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FULL PRESCRIBING INFORMATIONWARNING: AUTOIMMUNITY, INFUSION REACTIONS, STROKE, ANDMALIGNANCIES LEMTRADA causes serious, sometimes fatal, autoimmune conditions such as immunethrombocytopenia and anti-glomerular basement membrane disease. Monitor completeblood counts with differential, serum creatinine levels, and urinalysis with urine cellcounts before starting treatment and then at monthly intervals until 48 months after thelast dose of LEMTRADA [see Warnings and Precautions (5.1)]. LEMTRADA causes serious and life-threatening infusion reactions. LEMTRADA mustbe administered in a setting with appropriate equipment and personnel to manageanaphylaxis or serious infusion reactions. Monitor patients for two hours after eachinfusion. Make patients aware that serious infusion reactions can also occur after the 2hour monitoring period [see Warnings and Precautions (5.2)]. Serious and life-threatening stroke (including ischemic and hemorrhagic stroke) has beenreported within 3 days of LEMTRADA administration. Instruct patients to seekimmediate medical attention if symptoms of stroke occur [see Warnings and Precautions(5.3)]. 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 (5.4)]. Because of the risk of autoimmunity, infusion reactions, and malignancies, LEMTRADAis available only through restricted distribution under a Risk Evaluation MitigationStrategy (REMS) Program. Call 1-855-676-6326 to enroll in the LEMTRADA REMSprogram [see Warnings and Precautions (5.5)].1INDICATIONS AND USAGELEMTRADA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), toinclude relapsing-remitting disease and active secondary progressive disease, in adults. Becauseof its safety profile, the use of LEMTRADA should generally be reserved for patients who havehad an inadequate response to two or more drugs indicated for the treatment of MS [seeWarnings and Precautions (5)].Limitations of UseLEMTRADA is not recommended for use in patients with clinically isolated syndrome (CIS)because of its safety profile [see Warnings and Precautions (5)].2DOSAGE AND ADMINISTRATION2.1Testing and Procedures Prior to TreatmentBaseline laboratory tests are required prior to treatment with LEMTRADA [see Dosage andAdministration (2.6)]. In addition, prior to starting treatment with LEMTRADA [see Warningsand Precautions (5.13)]:3Reference ID: 4843715

complete any necessary immunizations at least 6 weeks prior to treatment.determine whether patients have a history of varicella or have been vaccinated forvaricella zoster virus (VZV). If not, test the patient for antibodies to VZV and considervaccination for those who are antibody-negative. Postpone treatment with LEMTRADAuntil 6 weeks after VZV vaccination. perform tuberculosis screening according to local guidelines. instruct patients to avoid potential sources of Listeria monocytogenes.2.2Recommended Premedication and Concomitant MedicationCorticosteroidsPremedicate 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 [seeWarnings and Precautions (5.2)].Herpes ProphylaxisAdminister antiviral prophylaxis for herpetic viral infections starting on the first day of eachtreatment course and continue for a minimum of two months following treatment withLEMTRADA or until the CD4 lymphocyte count is at least 200 cells per microliter, whicheveroccurs later [see Warnings and Precautions (5.13)].2.3Recommended Dosage The recommended dosage of LEMTRADA is 12 mg/day administered by intravenousinfusion 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) administered12 months after the first treatment course.Following the second treatment course, subsequent treatment courses of 12 mg per day on 3consecutive days (36 mg total dose) may be administered, as needed, at least 12 months after thelast dose of any prior treatment courses.2.4Preparation InstructionsFollow the steps below to prepare the diluted solution of LEMTRADA for intravenous infusion: Inspect LEMTRADA visually for particulate matter and discoloration prior toadministration. Do not use if particulate matter is present or the solution is discolored. Donot freeze or shake vials prior to use. Withdraw 1.2 mL of LEMTRADA from the vial into a syringe using aseptic techniqueand inject into a 100 mL bag of sterile 0.9% Sodium Chloride, USP or 5% Dextrose inWater, USP. Gently invert the bag to mix the solution. Ensure the sterility of the prepared solutionbecause 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 as8 hours either at room temperature 15 C to 25 C (59 F to 77 F) or keep refrigerated at4Reference ID: 4843715

conditions 2 C to 8 C (36 F to 46 F).2.5Infusion InstructionsInfuse LEMTRADA over 4 hours starting within 8 hours after dilution. Extend the duration ofthe infusion if clinically indicated.Administer LEMTRADA in a setting in which equipment and personnel to appropriately manageanaphylaxis, serious infusion reactions, myocardial ischemia, myocardial infarction, andcerebrovascular 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. Donot administer as an intravenous push or bolus.Obtain a baseline ECG. Monitor vital signs before the infusion and periodically during theinfusion. Provide appropriate symptomatic treatment for infusion reactions as needed. Considerimmediate discontinuation of the intravenous infusion if severe infusion reactions occur.Observe patients for infusion reactions during and for at least 2 hours after each LEMTRADAinfusion. Consider longer periods of observation if clinically indicated. Inform patients that theyshould report symptoms that occur during and after each infusion because they may indicate aneed for prompt medical intervention [see Warnings and Precautions (5.2)].2.6Laboratory Testing and Monitoring to Assess SafetyMeasure the urine protein to creatinine ratio prior to initiation of treatment. Conduct thefollowing laboratory tests at baseline and at periodic intervals until 48 months after the lasttreatment course of LEMTRADA in order to monitor for early signs of potentially seriousadverse effects: Complete blood count (CBC) with differential (prior to treatment initiation and atmonthly 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 intervalsthereafter) A test of thyroid function, such as thyroid stimulating hormone (TSH) level (prior totreatment 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 andPrecautions (5.4)].3DOSAGE FORMS AND STRENGTHSInjection: 12 mg/1.2 mL (10 mg/mL) in a single-dose vial. LEMTRADA is a clear and colorlessto slightly yellow solution that requires dilution prior to intravenous infusion.4CONTRAINDICATIONS5Reference ID: 4843715

LEMTRADA is contraindicated in patients: with known hypersensitivity or anaphylactic reactions to alemtuzumab or any of theexcipients in LEMTRADA who are infected with human immunodeficiency virus (HIV) because LEMTRADAcauses prolonged reductions of CD4 lymphocyte counts with active infection5WARNINGS AND PRECAUTIONS5.1AutoimmunityTreatment with LEMTRADA can result in the formation of autoantibodies and increase the riskof serious autoimmune mediated conditions, which may be life threatening.In clinical studies (controlled and open-label extension), LEMTRADA-treated patientsexperienced thyroid disorders (36.8%), immune thrombocytopenia (2%), and glomerularnephropathies (0.3%) [see Warnings and Precautions (5.7, 5.8, 5.9)]. Vitiligo and autoimmunehemolytic anemia occurred in 0.3% of patients. Autoimmune pancytopenia [see Warnings andPrecautions (5.9)], undifferentiated connective tissue disorders, and type 1 diabetes eachoccurred in 0.2% of patients. Rheumatoid arthritis, retinal pigment epitheliopathy, and acquiredhemophilia A (anti-Factor VIII antibodies) [see Warnings and Precautions (5.13)] occurred in0.1% of patients. During postmarketing use, cases of vasculitis, autoimmune hepatitis [seeWarnings and Precautions (5.10)], Guillain-Barré syndrome [see Adverse Reactions (6.5)], andthrombotic thrombocytopenic purpura [see Warnings and Precautions (5.12)] have beenreported.Chronic inflammatory demyelinating polyradiculoneuropathy has been reported in the treatmentof patients with B-cell chronic lymphocytic leukemia (B-CLL), as well as other autoimmunedisorders, generally at higher and more frequent doses than recommended in MS. An oncologypatient 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 oftransplacental 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 rangeof autoantibody formation with LEMTRADA.Measure the urine protein to creatinine ratio prior to initiation of treatment. Monitor completeblood counts with differential, serum creatinine levels, and urinalysis with urine cell countsbefore starting treatment and then at monthly intervals until 48 months after the last dose ofLEMTRADA to allow for early detection and treatment of autoimmune adverse reactions [seeDosage and Administration (2.6)]. After 48 months, testing should be performed based onclinical findings suggestive of autoimmunity.LEMTRADA is available only through a restricted program under a REMS [see Warnings andPrecautions (5.5)].5.2Infusion Reactions6Reference ID: 4843715

LEMTRADA causes cytokine release syndrome resulting in infusion reactions, some of whichmay be serious and life threatening. In clinical studies, 92% of LEMTRADA-treated patientsexperienced infusion reactions. In some patients, infusion reactions were reported more than 24hours after LEMTRADA infusion. Serious reactions occurred in 3% of patients and includedanaphylaxis in 2 patients (including anaphylactic shock), angioedema, bronchospasm,hypotension, chest pain, bradycardia, tachycardia (including atrial fibrillation), transientneurologic symptoms, hypertension, headache, pyrexia, and rash. Other infusion reactionsincluded nausea, urticaria, pruritus, insomnia, chills, flushing, fatigue, dyspnea, pulmonaryinfiltrates, dysgeusia, dyspepsia, dizziness, and pain. In clinical studies, 0.6% of patients withinfusion 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 followingany of the doses during the treatment course. In the majority of cases, time to onset was within 1to 3 days of LEMTRADA infusion. Patients should be informed about the signs and symptomsand 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 tomoderate decreases in platelet counts, starting at the time of alemtuzumab infusion and oftenresolving without treatment, have been reported. Other serious and sometimes fatal infusionreactions (e.g., hypoxia, syncope, acute respiratory distress syndrome, respiratory arrest,myocardial infarction, acute cardiac insufficiency, cardiac arrest) have been reported in thetreatment of patients with B-CLL, as well as other disorders, generally at higher and morefrequent doses than recommended in MS.Premedicate patients with corticosteroids immediately prior to LEMTRADA infusion for thefirst 3 days of each treatment course. In clinical studies, patients received 1,000 mg ofmethylprednisolone for the first 3 days of each LEMTRADA treatment course. Considerpretreatment 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 tocardiovascular or pulmonary compromise. Physicians should alert patients that an infusionreaction could occur within 48 hours of infusion.LEMTRADA can only be administered in certified healthcare settings that have on-site access toequipment and personnel trained to manage infusion reactions (including anaphylaxis,cerebrovascular, cardiac and respiratory emergencies) [see Dosage and Administration (2.5)].LEMTRADA is available only through a restricted program under a REMS [see Warnings andPrecautions (5.5)].5.3Stroke and Cervicocephalic Arterial DissectionStrokeIn the postmarketing setting, serious and life-threatening stroke (including ischemic andhemorrhagic stroke) has been reported within 3 days of LEMTRADA administration, with mostcases occurring within 1 day.Cervicocephalic Arterial Dissection7Reference ID: 4843715

In the postmarketing setting, cases of cervicocephalic (e.g., vertebral, carotid) arterial dissectioninvolving multiple arteries have been reported within 3 days of LEMTRADA administration.Ischemic stroke was reported in one of these cases.Educate patients on the symptoms of stroke and cervicocephalic (e.g., carotid, vertebral) arterialdissection. Instruct patients to seek immediate medical attention if symptoms of stroke orcervicocephalic arterial dissection occur.5.4MalignanciesThyroid CancerLEMTRADA 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 theinterferon beta-1a–treated group. However, screening for thyroid cancer was performed morefrequently in the LEMTRADA-treated group, because of the higher incidence of autoimmunethyroid disorders in those patients. Two additional cases of thyroid cancer in LEMTRADAtreated patients occurred in uncontrolled studies.Patients and healthcare providers should monitor for symptoms of thyroid cancer including anew lump or swelling in the neck, pain in the front of the neck, persistent hoarseness or othervoice changes, trouble swallowing or breathing, or a constant cough not due to an upperrespiratory tract infection.MelanomaLEMTRADA may increase the risk of melanoma. In MS clinical studies (controlled and openlabel extension), 5 of 1486 (0.3%) LEMTRADA-treated patients developed melanoma ormelanoma in situ. One of those patients had evidence of locally advanced disease.Perform baseline and yearly skin examinations to monitor for melanoma in patients receivingLEMTRADA.Lymphoproliferative Disorders and LymphomaCases of lymphoproliferative disorders and lymphoma have occurred in LEMTRADA-treatedpatients with MS, including a MALT lymphoma, Castleman’s Disease, and a fatality followingtreatment of non-Epstein Barr Virus–associated Burkitt’s lymphoma. There are postmarketingreports of Epstein Barr Virus–associated lymphoproliferative disorders in non-MS patients.Because LEMTRADA is an immunomodulatory therapy, caution should also be exercised ininitiating LEMTRADA in patients with preexisting or ongoing malignancies.LEMTRADA is available only through a restricted program under a REMS [see Warnings andPrecautions (5.5)].5.5LEMTRADA REMS ProgramLEMTRADA is available only through a restricted program under a REMS called theLEMTRADA REMS Program because of the risks of autoimmunity, infusion reactions, andmalignancies [see Warnings and Precautions (5.1, 5.2, 5.4)].Notable requirements of the LEMTRADA REMS Program include the following: Prescribers must be certified with the program by enrolling and completing training.8Reference ID: 4843715

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 certifiedhealthcare facilities that are authorized to receive LEMTRADA. Healthcare facilities must enroll in the program and verify that patients are authorizedbefore infusing LEMTRADA. Healthcare facilities must have on-site access toequipment and personnel trained to manage infusion reactions.Further information, including a list of qualified healthcare facilities, is available at 1-855-6766326.5.6Immune ThrombocytopeniaImmune thrombocytopenia (ITP) occurred in 2% of LEMTRADA-treated patients in MS clinicalstudies (controlled and open-label extension).In a controlled clinical study in patients with MS, one LEMTRADA-treated patient developedITP that went unrecognized prior to the implementation of monthly blood monitoringrequirements, and died from intracerebral hemorrhage. Nadir platelet counts 20,000 cells permicroliter as a result of ITP occurred in 2% of all LEMTRADA-treated patients in clinicalstudies in MS. Anti-platelet antibodies did not precede ITP onset. ITP has been diagnosed morethan 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 mayalso be indicative of anti-glomerular basement membrane (GBM) disease [see Warnings andPrecautions (5.7)], and an appropriate differential diagnosis has to be undertaken. Remind thepatient to remain vigilant for symptoms they may experience and to seek immediate medical helpif they have any concerns.Obtain complete blood counts (CBCs) with differential prior to initiation of treatment and atmonthly intervals thereafter until 48 months after the last infusion [see Dosage andAdministration (2.6)]. After this period of time, testing should be performed based on clinicalfindings suggestive of ITP. If ITP is suspected, a complete blood count should be obtainedimmediately. If ITP onset is confirmed, promptly initiate appropriate medical intervention.5.7Glomerular Nephropathies Including Anti-glomerular Basement MembraneDiseaseGlomerular nephropathies occurred in 0.3% of LEMTRADA-treated patients in MS clinicalstudies. There were 3 cases of membranous glomerulonephritis and 2 cases of anti-glomerularbasement membrane (anti-GBM) disease.In postmarketing cases, some LEMTRADA-treated patients with anti-GBM disease developedend-stage renal disease requiring dialysis or renal transplantation. Urgent evaluation andtreatment are required because early treatment can improve the preservation of renal function.Anti-GBM disease can be life-threatening if left untreated. Alveolar hemorrhage, manifested ashemoptysis, is a common component of anti-GBM disease and has been reported inpostmarketing cases. Cases of anti-GBM disease have been diagnosed up to 40 months after thelast dose of LEMTRADA.9Reference ID: 4843715

Symptoms of nephropathy may include edema, hematuria, change in urine color, decreased urineoutput, fatigue, dyspnea, and hemoptysis. Patients and caregivers should be instructed to seekmedical advice if they have concerns.Obtain serum creatinine levels, urinalysis with cell counts, and urine protein to creatinine ratioprior to initiation of treatment. Obtain serum creatinine levels and urinalysis with cell counts atmonthly 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.For urine dipstick results of 1 protein or greater, measure the urine protein to creatinine ratio.For urine protein to creatinine ratio greater than 200 mg/g, increase in serum creatinine greaterthan 30%, or unexplained hematuria, perform further evaluation for nephropathies. Increasedserum creatinine with hematuria or signs of pulmonary involvement of anti-GBM disease (e.g.,hemoptysis, exertional dyspnea) warrant immediate evaluation. Early detection and treatment ofnephropathies may decrease the risk of poor outcomes.5.8Thyroid DisordersThyroid endocrine disorders, including autoimmune thyroid disorders, occurred in 36.8% ofLEMTRADA-treated patients in MS clinical studies (controlled and open-label extension).Newly diagnosed thyroid disorders occurred throughout the uncontrolled clinical study follow-upperiod, more than 7 years after the first LEMTRADA dose. Autoimmune thyroid disordersincluded Graves’ d

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, STROKE, AND File Size: 302KBPage Count: 35