HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
` LEMTRADA safely and effectively. See full prescribing information for
`
`
` LEMTRADA.
`LEMTRADA® (alemtuzumab) injection, for intravenous use
`
`
`
`
`
`Initial U.S. Approval: 2001
`WARNING: AUTOIMMUNITY, INFUSION REACTIONS, AND
`
`
`MALIGNANCIES
`
`
`
`
`See full prescribing information for complete boxed warning.
`
`• LEMTRADA causes serious, sometimes fatal, autoimmune conditions
`
`
`such as immune thrombocytopenia and anti-glomerular basement
`
`
`
`membrane disease. Monitor complete blood counts with differential,
`
`
`
`
`serum creatinine levels, and urinalysis with urine counts at periodic
`
`
`
`
`intervals for 48 months after the last dose. (5.1)
`
`
`
`• LEMTRADA causes serious and life-threatening infusion reactions.
`
`
`LEMTRADA must be administered in a setting with appropriate
`
`equipment and personnel to manage anaphylaxis or serious infusion
`
`
`reactions. Monitor patients for two hours after each infusion. Make
`
`
`
`
`
`patients aware that serious infusion reactions can also occur after the
`2-hour monitoring period. (5.2)
`
`
`
`
`• LEMTRADA may cause an increased risk of malignancies, including
`
`thyroid cancer, melanoma, and lymphoproliferative disorders.
`
`
`Perform baseline and yearly skin exams. (5.3)
`
`• LEMTRADA is available only through a restricted distribution
`
`
`
`
` program. (5.4)
`
`
` --------------------------RECENT MAJOR CHANGES---------------------------­
`
`
`
`
` Dosage and Administration (2.2) 12/2017
` Warnings and Precautions, Infections (5.9)
`
`
`
`
` 12/2017
`
`
`
` Warnings and Precautions, Acute Acalculous Cholecystitis (5.10)
`
`
` 10/2017
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
` • LEMTRADA is a CD52-directed cytolytic monoclonal antibody indicated
`
`
` for the treatment of patients with relapsing forms of multiple sclerosis
`
`
`
`
`
` (MS). Because of its safety profile, the use of LEMTRADA should
` generally be reserved for patients who have had an inadequate response to
`
`
` two or more drugs indicated for the treatment of MS. (1)
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
` • Administer LEMTRADA by intravenous infusion over 4 hours for
`
`
`
`
` 2 treatment courses:
`o First course: 12 mg/day on 5 consecutive days. (2.1)
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`BOXED WARNING: AUTOIMMUNITY, INFUSION REACTIONS,
`AND MALIGNANCIES
`
`INDICATIONS AND USAGE
`1
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosage Information
`
`
`2.2 Testing and Precautions Prior to Treatment
`
`
`2.3 Recommended Premedication and Concomitant Medication
`
`
`2.4 Preparation Instructions
`
`
`2.5
`Infusion Instructions
`
`
`
`2.6 Laboratory Testing and Monitoring to Assess Safety
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Autoimmunity
`
`
`5.2
`Infusion Reactions
`
`
`5.3 Malignancies
`
`
`5.4 LEMTRADA REMS Program
`
`
`5.5
`Immune Thrombocytopenia
`
`
`5.6 Glomerular Nephropathies
`
`
`5.7 Thyroid Disorders
`
`
`
`5.8 Other Autoimmune Cytopenias
`
`
`5.9
`Infections
`
`
`5.10 Acute Acalculous Cholecystitis
`
`
`5.11 Pneumonitis
`
`
`5.12 Drug Products with Same Active Ingredient
`
`
`6 ADVERSE REACTIONS
`
`
`
`Reference ID: 4194892
`
`
`
`
`
`
`
`
`
`
`
`o Second course: 12 mg/day on 3 consecutive days 12 months after first
`
`
`
`
` treatment course. (2 1)
` • Premedicate with corticosteroids prior to LEMTRADA infusion for the first
`
`
`
`
`
` 3 days of each treatment course. (2.3)
`
`
` • Administer antiviral agents for herpetic prophylaxis starting on the first day
`
`
` of LEMTRADA dosing and continuing for a minimum of two months after
`
`
`
`
` completion of LEMTRADA dosing or until CD4+ lymphocyte count is
`
`
` more than 200 cells per microliter, whichever occurs later. (2.3)
`
`
`
` • Must be diluted prior to administration. (2.4)
`
`
` ---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`
`
` Injection: 12 mg/1.2 mL (10 mg/mL) in a single-use vial. (3)
`---------------------------CONTRAINDICATIONS---------------------------------­
`
`
` Infection with Human Immunodeficiency Virus. (4)
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
` • Thyroid Disorders: Obtain thyroid function tests prior to initiation of
`
`
`
` treatment and every 3 months until 48 months after the last infusion. (5.7)
`
`
`
`
`
` • Other Autoimmune Cytopenias: Monitor complete blood counts monthly
`
`
`
`
` until 48 months after the last infusion. (5.8)
`
`
` • Consider delaying initiation of LEMTRADA in patients with active
`
`
`
`
` infections until the infection is fully controlled. Do not administer live viral
` vaccines following a course of LEMTRADA. (5.9)
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`
` Most common adverse reactions (incidence ≥10% and > interferon beta-1a):
`rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection,
`
`
`fatigue, insomnia, upper respiratory tract infection, herpes viral infection,
`
`
`
`urticaria, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in
`
`extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia,
`
`
`
`
`dizziness, abdominal pain, flushing, and vomiting. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genzyme
`
`
`
`
`Corporation at 1-800-745-4447 (option 2) or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`----------------------------USE IN SPECIFIC POPULATIONS------------------­
`
`
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide
`
`
`
`
`
`
`
`
`Revised: 12/2017
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Lymphopenia
`
`
`
`6.3 Suicidal Behavior or Ideation
`
`
`6.4
`Immunogenicity
`
`
`6.5 Postmarketing Experience
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`10 OVERDOSAGE
`
`
`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 Storage and Handling
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`Biogen Exhibit 2169
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 29
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
` WARNING: AUTOIMMUNITY, INFUSION REACTIONS, AND MALIGNANCIES
`
`
`
`• LEMTRADA causes serious, sometimes fatal, autoimmune conditions such as immune
`
`
`thrombocytopenia and anti-glomerular basement membrane disease. Monitor complete
` blood counts with differential, serum creatinine levels, and urinalysis with urine cell
`
`
` counts at periodic intervals for 48 months after the last dose of LEMTRADA [see
`
`
`
` Warnings and Precautions (5.1)].
`
`
` • LEMTRADA causes serious and life threatening infusion reactions. LEMTRADA must
`
`
` be administered in a setting with appropriate equipment and personnel to manage
`
` anaphylaxis or serious infusion reactions. Monitor patients for two hours after each
`
`
`infusion. Make patients aware that serious infusion reactions can also occur after the 2­
` hour monitoring period [see Warnings and Precautions (5.2)].
`
`
`
`
`
`
` • LEMTRADA may cause an increased risk of malignancies, including thyroid cancer,
`
`
` melanoma, and lymphoproliferative disorders. Perform baseline and yearly skin exams
`
` [see Warnings and Precautions (5.3)].
`• Because of the risk of autoimmunity,
`infusion reactions, and malignancies,
`
`LEMTRADA is available only through restricted distribution under a Risk Evaluation
`
`
`
`Mitigation Strategy (REMS) Program. Call 1-855-676-6326 to enroll
`
` in the
`
` LEMTRADA REMS program [see Warnings and Precautions (5.4)].
`
`
` INDICATIONS AND USAGE
` 1
`
`
`
`
` LEMTRADA is indicated for the treatment of patients with relapsing forms of multiple sclerosis
`
` (MS). Because of its safety profile, the use of LEMTRADA should generally be reserved for
`
` patients who have had an inadequate response to two or more drugs indicated for the treatment of
`
`
`
` MS.
`
`
`
` 2
` DOSAGE AND ADMINISTRATION
`
`
`
`
` 2.1 Dosage Information
` The recommended dosage of LEMTRADA is 12 mg/day administered by intravenous infusion
`
` for 2 treatment courses:
`
`
`
`
` • First Treatment Course: 12 mg/day on 5 consecutive days (60 mg total dose)
`
` • Second Treatment Course: 12 mg/day on 3 consecutive days (36 mg total dose)
`
`
`
`
`
` administered 12 months after the first treatment course.
`
` 2.2
` Testing and Procedures Prior to Treatment
`
`
`
` Baseline laboratory tests are required prior to treatment with LEMTRADA [see Dosage and
`
` Administration (2.6)]. In addition, prior to starting treatment with LEMTRADA [see Warnings
`
`
`
`
` and Precautions (5.9)]:
`
`
`
`
`
`
`
`
`Reference ID: 4194892
`
`Page 2 of 29
`
`

`

`
`
` • complete any necessary immunizations at least 6 weeks prior to treatment
`
`
` • determine whether patients have a history of varicella or have been vaccinated for
`
`
` varicella zoster virus (VZV). If not, test the patient for antibodies to VZV and consider
`
` vaccination for those who are antibody-negative. Postpone treatment with LEMTRADA
`
`
`
`
`
`
` until 6 weeks after VZV vaccination.
` • perform tuberculosis screening according to local guidelines
`
`
`
`
`instruct patients to avoid potential sources of Listeria monocytogenes
`
`
`
`
`
`
`•
`
`2.3 Recommended Premedication and Concomitant Medication
`
`
`
`Corticosteroids
`
`Premedicate patients with high dose corticosteroids (1,000 mg methylprednisolone or equivalent)
`
`
`immediately prior to LEMTRADA infusion and for the first 3 days of each treatment course [see
`
`
`
`
`
`
`Warnings and Precautions (5.2)].
`
`Herpes Prophylaxis
`
`
`Administer anti-viral prophylaxis for herpetic viral infections starting on the first day of each
`
`
`treatment course and continue for a minimum of two months following treatment with
`
`
`
`LEMTRADA or until the CD4+ lymphocyte count is ≥200 cells per microliter, whichever occurs
`
`
`later [see Warnings and Precautions (5.9)].
`
`
`
`
`2.4 Preparation Instructions
`
`
`Follow the steps below to prepare the diluted solution of LEMTRADA for intravenous infusion:
`
`Inspect LEMTRADA visually for particulate matter and discoloration prior to
`
`•
`
`administration. Do not use if particulate matter is present or the solution is discolored.
`
`Do not freeze or shake vials prior to use.
`
`
`
`• Withdraw 1.2 mL of LEMTRADA from the vial into a syringe using aseptic technique
`
`
`and inject into a 100 mL bag of sterile 0.9% Sodium Chloride, USP or 5% Dextrose in
`
`Water, USP.
`
`• Gently invert the bag to mix the solution. Ensure the sterility of the prepared solution,
`
`
`because it contains no antimicrobial preservatives. Each vial is for single use only.
`
`
`
`Prior to administration, protect diluted LEMTRADA solution from light and store for as long as
`
`
`
`8 hours either at room temperature 15°C to 25°C (59°F to 77°F) or keep refrigerated at
`
`conditions 2°C to 8°C (36°F to 46°F).
`
`
`2.5
`Infusion Instructions
`
`
`
`Infuse LEMTRADA over 4 hours starting within 8 hours after dilution. Extend the duration of
`
`the infusion if clinically indicated.
`
`
`
`Administer LEMTRADA in a setting in which equipment and personnel to appropriately manage
`
`anaphylaxis or serious infusion reactions are available [see Warnings and Precautions (5.4)].
`
`Do not add or simultaneously infuse other drug substances through the same intravenous line. Do
`
`not administer as an intravenous push or bolus.
`
`Reference ID: 4194892
`
`Page 3 of 29
`
`

`

`Monitor vital signs before the infusion and periodically during the infusion. Provide appropriate
`
`symptomatic treatment for infusion reactions as needed. Consider immediate discontinuation of
`
`the intravenous infusion if severe infusion reactions occur.
`
`Observe patients for infusion reactions during and for at least 2 hours after each LEMTRADA
`
`
`infusion. Consider longer periods of observation if clinically indicated. Inform patients that they
`
`
`should report symptoms that occur during and after each infusion because they may indicate a
`
`
`
`need for prompt medical intervention [see Warnings and Precautions (5.2)].
`
`
`
`
`Laboratory Testing and Monitoring to Assess Safety
`2.6
`
`
`
`Conduct the following laboratory tests at baseline and at periodic intervals for 48 months
`
`
`following the last treatment course of LEMTRADA in order to monitor for early signs of
`
`
`potentially serious adverse effects:
`
`• Complete blood count (CBC) with differential (prior to treatment initiation and at
`
`
`monthly intervals thereafter)
`
`
`• Serum creatinine levels (prior to treatment initiation and at monthly intervals thereafter)
`
`
`• Urinalysis with urine cell counts (prior to treatment initiation and at monthly intervals
`
`
`
`
`thereafter)
`
`• A test of thyroid function, such as thyroid stimulating hormone (TSH) level (prior to
`
`
`treatment initiation and every 3 months thereafter)
`
`Conduct baseline and yearly skin exams to monitor for melanoma [see Warnings and
`
`
`
`Precautions (5.3)].
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`Injection: 12 mg/1.2 mL (10 mg/mL) in a single-use vial. LEMTRADA is a clear and colorless
`
`
`to slightly yellow solution that requires dilution prior to intravenous infusion.
`
`
`
`CONTRAINDICATIONS
`4
`
`
`LEMTRADA is contraindicated in patients who are infected with Human Immunodeficiency
`
`Virus (HIV) because LEMTRADA causes prolonged reductions of CD4+ lymphocyte counts.
`
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`
`5.1 Autoimmunity
`
`
`Treatment with LEMTRADA can result in the formation of autoantibodies and increase the risk
`of serious autoimmune mediated conditions. In clinical studies, LEMTRADA-treated patients
`
`
`
`
`experienced thyroid disorders (34%), immune thrombocytopenia (2%), and glomerular
`
`nephropathies (0.3%) [see Warnings and Precautions (5.5, 5.6, 5.7)]. Autoimmune hemolytic
`
`
`
`
`anemia and autoimmune pancytopenia [see Warnings and Precautions (5.8)], undifferentiated
`
`
`connective tissue disorders, and acquired hemophilia A (anti-Factor VIII antibodies) each
`
`
`occurred in 0.2% of patients. Rheumatoid arthritis, type I diabetes, vitiligo, and retinal pigment
`
`
`epitheliopathy occurred in 0.1% of patients.
`
`During postmarketing use, additional autoimmune events including Guillain-Barré syndrome and
`
`
`chronic inflammatory demyelinating polyradiculoneuropathy have been reported in the treatment
`
`
`Reference ID: 4194892
`
`Page 4 of 29
`
`

`

`of patients with B-cell chronic lymphocytic leukemia (B-CLL), as well as other disorders,
`
`
`generally at higher and more frequent doses than recommended in MS. An oncology patient
`
`treated with alemtuzumab had fatal transfusion-associated graft-versus-host disease.
`
`Autoantibodies may be transferred from the mother to the fetus during pregnancy. A case of
`
`
`
`
`transplacental transfer of anti-thyrotropin receptor antibodies resulting in neonatal Graves’
`
`disease occurred after alemtuzumab treatment in the mother [see Use in Specific Populations
`
`
`(8.1)].
`
`LEMTRADA may increase the risk of other autoimmune conditions because of the broad range
`
`of autoantibody formation with LEMTRADA.
`
`
`Monitor complete blood counts with differential, serum creatinine levels, and urinalysis with
`urine cell counts before starting treatment and then at monthly intervals for 48 months after the
`
`
`last dose of LEMTRADA to allow for early detection and treatment of autoimmune adverse
`
`
`
`reactions [see Dosage and Administration (2.6)]. After 48 months, testing should be performed
`
`
`based on clinical findings suggestive of autoimmunity.
`
`
`
`LEMTRADA is available only through a restricted program under a REMS [see Warnings and
`
`
`Precautions (5.4)].
`
`Infusion Reactions
`5.2
`
`
`LEMTRADA causes cytokine release syndrome resulting in infusion reactions, some of which
`
`
`may be serious and life threatening. In clinical studies, 92% of LEMTRADA-treated patients
`
`
`
`experienced infusion reactions. In some patients, infusion reactions were reported more than 24
`
`
`hours after LEMTRADA infusion. Serious reactions occurred in 3% of patients and included
`
`
`
`anaphylaxis
`in 2 patients (including anaphylactic shock), angioedema, bronchospasm,
`
`hypotension, chest pain, bradycardia, tachycardia (including atrial fibrillation), transient
`
`
`neurologic symptoms, hypertension, headache, pyrexia, and rash. Other infusion reactions
`
`
`included nausea, urticaria, pruritus, insomnia, chills, flushing, fatigue, dyspnea, pulmonary
`
`infiltrates, dysgeusia, dyspepsia, dizziness, and pain. In clinical studies, 0.6% of patients with
`
`infusion reactions received epinephrine or atropine.
`
`During postmarketing use, other serious and sometimes fatal infusion reactions included
`
`
`hypoxia, syncope, acute respiratory distress syndrome, respiratory arrest, myocardial infarction,
`
`
`
`acute cardiac insufficiency, and cardiac arrest have been reported in the treatment of patients
`
`
`
`with B-CLL, as well as other disorders, generally at higher and more frequent doses than
`
`recommended in MS.
`
`Premedicate patients with corticosteroids immediately prior to LEMTRADA infusion for the
`
`
`
`
`first 3 days of each treatment course. In clinical studies, patients received 1,000 mg of
`
`
`
`
`methylprednisolone for the first 3 days of each LEMTRADA treatment course. Consider
`
`
`
`pretreatment with antihistamines and/or antipyretics prior to LEMTRADA administration.
`
`
`Infusion reactions may occur despite pretreatment.
`
`Consider additional monitoring in patients with medical conditions which predispose them to
`cardiovascular or pulmonary compromise.
`
`LEMTRADA can only be administered in certified healthcare settings that have on-site access to
`
`equipment and personnel trained to manage infusion reactions (including anaphylaxis and
`
`cardiac and respiratory emergencies).
`
`
`
`Reference ID: 4194892
`
`Page 5 of 29
`
`

`

`
`
`
`
` LEMTRADA is available only through a restricted program under a REMS [see Warnings and
`
` Precautions (5.4)].
` 5.3 Malignancies
`
`
` Thyroid Cancer
`LEMTRADA may increase the risk of thyroid cancer. In controlled clinical studies, 3 of 919
`(0.3%) LEMTRADA-treated patients developed thyroid cancer, compared to none in the
`
`interferon beta-1a–treated group. However, screening for thyroid cancer was performed more
`
`
`frequently in the LEMTRADA-treated group, because of the higher incidence of autoimmune
`
`
`thyroid disorders in those patients. Two additional cases of thyroid cancer in LEMTRADA-
`treated patients occurred in uncontrolled studies.
`
`Patients and healthcare providers should monitor for symptoms of thyroid cancer including a
`
`
`
`new lump or swelling in the neck, pain in the front of the neck, persistent hoarseness or other
`
`
`voice changes, trouble swallowing or breathing, or a constant cough not due to an upper
`
`
`
`
`respiratory tract infection.
`
`Melanoma
`
`LEMTRADA may increase the risk of melanoma. In uncontrolled studies, 4 of 1486 (0.3%)
`
`
`LEMTRADA-treated patients developed melanoma or melanoma in situ. One of those patients
`
`had evidence of locally advanced disease.
`
`
`Perform baseline and yearly skin examinations to monitor for melanoma in patients receiving
`LEMTRADA.
`
`Lymphoproliferative Disorders and Lymphoma
`
`
`
`Cases of lymphoproliferative disorders and lymphoma have occurred in LEMTRADA-treated
`
`patients with MS, including a MALT lymphoma, Castleman’s Disease, and a fatality following
`treatment of non-Epstein Barr Virus–associated Burkitt’s lymphoma. There are postmarketing
`
`reports of Epstein Barr Virus–associated lymphoproliferative disorders in non-MS patients.
`
`Because LEMTRADA is an immunomodulatory therapy, caution should also be exercised in
`
`
`initiating LEMTRADA in patients with preexisting or ongoing malignancies.
`LEMTRADA is available only through a restricted program under a REMS [see Warnings and
`
`Precautions (5.4)].
`
`
`
`LEMTRADA REMS Program
`5.4
`
`
`LEMTRADA is available only through a restricted program under a REMS called the
`
`
`LEMTRADA REMS Program because of the risks of autoimmunity, infusion reactions, and
`
`
`malignancies [see Warnings and Precautions (5.1, 5.2, 5.3)].
`
`
`
`
`
`Notable requirements of the LEMTRADA REMS Program include the following:
`
`
`
`• Prescribers must be certified with the program by enrolling and completing training.
`
`
`
`• Patients must enroll in the program and comply with ongoing monitoring requirements
`
`[see Dosage and Administration (2.6)].
`
`
`• Pharmacies must be certified with the program and must only dispense to certified
`
`
`
`healthcare facilities that are authorized to receive LEMTRADA.
`
`
`
`
`Reference ID: 4194892
`
`Page 6 of 29
`
`

`

`
`
`
`
` • Healthcare facilities must enroll in the program and verify that patients are authorized
`
`
`
`
`
` before infusing LEMTRADA. Healthcare facilities must have on-site access to
` equipment and personnel trained to manage infusion reactions.
`
`
` Further information, including a list of qualified healthcare facilities, is available at 1-855-676­
`
` 6326.
` Immune Thrombocytopenia
`
`
` 5.5
` Immune thrombocytopenia (ITP) occurred in 2% of LEMTRADA-treated patients in clinical
` studies in MS.
`
`
`
`
`
` In a controlled clinical study in patients with MS, one LEMTRADA-treated patient developed
`
` ITP that went unrecognized prior to the implementation of monthly blood monitoring
`
` requirements, and died from intracerebral hemorrhage. Nadir platelet counts ≤20,000 cells per
`
`
`
`
`
`
` microliter as a result of ITP occurred in 2% of all LEMTRADA-treated patients in clinical
`
`
` studies in MS. Anti-platelet antibodies did not precede ITP onset. ITP has been diagnosed more
`
`
`
`
`
`
` than 3 years after the last LEMTRADA dose.
`
`
` Symptoms of ITP include easy bruising, petechiae, spontaneous mucocutaneous bleeding (e.g.,
`
`
` epistaxis, hemoptysis), and heavier than normal or irregular menstrual bleeding. Hemoptysis
`
` may also be indicative of anti-glomerular basement membrane (GBM) disease [see Warnings
`
`
`
`
`and Precautions (5.6)], and an appropriate differential diagnosis has to be undertaken. Remind
`
` the patient to remain vigilant for symptoms they may experience and to seek immediate medical
`
`
` help if they have any concerns.
`
` Obtain complete blood counts (CBCs) with differential prior to initiation of treatment and at
`
`
` monthly intervals thereafter until 48 months after the last infusion [see Dosage and
`
` Administration (2.6)]. After this period of time, testing should be performed based on clinical
`
` findings suggestive of ITP. If ITP is suspected, a complete blood count should be obtained
`
`
` immediately. If ITP onset is confirmed, promptly initiate appropriate medical intervention.
`
`
`
`
`
` 5.6 Glomerular Nephropathies
`
`
`
`
`
` Glomerular nephropathies occurred in 0.3% of LEMTRADA-treated patients in MS clinical
`
` studies. There were 3 cases of membranous glomerulonephritis and 2 cases of anti-glomerular
`
` basement membrane (anti-GBM) disease. There are published and postmarketing cases of MS
`
` patients treated with alemtuzumab who developed anti-GBM disease and subsequently
`
`developed end-stage renal disease requiring renal transplantation. Cases of anti-GBM disease
`
`have been diagnosed up to 40 months after the last dose of LEMTRADA. Urgent evaluation and
`
`
`treatment is required because anti-GBM disease can lead to renal failure requiring dialysis or
`
`transplantation and can be life-threatening if left untreated.
`
`Clinical manifestations of nephropathy may include elevated serum creatinine levels, hematuria,
`
`
`or proteinuria. Alveolar hemorrhage manifested as hemoptysis is a common component of anti-
`
`
`GBM disease but did not occur in clinical studies.
`
`
`Obtain serum creatinine levels and urinalysis with cell counts prior to initiation of treatment and
`
`at monthly intervals thereafter until 48 months after the last infusion. After this period of time,
`
`
`testing should be performed based on clinical findings suggestive of nephropathies.
`
`Reference ID: 4194892
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`If clinically significant changes from baseline in serum creatinine, unexplained hematuria, or
`
`
`proteinuria are observed, perform further evaluation for nephropathies. Early detection and
`
`treatment of nephropathies may decrease the risk of poor outcomes.
`
`5.7
`Thyroid Disorders
`
`
`Autoimmune thyroid disorders occurred in 34% of LEMTRADA-treated patients in clinical
`
`studies. Newly diagnosed thyroid disorders occurred throughout the uncontrolled clinical study
`
`follow-up period, more than 7 years after the first LEMTRADA dose. Autoimmune thyroid
`
`
`
`
`included Graves’ disease, hyperthyroidism and hypothyroidism. Graves’
`disorders
`
`ophthalmopathy with decreased vision, eye pain, and exophthalmos occurred in 1% of
`
`LEMTRADA-treated patients. Two patients required surgical orbital decompression. Serious
`
`thyroid events occurred in about 2% of LEMTRADA-treated patients in clinical studies and
`
`included cardiac and psychiatric events associated with thyroid disease. Of all LEMTRADA-
`
`treated patients, 3% underwent thyroidectomy.
`
`Thyroid disease poses special risks in women who are pregnant [see Use in Specific Populations
`
`
`(8.1)].
`
`Obtain thyroid function tests, such as TSH levels, prior to initiation of treatment and every 3
`
`
`months thereafter until 48 months after the last infusion. Continue to test thyroid function after
`
`48 months if clinically indicated.
`
`In patients with ongoing thyroid disorder, LEMTRADA should be administered only if the
`
`
`potential benefit justifies the potential risks.
`
`
`5.8 Other Autoimmune Cytopenias
`
`
`
`Autoimmune cytopenias such as neutropenia (0.1%), hemolytic anemia (0.2%), and
`
`pancytopenia (0.2%) occurred in LEMTRADA-treated patients in clinical studies in MS. In cases
`
`
`
`of autoimmune hemolytic anemia, patients tested positive for direct antiglobulin antibodies, and
`nadir hemoglobin levels ranged from 2.9-8.6 g/dL. Symptoms of autoimmune hemolytic anemia
`
`
`include weakness, chest pain, jaundice, dark urine, and tachycardia. One LEMTRADA-treated
`
`
`
`patient with autoimmune pancytopenia died from sepsis.
`
`
`During postmarketing use, additional autoimmune cytopenias including fatal autoimmune
`
`
`hemolytic anemia and aplastic anemia have been reported in the treatment of patients with B­
`
`CLL, as well as other disorders, generally at higher and more frequent doses than recommended
`in MS.
`
`Use CBC results to monitor for cytopenias. Prompt medical intervention is indicated if a
`cytopenia is confirmed.
`
`5.9
`Infections
`
`
`Infections occurred in 71% of LEMTRADA-treated patients compared to 53% of patients treated
`
`with interferon beta-1a in controlled clinical studies in MS up to 2 years in duration. Infections
`
`
`that occurred more often in LEMTRADA-treated patients than interferon beta-1a patients
`
`
`included nasopharyngitis, urinary tract infection, upper respiratory tract infection, sinusitis,
`herpetic infections, influenza, and bronchitis. Serious infections occurred in 3% of patients
`
`
`treated with LEMTRADA as compared to 1% of patients treated with interferon beta-1a. Serious
`
`
`
`Reference ID: 4194892
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`
`
`
`
`
`
`
`
` infections in the LEMTRADA group included: appendicitis, gastroenteritis, pneumonia, herpes
`
`
` zoster, and tooth infection.
` Do not administer live viral vaccines following a course of LEMTRADA. Patients treated with
`
`
`
`
`
` LEMTRADA have altered immunity and may be at increased risk of infection following
` administration of live viral vaccines.
`
`
` Consider delaying LEMTRADA administration in patients with active infection until the
` infection is fully controlled.
`
`
` Concomitant use of LEMTRADA with antineoplastic or immunosuppressive therapies could
` increase the risk of immunosuppression.
`
` Herpes Viral Infections
`
`In controlled clinical studies, 16% of LEMTRADA-treated patients developed a herpes viral
`
`
`
`
`infection compared to 3% of interferon beta-1a patients. These events included oral herpes
`
`(8.8%), herpes zoster (4.2%), herpes simplex (1.8%), and genital herpes (1.3%). Serious herpetic
`
`infections in LEMTRADA-treated patients included primary varicella (0.1%), herpes zoster
`
`(0.2%), and herpes meningitis (0.1%). Administer antiviral agents for herpetic prophylaxis at
`
`appropriate suppressive dosing regimens. Administer antiviral prophylaxis for herpetic viral
`
`infections starting on the first day of each treatment course and continue for a minimum of two
`
`
`
`
`months following treatment with LEMTRADA or until the CD4+ lymphocyte count is ≥200
`
`
`cells per microliter, whichever occurs later [see Dosage and Administration (2.3)].
`
`
`
`
`Human Papilloma Virus
`
`Cervical human papilloma virus (HPV) infection, including cervical dysplasia, occurred in 2% of
`
`LEMTRADA-treated patients. Annual HPV screening is recommended for female patients.
`
`Tuberculosis
`
`Tuberculosis occurred in patients treated with LEMTRADA and interferon beta-1a in controlled
`clinical studies. Active and latent tuberculosis cases occurred in 0.3% of LEMTRADA-treated
`
`
`patients, most often in endemic regions. Perform tuberculosis screening according to local
`
`
`guidelines prior to initiation of LEMTRADA. For patients testing positive in tuberculosis
`
`
`
`
`screening, treat by standard medical practice prior to therapy with LEMTRADA.
`
`
`
`Fungal Infections
`
`Fungal infections, especially oral and vaginal candidiasis, occurred more commonly in
`
`LEMTRADA-treated patients (12%) than in patients treated with interferon beta-1a (3%) in
`
`
`controlled clinical studies in MS.
`
`
`Listeria monocytogenes Infections
`
`
`Listeria monocytogenes infections (e.g., meningitis, encephalitis, sepsis, and gastroenteritis),
`
`
`including fatal cases of Listeria meningoencephalitis, have occurred in LEMTRADA-treated
`
`
`
`
`
`patients. Listeria infections have occurred as early as 3 days after treatment and up to 8 months
`
`
`
`
`
`
`
`
`after the last LEMTRADA dose. The duration of increased risk for Listeria infection after
`
`
`
`
`
`LEMTRADA treatment is unknown.
`
`Advise patients to avoid or adequately heat foods that are potential sources of Listeria
`
`
`
`
`
`monocytogenes (e.g., deli meat, dairy products made with unpasteurized milk, soft cheeses, or
`
`
`
`
`
`
`
`Reference ID: 4194892
`
`Page 9 of 29
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`
`
`
` undercooked meat, seafood, or poultry). Initiate these Listeria precautions prior to starting
`
`
` LEMTRADA treatment. The incubation period for Listeria monocytogenes ranges from 3 to 70
`
`
`
`
` days. In most cases, signs and symptoms of invasive listeriosis start within 1 month of exposure
`
`
` to Listeria monocytogenes. Symptoms of Listeria infection include fever, chills, diarrhea, nausea,
`
`
`
` vomiting, headache, pains in joints and muscles, neck stiffness, difficulty walking, mental status
`
`
` changes, coma, and other neurologic changes. As is the case with many infections, treatment
`
` cannot always prevent mortality and morbidity related to Listeria infections. Therefore, advise
`
`
` patients to watch for symptoms of Listeria infection and seek prompt medical help if symptoms
`
`
`
`occur.
` Infections in Non-MS Patients
`
`
`
`During postmarketing use, serious and sometimes fatal viral, bacterial, protozoan, and fungal
`
`infections, including some due to reactivation of latent infections, have been reported in the
`
`treatment of patients with B-CLL, as well as other disorders, generally at higher and more
`
`
`frequent doses than recommended in MS.
`
`Hepatitis
`
`No data are available on the association of LEMTRADA with Hepatitis B virus (HBV) or
`
`
`
`Hepatitis C virus (HCV) reactivation because patients with evidence of active or chronic
`
`infections were excluded from the clinical studies. Consider screening patients at high risk of
`
`
`HBV and/or HCV infection before initiation of LEMTRADA and exercise caution in prescribing
`
`
`
`
`LEMTRADA to patie