Drug: Betaseron

Betaseron® (interferon beta-lb) is a purified, sterile, lyophilized protein product produced by recombinant DNA techniques. Interferon beta-1b 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. Interferon beta-1b 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 Betaseron 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 Betaseron is a sterile, white to off-white powder, for subcutaneous injection after reconstitution with the diluent supplied (Sodium Chloride, 0.54% Solution). Albumin (Human) USP and Mannitol, USP (15 mg each/vial) are added as stabilizers.

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The following serious adverse reactions are discussed in more details in other sections of labeling:
  • Hepatic Injury [see WARNINGS AND PRECAUTIONS]
  • Anaphylaxis and Other Allergic-Reactions [see WARNINGS AND PRECAUTIONS]
  • Depression and Suicide [see WARNINGS AND PRECAUTIONS]
  • Congestive Heart Failure [see WARNINGS AND PRECAUTIONS]
  • Injection Site Necrosis and Reactions [see WARNINGS AND PRECAUTIONS]
  • Leukopenia [see WARNINGS AND PRECAUTIONS]
  • Flu-Like Symptom Complex [see WARNINGS AND PRECAUTIONS]
  • Seizures [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience Because clinical trials are conducted under widely varying conditions and over varying lengths of time, adverse reaction rates observed in the clinical trials of Betaseron 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 Betaseron 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 Betaseron 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 Betaseron, 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 Betaseron 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 [see Clinical Studies]. Table 2: Adverse Reactions and Laboratory Abnormalities in Patients with MS in Pooled Studies 1, 2, 3, and 4
Adverse Reaction Placebo (N=965) Betaseron (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 reactiona 26% 78% Asthenia 48% 53% Flu-like symptoms (complex)b 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% a"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.
b "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 Betaseron 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 Betaseron- 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 Betaseron 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 Betaseron for any laboratory abnormality, including four (0.3%) patients following dose reduction. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples were monitored for the development of antibodies to Betaseron during Study 1. In patients receiving 0.25 mg every other day 56/124 (45%) 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 Betaseron-treated patients. Such neutralizing activity was measured at least once in 75 (30%) out of 251 Betaseron 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 Betaseron 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 Betaseron with the incidence of antibodies to other products may be misleading. Anaphylactic reactions have been reported with the use of Betaseron [see WARNINGS AND PRECAUTIONS]. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Betaseron. 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 Reproductive system and breast disorder: Menorrhagia General disorders and administration site conditions: Fatal capillary leak syndrome* Read the Betaseron (interferon beta-1b) Side Effects Center for a complete guide to possible side effectsLearn More »

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Dosing Information 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 (see Table 1). Table 1: Schedule for Dose Titration
  Betaseron 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 1Dosed every other day, subcutaneously If a dose of Betaseron is missed, then it should be taken as soon as the patient remembers or is able to take it. The patient should not take Betaseron 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. Reconstitution of the Lyophilized Powder
  1. Prior to reconstitution, verify that the vial containing lyophilized Betaseron is not cracked or damaged. Do not use cracked or damaged vials.
  2. To reconstitute lyophilized Betaseron for injection, attach the pre-filled syringe containing the diluent (Sodium Chloride, 0.54% Solution) to the Betaseron vial using the vial adapter.
  3. Slowly inject 1.2 mL of diluent into the Betaseron vial.
  4. 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.
  5. 1 mL of reconstituted Betaseron solution contains 0.25 mg of interferon beta-1b.
  6. After reconstitution, if not used immediately, refrigerate the reconstituted Betaseron solution at 35°F to 46°F (2°C to 8°C) and use within three hours. Do not freeze.
Important Administration Instructions
  1. Perform the first Betaseron injection under the supervision of an appropriately qualified healthcare professional. If patients or caregivers are to administer Betaseron, train them in the proper subcutaneous injection technique and assess their ability to inject subcutaneously to ensure the proper administration of Betaseron.
  2. Visually inspect the reconstituted Betaseron solution before use; discard if it contains particulate matter or is discolored.
  3. Keeping the syringe and vial adapter in place, turn the assembly over so that the vial is on top. Withdraw the appropriate dose of Betaseron solution. Remove the vial from the vial adapter before injecting Betaseron.
  4. Use safe disposal procedures for needles and syringes.
  5. Do not re-use needles or syringes.
  6. Advise patients and caregivers to rotate sites for subcutaneous injections to minimize the likelihood of severe injection site reactions, including necrosis or localized infection.
Premedication for Flu-like Symptoms Concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with Betaseron use [see WARNINGS AND PRECAUTIONS].

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No information provided. *The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of this syndrome. Read the Betaseron Drug Interactions Center for a complete guide to possible interactions Learn More »

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Betaseron® (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.

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Betaseron is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, Albumin (Human), or any other component of the formulation. Last reviewed on RxList: 8/6/2013
This monograph has been modified to include the generic and brand name in many instances.

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No information provided.

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Dosage Forms And Strengths For injection: 0.3 mg lyophilized powder in a single use vial for reconstitution. Storage And Handling Betaseron is supplied as a lyophilized powder in a clear glass, single-use vial (3 mL capacity). Each carton contains 14 blister units: NDC # 50419-523-35 Each blister unit contains: A single-use vial containing 0.3 mg Betaseron (interferon beta-1b) A pre-filled single-use syringe containing 1.2 mL diluent (Sodium Chloride, 0.54% solution) A vial adapter with a 30 gauge needle attached 2 alcohol prep pads Stability and Storage Betaseron and the diluent are for single-use only. Discard unused portions. The reconstituted product contains no preservative. Store Betaseron 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. Manufactured by: Bayer HealthCare Pharmaceuticals Inc. Montville, NJ 07045. Revision Date: 06/2013 Last reviewed on RxList: 8/6/2013
This monograph has been modified to include the generic and brand name in many instances.

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Hepatic Injury Severe hepatic injury including cases of hepatic failure, some of which have been due to autoimmune hepatitis, has been rarely reported in patients taking Betaseron. 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 Betaseron used in combination with known hepatotoxic drugs or other products (e.g., alcohol) prior to Betaseron administration, or when adding new agents to the regimen of patients already on Betaseron. Monitor patients for signs and symptoms of hepatic injury. Consider discontinuing Betaseron 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 Betaseron. In controlled clinical trials, elevations of SGPT to greater than five times baseline value were reported in 12% of patients receiving Betaseron (compared to 4% on placebo), and increases of SGOT to greater than five times baseline value were reported in 4% of patients receiving Betaseron (compared to 1% on placebo), leading to dose-reduction or discontinuation of treatment in some patients [see ADVERSE REACTIONS]. Monitor liver function tests. Anaphylaxis and Other Allergic-Reactions Anaphylaxis has been reported as a rare complication of Betaseron use. Other allergic reactions have included dyspnea, bronchospasm, tongue edema, skin rash and urticaria [see ADVERSE REACTIONS]. Discontinue Betaseron if anaphylaxis occurs. Depression and Suicide Depression and suicide have been reported to occur with increased frequency in patients receiving interferon beta products, including Betaseron. Advise patients to report any symptom of depression and/or suicidal ideation to their healthcare provider. If a patient develops depression, discontinuation of Betaseron therapy should be considered. In randomized controlled clinical trials, there were three suicides and eight suicide attempts among the 1532 patients on Betaseron compared to one suicide and four suicide attempts among 965 patients on placebo. Congestive Heart Failure Monitor patients with pre-existing congestive heart failure (CHF) for worsening of their cardiac condition during initiation of and continued treatment with Betaseron. 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 Betaseron. Recurrence upon rechallenge was observed in some patients. Consider discontinuation of Betaseron if worsening of CHF occurs with no other etiology. Injection Site Necrosis and Reactions Injection site necrosis (ISN) was reported in 4% of Betaseron-treated patients in controlled clinical trials (compared to 0% on placebo) [see ADVERSE REACTIONS]. 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 three 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 Betaseron after injection site necrosis has occurred, avoid administration of Betaseron 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 Betaseron 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 Betaseron 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. Leukopenia In controlled clinical trials, leukopenia was reported in 18% of patients receiving Betaseron (compared to 6% on placebo), leading to a reduction of the dose of Betaseron in some patients [see ADVERSE REACTIONS]. 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. Flu-Like Symptom Complex In controlled clinical trials, the rate of flu-like symptom complex for patients on Betaseron was 57% [see ADVERSE REACTIONS]. 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 [see Clinical Studies]. Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with Betaseron use. Seizures 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. Monitoring for Laboratory Abnormalities 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 Betaseron therapy, and then periodically thereafter in the absence of clinical symptoms. Patient Counseling Information See FDA-approved patient labeling (Medication Guide and Instructions for Use). Instruct patients to carefully read the supplied Betaseron Medication Guide and caution patients not to change the Betaseron dose or schedule of administration without medical consultation. Instruction on Self-Injection Technique and Procedures Provide appropriate instruction for reconstitution of Betaseron and methods of self-injection, including careful review of the Betaseron Medication Guide. Instruct patients in the use of aseptic technique when administering Betaseron. 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 [see Medication Guide]. Hepatic Injury Advise patients that severe hepatic injury, including hepatic failure, has been reported during the use of Betaseron. Inform patients of symptoms of hepatic dysfunction, and instruct patients to report them immediately to their healthcare provider [see WARNINGS AND PRECAUTIONS]. 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 [see WARNINGS AND PRECAUTIONS]. Depression and Suicide Advise patients that depression and suicidal ideation have been reported during the use of Betaseron. Inform patients of the symptoms of depression or suicidal ideation, and instruct patients to report them immediately to their healthcare provider [see WARNINGS AND PRECAUTIONS]. Congestive Heart Failure Advise patients that worsening of pre-existing congestive heart failure have been reported in patients using Betaseron. Advise patients of symptoms of worsening cardiac condition, and instruct patients to report them immediately to their healthcare provider [see WARNINGS AND PRECAUTIONS]. Injection Site Necrosis and Reactions Advise patients that injection site reactions occur in most patients treated with Betaseron, 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 Betaseron therapy [see WARNINGS AND PRECAUTIONS]. Flu-like Symptom Complex Inform patients that flu-like symptoms are common following initiation of therapy with Betaseron, and that concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with Betaseron use [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION]. Seizures Instruct patients to report seizures immediately to their healthcare provider [see WARNINGS AND PRECAUTIONS]. Pregnancy Advise patients that Betaseron should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [see Use in Special Population]. Therefore, inform patients that if a pregnancy is considered, or does occur, the risks and benefits of continuing Betaseron should be discussed with their healthcare provider. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Betaseron has not been tested for its carcinogenic potential in animals. Mutagenesis Betaseron was not genotoxic in the in vitro Ames bacterial test or the in vitro chromosomal aberration assay in human peripheral blood lymphocytes. Betaseron treatment of mouse BALBc3T3 cells did not result in increased transformation frequency in an in vitro model of tumor transformation. Impairment of Fertility Administration of Betaseron (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. Use In Specific Populations Pregnancy 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 Betaseron RRMS clinical trial. Betaseron should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When Betaseron (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. Nursing Mothers It is not known whether Betaseron 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 Betaseron, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of drug to the mother. Pediatric Use Safety and efficacy in pediatric patients have not been established. Geriatric Use Clinical studies of Betaseron did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Last reviewed on RxList: 8/6/2013
This monograph has been modified to include the generic and brand name in many instances.

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