LEMTRADA™
(ALEMTUZUMAB) INJECTION FOR INTRAVENOUS INFUSION
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].
" 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].
" 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].
" 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].
FACEBOOK TWITTER EMAIL PRINT
DRUG DESCRIPTION
LEMTRADA (ALEMTUZUMAB) IS A RECOMBINANT HUMANIZED IGG1 KAPPA MONOCLONAL ANTIBODY DIRECTED AGAINST THE CELL SURFACE GLYCOPROTEIN, CD52. ALEMTUZUMAB HAS AN APPROXIMATE MOLECULAR WEIGHT OF 150KD. LEMTRADA IS PRODUCED IN MAMMALIAN CELL (CHINESE HAMSTER OVARY) SUSPENSION CULTURE IN A NUTRIENT MEDIUM CONTAINING NEOMYCIN. NEOMYCIN IS NOT DETECTABLE IN THE FINAL PRODUCT. LEMTRADA IS A STERILE, CLEAR AND COLORLESS TO SLIGHTLY YELLOW, SOLUTION (PH 7.2±0.2) FOR INFUSION.
EACH 1 ML OF SOLUTION CONTAINS ALEMTUZUMAB 10 MG, DIBASIC SODIUM PHOSPHATE (1.15 MG), DISODIUM EDETATE DIHYDRATE (0.0187 MG), POLYSORBATE 80 (0.1 MG), POTASSIUM CHLORIDE (0.2 MG), POTASSIUM DIHYDROGEN PHOSPHATE (0.2 MG), SODIUM CHLORIDE (8 MG), AND WATER FOR INJECTION.
INDICATIONS
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.
DOSAGE AND ADMINISTRATION
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.
VACCINATIONS
PATIENTS SHOULD COMPLETE ANY NECESSARY IMMUNIZATIONS AT LEAST 6 WEEKS PRIOR TO TREATMENT WITH LEMTRADA [SEE WARNINGS AND PRECAUTIONS].
PRIOR TO LEMTRADA 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.
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].
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 3GE; 200 CELLS PER MICROLITER, WHICHEVER OCCURS LATER [SEE WARNINGS AND PRECAUTIONS].
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).
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].
DO NOT ADD OR SIMULTANEOUSLY INFUSE OTHER DRUG SUBSTANCES THROUGH THE SAME INTRAVENOUS LINE. DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.
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].
LABORATORY TESTING AND MONITORING TO ASSESS SAFETY
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].
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
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.
EACH LEMTRADA CARTON (NDC: 58468-0200-1) CONTAINS 1 SINGLE-USE VIAL THAT DELIVERS 12 MG/1.2 ML (10 MG/ML). THE VIAL STOPPER IS NOT MADE WITH NATURAL RUBBER LATEX.
LEMTRADA IS A STERILE, CLEAR AND COLORLESS TO SLIGHTLY YELLOW SOLUTION FOR INFUSION, CONTAINING NO ANTIMICROBIAL PRESERVATIVES.
STORAGE AND HANDLING
STORE LEMTRADA VIALS AT 2°C TO 8°C (36°F TO 46°F). DO NOT FREEZE OR SHAKE. STORE IN ORIGINAL CARTON TO PROTECT FROM LIGHT.
MANUFACTURED AND DISTRIBUTED BY: GENZYME CORPORATION, 500 KENDALL STREET, CAMBRIDGE, MA 02142. ISSUED: NOVEMBER 2014
SIDE EFFECTS
THE FOLLOWING SERIOUS ADVERSE REACTIONS ARE DESCRIBED BELOW AND ELSEWHERE IN THE LABELING:
" AUTOIMMUNITY [SEE BOXED WARNINGAND WARNINGS AND PRECAUTIONS]
" INFUSION REACTIONS [SEE BOXED WARNING AND WARNINGS AND PRECAUTIONS]
" MALIGNANCIES [SEE WARNINGS AND PRECAUTIONS]
" IMMUNE THROMBOCYTOPENIA [SEE WARNINGS AND PRECAUTIONS]
" GLOMERULAR NEPHROPATHIES [SEE WARNINGS AND PRECAUTIONS]
" THYROID DISORDER [SEE WARNINGS AND PRECAUTIONS]
" OTHER AUTOIMMUNE CYTOPENIAS [SEE WARNINGS AND PRECAUTIONS]
" INFECTIONS [SEE WARNINGS AND PRECAUTIONS]
" PNEUMONITIS [SEE WARNINGS AND PRECAUTIONS]
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. 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, WITH AN ADDITIONAL 3411 PERSON-YEARS OF FOLLOW-UP IN AN OPEN LABEL EXTENSION STUDY. THE POPULATION WAS 1855 YEARS OF AGE, 65% WERE FEMALE, AND 92% WERE CAUCASIAN.
MOST COMMON ADVERSE REACTIONS
IN 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: ADVERSE REACTIONS IN THE POOLED 2-YEAR ACTIVE-CONTROLLED STUDIES IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS
LEMTRADA
(N=811) % INTERFERON BETA-1A
44 MCG
(N=389) %
RASH 53 6
HEADACHE 52 23
PYREXIA 29 9
NASOPHARYNGITIS 25 19
NAUSEA 21 9
URINARY TRACT INFECTION 19 8
FATIGUE 18 13
INSOMNIA. 16 15
UPPER RESPIRATORY TRACT INFECTION 16 13
HERPES VIRAL INFECTION 16 3
URTICARIA 16 2
PRURITUS 14 2
THYROID GLAND DISORDERS 13 3
FUNGAL INFECTION 13 4
ARTHRALGIA 12 9
PAIN IN EXTREMITY 12 9
BACK PAIN 12 8
DIARRHEA 12 6
SINUSITIS 11 8
OROPHARYNGEAL PAIN 11 5
PARESTHESIA 10 8
DIZZINESS 10 5
ABDOMINAL PAIN 10 5
FLUSHING 10 4
VOMITING 10 3
COUGH 9 4
CHILLS 9 3
DYSGEUSIA 8 7
INFLUENZA 8 6
DERMATITIS 8 5
DYSPEPSIA 8 4
BLOOD IN URINE 8 3
DYSPNEA 8 1
TACHYCARDIA 8 1
ANXIETY 7 6
MUSCULAR WEAKNESS 7 6
BRONCHITIS 7 4
CHEST DISCOMFORT 7 2
MUSCLE SPASMS 6 5
MYALGIA 6 5
DECREASE IN CD4 LYMPHOCYTES 6 2
DECREASE IN CD8 LYMPHOCYTES 6 2
ASTHENIA 5 4
DECREASE IN T-LYMPHOCYTE COUNT 5 3
ERYTHEMA 5 2
PERIPHERAL EDEMA 5 2
EPISTAXIS 5 2
NECK PAIN 5 2
ABNORMAL UTERINE BLEEDING 5 1
LYMPHOPENIA
NEARLY ALL (99.9%) PATIENTS TREATED WITH LEMTRADA IN MS CLINICAL TRIALS EXPERIENCED LYMPHOPENIA. THE LOWEST LYMPHOCYTE COUNTS OCCURRED APPROXIMATELY BY 1 MONTH AFTER EACH COURSE OF TREATMENT. THE MEAN LYMPHOCYTE COUNT AT 1 MONTH AFTER LEMTRADA TREATMENT WAS 0.25 X 109L (RANGE 0.02-2.30 X 109L) AND 0.32 (0.02-1.81 X 109L) FOR TREATMENT COURSES 1 AND 2, RESPECTIVELY. TOTAL LYMPHOCYTE COUNTS INCREASED TO REACH THE LOWER LIMIT OF NORMAL IN APPROXIMATELY 40% OF PATIENTS BY 6 MONTHS AFTER EACH LEMTRADA TREATMENT COURSE AND APPROXIMATELY 80% OF PATIENTS BY 12 MONTHS AFTER EACH COURSE [SEE CLINICAL PHARMACOLOGY].
SUICIDAL BEHAVIOR OR IDEATION
IN CLINICAL STUDIES, 0.6% OF PATIENTS IN BOTH THE LEMTRADA AND INTERFERON BETA-1A GROUPS HAD EVENTS OF ATTEMPTED SUICIDE OR SUICIDAL IDEATION. THERE WERE NO COMPLETED SUICIDES IN EITHER CLINICAL STUDY TREATMENT GROUP. SUICIDAL BEHAVIOR OR IDEATION OCCURRED IN PATIENTS WITH OR WITHOUT A HISTORY OF A PSYCHIATRIC OR THYROID DISORDER. ADVISE PATIENTS TO REPORT IMMEDIATELY ANY SYMPTOMS OF DEPRESSION OR SUICIDAL IDEATION TO THE PRESCRIBING PHYSICIAN.
IMMUNOGENICITY
AS WITH ALL THERAPEUTIC PROTEINS, THERE IS POTENTIAL FOR IMMUNOGENICITY. USING AN ENZYMELINKED IMMUNOSORBENT ASSAY (ELISA) AND A COMPETITIVE BINDING ASSAY, ANTI-ALEMTUZUMAB BINDING ANTIBODIES WERE DETECTED IN 62%, 67%, AND 29% OF LEMTRADA-TREATED PATIENTS, AT MONTHS 1, 3, 12 (COURSE 1) AS WELL AS 83%, 83%, AND 75% OF LEMTRADATREATED PATIENTS AT MONTHS 13, 15, AND 24 (COURSE 2). SAMPLES THAT TESTED POSITIVE FOR BINDING ANTIBODIES WERE FURTHER EVALUATED FOR EVIDENCE OF IN VITRO INHIBITION USING A FLOW CYTOMETRY ASSAY. NEUTRALIZING ANTIBODIES WERE DETECTED IN 87%, 46%, AND 5% OF POSITIVE BINDING ANTIBODY PATIENTS AT MONTHS 1, 3, 12 (COURSE 1) AS WELL AS 94%, 88%, AND 42% OF POSITIVE BINDING ANTIBODY PATIENTS AT MONTHS 13, 15, AND 24 (COURSE 2). ANTIALEMTUZUMAB ANTIBODIES WERE ASSOCIATED WITH DECREASED ALEMTUZUMAB CONCENTRATION DURING COURSE 2 BUT NOT COURSE 1. THERE WAS NO EVIDENCE FROM CLINICAL TRIALS THAT THE PRESENCE OF BINDING OR INHIBITORY ANTI-ALEMTUZUMAB ANTIBODIES HAD A SIGNIFICANT EFFECT ON CLINICAL OUTCOMES, TOTAL LYMPHOCYTE COUNT, OR ADVERSE EVENTS.
THE INCIDENCE OF ANTIBODIES IS HIGHLY DEPENDENT ON THE SENSITIVITY AND SPECIFICITY OF THE ASSAY. ADDITIONALLY, THE OBSERVED INCIDENCE OF ANTIBODY (INCLUDING INHIBITORY ANTIBODY) POSITIVITY IN AN ASSAY MAY BE INFLUENCED BY SEVERAL FACTORS INCLUDING ASSAY METHODOLOGY, SAMPLE HANDLING, TIMING OF SAMPLE COLLECTION, CONCOMITANT MEDICATIONS, AND UNDERLYING DISEASE. FOR THESE REASONS, COMPARISON OF THE INCIDENCE OF ANTIBODIES TO LEMTRADA WITH THE INCIDENCE OF ANTIBODIES TO OTHER PRODUCTS MAY BE MISLEADING.
POSTMARKETING EXPERIENCE
THE FOLLOWING ADVERSE REACTIONS, NOT DESCRIBED ELSEWHERE, WERE IDENTIFIED DURING POSTAPPROVAL USE OF ALEMTUZUMAB (CAMPATH) FOR THE TREATMENT OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL), AS WELL AS FOR THE TREATMENT OF OTHER DISORDERS, GENERALLY AT HIGHER AND MORE FREQUENT DOSES (E.G., 30 MG) THAN THAT RECOMMENDED IN THE TREATMENT OF MS. BECAUSE THESE REACTIONS ARE REPORTED VOLUNTARILY FROM A POPULATION OF UNCERTAIN SIZE, IT IS NOT ALWAYS POSSIBLE TO RELIABLY ESTIMATE THEIR FREQUENCY OR ESTABLISH A CAUSAL RELATIONSHIP TO DRUG EXPOSURE.
CARDIAC DISORDERS
CONGESTIVE HEART FAILURE, CARDIOMYOPATHY, AND DECREASED EJECTION FRACTION IN NON-MS PATIENTS PREVIOUSLY TREATED WITH POTENTIALLY CARDIOTOXIC AGENTS.
DRUG INTERACTIONS
NO INFORMATION PROVIDED
WARNINGS
INCLUDED AS PART OF THE PRECAUTIONS SECTION
OVERDOSE
TWO MS PATIENTS EXPERIENCED SERIOUS REACTIONS (HEADACHE, RASH, AND EITHER HYPOTENSION OR SINUS TACHYCARDIA) AFTER A SINGLE ACCIDENTAL INFUSION UP TO 60 MG OF LEMTRADA. DOSES OF LEMTRADA GREATER THAN THOSE RECOMMENDED MAY INCREASE THE INTENSITY AND/OR DURATION OF INFUSION REACTIONS OR ITS IMMUNE EFFECTS. THERE IS NO KNOWN ANTIDOTE FOR ALEMTUZUMAB OVERDOSAGE.
CONTRAINDICATIONS
LEMTRADA IS CONTRAINDICATED IN PATIENTS WHO ARE INFECTED WITH HUMAN
IMMUNODEFICIENCY VIRUS (HIV) BECAUSE LEMTRADA CAUSES PROLONGED REDUCTIONS OF CD4+ LYMPHOCYTE COUNTS.
CLINICAL PHARMACOLOGY
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.
PHARMACODYNAMICS
EFFECTS OF LEMTRADA ON THE LYMPHOCYTE POPULATION
LEMTRADA DEPLETES CIRCULATING T AND B LYMPHOCYTES AFTER EACH TREATMENT COURSE. IN CLINICAL TRIALS, THE LOWEST CELL COUNTS OCCURRED 1 MONTH AFTER A COURSE OF TREATMENT AT THE TIME OF THE FIRST POST-TREATMENT BLOOD COUNT. LYMPHOCYTE COUNTS THEN INCREASED OVER TIME: B CELL COUNTS USUALLY RECOVERED WITHIN 6 MONTHS; T CELL COUNTS INCREASED MORE SLOWLY AND USUALLY REMAINED BELOW BASELINE 12 MONTHS AFTER TREATMENT. APPROXIMATELY 60% OF PATIENTS HAD TOTAL LYMPHOCYTE COUNTS BELOW THE LOWER LIMIT OF NORMAL 6 MONTHS AFTER EACH TREATMENT COURSE AND 20% HAD COUNTS BELOW THE LOWER LIMIT OF NORMAL AFTER 12 MONTHS.
RECONSTITUTION OF THE LYMPHOCYTE POPULATION VARIES FOR THE DIFFERENT LYMPHOCYTE SUBTYPES. AT MONTH 1 IN CLINICAL TRIALS, THE MEAN CD4+ LYMPHOCYTE COUNT WAS 40 CELLS PER MICROLITER, AND, AT MONTH 12, 270 CELLS PER MICROLITER. AT 30 MONTHS, APPROXIMATELY HALF OF PATIENTS HAD CD4+ LYMPHOCYTE COUNTS THAT REMAINED BELOW THE LOWER LIMIT OF NORMAL.
CARDIAC ELECTROPHYSIOLOGY
IN A STUDY OF 53 MS PATIENTS, ALEMTUZUMAB 12 MG PER DAY FOR 5 DAYS CAUSED NO CHANGES IN THE QTC INTERVAL GREATER THAN 20MS. AN AVERAGE 22 TO 26 BEATS-PER-MINUTE INCREASE IN HEART RATE WAS OBSERVED FOR AT LEAST 2 HOURS AFTER THE FIRST BUT NOT SUBSEQUENT INFUSIONS.
PHARMACOKINETICS
THE PHARMACOKINETICS OF LEMTRADA WERE EVALUATED IN A TOTAL OF 148 PATIENTS WITH RELAPSING FORMS OF MS WHO RECEIVED 12 MG/DAY ON 5 CONSECUTIVE DAYS, FOLLOWED BY 12 MG/DAY ON 3 CONSECUTIVE DAYS 12 MONTHS FOLLOWING THE FIRST TREATMENT COURSE.
ABSORPTION
SERUM CONCENTRATIONS INCREASED WITH EACH CONSECUTIVE DOSE WITHIN A TREATMENT COURSE, WITH THE HIGHEST OBSERVED CONCENTRATIONS OCCURRING FOLLOWING THE LAST INFUSION OF A TREATMENT COURSE. THE MEAN MAXIMUM CONCENTRATION WAS 3014 NG/ML ON DAY 5 OF THE FIRST TREATMENT COURSE, AND 2276 NG/ML ON DAY 3 OF THE SECOND TREATMENT COURSE.
DISTRIBUTION
LEMTRADA IS LARGELY CONFINED TO THE BLOOD AND INTERSTITIAL SPACE WITH A CENTRAL VOLUME OF DISTRIBUTION OF 14.1 L.
ELIMINATION
THE ELIMINATION HALF-LIFE WAS APPROXIMATELY 2 WEEKS AND WAS COMPARABLE BETWEEN COURSES. THE SERUM CONCENTRATIONS WERE GENERALLY UNDETECTABLE ( < 60 NG/ML) WITHIN APPROXIMATELY 30 DAYS FOLLOWING EACH TREATMENT COURSE.
SPECIFIC POPULATIONS
AGE, RACE, OR GENDER HAD NO EFFECT ON THE PHARMACOKINETICS OF LEMTRADA.
CLINICAL STUDIES
THE EFFICACY OF LEMTRADA WAS DEMONSTRATED IN TWO STUDIES (STUDY 1 AND 2) THAT EVALUATED LEMTRADA 12 MG IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS (RRMS). LEMTRADA WAS ADMINISTERED BY INTRAVENOUS INFUSION ONCE DAILY OVER A 5- DAY COURSE, FOLLOWED ONE YEAR LATER BY INTRAVENOUS INFUSION ONCE DAILY OVER A 3-DAY COURSE. BOTH STUDIES INCLUDED PATIENTS WHO HAD EXPERIENCED AT LEAST 2 RELAPSES DURING THE 2 YEARS PRIOR TO TRIAL ENTRY AND AT LEAST 1 RELAPSE DURING THE YEAR PRIOR TO TRIAL ENTRY. NEUROLOGICAL EXAMINATIONS WERE PERFORMED EVERY 12 WEEKS AND AT THE TIME OF SUSPECTED RELAPSE. MAGNETIC RESONANCE IMAGING (MRI) EVALUATIONS WERE PERFORMED ANNUALLY.
STUDY 1
STUDY 1 WAS A 2 YEAR RANDOMIZED, OPEN-LABEL, RATER-BLINDED, ACTIVE COMPARATOR (INTERFERON BETA-1A 44 MICROGRAMS ADMINISTERED SUBCUTANEOUSLY THREE TIMES A WEEK) CONTROLLED STUDY IN PATIENTS WITH RRMS. PATIENTS ENTERING STUDY 1 HAD EXPANDED DISABILITY STATUS SCALE (EDSS) SCORES OF 5 OR LESS AND HAD TO HAVE EXPERIENCED AT LEAST ONE RELAPSE WHILE ON INTERFERON BETA OR GLATIRAMER ACETATE THERAPY.
PATIENTS WERE RANDOMIZED TO RECEIVE LEMTRADA (N=426) OR INTERFERON BETA-1A (N=202). AT BASELINE, THE MEAN AGE WAS 35 YEARS, THE MEAN DISEASE DURATION WAS 4.5 YEARS, AND THE MEAN EDSS SCORE WAS 2.7.
THE CLINICAL OUTCOME MEASURES WERE THE ANNUALIZED RELAPSE RATE (ARR) OVER 2 YEARS AND THE TIME TO CONFIRMED DISABILITY PROGRESSION. CONFIRMED DISABILITY PROGRESSION WAS DEFINED AS AT LEAST A 1 POINT INCREASE ABOVE BASELINE EDSS (1.5 POINT INCREASE FOR PATIENTS WITH BASELINE EDSS OF 0) SUSTAINED FOR 6 MONTHS. THE MRI OUTCOME MEASURE WAS THE CHANGE IN T2 LESION VOLUME.
THE ANNUALIZED RELAPSE RATE WAS SIGNIFICANTLY LOWER IN PATIENTS TREATED WITH LEMTRADA THAN IN PATIENTS WHO RECEIVED INTERFERON BETA-1A. TIME TO ONSET OF 6-MONTH CONFIRMED DISABILITY PROGRESSION WAS SIGNIFICANTLY DELAYED WITH LEMTRADA TREATMENT COMPARED TO INTERFERON BETA-1A. THERE WAS NO SIGNIFICANT DIFFERENCE BETWEEN THE TREATMENT GROUPS FOR THE CHANGE IN T2 LESION VOLUME. THE RESULTS OF STUDY 1 ARE SHOWN IN TABLE 2 AND FIGURE 1.
TABLE 2: CLINICAL AND MRI RESULTS OF STUDY 1
LEMTRADA (N=426) INTERFERON BETA-1A
44 MCG (N=202) P-VALUE
CLINICAL OUTCOMES
ANNUALIZED RELAPSE RATE 0.26 0.52 < 0.0001
RELATIVE REDUCTION 49%
PROPORTION OF PATIENTS WITH DISABILITY PROGRESSION AT YEAR 2 13% 21% 0.0084
RELATIVE RISK REDUCTION 42%
PERCENT OF PATIENTS REMAINING RELAPSE-FREE AT YEAR 2 65% 47% < 0.0001
MRI OUTCOMES
PERCENT CHANGE IN T2 LESION VOLUME FROM BASELINE -1.3 -1.2 0.14
FIGURE 1: TIME TO 6-MONTH CONFIRMED DISABILITY PROGRESSION (STUDY 1)
STUDY 2
STUDY 2 WAS A 2-YEAR RANDOMIZED, OPEN-LABEL, RATER-BLINDED, ACTIVE COMPARATOR (INTERFERON BETA-1A 44 MICROGRAMS ADMINISTERED SUBCUTANEOUSLY THREE TIMES A WEEK) CONTROLLED STUDY IN PATIENTS WITH RRMS. PATIENTS ENTERING STUDY 2 HAD EDSS SCORES OF 3 OR LESS AND NO PRIOR TREATMENT FOR MULTIPLE SCLEROSIS.
PATIENTS WERE RANDOMIZED TO RECEIVE LEMTRADA (N=376) OR INTERFERON BETA-1A (N=187). AT BASELINE, THE MEAN AGE WAS 33 YEARS, THE MEAN DISEASE DURATION WAS 2 YEARS, AND THE MEAN EDSS SCORE WAS 2.
THE CLINICAL OUTCOME MEASURES WERE THE ANNUALIZED RELAPSE RATE (ARR) OVER 2 YEARS AND THE TIME TO CONFIRMED DISABILITY PROGRESSION, AS DEFINED IN STUDY 1. THE MRI OUTCOME MEASURE WAS THE CHANGE IN T2 LESION VOLUME.
THE ANNUALIZED RELAPSE RATE WAS SIGNIFICANTLY LOWER IN PATIENTS TREATED WITH LEMTRADA THAN IN PATIENTS WHO RECEIVED INTERFERON BETA-1A. THERE WAS NO SIGNIFICANT DIFFERENCE BETWEEN THE TREATMENT GROUPS FOR THE TIME TO CONFIRMED DISABILITY PROGRESSION AND FOR THE PRIMARY MRI ENDPOINT (CHANGE IN T2 LESION VOLUME). THE RESULTS FOR STUDY 2 ARE SHOWN IN TABLE 3.
TABLE 3: CLINICAL AND MRI RESULTS OF STUDY 2
LEMTRADA
(N=376) INTERFERON BETA-1A
44 MCG
(N=187) P-VALUE
CLINICAL OUTCOMES
ANNUALIZED RELAPSE RATE 0.18 0.39 < 0.0001
RELATIVE REDUCTION 55%
PROPORTION OF PATIENTS WITH DISABILITY PROGRESSION AT YEAR 2 8% 11% 0.22
RELATIVE RISK REDUCTION 30%
PERCENT OF PATIENTS REMAINING RELAPSE-FREE AT YEAR 2 78% 59% < 0.0001
MRI OUTCOMES
PERCENT CHANGE IN T2 LESION VOLUME FROM BASELINE -9.3 -6.5 0.31