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Betaferon (Betaseron) 3 mL 15 Vials

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FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

2.2 Reconstitution of the Lyophilized Powder

2.3 Important Administration Instructions

2.4 Premedication for Flu-like Symptoms

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hepatic Injury

5.2 Anaphylaxis and Other Allergic-Reactions

5.3 Depression and Suicide

5.4 Congestive Heart Failure

5.5 Injection Site Necrosis and Reactions

5.6 Leukopenia

5.7 Flu-Like Symptom Complex

5.8 Seizures

5.9 Monitoring for Laboratory Abnormalities

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Immunogenicity

6.3 Postmarketing Experience

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Stability and Storage

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Betaferon (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.

2 DOSAGE AND ADMINISTRATION

2.1 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

*Dosed every other day, subcutaneously

 

Betaferon (Betaseron)

Dose*

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

2.2 Reconstitution of the Lyophilized Powder

(a) Prior to reconstitution, verify that the vial containing lyophilized Betaferon (Betaseron) is not cracked or damaged. Do not use cracked or damaged vials.

(b) To reconstitute lyophilized Betaferon (Betaseron) for injection, attach the prefilled syringe containing the diluent (Sodium Chloride, 0.54% Solution) to the Betaferon (Betaseron) vial using the vial adapter.

(c) Slowly inject 1.2 mL of diluent into the Betaferon (Betaseron) 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 Betaferon (Betaseron) solution contains 0.25 mg of interferon beta-1b.

(f) After reconstitution, if not used immediately, refrigerate the reconstituted Betaferon (Betaseron) solution at 2 to 8°C (35 to 46°F) and use within three hours. Do not freeze.

2.3 Important Administration Instructions

(a) Perform the first Betaferon (Betaseron) injection under the supervision of an appropriately qualified healthcare professional. If patients or caregivers are to administer Betaferon (Betaseron), train them in the proper subcutaneous injection technique and assess their ability to inject subcutaneously to ensure the proper administration of Betaferon (Betaseron).

(b) Visually inspect the reconstituted Betaferon (Betaseron) 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 Betaferon (Betaseron) solution. Remove the vial from the vial adapter before injecting Betaferon (Betaseron).

(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.

2.4 Premedication for Flu-like Symptoms

Concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with Betaferon (Betaseron) use [see Warnings and Precautions (5.7)].

3 DOSAGE FORMS AND STRENGTHS

For injection: 0.3 mg lyophilized powder in a single use vial for reconstitution.

4 CONTRAINDICATIONS

Betaferon (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.

5 WARNINGS AND PRECAUTIONS

5.1 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 Betaferon (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 Betaferon (Betaseron) used in combination with known hepatotoxic drugs or other products (e.g., alcohol) prior to Betaferon (Betaseron) administration, or when adding new agents to the regimen of patients already on Betaferon (Betaseron). Monitor patients for signs and symptoms of hepatic injury. Consider discontinuing Betaferon (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 Betaferon (Betaseron). In controlled clinical trials, elevations of SGPT to greater than five times baseline value were reported in 12% of patients receiving Betaferon (Betaseron) (compared to 4% on placebo), and increases of SGOT to greater than five times baseline value were reported in 4% of patients receiving Betaferon (Betaseron) (compared to 1% on placebo), leading to dose-reduction or discontinuation of treatment in some patients [see Adverse Reactions (6.1)]. Monitor liver function tests[see Warnings and Precautions (5.9)].

5.2 Anaphylaxis and Other Allergic-Reactions

Anaphylaxis has been reported as a rare complication of Betaferon (Betaseron) use. Other allergic reactions have included dyspnea, bronchospasm, tongue edema, skin rash and urticaria [see Adverse Reactions (6.1)]. Discontinue Betaferon (Betaseron) if anaphylaxis occurs.

5.3 Depression and Suicide

Depression and suicide have been reported to occur with increased frequency in patients receiving interferon beta products, including Betaferon (Betaseron). Advise patients to report any symptom of depression and/or suicidal ideation to their healthcare provider. If a patient develops depression, discontinuation of Betaferon (Betaseron) therapy should be considered.

In randomized controlled clinical trials, there were three suicides and eight suicide attempts among the 1532 patients on Betaferon (Betaseron) compared to one suicide and four suicide attempts among 965 patients on placebo.

5.4 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 Betaferon (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 Betaferon (Betaseron). Recurrence upon rechallenge was observed in some patients. Consider discontinuation of Betaferon (Betaseron) if worsening of CHF occurs with no other etiology.

5.5 Injection Site Necrosis and Reactions

Injection site necrosis (ISN) was reported in 4% of Betaferon (Betaseron)-treated patients in controlled clinical trials (compared to 0% on placebo) [see Adverse Reactions (6.1)]. 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 Betaferon (Betaseron) after injection site necrosis has occurred, avoid administration of Betaferon (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 Betaferon (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 Betaferon (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.

5.6 Leukopenia

In controlled clinical trials, leukopenia was reported in 18% of patients receiving Betaferon (Betaseron) (compared to 6% on placebo), leading to a reduction of the dose of Betaferon (Betaseron) in some patients[see Adverse Reactions (6.1)]. 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.

5.7 Flu-Like Symptom Complex

In controlled clinical trials, the rate of flu-like symptom complex for patients on Betaferon (Betaseron) was 57% [see Adverse Reactions (6.1)]. 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 (14)]. Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with Betaferon (Betaseron) use.

5.8 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.

5.9 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 Betaferon (Betaseron) therapy, and then periodically thereafter in the absence of clinical symptoms.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in more details in other sections of labeling:

•Hepatic Injury [see Warnings and Precautions (5.1)]

•Anaphylaxis and Other Allergic-Reactions [see Warnings and Precautions (5.2)]

•Depression and Suicide [see Warnings and Precautions (5.3)]

•Congestive Heart Failure [see Warnings and Precautions (5.4)]

•Injection Site Necrosis and Reactions [see Warnings and Precautions (5.5)]

•Leukopenia [see Warnings and Precautions (5.6)]

•Flu-Like Symptom Complex [see Warnings and Precautions (5.7)]

•Seizures [see Warnings and Precautions (5.8)]

6.1 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 Betaferon (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 Betaferon (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 Betaferon (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 Betaferon (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 Betaferon (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 (14)].

Table 2 Adverse Reactions and Laboratory Abnormalities in Patients with MS in Pooled Studies 1, 2, 3, and 4

Adverse Reaction

Placebo
(N=965)

Betaferon (Betaseron)
(N=1407)

*"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.

†"Flu-like symptom (complex)" denotes flu syndrome and/or a combination of at least two adverse reactions from fever, chills, myalgia, malaise, sweating.

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*

26%

78%

Asthenia

48%

53%

Flu-like symptoms (complex)†

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%

In addition to the Adverse Reactions listed in Table 2, the following adverse reactions occurred more frequently on Betaferon (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 Betaferon (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 Betaferon (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 Betaferon (Betaseron) for any laboratory abnormality, including four (0.3%) patients following dose reduction.

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples were monitored for the development of antibodies to Betaferon (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 Betaferon (Betaseron)-treated patients. Such neutralizing activity was measured at least once in 75 (30%) out of 251 Betaferon (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 Betaferon (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 Betaferon (Betaseron) with the incidence of antibodies to other products may be misleading.

Anaphylactic reactions have been reported with the use of Betaferon (Betaseron) [see Warnings and Precautions (5.2)].

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Betaferon (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: Triglycerideincreased, 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 syndrome1

1The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of this syndrome.

8 USE IN SPECIFIC POPULATIONS

8.1 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 Betaferon (Betaseron) RRMS clinical trial. Betaferon (Betaseron) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When Betaferon (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.

8.3 Nursing Mothers

It is not known whether Betaferon (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 Betaferon (Betaseron), a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of drug to the mother.

8.4 Pediatric Use

Safety and efficacy in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Betaferon (Betaseron) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.

11 DESCRIPTION

Betaferon (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 Betaferon (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 Betaferon (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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 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 inteferons 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 p

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Betaferon (Betaseron) 3 mL 15 Vials

  • Brand: Bayer
  • Product Code: 8699546799169
  • Availability: In Stock
  • $1thousand_point815.00

Tags: Betaferon (Betaseron) 3 mL 15 Vials, Bayer, All Products