or to a combination of both.40
Patients receiving interferon beta preparations should be closely monitored for evidence of depression or other psychiatric symptoms; discontinuance of therapy should be considered if any such symptoms occur.1, 19, 20, 42, 70 Because there is a high prevalence of mood disorders in patients with MS, a history of depression is not an absolute contraindication to the use of interferon beta.42 However, some clinicians state that interferon beta therapy may be inappropriate in patients with a history of suicide attempts or major depressive ideation requiring psychiatric intervention or admission to a psychiatric institution.42 Although dosage reduction or treatment cessation may lead to resolution of the depressive symptomatology, depression may persist and suicides have occurred even after withdrawing interferon beta.60, 61, 62 However, a causal relationship between these events and interferon beta has not been established.60, 61, 62
Congestive heart failure (CHF), cardiomyopathy (with or without CHF),1, 19, 70 palpitations,1, 70 and tachycardia,1, 70 have been reported with some preparations of interferon beta during post marketing surveillance.1, 19, 70 In some cases, these events are temporally related to the administration of interferon beta-1b; recurrence upon rechallenge was observed in some patients.1, 19, 70
Patients with preexisting CHF should be monitored for worsening of their clinical condition during initiation and continued treatment with interferon beta.1, 19, 70 Some manufacturers state that discontinuance of therapy should be considered if worsening of CHF occurs with no other etiology.1, 70
Necrosis, a potentially severe injection site reaction, has been reported in patients receiving subcutaneous or intramuscular injections of interferon beta-1a or beta-1b in controlled trials.1, 19, 20, 70 60 Injection site necrosis usually occurs within the first 3-4 months of therapy, although there have been post-marketing surveillance reports of this adverse reaction occurring more than 2 years after initiation of therapy.1, 20, 61, 70 Necrosis may occur at single or multiple injection sites.1, 20 The necrotic lesions typically are 3 cm or less in diameter, but larger areas have been reported.1, 70 While necrosis has commonly extended only to subcutaneous fat, there are reports of necrosis extending to and including fascia overlying muscle.1, 70 In some lesions where biopsy results are available, vasculitis has been reported.1, 70
Factors that may be associated with the development of skin necrosis at injection sites include nonsterile injection techniques, administering cold interferon beta solutions, failure to rotate injection sites, and exposure of recent injection sites to UV light.40, 42 The pathogenic mechanism of injection site necrosis is as yet unknown, but may be caused by a hypersensitivity reaction localized to the blood vessels.40 Antibiotic treatment and debridement and/or skin grafting have been required.1, 20, 70 In most cases, healing was associated with scarring.1, 70
Because injection site necrosis has been reported with subcutaneous injections of interferon, patients receiving subcutaneous preparations should be periodically evaluated on their understanding and use of aseptic technique and proper procedures for self-administration.1, 19, 20, 70 Patients should be advised to promptly report any possible manifestations of injection site necrosis (e.g., any break in the skin, which may be associated with blue-black discoloration, swelling, or drainage of fluid at the injection site).1, 20, 70 Whether to discontinue therapy following a single site of necrosis depends on the extent of necrosis; if therapy is continued, the drug should not be administered into the affected area until it is fully healed.1, 19, 70 If multiple sites of necrosis occur, therapy should be discontinued until healing occurs.1, 70, 19
Following subcutaneous injection of interferon beta-1a or beta-1b, mild to moderate injection site reactions (e.g., hemorrhage,1 hypersensitivity,1 inflammation,1 mass,1 pain,1, 21 edema,1 atrophy,1 redness,21 induration21 ) were reported in approximately 78-92% of patients in controlled trials.1, 20 Following IM injection of interferon beta-1a, mild to moderate injection site reactions (e.g., pain, inflammation) were reported in 3-8% of patients in clinical studies;19, 29 ecchymosis at the injection site has been reported in 6% of patients.19 Injection site abscess or cellulitis, possibly requiring surgical intervention, has rarely been reported during post marketing surveillance.1, 19 These local reactions following IM or subcutaneous injection generally are more severe with more frequent and higher doses of interferon beta.60, 62
Decreased peripheral blood counts in all cell lines (e.g., pancytopenia, leukopenia, thrombocytopenia) have been reported in patients receiving interferon beta preparations.1, 19, 20, 70 Leukopenia, in some cases requiring dosage reduction, was reported in 18% of patients receiving interferon beta-1b (Betaseron®) in clinical studies; lymphocyte count less than 1500/mm3, absolute neutrophil count (ANC) less than 1500/mm3, and white blood cell count less than 3000/mm3 occurred in 86, 13, and 13%, respectively, of patients receiving the drug.1 In clinical studies of interferon beta-1a, leukopenia, thrombocytopenia, and anemia were reported in 28-36, 2-8, and 3-5%, respectively, of patients receiving Rebif®,20 and anemia was reported in 4% of patients receiving Avonex®.19 Some reported cases of thrombocytopenia involved nadirs below 10,000/mm3, and some recurred with rechallenge.19 Monitor patients for symptoms or signs of decreased blood counts, and monitor complete blood and differential white blood cell counts.1, 19, 20, 70 Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.1, 70
Thrombotic microangiopathy (TMA), including sometimes fatal thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, has been reported in patients receiving interferon beta therapy.1, 19, 20, 70 The onset of TMA ranged from several weeks to years after the drug was initiated.1, 19, 20, 70 If TMA occurs, discontinue treatment and manage as clinically indicated. 1, 19, 20, 70
Flu-like syndrome is one of the most common adverse effects associated with interferon beta therapy1, 19, 20, 40, 61, 70 and has been reported in up to 59% of patients with relapsing forms of MS who received the drug in clinical studies.1, 19, 20, 70 Symptoms reported include headache,19, 20, 70 fatigue,20 fever,19, 20, 70 chills,1, 19 malaise,1, 20, 70 myalgia,19, 20, 70 rigors,20 and/or arthralgia.19 Although there is considerable interindividual variation in the development of flu-like symptoms, these symptoms occur most frequently during initiation of interferon beta therapy (e.g., within hours or days after an injection)19, 62 and usually subside within a few months with continued therapy.40, 42
To prevent or reduce flu-like symptoms, analgesic and/or antipyretic agents (e.g., nonsteroidal anti-inflammatory agents [NSAIDS], acetaminophen) may be administered prophylactically on treatment days.1, 19, 20, 70 Some experts suggest advising patients to take an NSAID (e.g., ibuprofen) or acetaminophen 4 hours before, at the time of, and 4 hours after interferon beta injections; advising patients to administer the drug in the evenings (just prior to bedtime) may also allow patients to sleep through many of the symptoms.40, 42
Seizures also have been reported in temporal association with the use of interferon beta in clinical studies and during post marketing experience.1, 19, 20, 70 It is not known whether these events were related to a preexisting seizure disorder, to the effects of MS, to interferon beta therapy, or to a combination of these and other potential risk factors (e.g., fever).1, 19, 70
Some manufacturers recommend that the drug be used with caution in patients with preexisting seizure disorders.20 If patients with no seizure history develop seizures during interferon beta therapy, an etiologic basis should be established and appropriate anticonvulsant therapy instituted prior to considering resumption of therapy.60, 62
Drug-induced Lupus Erythematosus
Because autoimmune disorders of multiple target organs, including idiopathic thrombocytopenia, hyperthyroidism, hypothyroidism, and autoimmune hepatitis, have been reported during postmarketing experience with interferon beta,19, 20, 70 discontinuance of the drug should be considered if a new autoimmune disorder develops.19 Cases of drug-induced lupus ery19, 20 thematosus, sometimes associated with positive autoantibody test results (i.e., antinuclear antibodies [ANA] or antibodies to double-stranded DNA [anti-dsDNA]), also have been reported in patients receiving interferon beta.1, 20 Interferon beta therapy should be discontinued if patients develop any manifestations of lupus (e.g., rash, serositis, polyarthritis, nephritis, Raynaud phenomenon).1
Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) has been reported in patients administered interferon products in the absence of other contributory factors.1, 19, 20 Many reported cases of PAH required hospitalization; one patient underwent a lung transplant.1, 19, 20 PAH may occur at varying time points during interferon beta therapy including several years after treatment initiation.1, 19, 20
Assess patients who develop new onset dyspnea or increasing fatigue for the potential development of PAH.1, 19, 20 If alternative causes have been ruled out and a PAH diagnosis confirmed, discontinue interferon beta therapy and manage as clinically indicated.1, 19, 20
As with all therapeutic proteins, there is a potential for immunogenicity with interferon beta therapy.1, 19, 20, 70 Most patients with MS who receive long-term interferon beta therapy will develop either binding or neutralizing antibodies to the drug.21, 54, 55 Of the two types of antibodies, binding antibodies are the most prevalent and, in many cases, do not interfere with the receptor-mediated functions of interferon beta.21 It is possible, however, that these antibodies might increase the clearance of interferon beta through the reticuloendothelial system and, thereby, lower serum interferon beta concentrations.21 Development of binding antibodies has not been shown to be predictive of later development of neutralizing antibodies,56 which are capable of interfering with receptor-mediated functions and have been associated with reduced bioavailability and/or loss of biologic activity.21, 56, 57, 58, 59 The presence of neutralizing antibodies, particularly in persistently high titers, has been associated with reductions in radiographic and clinical efficacy of interferon beta therapy.74 Although patients who developed antibodies to interferon beta in some clinical studies did worse over time compared with those who did not develop these antibodies,60 the long-term consequences of neutralizing antibodies are as yet unknown.21 Neutralizing antibodies generally develop 6-24 months after initiation of therapy, after which the risk of developing such antibodies is low.74
In pivotal clinical studies in patients with MS, neutralizing antibodies were detected in 24-31% or 5% of patients receiving subcutaneous or IM interferon beta-1a, respectively, and in up to 45% of patients receiving interferon beta-1b.1, 19, 20, 70 Type of interferon preparation, dosing frequency, total dose,61 and route of administration have been suggested as factors that may affect the risk of antibody development.21, 55, 56, 57, 58, 74 Interferon beta-1a administered IM has been shown to be less immunogenic than subcutaneous administered interferon beta-1a or beta-1b, and some evidence also indicates that the rate of neutralizing antibody production is lower with interferon beta-1a compared with interferon beta-1b, although the persistence of these differences is difficult to determine.74
Because neutralizing antibody titers fluctuate over time and may even become undetectable despite continuous treatment,56, 58, 74 the development of antibodies during interferon beta therapy should not necessarily be interpreted as indicating permanent resistance to the drug. Some clinicians recommend that patients with MS who continue to have relapses despite several months of interferon beta (beta-1a or beta-1b) be tested for neutralizing antibodies.54, 61, 62 Neutralizing antibodies to interferon beta-1a and beta-1b are cross-reactive and switching from one interferon beta preparation (beta-1a, beta-1b) to another is unlikely to benefit patients in whom antibodies already have been induced.54, 55 Because the titer of serum neutralizing antibody level that is biologically important remains uncertain,54, 56 the benefits of routine testing for neutralizing antibodies in patients receiving interferon beta therapy are uncertain.21, 54, 74
There are no well-controlled studies in pregnant women; however, available data, including prospective observational studies, have generally not identified a drug-associated risk of major birth defects with the use of interferon beta during pregnancy.1, 19, 20, 70 Findings regarding a potential risk for low birth weight or miscarriage with the use of interferon beta in pregnancy have been inconsistent.20, 70 In a study in pregnant monkeys, administration of interferon beta during pregnancy resulted in an increased rate of abortion at doses greater than those used clinically; however, it is unclear whether, as a class of products, administration of interferon beta therapies to pregnant animals at doses greater than those used clinically results in an increased rate of abortion.19, 20, 70 Use interferon beta during pregnancy only if the potential benefits justify the possible risks to the fetus.1, 19, 20, 70
A population-based cohort study collected data from 1996--2014 in Finland and from 2005-2014 in Sweden for 2,831 pregnancy outcomes in women with MS.19, 20 In 797 of the pregnancies, women were exposed to only interferon beta; no evidence for an increased risk of birth defects was identified in comparison of women with MS exposed to interferon beta, and women with MS that were not exposed to any non-steroid therapies within the study.19, 20 Increased risk of miscarriage or ectopic pregnancy was not observed; however, data for these outcomes may have been incomplete, making interpretation of the findings more difficult.19, 20
Two smaller cohort studies that collected data on women exposed to interferon beta during pregnancy found that a decrease in mean birth weight may be associated with interferon beta exposure during pregnancy; however, this finding has not been replicated in larger observational studies.19, 20 Additionally, two small studies observed an increased rate of miscarriage, with only one study determining the findings to be statistically significant.19, 20 In a small cohort study, an increased risk of preterm birth was observed following exposure to interferon beta.19, 20
Limited data suggest that interferon beta-1a distributes into human milk.19, 20 There are no data on the presence of interferon beta-1b in human milk.1, 70 It is not known whether interferon beta has any effects on the breastfed infant or on milk production.1, 19, 20, 70 The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for interferon beta and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.1, 19, 20, 70
Females and Males of Reproductive Potential
Studies have not been conducted to date to determine whether interferon beta affects fertility in humans.19, 20 Menstrual irregularities, anovulation, and decreased serum progesterone concentrations have been observed in monkeys administered interferon beta at a dosage 100 times the recommended weekly human dosage (based on body surface area), with no effects observed at a dosage approximately 2 times the recommended weekly human dosage.19 These effects were reversible after discontinuance of the drug.19, 60 No effects of interferon beta were observed on either the menstrual cycle or associated hormonal profiles (e.g., progesterone, estradiol) in female cynomolgus or rhesus monkeys.1, 20
Studies in male cynomolgus monkeys treated with interferon beta-1a dosages up to 9 times the recommended human dosage (based on body surface area) did not result in any demonstrable adverse effect on sperm count, motility, morphology, or reproductive function.20
Interferon beta did not exhibit mutagenic potential in in vitro chromosomal aberration studies in human lymphocytes or in microbial (Ames) test systems with or without metabolic activation.1, 19, 20, 70
Although safety and efficacy of interferon beta in pediatric patients have not been established,1, 19, 20, 70 the drug has been used with variable results for the management of childhood onset MS.22, 77, 80 In the PARADIGMS trial, a double-dummy randomized trial comparing fingolimod to interferon beta-1a by weekly intramuscular injection, fingolimod was superior to interferon in reducing relapsing rates.77, 80 In another study that included a limited number of patients, treatment failure rates in children 10.5-17 years of age who received interferon beta-1a or beta-1b were higher than those reported in well-controlled studies in adults, but these results may be attributed to the selection of children with severe forms of childhood onset MS (i.e., with numerous relapses) or other unknown factors.22, 62 Adverse effects reported when interferon beta was used in children were similar to those reported in adults.22
Clinical studies of interferon beta did not include sufficient numbers of patients ≥65 years of age and older to determine whether geriatric patients respond differently than younger patients.1, 19, 20, 70
The safety and efficacy of interferon beta therapy have not been evaluated in hepatic impairment.1, 19, 20, 70
The safety and efficacy of interferon beta therapy have not been evaluated in renal impairment.1, 19, 20, 70
Interferon beta-1a (Avonex®): The most common adverse reactions (≥5%) in clinical studies were flu-like symptoms including chills, fever, myalgia, and asthenia.19
Interferon beta-1a (Rebif®): The most common adverse reactions in controlled clinical trials were injection site disorders, influenza-like symptoms, abdominal pain, depression, elevation of liver enzymes, and hematologic abnormalities.20
Interferon beta-1b (Betaseron®): The most common adverse reactions (≥5%) in clinical studies were injection site reaction, lymphopenia, flu-like symptoms, myalgia, leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, and asthenia.1
Interferon beta-1b (Extavia®): The most common adverse reactions (≥5%) in clinical studies were injection site reaction, lymphopenia, flu-like symptoms, myalgia, leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, and asthenia.70
Formal drug interaction studies have not been performed to date with interferon beta.1, 19, 20, 70
Drugs Affecting or Affected by Hepatic Microsomal Enzymes
No formal drug interaction studies have been conducted with interferon beta.1, 19, 20
Interferons are a family of naturally occurring proteins, produced by eukaryotic cells in response to viral infection and other biologic agents.1, 19, 70 Endogenous interferons (interferon alfa, interferon beta, interferon gamma) are potent cytokines produced and secreted principally by peripheral blood leukocytes, fibroblasts, and epithelial cells.2, 5 Interferon beta is a member of the type I subset of interferons.1, 19, 70 Binding of interferon beta to specific receptors on the surface of human cells initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers.1, 2, 5, 19, 21, 37, 70 These markers reflect a range of biologic activities of interferon beta, including effects on major histocompatibility complex (MHC) class-I gene expression, antiviral and anti-proliferative actions, and monocyte activation.2, 4, 5, 9, 21, 62
Interferon beta is a biosynthetic (recombinant DNA origin) form of naturally occurring interferon beta.1, 19, 20, 70 There currently are 2 different types of interferon beta (recombinant) commercially available in the US, interferon beta-1a19, 20 and interferon beta-1b.1, 70 Commercially available interferon beta-1a preparations (Avonex®, Rebif®) are recombinant preparations derived from Chinese hamster ovary (CHO) cells.19, 20 Commercially available interferon beta-1b preparations (Betaseron®, Extavia®) are nonglycosylated recombinant products derived from cultures of genetically modified Escherichia coli .1, 70
Although results of one pharmacodynamic study suggested that IM administration of interferon beta-1a resulted in substantially greater AUC for interferon beta activity compared with subcutaneous administration of the drug, results of subsequent studies have failed to find differences in terms of induction of the biologic response markers between the 2 types of interferon beta or between the different routes of administration.21, 46, 47
The mechanisms of action of interferon beta in the treatment of multiple sclerosis (MS) have not been fully elucidated1, 19, 20, 26, 70 but may involve immunomodulating effects, including anti-inflammatory effects.4, 8, 9, 37 It has been suggested that one mechanism may involve inhibition or suppression of the production and immunoactivating effects of interferon gamma;4, 8, 9, 37 interferon beta inhibits the production of interferon gamma, which appears to be involved in exacerbations of MS.4, 9, 26 The mechanism of action of the drug also may involve inhibition of release of other cytokines, such as tumor necrosis factor (TNF) and lymphotoxin (which both damage oligodendrocytes); inhibition of the proliferation of T cells, which release interferon gamma and lymphotoxin; and augmentation of suppressor T-cell function, which is deficient in MS.4, 9 Although the clinical importance is unclear, there is evidence that interleukin 10 (IL-10) concentrations in serum and CSF are increased in patients receiving interferon beta-1a.19, 26
The contribution, if any, of the antiviral activity of interferon beta to the drug's effect in MS currently is not known.4, 6, 62 While viral infection may precipitate acute exacerbations of MS, the precise pathophysiologic role of viral infection in the disease currently is unclear.4, 6, 62
Potency of interferon beta (recombinant DNA origin) has been expressed in international units (IU, units) of antiviral activity using a reference standard calibrated against the standard established by the World Health Organization (WHO) for natural interferon beta.1, 19, 20, 70
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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.
Betaseron®, Avonex®, Rebif®, and Extavia® are available through specialty pharmacy networks.1, 19, 20, 70 Clinicians may consult the respective manufacturer websites at [Web], [Web], [Web], or [Web] for specific availability information.1, 19, 20, 70
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IM use | 30 mcg per 0.5 mL | Avonex® (available as prefilled syringes and prefilled auto-injectors [Avonex Pen®]) | |
Injection, for subcutaneous use | 8.8 mcg per 0.2 mL | Rebif® (available as prefilled syringes and prefilled auto-injectors [Rebidose®]) | ||
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 |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | 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]) | |
Extavia® (with prefilled syringe containing 0.54% sodium chloride diluent, 27-gauge needle, vial adapter, and alcohol swabs) |
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