Interferon Beta 1b

Mechanism Of Action

The mechanism of action of BETASERON (interferon beta-1b) in patients with multiple sclerosis is unknown.

Pharmacodynamics

Interferons (IFNs) are a family of naturally occurring proteins, produced by eukaryotic cells in response to viral infection and other biologic agents. Three major types of interferons have been defined: type 1 (IFN-alpha, beta, epsilon, kappa and omega), type II (IFN–gamma) and type III (IFN-lambda). Interferon-beta is a member of the type I subset of interferons. The type I interferons have considerably overlapping but also distinct biologic activities. The bioactivities of all IFNs, including IFN-beta, are induced via their binding to specific receptors on the membranes of human cells. Differences in the bioactivities induced by the three major subtypes of IFNs likely reflect differences in the signal transduction pathways induced by signaling through their cognate receptors.

Interferon beta-1b receptor binding induces the expression of proteins that are responsible for the pleiotropic bioactivities of interferon beta-1b. A number of these proteins (including neopterin, β2-microglobulin, MxA protein, and IL-10) have been measured in blood fractions from BETASERON-treated patients and BETASERON-treated healthy volunteers. Immunomodulatory effects of interferon beta-1b include the enhancement of suppressor T cell activity, reduction of proinflammatory cytokine production, down-regulation of antigen presentation, and inhibition of lymphocyte trafficking into the central nervous system. It is not known if these effects play an important role in the observed clinical activity of BETASERON in multiple sclerosis (MS).

Pharmacokinetics

Because serum concentrations of interferon beta-1b are low or not detectable following subcutaneous administration of 0.25 mg or less of BETASERON, pharmacokinetic information in patients with MS receiving the recommended dose of BETASERON is not available.

Following single and multiple daily subcutaneous administrations of 0.5 mg BETASERON to healthy volunteers (N=12), serum interferon beta-1b concentrations were generally below 100 IU/mL. Peak serum interferon beta-1b concentrations occurred between one to eight hours, with a mean peak serum interferon concentration of 40 IU/mL. Bioavailability, based on a total dose of 0.5 mg BETASERON given as two subcutaneous injections at different sites, was approximately 50%.

After intravenous administration of BETASERON (0.006 mg to 2 mg), similar pharmacokinetic profiles were obtained from healthy volunteers (N=12) and from patients with diseases other than MS (N=142). In patients receiving single intravenous doses up to 2 mg, increases in serum concentrations were dose proportional. Mean serum clearance values ranged from 9.4 mL/min•kg-1 to 28.9 mL/min•kg-1 and were independent of dose. Mean terminal elimination half-life values ranged from 8 minutes to 4.3 hours and mean steady-state volume of distribution values ranged from 0.25 L/kg to 2.88 L/kg. Three-times-a-week intravenous dosing for two weeks resulted in no accumulation of interferon beta-1b in sera of patients. Pharmacokinetic parameters after single and multiple intravenous doses of BETASERON were comparable.

Following every other day subcutaneous administration of 0.25 mg BETASERON in healthy volunteers, biologic response marker levels (neopterin, β2- microglobulin, MxA protein, and the immunosuppressive cytokine, IL-10) increased significantly above baseline six-twelve hours after the first BETASERON dose. Biologic response marker levels peaked between 40 and 124 hours and remained elevated above baseline throughout the seven-day (168-hour) study. The relationship between serum interferon beta-1b levels or induced biologic response marker levels and the clinical effects of interferon beta-1b in multiple sclerosis is unknown.

Drug Interaction Studies

No formal drug interaction studies have been conducted with BETASERON.

Clinical Studies

The clinical effects of BETASERON were studied in four randomized, multicenter, double-blind, placebo-controlled studies in patients with multiple sclerosis (Studies 1, 2, 3, and 4).

The effectiveness of BETASERON in relapsing-remitting MS (RRMS) was evaluated in a double blind, multiclinic, randomized, parallel, placebo controlled clinical study of two years duration (Study 1). The study enrolled MS patients, aged 18 to 50, who were ambulatory [Kurtzke Expanded Disability Status Scale (EDSS) of ≤ 5.5 – score 5.5 is ambulatory for 100 meters, disability precludes full daily activities], exhibited a relapsing-remitting clinical course, met Poser's criteria for clinically definite and/or laboratory supported definite MS and had experienced at least two exacerbations over two years preceding the trial without exacerbation in the preceding month. The EDSS score is a method of quantifying disability in patients with MS and ranges from 0 (normal neurologic exam) to 10 (death due to MS). Patients who had received prior immunosuppressant therapy were excluded.

An exacerbation was defined as the appearance of a new clinical sign/symptom or the clinical worsening of a previous sign/symptom (one that had been stable for at least 30 days) that persisted for a minimum of 24 hours.

Patients selected for study were randomized to treatment with either placebo (N=123), 0.05 mg of BETASERON (N=125), or 0.25 mg of BETASERON (N=124) self-administered subcutaneously every other day. Outcome based on the 372 randomized patients was evaluated after two years.

Patients who required more than three 28-day courses of corticosteroids were removed from the study. Minor analgesics (acetaminophen, codeine), antidepressants, and oral baclofen were allowed ad libitum, but chronic nonsteroidal anti-inflammatory drug (NSAID) use was not allowed.

The primary protocol-defined outcome measures were 1) frequency of exacerbations per patient and 2) proportion of exacerbation free patients. A number of secondary clinical and magnetic resonance imaging (MRI) measures were also employed. All patients underwent annual T2 MRI imaging and a subset of 52 patients at one site had MRIs performed every six weeks for assessment of new or expanding lesions.

The study results are shown in Table 3.

Table 3: Two Year RRMS Study Results of Primary and Secondary Clinical Outcomes (Study 1)

Of the 372 RRMS patients randomized, 72 (19%) failed to complete two full years on their assigned treatments.

Over the two-year period in Study 1, there were 25 MS-related hospitalizations in the 0.25 mg BETASERON-treated group compared to 48 hospitalizations in the placebo group. In comparison, non-MS hospitalizations were evenly distributed among the groups, with 16 in the 0.25 mg BETASERON group and 15 in the placebo group. The average number of days of MS-related steroid use was 41 days in the 0.25 mg BETASERON group and 55 days in the placebo group (p=0.004).

MRI data were also analyzed for patients in this study. A frequency distribution of the observed percent changes in MRI area at the end of two years was obtained by grouping the percentages in successive intervals of equal width. Figure 1 displays a histogram of the proportions of patients, which fell into each of these intervals. The median percent change in MRI area for the 0.25 mg group was -1.1%, which was significantly smaller than the 16.5% observed for the placebo group (p=0.0001).

Figure 1: Distribution of Change in MRI Area in Patients with RRMS in Study 1

In an evaluation of frequent MRI scans (every six weeks) on 52 patients at one site in Study 1, the percent of scans with new or expanding lesions was 29% in the placebo group and 6% in the 0.25 mg treatment group (p=0.006).

The exact relationship between MRI findings and clinical status of patients is unknown. Changes in lesion area often do not correlate with changes in disability progression. The prognostic significance of the MRI findings in this study has not been evaluated.

Studies 2 and 3 were multicenter, randomized, double-blind, placebo controlled trials conducted to assess the effect of BETASERON in patients with secondary progressive MS (SPMS). Study 2 was conducted in Europe and Study 3 was conducted in North America. Both studies enrolled patients with clinically definite or laboratory-supported MS in the secondary progressive phase, and who had evidence of disability progression (both Study 2 and 3) or two relapses (Study 2 only) within the previous two years. Baseline Kurtzke expanded disability status scale (EDSS) scores ranged from 3.0 to 6.5. Patients in Study 2 were randomized to receive BETASERON 0.25 mg (N=360) or placebo (N=358). Patients in Study 3 were randomized to BETASERON 0.25 mg (N=317), BETASERON 0.16 mg/m² of body surface area (N=314, mean assigned dose 0.3 mg), or placebo (N=308). Test agents were administered subcutaneously, every other day for three years.

The primary outcome measure was progression of disability, defined as a 1.0 point increase in the EDSS score, or a 0.5 point increase for patients with baseline EDSS ≥ 6.0. In Study 2, time to progression in EDSS was longer in the BETASERON treatment group (p=0.005), with estimated annualized rates of progression of 16% and 19% in the BETASERON and placebo groups, respectively. In Study 3, the rates of progression did not differ significantly between treatment groups, with estimated annualized rates of progression of 12%, 14%, and 12% in the BETASERON fixed dose, surface area-adjusted dose, and placebo groups, respectively.

Multiple analyses, including covariate and subset analyses based on sex, age, disease duration, clinical disease activity prior to study enrollment, MRI measures at baseline and early changes in MRI following treatment were evaluated in order to interpret the discordant study results. No demographic or disease-related factors enabled identification of a patient subset where BETASERON treatment was predictably associated with delayed progression of disability.

In Studies 2 and 3, like Study 1, a statistically significant decrease in the incidence of relapses associated with BETASERON treatment was demonstrated. In Study 2, the mean annual relapse rates were 0.42 and 0.63 in the BETASERON and placebo groups, respectively (p < 0.001). In Study 3, the mean annual relapse rates were 0.16, 0.20, and 0.28, for the fixed dose, surface area-adjusted dose, and placebo groups, respectively (p < 0.02).

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 in the BETASERON groups compared to the placebo group. The exact relationship between MRI findings and the clinical status of patients is unknown. Changes in MRI findings often do not correlate with changes in disability progression. The prognostic significance of the MRI findings in these studies is not known.

In Study 4, 468 patients who had recently (within 60 days) experienced an isolated demyelinating event, and who had lesions typical of multiple sclerosis on brain MRI were randomized to receive either 0.25 mg BETASERON (N=292) or placebo (N=176) subcutaneously every other day (ratio 5:3). The primary outcome measure was time to development of a second exacerbation with involvement of at least two distinct anatomical regions. Secondary outcomes were brain MRI measures, including the cumulative number of newly active lesions, and the absolute change in T2 lesion volume. Patients were followed for up to two years or until they fulfilled the primary endpoint.

Eight percent of subjects on BETASERON and 6% of subjects on placebo withdrew from the study for a reason other than the development of a second exacerbation. Time to development of a second exacerbation was significantly delayed in patients treated with BETASERON compared to patients treated with placebo (p < 0.0001). The Kaplan-Meier estimates of the percentage of patients developing an exacerbation within 24 months were 45% in the placebo group and 28% of the BETASERON group (Figure 2). The risk for developing a second exacerbation in the BETASERON group was 53% of the risk in the placebo group (Hazard ratio= 0.53; 95% confidence interval 0.39 to 0.73).

Figure 2: Onset of Second Exacerbation by Time in Patients with Isolated Demyelinating Event with Typical MS Lesions on Brain MRI in Study 4*

In Study 4, patients treated with BETASERON demonstrated a lower number of newly active lesions during the course of the study. A significant difference between BETASERON and placebo was not seen in the absolute change in T2 lesion volume during the course of the study.

Safety and efficacy of treatment with BETASERON beyond three years are not known.

Use the medication as soon as you remember the missed dose. Then wait at least 48 hours before using another injection, and restart your dosing schedule at that time. Do not use more than one injection every 48 hours (2 days).

Tell your doctor about all your medical conditions, including if you have:  

• or had depression, anxiety (feeling uneasy, nervous, or fearful), or trouble sleeping 
• liver problems 
• thyroid problems
• blood problems, such as bleeding or bruising easily, and low red blood cells (anemia) or low white blood cells
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Interferon beta-1b falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Interferon beta-1b is injected under the skin once every 48 hours (2 days). You may be shown how to use injections at home. Do not self-inject this medicine if you do not understand how to give the injection and properly dispose of used needles and syringes.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Interferon beta-1b is a powder medicine that must be mixed with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix the medicine.

Store unmixed medicine at room temperature away from moisture and heat.

After mixing interferon beta-1b, store in the refrigerator and use within 3 hours. Do not freeze.

Each single-use vial (bottle) of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Your care provider will show you the best places on your body to inject interferon beta-1b. Use a different place each time you give an injection. Do not inject into the same place two times in a row.

You will need frequent blood tests to check your liver function.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

• If you have an allergy to interferon beta-1b or any other part of interferon beta-1b.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are breast-feeding or plan to breast-feed.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about interferon beta-1b, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about interferon beta-1b. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using interferon beta-1b.

Review Date: October 4, 2017

(in ter FEER on BAY ta won bee)

Refer to adult dosing.

>10%:

Cardiovascular: Peripheral edema (12% to 15%), chest pain (9% to 11%)

Central nervous system: Headache (50% to 57%), pain (42% to 51%), hypertonia (40% to 50%), myasthenia (46%), chills (21% to 25%), dizziness (24%), insomnia (21% to 24%), ataxia (17% to 21%)

Dermatologic: Skin rash (21% to 24%), dermatological disease (10% to 12%)

Gastrointestinal: Nausea (27%), constipation (20%), diarrhea (19%), abdominal pain (16% to 19%), dyspepsia (14%)

Genitourinary: Urinary urgency (11% to 13%), uterine hemorrhage (9% to 11%)

Hematologic & oncologic: Lymphocytopenia (86% to 88%), leukopenia (13% to 18%), neutropenia (13% to 14%)

Immunologic: Antibody development (≤45%; neutralizing; significance not known)

Local: Injection site reaction (78% to 85%; including inflammation [53%], pain [18%], tissue necrosis [4% to 5%], hypersensitivity reaction [4%], swelling [2% to 3%], residual mass [2%])

Neuromuscular & skeletal: Weakness (53% to 61%), arthralgia (31%), myalgia (23% to 27%)

Respiratory: Flu-like symptoms (decreases over treatment course; 57% to 60%)

Miscellaneous: Fever (31% to 36%)

1% to 10%:

Cardiovascular: Vasodilatation (8%), hypertension (6% to 7%), peripheral vascular disease (6%), palpitations (4%), tachycardia (4%)

Central nervous system: Anxiety (10%), malaise (6% to 8%), nervousness (7%)

Dermatologic: Diaphoresis (8%), alopecia (4%)

Endocrine & metabolic: Hypermenorrhea (8%), dysmenorrhea (7%), weight gain (7%)

Genitourinary: Impotence (8% to 9%), cystitis (8%), urinary frequency (7%), pelvic pain (6%), prostatic disease (3%)

Hematologic & oncologic: Lymphadenopathy (6% to 8%)

Hepatic: Increased serum ALT (>5x baseline: 10% to 12%), increased serum AST (>5x baseline: 3% to 4%)

Hypersensitivity: Hypersensitivity (3%)

Neuromuscular & skeletal: Leg cramps (4%)

Respiratory: Dyspnea (6% to 7%)

<1% (Limited to important or life-threatening): Anaphylaxis, anorexia, apnea, ataxia, autoimmune hepatitis, capillary leak syndrome (in patients with preexisting monoclonal gammopathy), cardiac arrhythmia, cardiomegaly, cardiomyopathy, cerebral hemorrhage, coma, confusion, convulsion, deep vein thrombosis, delirium, depersonalization, depression, emotional lability, erythema nodosum, ethanol sensitization, exfoliative dermatitis, gastrointestinal hemorrhage, hallucinations, hematemesis, hemolytic-uremic syndrome, hepatic failure, hepatitis, hepatotoxicity (idiosyncratic) (Chalasani 2014), hyperthyroidism, hyperuricemia, hypocalcemia, increased gamma-glutamyl transferase, increased serum triglycerides, lupus erythematosus, maculopapular rash, manic behavior, myocardial infarction, pancreatitis, pericardial effusion, pneumonia, pruritus, psychosis, pulmonary embolism, pulmonary hypertension (Govern 2015; Health Canada Nov. 2, 2016), rash, sepsis, shock, skin discoloration, skin photosensitivity, suicidal ideation, syncope, SIADH, thrombocytopenia, thrombotic thrombocytopenic purpura, thyroid dysfunction, urinary tract infection, urosepsis, vasculitis, vaginal hemorrhage, vesiculobullous dermatitis, weight loss