---------------------------------DOSAGE AND ADMINISTRATION ---------------------------------
`• 300 mg infused intravenously over approximately one hour, every four weeks. Do
`not give as an intravenous push or bolus (2.1, 2.2).
`• TYSABRI solution must be administered within 8 hours of preparation (2.3).
`• Observe patients during the infusion and for one hour after the infusion is complete
`(2.4).
`• In CD, discontinue in patients that have not experienced therapeutic benefit by 12
`weeks of induction therapy, and in patients that cannot discontinue chronic
`concomitant steroids within six months of starting therapy (2.2).
`---------------------------------DOSAGE FORMS AND STRENGTH --------------------------------
`• Solution [300 mg per 15 mL vial] for dilution prior to infusion (3).
`-----------------------------------------CONTRAINDICATIONS ---------------------------------------
`• Patients who have or have had PML (4).
`• Patients who have had a hypersensitivity reaction to TYSABRI (4).
`---------------------------------WARNINGS AND PRECAUTIONS----------------------------------
`• Progressive Multifocal Leukoencephalopathy (PML): Has occurred in patients who
`received TYSABRI. Patients who have significantly compromised immune system
`function should not ordinarily be treated with TYSABRI. Obtain an MRI scan in MS
`patients prior to initiating TYSABRI. Monitor MS and CD patients and withhold
`TYSABRI at the first sign or symptom suggestive of PML (5.1).
`• Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis)
`have occurred. Permanently discontinue TYSABRI if such a reaction occurs (5.3).
`• Immunosuppression/Infections: TYSABRI may increase the risk for certain
`infections. Monitor patients for development of infections due to increased risk with
`use of TYSABRI (5.4).
`• Hepatotoxicity: Clinically significant liver injury has occurred. Discontinue TYSABRI
`in patients with jaundice or evidence of liver injury (5.5).
`-----------------------------------------ADVERSE REACTIONS ----------------------------------------
`The most common adverse reactions (incidence ≥ 10%) in MS were headache, fatigue,
`arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis,
`vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash;
`and in CD were headache, upper respiratory tract infections, nausea, and fatigue (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Biogen Idec or Elan at 1-
`800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`-----------------------------------USE IN SPECIFIC POPULATIONS---------------------- -----------
`• Pregnancy: Physicians are encouraged to enroll pregnant patients in the TYSABRI
`Pregnancy Exposure Registry by calling 1-800-456-2255 (8.1)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
`Revised: 10/2008
`
` 8
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`
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`10
`11
`12
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`13
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`14
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`15
`16
`17
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`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`CLINICAL STUDIES
`14.1 Multiple Sclerosis
`14.2 Crohn’s Disease
`REFERENCES
`HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`17.1 General Counseling Information
`17.2 Progressive Multifocal Leukoencephalopathy
`17.3 Hypersensitivity Reactions
`17.4 Immunosuppression/Infections
`17.5 Hepatotoxicity
`17.6 Medication Guide
`*Sections or subsections omitted from the Full Prescribing Information are not listed.
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use TYSABRI
`safely and effectively. See full prescribing information for TYSABRI.
`TYSABRI (natalizumab) injection for intravenous use
`Initial U.S. Approval: 2004
`WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
`See full prescribing information for complete boxed warning
`• TYSABRI increases the risk of progressive multifocal
`leukoencephalopathy (PML), an opportunistic viral infection of the brain
`that usually leads to death or severe disability (5.1)
` • Monitor patients, and withhold TYSABRI immediately at the first sign or
`symptom suggestive of PML (4, 5.1)
`• TYSABRI is available only through a special restricted distribution
`program called the TOUCH™ Prescribing Program and must be
`administered only to patients enrolled in this program (5.1, 5.2)
`--------------------------------------RECENT MAJOR CHANGES -------------------------------------
`Indications and Usage
`Crohn’s Disease (1.2)
`Dosage and Administration
`Crohn’s Disease (2.2)
`Warnings and Precautions
`10/2008
`Progressive Multifocal Leukoencephalopathy (5.1)
`Distribution Program for TYSABRI (5.2)
`1/2008
`
`1/2008
`Immunosuppression/Infections (5.4)
`
`1/2008
`Hepatotoxicity (5.5)
`
`
`--------------------------------------INDICATIONS AND USAGE -------------------------------------
`TYSABRI is an integrin receptor antagonist indicated for treatment of:
`Multiple Sclerosis (MS) (1.1)
`• As monotherapy for the treatment of patients with relapsing forms of multiple
`sclerosis to delay the accumulation of physical disability and reduce the frequency
`of clinical exacerbations. TYSABRI is generally recommended for patients who
`have had an inadequate response to, or are unable to tolerate, an alternate MS
`therapy.
`Crohn’s Disease (CD) (1.2)
`• Inducing and maintaining clinical response and remission in adult patients with
`moderately to severely active Crohn’s disease with evidence of inflammation who
`have had an inadequate response to, or are unable to tolerate, conventional CD
`therapies and inhibitors of TNF-α.
`Important Limitations:
`• In CD, TYSABRI should not be used in combination with immunosuppressants or
`inhibitors of TNF-α.
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1/2008
`
`1/2008
`
`
`
`
`
`
`
`
`
`2
`
`3
`4
`5
`
`WARNING – PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
`1
` INDICATIONS AND USAGE
`1.1 Multiple Sclerosis (MS)
`1.2 Crohn’s Disease (CD)
` DOSAGE AND ADMINISTRATION
`2.1 Multiple Sclerosis
`Crohn’s Disease
`2.2
`2.3
`Preparation Instructions
`2.4
`Administration Instructions
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Progressive Multifocal Leukoencephalopathy (PML)
`5.2
`Distribution Program for TYSABRI
`5.3
`Hypersensitivity/Antibody Formation
`5.4
`Immunosuppression/Infections
`5.5
`Hepatotoxicity
`5.6
`Laboratory Test Abnormalities
`Immunizations
`5.7
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Immunogenicity
`Postmarketing Experience
`6.3
`DRUG INTERACTIONS
`
`6
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`7
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`Mylan Pharms. Inc. Exhibit 1048 Page 1
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`TYSABRI® (natalizumab) Injection
`FULL PRESCRIBING INFORMATION
`
`
`WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
`
`
`TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an
`opportunistic viral infection of the brain that usually leads to death or severe disability.
`Cases of PML have been reported in patients taking TYSABRI who were recently or
`concomitantly treated with immunomodulators or immunosuppressants, as well as in
`patients receiving TYSABRI as monotherapy[see Warnings and Precautions (5.1)].
`
`
`• Because of the risk of PML, TYSABRI is available only through a special restricted
`distribution program called the TOUCH™ Prescribing Program. Under the
`TOUCH™ Prescribing Program, only prescribers, infusion centers, and pharmacies
`associated with infusion centers registered with the program are able to prescribe,
`distribute, or infuse the product. In addition, TYSABRI must be administered only
`to patients who are enrolled in and meet all the conditions of the TOUCH™
`Prescribing Program [see Warnings and Precautions (5.1, 5.2)].
`
` Healthcare professionals should monitor patients on TYSABRI for any new sign or
`symptom that may be suggestive of PML. TYSABRI dosing should be withheld
`immediately at the first sign or symptom suggestive of PML. For diagnosis, an
`evaluation that includes a gadolinium-enhanced magnetic resonance imaging (MRI)
`scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA
`are recommended [see Contraindications (4), Warnings and Precautions (5.1)].
`
`INDICATIONS AND USAGE
`
` •
`
` 1
`
`
`
`1.1 Multiple Sclerosis (MS)
`TYSABRI is indicated as monotherapy for the treatment of patients with relapsing forms of
`multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of
`clinical exacerbations. The safety and efficacy of TYSABRI beyond two years are unknown.
`
`Because TYSABRI increases the risk of progressive multifocal leukoencephalopathy
`(PML), an opportunistic viral infection of the brain that usually leads to death or severe
`disability, TYSABRI is generally recommended for patients who have had an inadequate
`response to, or are unable to tolerate, an alternate multiple sclerosis therapy [see Boxed Warning,
`Warnings and Precautions (5.1)].
`
` Safety and efficacy in patients with chronic progressive multiple sclerosis have not been
`studied.
`1.2
`Crohn’s Disease (CD)
`TYSABRI is indicated for inducing and maintaining clinical response and remission in
`adult patients with moderately to severely active Crohn’s disease with evidence of inflammation
`who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and
`inhibitors of TNF-α. TYSABRI should not be used in combination with immunosuppressants
`
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`(e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α [see
`Boxed Warning, Warnings and Precautions (5.1)].
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Multiple Sclerosis (MS)
`Only prescribers registered in the MS TOUCH™ Prescribing Program may prescribe
`TYSABRI for multiple sclerosis [see Boxed Warning, Warnings and Precautions (5.2)]. The
`recommended dose of TYSABRI for multiple sclerosis is 300 mg intravenous infusion over one
`hour every four weeks.
`2.2
`Crohn’s Disease (CD)
`Only prescribers registered in the CD TOUCH™ Prescribing Program may prescribe
`TYSABRI for Crohn’s disease [see Boxed Warning, Warnings and Precautions (5.1)].
`The recommended dose of TYSABRI for Crohn’s disease is 300 mg intravenous infusion
`over one hour every four weeks. TYSABRI should not be used with concomitant
`immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or
`concomitant inhibitors of TNF-α. Aminosalicylates may be continued during treatment with
`TYSABRI.
`If the patient with Crohn’s disease has not experienced therapeutic benefit by 12 weeks of
`induction therapy, discontinue TYSABRI. For patients with Crohn’s disease that start
`TYSABRI while on chronic oral corticosteroids, commence steroid tapering as soon as a
`therapeutic benefit of TYSABRI has occurred; if the patient with Crohn’s disease cannot be
`tapered off of oral corticosteroids within six months of starting TYSABRI, discontinue
`TYSABRI. Other than the initial six-month taper, prescribers should consider discontinuing
`TYSABRI for patients who require additional steroid use that exceeds three months in a calendar
`year to control their Crohn’s disease.
`2.3
`Dilution Instructions
`(1) Use aseptic technique when preparing TYSABRI solution for intravenous infusion.
`Each vial is intended for single use only.
`(2) TYSABRI is a colorless, clear to slightly opalescent concentrate. Inspect the TYSABRI
`vial for particulate material and discoloration prior to dilution and administration. If
`visible particulates are observed and/or the liquid in the vial is discolored, the vial must
`not be used.
`(3) To prepare the solution, withdraw 15 mL of TYSABRI concentrate from the vial using a
`sterile needle and syringe. Inject the concentrate into 100 mL 0.9% Sodium Chloride
`Injection, USP. No other IV diluents may be used to prepare the TYSABRI solution.
`(4) Gently invert the TYSABRI solution to mix completely. Do not shake. Inspect the
`solution visually for particulate material prior to administration.
`(5) The final dosage solution has a concentration of 2.6 mg/mL.
`(6) Following dilution, infuse TYSABRI solution immediately, or refrigerate solution at
`2 to 8°C, and use within 8 hours. If stored at 2 to 8°C, allow the solution to warm to room
`temperature prior to infusion. DO NOT FREEZE.
`Administration Instructions
`•
`Infuse TYSABRI 300 mg in 100 mL 0.9% Sodium Chloride Injection, USP, over
`approximately one hour (infusion rate approximately 5 mg per minute). Do not
`
`2.4
`
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`administer TYSABRI as an intravenous push or bolus injection. After the infusion is
`complete, flush with 0.9% Sodium Chloride Injection, USP.
`• Observe patients during the infusion and for one hour after the infusion is complete.
`Promptly discontinue the infusion upon the first observation of any signs or
`symptoms consistent with a hypersensitivity-type reaction [see Warnings and
`Precautions (5.3)].
`• Use of filtration devices during administration has not been evaluated. Other
`medications should not be injected into infusion set side ports or mixed with TYSABRI.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`TYSABRI is a concentrated solution that must be diluted prior to intravenous infusion.
`
`TYSABRI injection is supplied as 300 mg natalizumab in 15 mL (20 mg/mL) in a sterile, single-use
`vial free of preservatives.
`
`4
`
`CONTRAINDICATIONS
`
`• TYSABRI is contraindicated in patients who have or have had progressive multifocal
`leukoencephalopathy (PML) [see Boxed Warning, Warnings and Precautions (5.1)].
`• TYSABRI should not be administered to a patient who has had a hypersensitivity
`reaction to TYSABRI. Observed reactions range from urticaria to anaphylaxis [see
`Warnings and Precautions (5.3)].
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`5.1
`
`Progressive Multifocal Leukoencephalopathy (PML)
`Progressive multifocal leukoencephalopathy, an opportunistic infection caused by the JC
`virus that typically only occurs in patients who are immunocompromised, developed in three patients
`who received TYSABRI in clinical trials [see Boxed Warning]. Two cases of PML were observed
`among 1869 patients with multiple sclerosis treated for a median of 120 weeks. The third case
`occurred among 1043 patients with Crohn’s disease after the patient received eight doses. Both
`multiple sclerosis patients were receiving concomitant immunomodulatory therapy and the Crohn’s
`disease patient had been treated in the past with immunosuppressive therapy. In the postmarketing
`setting, additional cases of PML have been reported in multiple sclerosis patients who were receiving
`no concomitant immunomodulatory therapy. The absolute risk for PML in patients treated with
`TYSABRI cannot be precisely estimated, and factors that might increase an individual patient’s risk
`for PML have not been identified. There are no known interventions that can reliably prevent PML
`or adequately treat PML if it occurs. It is not known whether early detection of PML and
`discontinuation of TYSABRI will mitigate the disease. There is limited experience beyond two
`years of treatment. The relationship between the risk of PML and the duration of treatment is
`unknown, but most cases of PML were in patients who received more than one year of treatment.
`Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy or
`who have systemic medical conditions resulting in significantly compromised immune system
`function should not be treated with TYSABRI. The incidence of PML appears to be lower in
`patients receiving TYSABRI as monotherapy; however, the number of cases is too few and the
`number of patients treated too small to reliably conclude that the true risk of PML is lower in patients
`
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`treated with TYSABRI alone than in patients who are receiving other drugs that decrease immune
`function or who are otherwise immunocompromised.
`Because of the risk of PML, TYSABRI is available only under a special restricted
`distribution program, the TOUCH™ Prescribing Program.
`In multiple sclerosis patients, an MRI scan should be obtained prior to initiating therapy with
`TYSABRI. This MRI may be helpful in differentiating subsequent multiple sclerosis symptoms
`from PML.
`In Crohn’s disease patients, a baseline brain MRI may also be helpful to distinguish pre-
`existent lesions from newly developed lesions, but brain lesions at baseline that could cause
`diagnostic difficulty while on TYSABRI therapy are uncommon.
`Healthcare professionals should monitor patients on TYSABRI for any new sign or
`
`symptom suggestive of PML. Typical symptoms associated with PML are diverse, progress over
`days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs,
`disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and
`personality changes. The progression of deficits usually leads to death or severe disability over
`weeks or months. Withhold TYSABRI dosing immediately at the first sign or symptom suggestive
`of PML. For diagnosis, an evaluation including a gadolinium-enhanced MRI scan of the brain and,
`when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. There are no
`known interventions that can adequately treat PML if it occurs. Three sessions of plasma exchange
`over 5 to 8 days were shown to accelerate TYSABRI clearance in a study of 12 patients, although in
`the majority of patients alpha-4 integrin receptor binding remained high. Adverse events which may
`occur during plasma exchange include clearance of other medications and volume shifts, which have
`the potential to lead to hypotension or pulmonary edema. There is no evidence that plasma exchange
`has any benefit in the treatment of opportunistic infections such as PML.
`5.2
`Distribution Program for TYSABRI
`TYSABRI is available only under a special restricted distribution program called the
`TOUCH™ Prescribing Program. Under the TOUCH™ Prescribing Program, only prescribers,
`infusion centers, and pharmacies associated with infusion centers registered with the program are
`able to prescribe, distribute, or infuse the product. For prescribers and patients, the TOUCH™
`Prescribing Program has two components: MS TOUCH™ (for patients with multiple sclerosis)
`and CD TOUCH™ (for patients with Crohn's disease). TYSABRI must be administered only to
`patients who are enrolled in and meet all the conditions of the MS or CD TOUCH™ Prescribing
`Program. Contact the TOUCH™ Prescribing Program at 1-800-456-2255 [see Boxed Warning].
`To enroll in the TOUCH™ Prescribing Program, prescribers and patients are required to
`understand the risks of treatment with TYSABRI, including PML and other opportunistic
`infections. Prescribers are required to understand the information in the Prescribing Information
`and to be able to:
`• Educate patients on the benefits and risks of treatment with TYSABRI, ensure that the
`patient receives the Medication Guide, instruct them to read it, and encourage them to ask
`questions when considering TYSABRI. Patients may be educated by the enrolled
`prescriber or a healthcare provider under that prescriber’s direction.
`• Review the TOUCH™ Prescriber/Patient Enrollment form for TYSABRI with the patient
`and answer all questions.
`• As part of the initial prescription process for TYSABRI, obtain the patient’s signature
`and initials on the TOUCH™ program enrollment form, sign it, place the original signed
`
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`form in the patient’s medical record, send a copy to Biogen Idec, and give a copy to the
`patient.
`• Report serious opportunistic and atypical infections with TYSABRI to Biogen Idec or
`Elan at 1-800-456-2255 and to the Food and Drug Administration’s MedWatch Program
`at 1-800-FDA-1088.
`• Evaluate the patient three months after the first infusion, six months after the first
`infusion, and every six months thereafter.
`• Determine every six months whether patients should continue on treatment and if so
`reauthorize treatment every six months.
`• Submit to Biogen Idec the TYSABRI Patient Status Report and Reauthorization
`Questionnaire six months after initiating treatment and every six months thereafter.
`5.3 Hypersensitivity/Antibody Formation
`Hypersensitivity reactions have occurred in patients receiving TYSABRI, including
`serious systemic reactions (e.g., anaphylaxis) which occurred at an incidence of <1%. These
`reactions usually occur within two hours of the start of the infusion. Symptoms associated with
`these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing,
`hypotension, dyspnea, and chest pain. Generally, these reactions are associated with antibodies
`to TYSABRI.
`
`If a hypersensitivity reaction occurs, discontinue administration of TYSABRI and initiate
`appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated
`with TYSABRI. Hypersensitivity reactions were more frequent in patients with antibodies to
`TYSABRI compared to patients who did not develop antibodies to TYSABRI in both MS and
`CD studies. Therefore, the possibility of antibodies to TYSABRI should be considered in
`patients who have hypersensitivity reactions [see Adverse Reactions (6.2)].
`Antibody testing: If the presence of persistent antibodies is suspected, antibody testing
`should be performed. Antibodies may be detected and confirmed with sequential serum antibody
`tests. Antibodies detected early in the treatment course (e.g., within the first six months) may be
`transient and disappear with continued dosing. Repeat testing at three months after the initial
`positive result is recommended in patients in whom antibodies are detected to confirm that
`antibodies are persistent. Prescribers should consider the overall benefits and risks of TYSABRI
`in a patient with persistent antibodies.
`
`Experience with monoclonal antibodies, including TYSABRI, suggests that patients who
`receive therapeutic monoclonal antibodies after an extended period without treatment may be at
`higher risk of hypersensitivity reactions than patients who received regularly scheduled
`treatment. Given that patients with persistent antibodies to TYSABRI experience reduced
`efficacy, and that hypersensitivity reactions are more common in such patients, consideration
`should be given to testing for the presence of antibodies in patients who wish to recommence
`therapy following a dose interruption. Following a period of dose interruption, patients testing
`negative for antibodies prior to re-dosing have a risk of antibody development with re-treatment
`that is similar to TYSABRI naïve patients [see Adverse Reactions (6.2)].
`5.4
`Immunosuppression/Infections
`The immune system effects of TYSABRI may increase the risk for infections. In Study
`MS1 [see Clinical Studies (14.1)], certain types of infections, including pneumonias and urinary
`tract infections (including serious cases), gastroenteritis, vaginal infections, tooth infections,
`tonsillitis, and herpes infections, occurred more often in TYSABRI-treated patients than in
`
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`placebo-treated patients [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. One
`opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed
`in a patient who received TYSABRI in Study MS1.
`In Studies MS1 and MS2, an increase in infections was seen in patients concurrently
`receiving short courses of corticosteroids. However, the increase in infections in TYSABRI-
`treated patients who received steroids was similar to the increase in placebo-treated patients who
`received steroids.
`In CD clinical studies, opportunistic infections (pneumocystis carinii pneumonia,
`pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and
`burkholderia cepacia) have been observed in <1% of TYSABRI-treated patients; some of these
`patients were receiving concurrent immunosuppressants [see Boxed Warning, Warnings and
`Precautions (5.1, 5.4), Adverse Reactions (6.1)].
`In Studies CD1 and CD2, an increase in infections was seen in patients concurrently
`receiving corticosteroids. However, the increase in infections was similar in placebo-treated and
`TYSABRI-treated patients who received steroids.
`Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may
`further increase the risk of infections, including PML and other opportunistic infections, over the
`risk observed with use of TYSABRI alone [see Boxed Warning, Warnings and Precautions (5.1),
`Adverse Reactions (6.1)]. The safety and efficacy of TYSABRI in combination with
`antineoplastic, immunosuppressant, or immunomodulating agents have not been established.
`Patients receiving chronic immunosuppressant or immunomodulatory therapy or who have
`systemic medical conditions resulting in significantly compromised immune system function
`should not ordinarily be treated with TYSABRI.
`For patients with Crohn’s disease who start TYSABRI while on chronic corticosteroids,
`commence steroid withdrawal as soon as a therapeutic benefit has occurred. If the patient cannot
`discontinue systemic corticosteroids within six months, discontinue TYSABRI.
`5.5 Hepatotoxicity
`
`Clinically significant liver injury has been reported in patients treated with TYSABRI in
`the postmarketing setting. Signs of liver injury, including markedly elevated serum hepatic
`enzymes and elevated total bilirubin, occurred as early as six days after the first dose; signs of
`liver injury have also been reported for the first time after multiple doses. In some patients, liver
`injury recurred upon rechallenge, providing evidence that TYSABRI caused the injury. The
`combination of transaminase elevations and elevated bilirubin without evidence of obstruction is
`generally recognized as an important predictor of severe liver injury that may lead to death or the
`need for a liver transplant in some patients.
`
`TYSABRI should be discontinued in patients with jaundice or other evidence of
`significant liver injury (e.g., laboratory evidence).
`5.6
`Laboratory Test Abnormalities
`TYSABRI induces increases in circulating lymphocytes, monocytes, eosinophils,
`basophils, and nucleated red blood cells. Observed changes persist during TYSABRI exposure, but
`are reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations
`of neutrophils are not observed. TYSABRI induces mild decreases in hemoglobin levels that are
`frequently transient.
`
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`5.7
`
`Immunizations
`No data are available on the effects of vaccination in patients receiving TYSABRI. No
`data are available on the secondary transmission of infection by live vaccines in patients receiving
`TYSABRI.
`
`6
`
`ADVERSE REACTIONS
`
`6.1
`
`
`Clinical Trials Experience
`The most serious adverse reactions were [see Warnings and Precautions (5)]:
`• Progressive Multifocal Leukoencephalopathy (PML)
`• Hypersensitivity
`•
`Immunosuppression/Infections
`The most common adverse reactions (incidence ≥ 10%) were headache and fatigue in
`
`both the multiple sclerosis (MS) and Crohn’s disease (CD) studies. Other common adverse
`reactions (incidence ≥ 10%) in the MS population were arthralgia, urinary tract infection, lower
`respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal
`discomfort, diarrhea NOS, and rash. Other common adverse reactions (incidence ≥ 10%) in the
`CD population were upper respiratory tract infections and nausea.
`The most frequently reported adverse reactions resulting in clinical intervention (i.e.,
`discontinuation of TYSABRI), in the MS studies were urticaria (1%) and other hypersensitivity
`reactions (1%), and in the CD studies (Studies CD1 and CD2) were the exacerbation of Crohn’s
`disease (4.2%) and acute hypersensitivity reactions (1.5%) [see Warnings and Precautions
`(5.3)].
`
`A total of 1617 multiple sclerosis patients in controlled studies received TYSABRI, with a
`median duration of exposure of 28 months. A total of 1563 patients received TYSABRI in all CD
`studies for a median exposure of 5 months; of these patients, 33% (n=518) received at least one year
`of treatment and 19% (n=297) received at least two years of treatment.
`
`Because clinical trials are conducted under widely varying and controlled conditions, adverse
`reaction rates observed in clinical trials of TYSABRI cannot be directly compared to rates in the
`clinical trials of other drugs and may not reflect the rates observed in practice. The adverse
`reaction information does, however, provide a basis for identifying the adverse events that appear to
`be related to drug use and a basis for approximating rates.
`Multiple Sclerosis Clinical Studies
`The most frequently reported serious adverse reactions in Study MS1 [see Clinical
`Studies (14.1)] with TYSABRI were infections (3.2% versus 2.6% in placebo, including urinary
`tract infection [0.8% versus 0.3%] and pneumonia [0.6% versus 0%]), acute hypersensitivity
`reactions (1.1% versus 0.3%, including anaphylaxis/anaphylactoid reaction [0.8% versus 0%]),
`depression (1.0% versus 1.0%, including suicidal ideation or attempt [0.6% versus 0.3%]), and
`cholelithiasis (1.0% versus 0.3%). In Study MS2, serious adverse reactions of appendicitis were
`also more common in patients who received TYSABRI (0.8% versus 0.2% in placebo) [see
`Warnings and Precautions (5.4), Adverse Reactions - Infections].
`Table 1 enumerates adverse reactions and selected laboratory abnormalities that occurred in
`Study MS1 at an incidence of at least 1 percentage point higher in TYSABRI-treated patients than was
`observed in placebo-treated patients.
`
`
`
`8
`
`Mylan Pharms. Inc. Exhibit 1048 Page 8
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`

`
`
`
`
`
`Table 1. Adverse Reactions in Study MS1 (Monotherapy Study)
`
`
`Adverse Reactions
`(Preferred Term)
`
`Placebo
`n=312
`Percentage
`
`33%
`21%
`14%
`3%
`<1%
` 2%
` 2%
`<1%
`<1%
`<1%
`
`
`
`17%
`16%
`9%
` 6%
`7%
`7%
`5%
`
`
`
`16%
`
`
`
`14%
`3%
`1%
`
`
`
`10%
`9%
`4%
`
`
`
`9%
`4%
`2%
`0%
`
`
`TYSABRI
`n=627
`Percentage
`
`38%
`27%
`19%
`5%
`4%
`5%
`3%
`3%
`2%
`2%
`
`
`
`21%
`17%
`11%
`10%
`9%
`8%
`7%
`
`
`
`19%
`
`
`
`16%
`5%
`2%
`
`
`
`11%
`10%
`5%
`
`
`
`12%
`7%
`4%
`1%
`
`
`
`
`General
`Headache
`Fatigue
`Arthralgia
` Chest discomfort
` Acute hypersensitivity reactions**
`Other hypersensitivity reactions**
`Seasonal allergy
`Rigors
`Weight increased
`Weight decreased
`
`Infection
`Urinary tract infection
`Lower respiratory tract infection
`Gastroenteritis
`Vaginitis*
`Tooth infections
`Herpes
`Tonsillitis
`
`Psychiatric
`Depression
`
`Musculoskeletal/Connective Tissue
`Disorders
`Pain in extremity
`Muscle cramp
` Joint swelling
`
`Gastrointestinal
`Abdominal discomfort
`Diarrhea NOS
`Abnormal liver function test
`
`Skin
`Rash
`Dermatitis
`Pruritus
`Night sweats
`
`
`
`
`9
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`Mylan Pharms. Inc. Exhibit 1048 Page 9
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`

`
`
`
`
`
`Placebo
`n=312
`Percentage
`
`4%
`<1%
`1%
`<1%
`
`
`
`<1%
`5%
`
`
`
`3%
`7%
`
`
`
`2%
`<1%
`<1%
`
`TYSABRI
`n=627
`Percentage
`
`5%
`3%
`2%
`2%
`
`
`
`2%
`6%
`
`
`
`4%
`9%
`
`
`
`3%
`2%
`1%
`
`Adverse Reactions
`(Preferred Term)
`
`Menstrual Disorders*
`Irregular menstruation
`Dysmenorrhea
`Amenorrhea
`Ovarian cyst
`
`Neurologic Disorders
`Somnolence
`Vertigo
`
`
`
`Renal and Urinary Disorders
`Urinary incontinence
`Urinary urgency/frequency
`
`Injury
`Limb injury NOS
`Skin laceration
`Thermal burn
`
`
`
` *Percentage based on female patients only.
`** Acute versus other hypersensitivity reactions are
`defined as occurring within 2 hours post-infusion
`versus more than 2 hours.
`
`
`
`
`In Study MS2, peripheral edema was more common in patients who received TYSABRI
`(5% versus 1% in placebo).
`Crohn’s Disease Clinical Studies
`The following serious adverse events in the induction Studies CD1 and CD2 [see Clinical
`Studies (14.2)] were reported more commonly with TYSABRI than placebo and occurred at an
`incidence of at least 0.3%: intestinal obstruction or stenosis (2% vs. 1% in placebo), acute
`hypersensitivity reactions (0.5% vs. 0%), abdominal adhesions (0.3% vs