1.2 ML alemtuzumab 10 MG/ML Injection [Lemtrada]

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) ].

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 the infusion if clinically indicated. Administer LEMTRADA in a setting in which equipment and personnel to appropriately manage anaphylaxis, serious infusion reactions, myocardial ischemia, myocardial infarction, and cerebrovascular and respiratory adverse reactions are available [see Warnings and Precautions (5.2) ] . Do not add or simultaneously infuse other drug substances through the same intravenous line. Do not administer as an intravenous push or bolus. Obtain a baseline ECG. 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) ] . 2.6 Laboratory Testing and Monitoring to Assess Safety Measure the urine protein to creatinine ratio prior to initiation of treatment. Conduct the following laboratory tests at baseline and at periodic intervals until 48 months after 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) Serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and total bilirubin levels (prior to treatment initiation and periodically thereafter) Conduct baseline and yearly skin exams to monitor for melanoma [see Warnings and Precautions (5.4) ] .

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 Precautions (5.14) ] , immune-mediated colitis [see Warnings and Precautions (5.16) ], Guillain-Barré syndrome, and vasculitis have been reported. Chronic inflammatory demyelinating polyradiculoneuropathy has been reported in the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL), as well as other autoimmune disorders, generally at higher and more frequent doses than recommended in MS. 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. Measure the urine protein to creatinine ratio prior to initiation of treatment. Monitor complete blood counts with differential, serum creatinine levels, and urinalysis with urine cell counts before starting treatment and then at monthly intervals until 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 (5.5) ] . 5.2 Infusion Reactions 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, cases of pulmonary alveolar hemorrhage, myocardial ischemia, myocardial infarction, stroke (including ischemic and hemorrhagic stroke), and cervicocephalic (e.g., vertebral, carotid) arterial dissection have been reported. Reactions may occur following any of the doses during the treatment course. In the majority of cases, time to onset was within 1 to 3 days of LEMTRADA infusion. Patients should be informed about the signs and symptoms and advised to seek immediate medical attention if any of these symptoms occur. Cases of severe (including fatal) neutropenia have been reported within 2 months of LEMTRADA infusion; some cases resolved with receiving granulocyte-colony stimulating factor treatment. Mild to moderate decreases in platelet counts, starting at the time of alemtuzumab infusion and often resolving without treatment, have been reported. Other serious and sometimes fatal infusion reactions (e.g., hypoxia, syncope, acute respiratory distress syndrome, respiratory arrest, myocardial infarction, acute cardiac insufficiency, 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 ad

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 )

Mechanism of Action The precise mechanism by which alemtuzumab exerts its therapeutic effects in multiple sclerosis is unknown but is presumed to involve binding to CD52, a cell surface antigen present on T and B lymphocytes, and on natural killer cells, monocytes, and macrophages. Following cell surface binding to T and B lymphocytes, alemtuzumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.