HIGHLIGHTS OF PRESCRIBING INFORMATION
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`These highlights do not include all the information needed to use Extavia
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`safely and effectively. See full prescribing information for Extavia.
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`Extavia (Interferon beta-1b) Kit for subcutaneous use
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`Initial U.S. Approval: 7/23/93
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`-----------INDICATIONS AND USAGE-—--—---------—
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`Extavia is an interferon beta indicated for the treatment of relapsing forms of
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`multiple sclerosis to reduce the frequency of clinical exacerbations. Patients
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`patients who have experienced a first clinical episode and have MRI features
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`consistent with multiple sclerosis. (l)
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`---------DOSAGE AND ADMINISTRATION-—--———---
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`For subcutaneous use only. (2)
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`The recommended dose is 0.25 mg injected subcutaneously every
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`other day. Generally, start at 0.0625 mg (0.25 mL) subcutaneously
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`every other day, and increase over a six week period to 0.25 mg
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`(1 mL) every other day. (2)
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`Instruct patients in the use of aseptic technique when administering
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`Extavia. (17.5)
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`Anaphylaxis and other allergic reactions. (5 .4)
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`Leukopenia: monitor CBC. (5.6, 5.8)
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`Liver enzymes abnormalities: monitor liver fimction tests. (5.7,
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`5.8)
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`Monitor thyroid fimction tests every 6 months in patients with
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`history of thyroid dysfunction. (5.8)
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`-------—-----g---ADVERSE REACTIONS-----------------
`In controlled studies with interferon beta-1b, the most common adverse
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`reactions (at least 2% more than placebo) were: Lymphopenia, neutropenia,
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`leukopenia, lymphadenopathy, headache, insomnia, incoordination,
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`hypertension, dyspnea, abdominal pain, increased liver enzymes, rash, skin
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`disorder, hypertonia, myalgia, urinary urgency, metrorrhagia, impotence,
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`injection Site reaction, asthenia, flu-like symptom complex, pain, , fever,
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`chills, peripheral edema, chest pain, malaise, and injection site necrosis (6.1)
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`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
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`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at l-800-FDA-
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`1088 orW
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`-------------------DRUG INTERACTIONS--—------—-----—-
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`No formal drug interaction Studies have been conducted. (7)
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`--------DOSAGE FORMS AND STRENGTHS--—-----
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`Lyophilized powder containing 0.3 mg Of Interferon beta-1b, 15 mg Albumin
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`(Human), USP, and 15 mg Mannitol, USP. (3).
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`---------—CONTRAINDICATIONS—---—----—----
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`History of hypersensitivity to natural or recombinant interferon beta, Albumin
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`(Human), USP, or any other component of the formulation. (4)
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`—---------WARNINGS AND PRECAUTIONS----------
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`Depression and suicide: advise patients to immediately report any
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`symptom of depression and/or suicidal ideation; consider
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`discontinuation of Extavia if depression occurs. (5.1)
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`Injection site necrosis: do not administer Extavia into affected area
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`until it is fully healed; if multiple lesions occur, therapy should be
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`discontinued until healing occurs. (5.2)
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`Injection site reactions. (5.3)
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`—-—------USE IN SPECIFIC POPULATIONS-—----¥——
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`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
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`Nursing Mothers: use EXTAVIA with caution. (8.3)
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`Pediatric Use: Safety and efficacy not established in patients under
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`18 years ofage. (8.3)
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`Geriatric Use: Safety and efficacy not established in patients age
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`65 years or older. (8.4)
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`See 17 for PATIENT COUNSELING INFORMATION and Medication
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`Guide
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`Revised: July 2009
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`8.4 Pediatric Use
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`8.5 Geriatric Use
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`10 OVERDOSAGE
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`11 DESCRIPTION
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.2 Pharmacodynamics
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`12.3 Pharmacokinetics
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`l4 CLINICAL STUDIES
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`15 REFERENCES
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`17 PATIENT COUNSELING INFORMATION
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`17.1 Depression
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`17.2 Injection site reactions, including necrosis
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`17.3 Allergic reactions and Anaphylaxis
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`17.4 Flu-like Symptoms
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`* Sections or subsections omitted from the full prescribing
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`information are not listed
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`FULL PRESCRIBING INFORMATION: CONTENTS"
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`INDICATIONS AND USAGE
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`DOSAGE AND ADMINISTRATION
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`DOSAGE FORMS AND STRENGTHS
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`CONTRAINDICATIONS
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`WARNINGS AND PRECAUTIONS
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`5.1 Depression and Suicide
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`5.2 Injection Site Necrosis
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`5.3 Injection Site Reactions
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`5.4 Anaphylaxis
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`5.5 Flu-Like Symptom Complex
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`5.6 Leukopenia
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`5.7 Hepatic enzymes elevations
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`5.8 Laboratory Tests
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`6 ADVERSE REACTIONS
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`6.1 Clinical Studies Experience
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`6.2 Postmarketing Experience
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`DRUG INTERACTIONS
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`USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`8.3 Nursing Mothers
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`Ul§WNH
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`“\l
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`Page 1 of 21
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`Biogen Exhibits 2158
`Mylan v. Biogen
`IPR 2018-01403
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`Biogen Exhibits 2158
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 21
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`

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`FULL PRESCRIBING INFORMATION
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`1 INDICATIONS AND USAGE
`EXTAVIA (Interferon beta-1b) is indicated for the treatment of relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations.
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`Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features
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`consistent with multiple sclerosis.
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`2 DOSAGE AND ADMINISTRATION
`The recommended dose of EXTAVIA is 0.25 mg injected subcutaneously every other day.
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`Generally, patients should be started at 0.0625 mg (0.25 mL) subcutaneously every other day, and increased over a six week period to 0.25 mg (1 mL) every
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`other day (see Table 1).
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`Table 1. Schedule for Dose Titration
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`Volume
`Recommended Titration
`EXTAVIA Dose
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`0.25 mL
`0.0625 mg
`Weeks l-2
`25%
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`Weeks 3—4
`50% ‘
`0.125 mg
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`Weeks 5-6
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`Week 7+
`100%
`0.25 mg
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`1 mL
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`To reconstitute lyophilized EXTAVIA for injection, attach the prefilled syringe containing the diluent (Sodium Chloride, 0.54% Solution) to the EXTAVIA
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`vial using the vial adapter. Slowly inject 1.2 mL of diluent into the EXTAVIA vial. Gently swirl the vial to dissolve the drug completely; do not shake. Foaming may
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`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. Visually inspect
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`the reconstituted product before use; discard the product if it contains particulate matter or is discolored. Keeping the syringe and vial adapter in place, turn the
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`assembly over so that the vial is on top. Withdraw the appropriate dose of EXTAVIA solution. Remove the vial from the vial adapter before injecting EXTAVIA. One
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`mL of reconstituted EXTAVIA solution contains 0.25 mg of Interferon beta-Ib/mL.
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`EXTAVIA is intended for use under the guidance and supervision of a physician. It is recommended that physicians or qualified medical personnel train
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`patients in the proper technique for self-administering subcutaneous injections. Patients should be advised to rotate sites for subcutaneous injections (see Patient
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`Counseling Information 17.5). Concurrent use of analgesics and/0r antipyretics may help ameliorate flu—like symptoms on treatment days. EXTAVIA should be visually
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`inspected for particulate matter and discoloration prior to administration.
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`3 DOSAGE FORMS AND STRENGTHS
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`EXTAVIA is supplied as a lyophilized powder containing 0.3 mg of Interferon beta-lb, 15 mg Albumin (Human), USP, and 15 mg Mannitol, USP. Drug is
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`packaged in a clear glass, single-use vial (3 mL capacity). A pre—filled single-use syringe containing 1.2 mL of diluent (Sodium Chloride, 0.54% solution), two alcohol
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`prep pads, and one vial adapter with attached 27 gauge needle are included for each vial of drug. EXTAVIA and the diluent are for single-use only. Unused portions
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`should be discarded. Store at room temperature.
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`4 CONTRAINDICATIONS
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`EXTAVIA is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, Albumin (Human), USP, or any other
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`component of the formulation.
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`5_ WARNINGS AND PRECAUTIONS
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`5.1 Depression and Suicide
`EXTAVIA (Interferon beta-1b) should be used with caution in patients with depression, a condition that is common in people with multiple sclerosis.
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`Depression and suicide have been reported to occur with increased frequency in patients receiving interferon compounds, including Interferon beta-1b. Patients treated
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`with EXTAVIA should be advised to report immediately any symptoms of depression and/or suicidal ideation to their prescribing physicians. If a patient develops
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`depression, cessation of EXTAVIA therapy should be considered.
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`In the four randomized controlled studies there were three suicides and eight suicide attempts among the 1532 patients in the Interferon beta—1b treated
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`groups compared to one suicide and four suicide attempts among the 965 patients in the placebo groups.
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`5.2 Injection Site Necrosis
`Injection site necrosis (ISN) has been reported in 4% of patients in controlled clinical trials [see Adverse Reactions (6.1)]. Typically, injection site necrosis
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`occurs within the first four months of therapy, although post-marketing reports have been received of [SN occurring over one year after initiation of therapy. Necrosis
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`may occur at a single or multiple injection sites. The necrotic lesions are typically three cm or less in diameter, but larger areas have been reported._ Generally the
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`necrosis has extended only to subcutaneous fat. However, there are also reports of necrosis extending to and including fascia overlying muscle. In some lesions where
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`biopsy results are available, vasculitis has been reported. For some lesions debridement and, infrequently, skin grafting have been required.
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`As with any open lesion, it is important to avoid infection and, if it occurs, to treat the infection. Time to healing was varied depending on the severity of the
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`necrosis at the time treatment was begun. In most cases healing was associated with scarring.
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`Some patients have experienced healing of necrotic skin lesions while Interferon beta-1b therapy continued; others have not. Whether to discontinue therapy
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`following a single site of necrosis is dependent on the extent of necrosis. For patients who continue therapy with EXTAVIA after injection site necrosis has occurred,
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`EXTAVIA should not be administered into the affected area until it is fully healed. If multiple lesions occur, therapy should be discontinued until healing occurs.
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`Page 2 of 21
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`Page 2 of 21
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`Patient understanding and use of aseptic self-inj ection techniques and procedures should be periodically reevaluated, particularly if injection site necrosis has
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`occurred.
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`5.3 Injection Site Reactions
`In controlled clinical trials, injection site reactions occurred in 78% of patients receiving Interferon beta-1b with injection site necrosis in 4%. Injection site
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`inflammation (42%), injection site pain (16%), injection site hypersensitivity (4%), injection site necrosis (4%), injection site mass (2%), injection site edema (2%) and
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`non-specific reactions were significantly associated with Interferon beta-l b treatment . The incidence of injection site reactions tended to decrease over time.
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`Approximately 69% of patients experienced the event during the first three months of treatment, compared to approximately 40% at the end of the studies.
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`5.4 Anaphylaxis
`Anaphylaxis has been reported as a rare complication of Interferon beta-l b use. Other allergic reactions have included dyspnea, bronchospasm, tongue
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`edema, skin rash and urticaria [see Adverse Reactions (6.1)].
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`5.5 Flu-Like Symptom Complex
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`In controlled clinical trials, the rate of flu-like symptom complex was approximately 57%. The incidence decreased over time, with only 10% of patients
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`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)].
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`5.6 Leukopenia
`In controlled clinical trials, leukopenia was reported in 18% of patients receiving Interferon beta-1b, leading to a reduction of the dose of Interferon beta-1b
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`in some patients [see Adverse Reactions (6.1)]. Monitoring of complete blood and differential white blood cell counts is recommended [see Warnings and Precautions
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`(5.8)].
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`5.7 Hepatic enzymes elevations
`In controlled clinical trials, elevations of SGPT to greater than five times baseline value were reported in 12% of patients receiving Interferon beta-lb, and
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`increase of SGOT to greater than five times baseline value were reported in 4% of patients receiving Interferon beta-1b, leading to dose-reduction or discontinuation of
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`treatment in some patients [see Adverse Reactions (6.1)]. Monitoring of liver function tests is recommended [see Warnings and Precautions (5.8)].
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`5.8 Laboratory Tests
`In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and difierential white blood cell
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`counts, platelet counts and blood chemistries, including liver function tests, are recommended at regular intervals (one, three, and six months) following introduction of
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`EXTAVIA therapy, and then periodically thereafier in the absence of clinical symptoms. Thyroid firnction tests are recommended every six months in patients with a
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`history of thyroid dysfunction or as clinically indicated. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with
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`differential and platelet counts.
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`5.9 Albumin (Human), USP
`This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an
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`extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt—Jakob disease (CJD) also is considered extremely remote. No
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`cases of transmission of viral diseases or CJD have-ever been identified for albumin.
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`6 ADVERSE REACTIONS
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`6.1 Clinical Studies Experience
`In all studies, the most serious adverse reactions with Interferon beta-1b were depression, suicidal ideation and injection site necrosis (see Warnings and
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`Precautions). The incidence of depression of any severity was approximately 30% in both Interferon beta-lb-treated patients and placebo-treated patients. Anaphylaxis
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`and other allergic reactions have been reported in patients using Interferon beta-1b [see Warnings and Precautions (5.4)]. The most commonly reported adverse
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`reactions were lymphopenia (lynnphocytes<1500/mm3), injection site reaction, asthenia, flu—like symptom complex, headache, and pain. The most frequently reported
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`adverse reactions resulting in clinical intervention (e.g., discontinuation of Interferon beta-lb, adjustment in dosage, or the need for concomitant medication to treat an
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`adverse reaction symptom) were depression, flu-like symptom complex, injection site reactions, leukopenia, increased liver enzymes, asthenia, hypertonia, and
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`myasthenia.
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`Because clinical trials are conducted under widely varying conditions and over varying lengths of time, adverse reaction rates observed in the clinical trials
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`of Interferon beta-lb cannot be directly compared to rates in clinical trials of other drugs, and may not reflect the rates observed in practice. The adverse reaction
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`information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
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`The data described below reflect exposure to Interferon beta-1b in the four placebo controlled trials of 1407 patients with MS treated with 0.25 mg or 0.16
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`mg/mz, including 1261 exposed for greater than one year. The population encompassed an age range from 18 — 65 years. Sixty-four percent (64%) of the patients were
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`female. The percentages of Caucasian, Black, Asian, and Hispanic patients were 94.8%, 3.5%, 0.1%, and 0.7%, respectively.
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`,
`The safety profiles for Interferon beta-lb-treated patients with SPMS and RRMS were similar. Clinical experience with Interferon beta-1b in other
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`populations (patients with cancer, HIV positive patients, etc.) provides additional data regarding adverse reactions; however, experience in non-MS populations may not
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`be frilly applicable to the MS population.
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`Table 2 enumerates adverse events and laboratory abnormalities that occurred among all patients treated with 0.25 mg or 0.16 mg/m2 Interferon beta-1b
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`every other day for periods of up to three years in the four placebo controlled trials (Study 1-4) at an incidence that was at least 2.0% more than that observed in the
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`placebo patients (System Organ Class, MedDRA v. 8.0).
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`Table 2 Adverse Reactions and Laboratory Abnormalities
`__—___—____—____—_______._______._————~—————-———-——-——-——
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`Interferon beta-1b (n=l407)
`System Organ Class MedDRA v. 8.0 ”
`Placebo (n=965)
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`Adverse Reaction
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`_____________—_____—__.__————-—-—————-————-—-——-—-———-
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`Blood and lymphatic system disorders
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`Lymphocytes count decreased (< 1500/mm3) "
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`Page 3 of 21
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`66%
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`86%
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`Absolute neutroghil count decreased §< lSOO/mm3 ! "
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`White blood cell count decreased 1< 3000/mm3! "
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`5%
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`4%
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`13%
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`13%
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`6%
`3%
`LymEhadenoEathy
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`_______________________.___._.._———————-——————-——
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`Nervous system disorders
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`Headache
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`Insomnia
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`Incoordination
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`16%
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`50%
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`21%
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`__________________________._—————————-————
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`1 5 %
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`17%
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`________,_____________________——-———————-—-—————
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`MM
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`H ertension V
`6%
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`____L_______________________.______————————————
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`_______________________—____————————————
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`ResEiratory, thoracic and mediastinal disorders
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`6%
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`stgnea
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`_____________________.___________————————————
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`Gastrointestinal disorders
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`16%
`1 1%
`Abdominal gain
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`____________________—_______—_—————————————-——
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`Hegatobiliary disorders
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`Alanine aminotransferase increased(SGPT > 5 times baseline}x
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`4%
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`12%
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`4%
`1%
`Aspartate aminotransferase increased! SGOT > 5 times baseline2"
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`_________________________________———————-——-———-————
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`WWW——
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`___Ras_h________________________15°/L___———3-li———
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`Skin disorder
`8%
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`______________________—__________———_——————————-—-_—-————
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`Musculoskeletal and connective tissue disorders
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`Hypertonia
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`33%
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`40%
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`14%
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`Myalgia
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`Renal and urinagy disorders
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`l 1%
`8%
`Urinary urgency
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`—____________________..____———————————————-——-—-
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`Reproductive system and breast disorders
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`Metron'hagia*
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`9%
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`6%
`ImlgotenceM
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`7%
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`General disorders and administration site conditions
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`Injection site reaction {various kinds 2 °
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`Asthenia
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`Flu—like smptoms {complex}§
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`Pain
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`26%
`48%
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`37%
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`19%
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`57%
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`3 1%
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`Chills
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`Peripheral edema
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`9%
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`1 0%
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`21%.,
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`12%
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`9%
`6%
`Chest pain
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`3%
`Malaise
`6%
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`Injection site necrosis
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`0%
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`# except for "inj ection site reaction (various kinds)°" and "flu-like symptom complex§ " the most appropriate MedDRA term is used to describe a certain
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`reaction and its synonyms and related conditions.
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`" laboratory abnormality
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`* pre—menopausal women
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`° "Injection site reaction (various kinds)" comprises all adverse events occurring at the injection site (except injection site necrosis), i.e., the following terms:
`injection site reaction, injection site hemorrhage, injection site hypersensitivity, injection site inflammation, injection site mass, injection site pain, injection site edema
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`and injection site atrophy.
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`§ "Flu-like symptom complex" denotes flu syndrome and/or a combination of at least two AEs from fever, chills, myalgia, malaise, sweating.
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`Labgratgry Abnormalities
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`In the four clinical trials, leukopenia was reported in 18% and 6% of patients in Interferon beta-lb- and placebo-treated groups, respectively. No patients
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`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.
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`Monitoring of complete blood and differential white blood cell counts is recommended [see Warnings and Precautions (5.6, 5.8)].
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`Other abnormalities included increase of SGPT to greater than five times baseline value (12%), and increase of SGOT to greater than five times baseline
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`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
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`3, 1.5% of Interferon beta-lb patients were dose-reduced or interrupted treatment for increased hepatic enzymes. In Study 4, 1.7% of patients were withdrawn from
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`treatment due to increased hepatic enzymes, two of them after a dose reduction. In Studies 14, nine (0.6%) patients were withdrawn from treatment with Interferon
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`beta-lb for any laboratory abnormality, including four (0.3%) patients following dose reduction. Monitoring of liver function tests is recommended [see Warnings and
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`Precautions (5.7, 5.8)].
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`6.2 Postmarketing Experience
`The following adverse events have been observed during postmarketing experience with Interferon beta-lb and are classified within body system categories:
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`Blood and lymphatic system disorders: Anemia, Thrombocytopenia
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`Endocrine disorders: Hypothyroidism, Hyperthyroidism, Thyroid dysfunction
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`Metabolism and nutrition disorders: Hypocalcemia, Hyperuricemia, Triglyceride increased, Anorexia, Weight decrease
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`Psychiatric disorders: Confusion, Depersonalization, Emotional lability
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`I
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`Nervous system disorders: Ataxia, Convulsion, Paresthesia, Psychotic symptoms
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`Cardiac disorders: Cardiomyopathy
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`Vascular disorders: Deep vein thrombosis, Pulmonary embolism
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`Respiratory, thoracic and mediastinal disorders: Bronchospasm, Pneumonia
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`Gastrointestinal disorders: Pancreatitis, Vomiting
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`Hepatobiliary disorders: Hepatitis, Gamma GT increased
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`Skin and subcutaneous tissue disorders: Pruritus, Skin discoloration, Urticaria
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`Renal and urinary disorders: Urinary tract infection, Urosepsis
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`General disorders and administration site conditions: Fatal capillary leak syndrome*.
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`*The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of this syndrome.
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`6.3 Immunogenicity
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`As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples were monitored for the development of antibodies to Interferon
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`beta-1b during Study 1 [see Clinical Studies (14)]. In patients receiving 0.25 mg every other day 56/124 (45%) were found to have serum neutralizing activity at one or
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`more of the time points tested. In Study 4 [see Clinical Studies (14)], neutralizing activity was measured every 6 months and at end of study. At individual visits after
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`start of therapy, activity was observed in 16.5% up to 25.2% of the Interferon beta-lb treated patients. Such neutralizing activity was measured at least once in 75
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`(29.9%) out of 251 Interferon beta-1b patients who provided samples during treatment phase; of these, 17 (22.7%) converted to negative status later in the study.
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`Based on all the available evidence, the relationship between antibody formation and clinical safety or efficacy is not known.
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`These data reflect the percentage of patients whose test results were considered positive for antibodies to Interferon beta-1b using a biological neutralization
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`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
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`sensitivity and specificity of the assay. Additionally, the observed incidence of neutralizing activity in an assay may be influenced by several factors including sample
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`handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Interferon beta-
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`lb with the incidence of antibodies to other products may be misleading.
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`Anaphylactic reactions have rarely been reported with the use of Interferon beta-lb [See Warnings and Precautions (5. 4)].
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`Page 5 of 21
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`Page 5 of 21
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`7 DRUG INTERACTIONS
`No formal drug interaction studies have been conducted with Interferon beta-1b. In the placebo controlled studies in MS, corticosteroids or ACTH were
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`administered for treatment of relapses for periods of up to 28 days in patients (N=664) receiving Interferon beta-lb.
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`8 USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
`Pregnancy Category C: There are no adequate and well-controlled studies of Interferon beta-lb in pregnant women; however, spontaneous abortions while
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`on treatment were reported in four patients participating in the Interferon beta—1b RRMS clinical trial. Interferon beta—1b should be used during pregnancy only if the
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`potential benefit justifies the potential risk to the fetus.
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`When Interferon beta-lb (doses ranging from 0.028 to 0.42 mg/kg) was administered to pregnant rhesus monkeys throughout the period of organogenesis
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`(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
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`body surface are (mg/1n2) basis. A no-effect dose for embryo-fetal developmental toxicity in rhesus monkeys was not established.
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`8.3 Nursing Mothers
`It is not known whether Interferon beta-1b is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for
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`serious adverse reactions in nursing infants from Interferon beta-lb, a decision should be made to either discontinue nursing or discontinue the drug, taking into account
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`the importance of drug to the mother.
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`8.4 Pediatric Use
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`Safety and efficacy in pediatric patients have not been established.
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`8.5 Geriatric Use
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`Clinical studies of Interferon beta-lb did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than
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`younger patients.
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`10 OVERDOSAGE
`Safety of doses higher than 0.25 mg every other day has not been adequately evaluated. The