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DRUGS & SUPPLEMENTS
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When are you taking this medicine? |
Uribeta (interferon beta-1b) is indicated for the treatment of relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations. Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis.
Uribeta is an interferon beta indicated for the treatment of relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations. Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. (1)
The recommended starting dose is 0.0625 mg (0.25 mL) subcutaneously every other day, with dose increases over a six-week period to the recommended dose of 0.25 mg (1 mL) every other day.
1 Dosed every other day, subcutaneously | |||
Uribeta Dose1 | Percentage of recommended dose | Volume | |
Weeks 1-2 | 0.0625 mg | 25% | 0.25 mL |
Weeks 3-4 | 0.125 mg | 50% | 0.5 mL |
Weeks 5-6 | 0.1875 mg | 75% | 0.75 mL |
Week 7 and thereafter | 0.25 mg | 100% | 1 mL |
If a dose of Uribeta is missed, then it should be taken as soon as the patient remembers or is able to take it. The patient should not take Uribeta on two consecutive days. The next injection should be taken about 48 hours (two days) after that dose. If the patient accidentally takes more than their prescribed dose, or takes it on two consecutive days, they should be instructed to call their healthcare provider immediately.
Prior to reconstitution, verify that the vial containing lyophilized Uribeta is not cracked or damaged. Do not use cracked or damaged vials.
(b) To reconstitute lyophilized Uribeta for injection, attach the pre-filled syringe containing the diluent (Sodium Chloride, 0.54% Solution) to the Uribeta vial using the vial adapter.
The removable rubber cap of the diluent (Sodium Chloride, 0.54% Solution) pre-filled syringe contains natural rubber latex, which may cause allergic reactions and should not be handled by latex-sensitive individuals.
(c) Slowly inject 1.2 mL of diluent into the Uribeta vial.
(d) Gently swirl the vial to dissolve the lyophilized powder completely; do not shake. Foaming may occur during reconstitution or if the vial is swirled or shaken too vigorously. If foaming occurs, allow the vial to sit undisturbed until the foam settles.
(e) 1 mL of reconstituted Uribeta solution contains 0.25 mg of Uribeta.
(f) After reconstitution, if not used immediately, refrigerate the reconstituted Uribeta solution at 35°F to 46°F (2°C to 8°C) and use within three hours. Do not freeze.
(a) Perform the first Uribeta injection under the supervision of an appropriately qualified healthcare professional. If patients or caregivers are to administer Uribeta, train them in the proper subcutaneous injection technique and assess their ability to inject subcutaneously to ensure the proper administration of Uribeta.
(b) Visually inspect the reconstituted Uribeta solution before use; discard if it contains particulate matter or is discolored.
(c) Keeping the syringe and vial adapter in place, turn the assembly over so that the vial is on top. Withdraw the appropriate dose of Uribeta solution. Remove the vial from the vial adapter before injecting Uribeta.
(d) Use safe disposal procedures for needles and syringes.
(e) Do not re-use needles or syringes.
(f) Advise patients and caregivers to rotate sites for subcutaneous injections to minimize the likelihood of severe injection site reactions, including necrosis or localized infection.
Concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with Uribeta use .
For injection: 0.3 mg lyophilized powder in a single-use vial for reconstitution.
For injection: 0.3 mg of lyophilized powder in a single-use vial for reconstitution (3)
Uribeta is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, Albumin (Human), or any other component of the formulation.
History of hypersensitivity to natural or recombinant interferon beta, albumin or mannitol (4)
Severe hepatic injury including cases of hepatic failure, some of which have been due to autoimmune hepatitis, has been rarely reported in patients taking Uribeta. In some cases, these events have occurred in the presence of other drugs or comorbid medical conditions that have been associated with hepatic injury. Consider the potential risk of Uribeta used in combination with known hepatotoxic drugs or other products (e.g., alcohol) prior to Uribeta administration, or when adding new agents to the regimen of patients already on Uribeta. Monitor patients for signs and symptoms of hepatic injury. Consider discontinuing Uribeta if serum transaminase levels significantly increase, or if they are associated with clinical symptoms such as jaundice.
Asymptomatic elevation of serum transaminases is common in patients treated with Uribeta. In controlled clinical trials, elevations of SGPT to greater than five times baseline value were reported in 12% of patients receiving Uribeta (compared to 4% on placebo), and increases of SGOT to greater than five times baseline value were reported in 4% of patients receiving Uribeta (compared to 1% on placebo), leading to dose-reduction or discontinuation of treatment in some patients . Monitor liver function tests .
Anaphylaxis has been reported as a rare complication of Uribeta use. Other allergic reactions have included dyspnea, bronchospasm, tongue edema, skin rash, and urticaria . Discontinue Uribeta if anaphylaxis occurs.
The removable rubber cap of the diluent (Sodium Chloride, 0.54% Solution) pre-filled syringe contains natural rubber latex, which may cause allergic reactions and should not be handled by latex-sensitive individuals. The safe use of Uribeta pre-filled syringe in latex-sensitive individuals has not been studied.
Depression and suicide have been reported to occur with increased frequency in patients receiving interferon beta products, including Uribeta. Advise patients to report any symptom of depression and/or suicidal ideation to their healthcare provider. If a patient develops depression, discontinuation of Uribeta therapy should be considered.
In randomized controlled clinical trials, there were three suicides and eight suicide attempts among the 1532 patients on Uribeta compared to one suicide and four suicide attempts among 965 patients on placebo.
Monitor patients with preexisting congestive heart failure for worsening of their cardiac condition during initiation of and continued treatment with Uribeta. While beta interferons do not have any known direct-acting cardiac toxicity, cases of CHF, cardiomyopathy, and cardiomyopathy with CHF have been reported in patients without known predisposition to these events, and without other known etiologies being established. In some cases, these events have been temporally related to the administration of Uribeta. Recurrence upon rechallenge was observed in some patients. Consider discontinuation of Uribeta if worsening of CHF occurs with no other etiology.
Injection site necrosis (ISN) was reported in 4% of interferon beta-1b-treated patients in controlled clinical trials (compared to 0% on placebo) . Typically, ISN occurs within the first four months of therapy, although postmarketing reports have been received of ISN occurring over one year after initiation of therapy. The necrotic lesions are typically 3 cm or less in diameter, but larger areas have been reported. Generally the necrosis has extended only to subcutaneous fat, but has extended to the fascia overlying muscle. In some lesions where biopsy results are available, vasculitis has been reported. For some lesions, debridement, and/or skin grafting have been required. In most cases healing was associated with scarring.
Whether to discontinue therapy following a single site of necrosis is dependent on the extent of necrosis. For patients who continue therapy with Uribeta after injection site necrosis has occurred, avoid administration of Uribeta into the affected area until it is fully healed. If multiple lesions occur, discontinue therapy until healing occurs.
Periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures, particularly if injection site necrosis has occurred.
In controlled clinical trials, injection site reactions occurred in 78% of patients receiving Uribeta with injection site necrosis in 4%. Injection site inflammation (42%), injection site pain (16%), injection site hypersensitivity (4%), injection site necrosis (4%), injection site mass (2%), injection site edema (2%) and nonspecific reactions were significantly associated with Uribeta treatment. The incidence of injection site reactions tended to decrease over time. Approximately 69% of patients experienced injection site reactions during the first three months of treatment, compared to approximately 40% at the end of the studies.
In controlled clinical trials, leukopenia was reported in 18% of patients receiving Uribeta, leading to a reduction of the dose of Uribeta in some patients . Monitoring of complete blood and differential white blood cell counts is recommended. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.
Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with interferon beta products, including Uribeta. Cases have been reported several weeks to years after starting interferon beta products. Discontinue Uribeta if clinical symptoms and laboratory findings consistent with TMA occur, and manage as clinically indicated.
In controlled clinical trials, the rate of flu-like symptom complex for patients on Uribeta was 57% . The incidence decreased over time, with 10% of patients reporting flu-like symptom complex at the end of the studies. The median duration of flu-like symptom complex in Study 1 was 7.5 days . Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with Uribeta use.
Seizures have been temporally associated with the use of beta interferons in clinical trials and postmarketing safety surveillance. It is not known whether these events were related to a primary seizure disorder, the effects of multiple sclerosis alone, the use of beta interferons, other potential precipitants of seizures (e.g., fever), or to some combination of these.
Cases of drug-induced lupus erythematosus have been reported with some interferon beta products, including Uribeta. Signs and symptoms of drug-induced lupus reported in EXTAVIA-treated patients have included rash, serositis, polyarthritis, nephritis, and Raynaud’s phenomenon. Cases have occurred with positive serologic testing. If EXTAVIA-treated patients develop new signs and symptoms characteristic of this syndrome, Uribeta therapy should be stopped.
In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and differential white blood cell counts, platelet counts and blood chemistries, including liver function tests, are recommended at regular intervals (one, three, and six months) following introduction of Uribeta therapy, and then periodically thereafter in the absence of clinical symptoms.
The following serious adverse reactions are discussed in more details in other sections of labeling:
In controlled clinical trials, the most common adverse reactions (at least 5% more frequent on Uribeta than on placebo) were: injection site reaction, lymphopenia, flu-like symptoms, myalgia, leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, and asthenia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Because clinical trials are conducted under widely varying conditions and over varying lengths of time, adverse reaction rates observed in the clinical trials of Uribeta cannot be directly compared to rates in clinical trials of other drugs, and may not reflect the rates observed in practice.
Among 1407 patients with MS treated with Uribeta 0.25 mg every other day (including 1261 patients treated for greater than one year), the most commonly reported adverse reactions (at least 5% more frequent on Uribeta than on placebo) were injection site reaction, lymphopenia, flu-like symptoms, myalgia leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, and asthenia. The most frequently reported adverse reactions resulting in clinical intervention (for example, discontinuation of Uribeta, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) were depression, flu-like symptom complex, injection site reactions, leukopenia, increased liver enzymes, asthenia, hypertonia, and myasthenia.
Table 2 enumerates adverse reactions and laboratory abnormalities that occurred among patients treated with 0.25 mg of Uribeta every other day by subcutaneous injection in the pooled placebo-controlled trials (Study 1-4) at an incidence that was at least 2% more than that observed in the placebo-treated patients .
Adverse Reaction | Placebo (N=965) | Uribeta (N=1407) |
Blood and lymphatic system disorders | ||
Lymphocytes count decreased (<1500/mm3) | 66% | 86% |
Absolute neutrophil count decreased (<1500/mm3) | 5% | 13% |
White blood cell count decreased (<3000/mm3) | 4% | 13% |
Lymphadenopathy | 3% | 6% |
Nervous system disorders | ||
Headache | 43% | 50% |
Insomnia | 16% | 21% |
Incoordination | 15% | 17% |
Vascular disorders | ||
Hypertension | 4% | 6% |
Respiratory, thoracic and mediastinal disorders | ||
Dyspnea | 3% | 6% |
Gastrointestinal disorders | ||
Abdominal pain | 11% | 16% |
Hepatobiliary disorders | ||
Alanine aminotransferase increased (SGPT > 5 times baseline) | 4% | 12% |
Aspartate aminotransferase increased (SGOT > 5 times baseline) | 1% | 4% |
Skin and subcutaneous tissue disorders | ||
Rash | 15% | 21% |
Skin disorder | 8% | 10% |
Musculoskeletal and connective tissue disorders | ||
Hypertonia | 33% | 40% |
Myalgia | 14% | 23% |
Renal and urinary disorders | ||
Urinary urgency | 8% | 11% |
Reproductive system and breast disorders | ||
Metrorrhagia | 7% | 9% |
Impotence | 6% | 8% |
General disorders and administration site conditions | ||
Injection site reaction 1 | 26% | 78% |
Asthenia | 48% | 53% |
Flu-like symptoms (complex) 2 | 37% | 57% |
Pain | 35% | 42% |
Fever | 19% | 31% |
Chills | 9% | 21% |
Peripheral edema | 10% | 12% |
Chest pain | 6% | 9% |
Malaise | 3% | 6% |
Injection site necrosis | 0% | 4% |
1 "Injection site reaction" comprises all adverse reactions occurring at the injection site (except injection site necrosis), that is, the following terms: injection site reaction, injection site hemorrhage, injection site hypersensitivity, injection site inflammation, injection site mass, injection site pain, injection site edema and injection site atrophy. 2 "Flu-like symptom (complex)" denotes flu syndrome and/or a combination of at least two adverse reactions from fever, chills, myalgia, malaise, sweating. |
In addition to the adverse reactions listed in Table 2, the following adverse reactions occurred more frequently on Uribeta than on placebo, but with a difference smaller than 2%: alopecia, anxiety, arthralgia, constipation, diarrhea, dizziness, dyspepsia, dysmenorrhea, leg cramps, menorrhagia, myasthenia, nausea, nervousness, palpitations, peripheral vascular disorder, prostatic disorder, tachycardia, urinary frequency, vasodilatation, and weight increase.
Laboratory Abnormalities
In the four clinical trials (Studies 1, 2, 3, and 4), leukopenia was reported in 18% and 6% of patients in interferon beta-1b- and placebo-treated groups, respectively. No patients were withdrawn or dose reduced for neutropenia in Study 1. Three percent (3%) of patients in Studies 2 and 3 experienced leukopenia and were dose-reduced. Other abnormalities included increase of SGPT to greater than five times baseline value (12%), and increase of SGOT to greater than five times baseline value (4%). In Study 1, two patients were dose reduced for increased hepatic enzymes; one continued on treatment and one was ultimately withdrawn. In Studies 2 and 3, 1.5% of Uribeta patients were dose-reduced or interrupted treatment for increased hepatic enzymes. In Study 4, 1.7% of patients were withdrawn from treatment due to increased hepatic enzymes, two of them after a dose reduction. In Studies 1-4, nine (0.6%) patients were withdrawn from treatment with Uribeta for any laboratory abnormality, including four (0.3%) patients following dose reduction.
As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples were monitored for the development of antibodies to Uribeta during Study 1. In patients receiving 0.25 mg every other day 56/124 were found to have serum neutralizing activity at one or more of the time points tested. In Study 4, neutralizing activity was measured every 6 months and at end of study. At individual visits after start of therapy, activity was observed in 17% up to 25% of the interferon beta-1b-treated patients. Such neutralizing activity was measured at least once in 75 (30%) out of 251 Uribeta patients who provided samples during treatment phase; of these, 17 (23%) converted to negative status later in the study. Based on all the available evidence, the relationship between antibody formation and clinical safety or efficacy is not known.
These data reflect the percentage of patients whose test results were considered positive for antibodies to Uribeta using a biological neutralization assay that measures the ability of immune sera to inhibit the production of the interferon-inducible protein, MxA. Neutralization assays are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of neutralizing activity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Uribeta with the incidence of antibodies to other products may be misleading.
Anaphylactic reactions have been reported with the use of Uribeta .
The following adverse reactions have been identified during postapproval use of Uribeta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: Anemia, Thrombocytopenia
Endocrine disorders: Hypothyroidism, Hyperthyroidism, Thyroid dysfunction
Metabolism and nutrition disorders: Triglyceride increased, Anorexia, Weight decrease, Weight increase
Psychiatric disorders: Anxiety, Confusion, Emotional lability
Nervous system disorders: Convulsion, Dizziness, Psychotic symptoms
Cardiac disorders: Cardiomyopathy, Palpitations, Tachycardia
Vascular disorders: Vasodilatation
Respiratory, thoracic and mediastinal disorders: Bronchospasm
Gastrointestinal disorders: Diarrhea, Nausea, Pancreatitis, Vomiting
Hepatobiliary disorders: Hepatitis, Gamma GT increased
Skin and subcutaneous tissue disorders: Alopecia, Pruritus, Skin discoloration, Urticaria
Musculoskeletal and connective tissue disorders: Arthralgia; drug-induced lupus erythematosus
Reproductive system and breast disorder: Menorrhagia
General disorders and administration site conditions: Fatal capillary leak syndrome*
*The administration of cytokines to patients with a preexisting monoclonal gammopathy has been associated with the development of this syndrome.
Pregnancy: Based on animal data, may cause fetal harm
Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women; however, spontaneous abortions while on treatment were reported in four patients participating in the Uribeta RRMS clinical trial. Uribeta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
When Uribeta (doses ranging from 0.028 to 0.42 mg/kg/day) was administered to pregnant rhesus monkeys throughout the period of organogenesis (gestation days 20 to 70), a dose-related abortifacient effect was observed. The low-effect dose is approximately 3 times the recommended human dose of 0.25 mg on a body surface area (mg/m2) basis. A no-effect dose for embryo-fetal developmental toxicity in rhesus monkeys was not established.
It is not known whether Uribeta is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Uribeta, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of drug to the mother.
Safety and efficacy in pediatric patients have not been established.
Clinical studies of Uribeta did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.
Uribeta (interferon beta-lb) is a purified, sterile, lyophilized protein product produced by recombinant DNA techniques. Uribeta is manufactured by bacterial fermentation of a strain of Escherichia coli that bears a genetically engineered plasmid containing the gene for human interferon betaser17. The native gene was obtained from human fibroblasts and altered in a way that substitutes serine for the cysteine residue found at position 17. Uribeta has 165 amino acids and an approximate molecular weight of 18,500 daltons. It does not include the carbohydrate side chains found in the natural material.
The specific activity of Uribeta is approximately 32 million international units (IU)/mg interferon beta-lb. Each vial contains 0.3 mg of interferon beta-lb. The unit measurement is derived by comparing the antiviral activity of the product to the World Health Organization (WHO) reference standard of recombinant human interferon beta. Mannitol, USP and Albumin (Human), USP (15 mg each/vial) are added as stabilizers.
Lyophilized Uribeta is a sterile, white to off-white powder, for subcutaneous injection after reconstitution with the diluent supplied (Sodium Chloride, 0.54% Solution). Each vial contains Albumin (Human) USP (15 mg) and Mannitol, USP (15 mg).
The mechanism of action of Uribeta in patients with multiple sclerosis is unknown.
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.
Uribeta receptor binding induces the expression of proteins that are responsible for the pleiotropic bioactivities of Uribeta. A number of these proteins (including neopterin, β2-microglobulin, MxA protein, and IL-10) have been measured in blood fractions from interferon beta-1b-treated patients and interferon beta-1b-treated healthy volunteers. Immunomodulatory effects of Uribeta include the enhancement of suppressor T cell activity, reduction of pro-inflammatory 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 Uribeta in multiple sclerosis (MS).
Because serum concentrations of Uribeta are low or not detectable following subcutaneous administration of 0.25 mg or less of Uribeta, pharmacokinetic information in patients with MS receiving the recommended dose of Uribeta is not available.
Following single and multiple daily subcutaneous administrations of 0.5 mg Uribeta to healthy volunteers (N=12), serum Uribeta concentrations were generally below 100 IU/mL. Peak serum Uribeta 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 Uribeta given as two subcutaneous injections at different sites, was approximately 50%.
After intravenous administration of Uribeta (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 Uribeta in sera of patients. Pharmacokinetic parameters after single and multiple intravenous doses of Uribeta were comparable.
Following every other day subcutaneous administration of 0.25 mg Uribeta 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 Uribeta 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 Uribeta levels or induced biologic response marker levels and the clinical effects of Uribeta in multiple sclerosis is unknown.
Drug Interaction Studies
No formal drug interaction studies have been conducted with Uribeta.
Carcinogenesis
Uribeta has not been tested for its carcinogenic potential in animals.
Mutagenesis
Uribeta was not genotoxic in the in vitro Ames bacterial test or the in vitro chromosomal aberration assay in human peripheral blood lymphocytes. Uribeta treatment of mouse BALBc-3T3 cells did not result in increased transformation frequency in an in vitro model of tumor transformation.
Impairment of Fertility
Administration of Uribeta (doses of up to 0.33 mg/kg/day) to normally cycling female rhesus monkeys had no apparent adverse effects on either menstrual cycle duration or associated hormonal profiles (progesterone and estradiol) when administered over three consecutive menstrual cycles. The highest dose tested is approximately 30 times the recommended human dose of 0.25 mg on a body surface area (mg/m2) basis. The potential for other effects on fertility or reproductive performance was not evaluated.
The clinical effects of Uribeta were studied in four randomized, multicenter, double-blind, placebo-controlled studies in patients with multiple sclerosis (Studies 1, 2, 3, and 4).
Patients with Relapsing-Remitting Multiple Sclerosis
The effectiveness of Uribeta 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 Uribeta (N=125), or 0.25 mg of Uribeta (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.
Efficacy Parameters | Treatment Groups | Statistical Comparisons p-value | |||||
Primary End Points | Placebo (N=123) | Uribeta 0.05 mg (N=125) | Uribeta 0.25 mg (N=124) | Placebo vs 0.05 mg | 0.05 mg vs 0.25 mg | Placebo vs 0.25 mg | |
Annual exacerbation rate | 1.31 | 1.14 | 0.9 | 0.005 | 0.113 | 0.0001 | |
Proportion of exacerbation-free patients1 | 16% | 18% | 25% | 0.609 | 0.288 | 0.094 | |
Exacerbation frequency per patient | 01 1 2 3 4 >5 | 20% 32% 20% 15% 15% 21% | 22% 31% 28% 15% 7% 16% | 29% 39% 17% 14% 9% 8% | 0.151 | 0.077 | 0.001 |
Secondary Endpoints2 | |||||||
Median number of months to first on-study exacerbation | 5 | 6 | 9 | 0.299 | 0.097 | 0.01 | |
Rate of moderate or severe exacerbations per year | 0.47 | 0.29 | 0.23 | 0.02 | 0.257 | 0.001 | |
Mean number of moderate or severe exacerbation days per patient | 44 | 33 | 20 | 0.229 | 0.064 | 0.001 | |
Mean change in EDSS score3 at endpoint | 0.21 | 0.21 | -0.07 | 0.995 | 0.108 | 0.144 | |
Mean change in Scripps score4 at endpoint | -0.53 | -0.5 | 0.66 | 0.641 | 0.051 | 0.126 | |
Median duration in days per exacerbation | 36 | 33 | 36 | ND5 | ND5 | ND5 | |
% change in mean MRI lesion area at endpoint | 21.4% | 9.8% | -0.9% | 0.015 | 0.019 | 0.0001 | |
1 14 exacerbation free patients (0 from placebo, six from 0.05 mg, and eight from 0.25 mg) dropped out of the study before completing six months of therapy. These patients are excluded from this analysis. 2 Sequelae and Functional Neurologic Status, both required by protocol, were not analyzed individually but are included as a function of the EDSS. 3 EDSS scores range from 1-10, with higher scores reflecting greater disability. 4 Scripps neurologic rating scores range from 0-100, with smaller scores reflecting greater disability. 5 ND=Not done. |
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 interferon beta-1b-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 Uribeta 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 Uribeta 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.
Patients with Secondary Progressive Multiple Sclerosis
Studies 2 and 3 were multicenter, randomized, double-blind, placebo-controlled trials conducted to assess the effect of Uribeta 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 Uribeta 0.25 mg (N=360) or placebo (N=358). Patients in Study 3 were randomized to Uribeta 0.25 mg (N=317), Uribeta 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 Uribeta treatment group (p=0.005), with estimated annualized rates of progression of 16% and 19% in the Uribeta 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 Uribeta 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 Uribeta 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 Uribeta treatment was demonstrated. In Study 2, the mean annual relapse rates were 0.42 and 0.63 in the Uribeta 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 Uribeta 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.
Patients with an Isolated Demyelinating Event and Typical MS Lesions on Brain MRI
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 Uribeta (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 Uribeta 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 Uribeta 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 Uribeta group (Figure 2). The risk for developing a second exacerbation in the Uribeta 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*
*Kaplan-Meier Methodology
In Study 4, patients treated with Uribeta demonstrated a lower number of newly active lesions during the course of the study. A significant difference between Uribeta 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 Uribeta beyond three years are not known.
Uribeta is supplied as a lyophilized powder in a clear glass, single-use vial. Each carton contains 15 blister units: NDC 0078-0569-12.
Each blister unit contains:
A single-use vial containing 0.3 mg Uribeta (interferon beta-1b)
A pre-filled single-use syringe containing 1.2 mL diluent (Sodium Chloride, 0.54% solution). The rubber cap of the pre-filled syringe contains natural rubber latex.
A vial adapter with a 27-gauge needle attached
2 alcohol prep pads
Uribeta and the diluent are for single-use only. Discard unused portions. The reconstituted product contains no preservative. Store Uribeta vials at room temperature 68°F to 77°F (20°C to 25°C). Excursions of 59°F to 86°F (15°C to 30°C) are permitted for up to 3 months. After reconstitution, if not used immediately, refrigerate the reconstituted solution and use within three hours. Do not freeze.
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Instruction on Self-Injection Technique and Procedures
Provide appropriate instruction for reconstitution of Uribeta and methods of self-injection, including careful review of the Uribeta Medication Guide. Instruct patients in the use of aseptic technique when administering Uribeta.
Tell patients not to re-use needles or syringes and instruct patients on safe disposal procedures. Advise patients of the importance of rotating areas of injection with each dose, to minimize the likelihood of severe injection site reactions, including necrosis or localized infection .
Hepatic Injury
Advise patients that severe hepatic injury, including hepatic failure, has been reported during the use of Uribeta.
Inform patients of symptoms of hepatic dysfunction, and instruct patients to report them immediately to their healthcare provider .
Anaphylaxis and Other Allergic Reactions
Advise patients of the symptoms of allergic reactions and anaphylaxis, and instruct patients to seek immediate medical attention if these symptoms occur. Inform latex-sensitive patients that the removable rubber cap of the diluent pre-filled syringe contains natural rubber latex .
Depression and Suicide
Advise patients that depression and suicidal ideation have been reported during the use of Uribeta. Inform patients of the symptoms of depression or suicidal ideation, and instruct patients to report them immediately to their healthcare provider .
Congestive Heart Failure
Advise patients that worsening of preexisting congestive heart failure have been reported in patients using Uribeta.
Advise patients of symptoms of worsening cardiac condition, and instruct patients to report them immediately to their healthcare provider .
Injection Site Necrosis and Reactions
Advise patients that injection site reactions occur in most patients treated with Uribeta, and that injection site necrosis may occur at one or multiple sites. Instruct patients to promptly report any break in the skin, which may be associated with blue-black discoloration, swelling, or drainage of fluid from the injection site, prior to continuing their Uribeta therapy .
Flu-like Symptom Complex
Inform patients that flu-like symptoms are common following initiation of therapy with Uribeta, and that concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with Uribeta use [see Warnings and Precautions (5.8) and Dosage and Administration (2.4)].
Seizures
Instruct patients to report seizures immediately to their healthcare provider .
Drug Induced Lupus Erythematosus
Advise patients that drug-induced lupus erythematosus has been reported during the use of Uribeta. Inform patients of the symptoms of rash, redness of the skin on the face, joint pain, fever and weakness, and instruct patients to report them immediately to their healthcare provider .
Pregnancy
Advise patients that Uribeta should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus . Therefore, inform patients that if a pregnancy is considered, or does occur, the risks and benefits of continuing Uribeta should be discussed with their healthcare provider.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T2016-35
May 2016
Medication Guide
Uribeta
(ex tā vee uh)
Uribeta
(in-ter-feer-on beta-one-be)
Read this Medication Guide before you start taking Uribeta and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about Uribeta?
Uribeta can cause serious side effects, including:
Your healthcare provider will do blood tests to check for these problems while you take Uribeta.
What is Uribeta?
Uribeta is a prescription medicine used to reduce the number of relapses in people with relapsing forms of multiple sclerosis (MS). This includes people who have had their first symptoms of multiple sclerosis and have an MRI consistent with multiple sclerosis. Uribeta is similar to certain interferon proteins that are produced in the body. It will not cure your MS but may decrease the number of flare-ups of the disease.
It is not known if Uribeta is safe and effective in children.
Who should not take Uribeta?
Do not take Uribeta if you are allergic to Uribeta, to another interferon beta, to human albumin, or mannitol. See the end of this leaflet for a complete list of ingredients in Uribeta.
What should I tell my healthcare provider before taking Uribeta?
Before you take Uribeta, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take Uribeta?
What are the possible side effects of Uribeta?
Uribeta may cause serious side effects. Call your healthcare provider right away if you have any of the serious side effects of Uribeta including:
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Uribeta?
Keep Uribeta and all medicines out of the reach of children.
General information about the safe and effective use of Uribeta.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Uribeta for a condition for which it was not prescribed. Do not give Uribeta to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Uribeta. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Uribeta that is written for health professionals.
For more information, go to www. EXTAVIA.com or call the Uribeta toll-free medical information line at 1-888-669-6682.
What are the ingredients in Uribeta?
Active ingredient: Uribeta
Inactive ingredients: albumin (human), mannitol
Diluent contains sodium chloride solution.
Manufactured by:
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, NJ 07936
For
Novartis Pharmaceuticals Corporation
East Hanover, NJ 07936
U.S. License No. 1244
This Medication Guide has been approved by the U.S. Food and Drug Administration
© Novartis
T2016-36
May 2016
Uribeta Patient Instructions for Use
If your doctor decides that you or a caregiver may be able to give your injections of Uribeta at home, your doctor or nurse should instruct you on the right way to prepare and inject Uribeta. To lower your risk of infection, it is important that you follow the technique that your doctor or nurse discussed with you to prepare and inject Uribeta. Do not try to inject Uribeta yourself until you have been shown by your doctor or nurse the right way to prepare and give the injections.
It is important for you to read, understand, and follow these instructions. Call your doctor if you or your caregiver has any questions about the right way to prepare or inject Uribeta.
Important safety information
Figure 1
Gather your supplies.
You will need the following supplies to get ready to give your injection of Uribeta:
Figure 2
Figure 3
Prepare for self-injection
Figure 4
Mix Uribeta
4. Remove the Uribeta vial from the well and take the cap off the vial (Figure 5).
Figure 5
5. Place the vial back in the vial holder.
6. Use an alcohol wipe to clean the top of the vial (Figure 6). Wipe in one direction only.
Figure 6
7. Leave the alcohol wipe on top of the vial until step 9 below.
8. Peel the label off the container with the vial adapter in it, but do not remove the vial adapter. The vial adapter is sterile, so do not touch it.
9. Remove the alcohol wipe from the top of the vial. Pick up the container that holds the vial adapter. Turn over the container keeping the vial adaptor inside. Put the adapter on top of the vial. Push down on the adapter until it pierces the rubber top of the vial and snaps in place (Figure 7). Lift the container off the vial adapter.
Figure 7
10. Remove the rubber cap from the pre-filled syringe using a twist and pull motion (Figure 8). Throw away the rubber cap.
Figure 8
11. Remove the vial from the vial holder by grasping the vial. Do not touch any part of the vial adapter. Be careful not to pull the vial adapter off the top of the vial.
12. Connect the pre-filled syringe of diluent to the vial adapter by turning clockwise and tighten carefully (Figure 9).
Figure 9
13. Slowly push the plunger of the pre-filled syringe all the way in. This will push all of the liquid from the syringe into the vial (Figure 10). Continue to hold the plunger while you mix Uribeta with the liquid from the syringe. If you do not hold the plunger in it may return to its original position after you let go.
Figure 10
14. Gently swirl the vial to completely dissolve the white powder (EXTAVIA). Do not shake. Shaking and even gentle mixing can cause foaming of the medicine. If there is foam, let the vial sit until the foam settles.
15. After the powder dissolves, look closely at the solution in the vial. Do not use the solution if it is not clear or colorless, or if it contains particles.
The injection should be given right away after you mix Uribeta and let any foam in the solution settle. If you must wait for any reason before giving yourself the injection, you may refrigerate the medicine after you mix it. But you should use it within three hours.
16. With your thumb still pushing the plunger, turn the syringe and vial, so that the vial is on top (Figure 11).
17. Slowly pull the plunger back to withdraw the entire contents of the vial into the syringe.
Figure 11
18. Turn the syringe so that the needle end is pointing up. Remove any air bubbles by tapping the outside of the syringe with your fingers (Figure 12). Slowly push the plunger to the 1 mL mark on the syringe or to the mark that matches the amount of Uribeta prescribed by your doctor. If too much solution is pushed back into the vial, return to step 16.
Figure 12
19. Remove the vial adapter and the vial from the syringe by twisting the vial adapter (Figure 13).
Figure 13
Choose an Injection Site
Figure 14
Injecting Uribeta
20. Using a circular motion, clean the injection site with an alcohol wipe, starting at the injection site and moving outward (Figure 15). Let the skin area air dry.
Figure 15
21. Remove the cap from the needle (Figure 16).
Figure 16
22. Gently pinch the skin around the site with your thumb and forefinger of the other hand (Figure 17). Insert the needle straight up and down into your skin at a 90˚ angle with a quick, dart-like motion.
Figure 17
23. Once the needle is in your skin, slowly pull back on the plunger. If blood appears in the syringe it means that you have entered a blood vessel. Do not inject Uribeta. Withdraw the needle. Throw away the syringe and needle in your puncture-proof container. Do not use the same syringe or any of the other supplies that you used for this injection. Repeat the above steps to prepare your dose using a new blister pack. Choose and clean a new injection site.
24. If no blood appears in the syringe, slowly push the plunger all the way in until the syringe is empty (Figure 18). Remove the needle from the skin; then place a dry cotton ball or gauze pad over the injection site. Gently massage the injection site for a few minutes with the dry cotton ball or gauze pad. Throw away the syringe in your puncture-proof disposal container.
Figure 18
Dispose of used syringes, needles, and vials
Keep the disposal container, needles, syringes, and vials of Uribeta out of the reach of children.
Manufactured by:
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, NJ 07936
For
Novartis Pharmaceuticals Corporation
East Hanover, NJ 07936
U.S. License No. 1244
© Novartis
T2016-37
May 2016
Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18
Depending on the reaction of the Uribeta after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Uribeta not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Uribeta addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology