LEMTRADA

1 INDICATIONS AND USAGE LEMTRADA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. 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 [see Warnings and Precautions (5) ] . LEMTRADA is a CD52-directed cytolytic monoclonal antibody indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. 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. (1.5) Limitations of Use : LEMTRADA is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile. (1.5) Limitations of Use LEMTRADA is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile [see Warnings and Precautions (5) ].

2 DOSAGE AND ADMINISTRATION Baseline laboratory tests are required prior to treatment. ( 2.1 ) Administer LEMTRADA by intravenous infusion over 4 hours for 2 or more treatment courses: Initial treatment of 2 courses: First course: 12 mg/day on 5 consecutive days. ( 2.3 ) Second course: 12 mg/day on 3 consecutive days 12 months after first treatment course. ( 2.3 ) Subsequent treatment courses of 12 mg per day on 3 consecutive days (36 mg total dose) may be administered, as needed, at least 12 months after the last dose of any prior treatment course. ( 2.3 ) Premedicate with corticosteroids prior to LEMTRADA infusion for the first 3 days of each treatment course. ( 2.2 ) 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. ( 2.2 ) Must be diluted prior to administration. ( 2.4 ) 2.1 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 (5.15) ] : 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. 2.2 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 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 at least 200 cells per microliter, whichever occurs later [see Warnings and Precautions (5.15) ] . 2.3 Recommended Dosage 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. Following the second treatment course, subsequent treatment courses of 12 mg per day on 3 consecutive days (36 mg total dose) may be administered, as needed, at least 12 months after the last dose of any prior treatment courses. 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 th…

5 WARNINGS AND PRECAUTIONS Immune Thrombocytopenia: Obtain complete blood counts (CBCs) with differential prior to initiation of treatment and at monthly intervals thereafter until 48 months after the last infusion. ( 5.6 ) Glomerular Nephropathies: Obtain serum creatinine levels, urinalysis with cell counts and urine protein to creatinine ratio prior to initiation of treatment. Monitor serum creatinine levels and urinalysis with cell counts at monthly intervals thereafter until 48 months after the last infusion. ( 5.7 ) Thyroid Disorders: Obtain thyroid function tests prior to initiation of treatment and every 3 months until 48 months after the last infusion. ( 5.8 ) Other Autoimmune Cytopenias: Monitor CBCs monthly until 48 months after the last infusion. ( 2.6 , 5.9 ) Autoimmune Hepatitis: If signs of hepatic dysfunction occur, promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment. ( 5.10 ) Hemophagocytic Lymphohistiocytosis : Consider this diagnosis and evaluate patients immediately if they develop signs or symptoms of systemic inflammation. Discontinue LEMTRADA if an alternative etiology is not established. ( 5.11 ) Adult Onset Still's Disease (AOSD): If a patient develops AOSD, they require prompt evaluation and treatment. ( 5.12 ) Thrombotic Thrombocytopenic Purpura (TTP): Evaluate patients immediately if they develop clinical symptoms or laboratory findings consistent with TTP. Discontinue LEMTRADA if TTP is confirmed or if an alternative etiology is not established. ( 5.13 ) Autoimmune Encephalitis (AIE): Evaluate patients if they develop signs and symptoms suggestive of AIE, such as subacute onset of memory impairment, altered mental status, psychiatric symptoms, neurological findings, and seizures. ( 5.14 ) Acquired Hemophilia A: Obtain a coagulopathy panel including aPTT in patients who present with signs such as spontaneous subcutaneous hematomas, extensive bruising, hematuria, epistaxis, or gastrointestinal or other types of bleeding. ( 5.15 ) Immune-Mediated Colitis: Immune-mediated colitis has been reported in the postmarketing setting. Monitor patients for new or persistent diarrhea or other gastrointestinal symptoms, and evaluate promptly if colitis is suspected. ( 5.16 ) Infections: Administration is contraindicated in patients with active infection. Do not administer live viral vaccines following a course of LEMTRADA. ( 4 , 5.17 ) Progressive Multifocal Leukoencephalopathy (PML): Withhold LEMTRADA at the first sign or symptom suggestive of PML. ( 5.18 ) 5.1 Autoimmunity Treatment with LEMTRADA can result in the formation of autoantibodies and increase the risk of serious autoimmune conditions, which may be life threatening. In clinical studies (controlled and open-label extension), the following serious autoimmune conditions were reported in LEMTRADA-treated patients, which are described in separate warnings: thyroid disorders (36.8%) [see Warnings and Precautions (5.8) ] immune thrombocytopenia (2%) [see Warnings and Precautions (5.6) ] glomerular nephropathies (0.3%) [see Warnings and Precautions 5.7 ] autoimmune hemolytic anemia (0.3%), autoimmune pancytopenia (0.2%), and autoimmune neutropenia (0.1%) [see Warnings and Precautions (5.9) ] acquired hemophilia A (anti-Factor VIII antibodies) (0.1%) [see Warnings and Precautions (5.15) ] In clinical studies (controlled and open-label extension), vitiligo (0.3%), undifferentiated connective tissue disorders (0.2%), type 1 diabetes (0.2%), rheumatoid arthritis (0.1%), and retinal pigment epitheliopathy (0.1%) were also reported in LEMTRADA-treated patients. In the postmarketing setting, cases of autoimmune hepatitis [see Warnings and Precautions (5.10) ] , hemophagocytic lymphohistiocytosis [ see Warnings and Precautions (5.11) ] , Adult Onset Still's Disease [see Warnings and Precautions (5.12) ] , thrombotic thrombocytopenic purpura [see Warnings and Precautions (5.13) ] , autoimmune encephalitis [see Warnings and P…

4 CONTRAINDICATIONS LEMTRADA is contraindicated in patients: with known hypersensitivity or anaphylactic reactions to alemtuzumab or any of the excipients in LEMTRADA who are infected with human immunodeficiency virus (HIV) because LEMTRADA causes prolonged reductions of CD4+ lymphocyte counts with active infection Known hypersensitivity or anaphylactic reactions to alemtuzumab or any of the excipients in LEMTRADA ( 4 ) Infection with Human Immunodeficiency Virus ( 4 ) Active infection ( 4 )

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of LEMTRADA in pregnant women. LEMTRADA was embryolethal in pregnant huCD52 transgenic mice when administered during organogenesis [see Animal data ] . Auto-antibodies may develop after administration of LEMTRADA. Placental transfer of anti-thyroid antibodies resulting in neonatal Graves' disease has been reported. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. There is a pregnancy surveillance program for LEMTRADA. If LEMTRADA exposure occurs during pregnancy, healthcare providers and patients are encouraged to report pregnancies by calling 1-800-745-4447, option 2. Clinical Considerations LEMTRADA induces persistent thyroid disorders [see Warnings and Precautions (5.8) ] . Untreated hypothyroidism in pregnant women increases the risk for miscarriage and may have effects on the fetus including mental retardation and dwarfism. In mothers with Graves' disease, maternal thyroid stimulating hormone receptor antibodies can be transferred to a developing fetus and can cause neonatal Graves' disease. In a patient who developed Graves' disease after treatment with alemtuzumab, placental transfer of anti-thyrotropin receptor antibodies resulted in neonatal Graves' disease with thyroid storm in her infant who was born 1 year after alemtuzumab dosing [see Warnings and Precautions (5.1) ] . Data Animal data When LEMTRADA was administered to pregnant huCD52 transgenic mice during organogenesis (gestation days [GD] 6–10 or GD 11–15) at doses of 3 or 10 mg/kg IV, no teratogenic effects were observed. However, there was an increase in embryolethality (increased postimplantation loss and the number of dams with all fetuses dead or resorbed) in pregnant animals dosed during GD 11–15. In a separate study in pregnant huCD52 transgenic mice, administration of LEMTRADA during organogenesis (GD 6–10 or GD 11–15) at doses of 3 or 10 mg/kg IV, decreases in B- and T-lymphocyte populations were observed in the offspring at both doses tested. In pregnant huCD52 transgenic mice administered LEMTRADA at doses of 3 or 10 mg/kg/day IV throughout gestation and lactation, there was an increase in pup deaths during the lactation period at 10 mg/kg. Decreases in T- and B-lymphocyte populations and in antibody response were observed in offspring at both doses tested.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Autoimmunity [see Boxed Warning and Warnings and Precautions (5.1) ] Infusion Reactions [see Boxed Warning and Warnings and Precautions (5.2) ] Stroke and Cervicocephalic Arterial Dissection [see Warnings and Precautions (5.3) ] Malignancies [see Warnings and Precautions (5.4) ] Immune Thrombocytopenia [see Warnings and Precautions (5.6) ] Glomerular Nephropathies Including Anti-glomerular Basement Membrane Disease [see Warnings and Precautions (5.7) ] Thyroid Disorders [see Warnings and Precautions (5.8) ] Other Autoimmune Cytopenias [see Warnings and Precautions (5.9) ] Autoimmune Hepatitis [see Warnings and Precautions (5.10) ] Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.11) ] Adult Onset Still's Disease [see Warnings and Precautions (5.12) ] Thrombotic Thrombocytopenic Purpura (TTP) [see Warnings and Precautions (5.13) ] Autoimmune Encephalitis (AIE) [see Warnings and Precautions (5.14) ] Acquired Hemophilia A [see Warnings and Precautions (5.15) ] Immune-Mediated Colitis [see Warnings and Precautions (5.16) ] Infections [see Warnings and Precautions (5.17) ] Progressive Multifocal Leukoencephalopathy (PML) [see Warnings and Precautions (5.18) ] Acute Acalculous Cholecystitis [see Warnings and Precautions (5.19) ] Pneumonitis [see Warnings and Precautions (5.20) ] 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 . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In controlled clinical trials (Study 1 and Study 2), a total of 811 patients with relapsing forms of MS received LEMTRADA. The population was 18 to 55 years of age, 65% were female, and 92% were Caucasian. A total of 811 patients received 1 course of therapy, and 789 patients received a second course of therapy at 12 months. The overall follow-up in the controlled trials was equivalent to 1622 patient years. In MS clinical studies (controlled and open-label extension), overall, a total of 1217 patients received LEMTRADA. Approximately 60% of patients received a total of 2 treatment courses and approximately 24% of patients received a total of 3 treatment courses; others received a total of 4 or more treatment courses, although data beyond 3 treatment courses are limited. The overall follow-up was 6858 person-years. Patients had a median of 6 years of follow-up from the first LEMTRADA dose, with approximately 14% having at least 7 years of follow-up. Most Common Adverse Reactions In controlled clinical trials, the most common adverse reactions with LEMTRADA (in at least 10% of patients and more frequently than in interferon beta-1a) were 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. Table 1 lists adverse reactions occurring in ≥5% of LEMTRADA-treated patients in Study 1 and 2 and at the same or at a higher rate than interferon beta-1a. Table 1: Advers…