LEMTRADA 12mg / 1.2ml perfusive solution concentrate medication leaflet

LEMTRADA 12 mg concentrate for solution for infusion

Each vial contains 12 mg alemtuzumab in 1.2 ml (10 mg/ml).

Alemtuzumab is a monoclonal antibody produced in mammalian cell (Chinese Hamster Ovary) suspensionculture in a nutrient medium by recombinant DNA technology.

This medicine contains less than 1 mmol potassium (39 mg) per infusion, i.e. it is essentially ‘potassium-free’.

This medicine contains less than 1 mmol sodium (23 mg) per infusion, i.e. it is essentially ‘sodium- free’.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

A clear, colourless to slightly yellow concentrate with pH 7.0 - 7.4.

LEMTRADA is indicated as a single disease modifying therapy in adults with highly active relapsingremitting multiple sclerosis (RRMS) for the following patient groups:

* Patients with highly active disease despite a full and adequate course of treatment with at least onedisease modifying therapy (DMT) or

* Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or moredisabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or asignificant increase in T2 lesion load as compared to a previous recent MRI.

LEMTRADA treatment should only be initiated and supervised by a neurologist experienced in the treatmentof patients with multiple sclerosis (MS) in a hospital with ready access to intensive care. Specialists andequipment required for the timely diagnosis and management of adverse reactions, especially myocardialischaemia and myocardial infarction, cerebrovascular adverse reactions, autoimmune conditions, andinfections, should be available.

Resources for the management of cytokine release syndrome, hypersensitivity and/or anaphylactic reactionsshould be available.

Patients treated with LEMTRADA must be given the Patient Alert Card and Patient Guide and be informedabout the risks of LEMTRADA (see also package leaflet).

The recommended dose of alemtuzumab is 12 mg/day administered by intravenous infusion for 2 initialtreatment courses, with up to 2 additional treatment courses if needed.

Initial treatment of 2 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 monthsafter the first treatment course.

Up to two additional treatment courses, as needed, may be considered (see section 5.1):

* Third or fourth course: 12 mg/day on 3 consecutive days (36 mg total dose) administered at least12 months after the prior treatment course (see section 4.1, 5.1).

Missed doses should not be given on the same day as a scheduled dose.

Follow-up of patients

The therapy is recommended as an initial treatment of 2 courses with up to 2 additional treatment courses ifneeded (see posology) with safety follow-up of patients from initiation of the first treatment course and for atleast 48 months after the last infusion of the second treatment course. If an additional third or fourth course isadministered, continue safety follow-up for at least 48 months after the last infusion (see section 4.4).

Pre-treatment

Patients should be pre-treated with corticosteroids immediately prior to LEMTRADA administration on eachof the first 3 days of any treatment course. In clinical trials, patients were pre-treated with 1,000 mgmethylprednisolone for the first 3 days of each LEMTRADA treatment course.

Pretreatment with antihistamines and/or antipyretics prior to LEMTRADA administration may also beconsidered.

Oral prophylaxis for herpes infection should be administered to all patients starting on the first day of eachtreatment course and continuing for a minimum of 1 month following treatment with LEMTRADA (see alsounder ‘Infections’ in section 4.4). In clinical trials, patients were administered aciclovir 200 mg twice a dayor equivalent.

Clinical studies did not include any patients aged over 61 years old. It has not been determined whether theyrespond differently than younger patients.

LEMTRADA has not been studied in patients with renal or hepatic impairment.

The safety and efficacy of LEMTRADA in children with MS aged 0 to 18 years have not yet beenestablished. There is no relevant use of alemtuzumab in children aged from birth to less than 10 years for thetreatment of multiple sclerosis. No data are available.

LEMTRADA must be diluted before infusion. The diluted solution should be administered by intravenousinfusion over a period of approximately 4 hours.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1.

Human Immunodeficiency Virus (HIV) infection.

Patients with severe active infection until complete resolution.

Patients with uncontrolled hypertension.

Patients with a history of arterial dissection of the cervicocephalic arteries.

Patients with a history of stroke.

Patients with a history of angina pectoris or myocardial infarction.

Patients with known coagulopathy, on anti-platelet or anti-coagulant therapy.

Patients with other concomitant autoimmune diseases (besides MS).

LEMTRADA is not recommended for patients with inactive disease or those stable on current therapy.

Patients treated with LEMTRADA must be given the Package Leaflet, the Patient Alert Card and the Patient

Guide. Before treatment, patients must be informed about the risks and benefits, and the need to commit tofollow-up from treatment initiation until at least 48 months after the last infusion of the second LEMTRADAtreatment course. If an additional course is administered, safety-follow up should be continued until at least48 months after the last infusion.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Autoimmunity

Treatment may result in the formation of autoantibodies and increase the risk of autoimmune mediatedconditions which may be serious and life threatening. Reported autoimmune conditions, include thyroiddisorders, immune thrombocytopenic purpura (ITP), nephropathies (e.g. anti-glomerular basementmembrane disease), autoimmune hepatitis (AIH), acquired haemophilia A, thrombotic thrombocytopenicpurpura, sarcoidosis, and autoimmune encephalitis. In the post-marketing setting, patients developingmultiple autoimmune disorders after LEMTRADA treatment have been observed. Patients who developautoimmunity should be assessed for other autoimmune mediated conditions (see section 4.3). Patients andphysicians should be made aware of the potential later onset of autoimmune disorders after the 48 monthsmonitoring period.

Acquired haemophilia A

Cases of acquired haemophilia A (anti-factor VIII antibodies) have been reported in both clinical trial andpost-marketing setting. Patients typically present with spontaneous subcutaneous haematomas and extensivebruising although haematuria, epistaxis, gastrointestinal or other types of bleeding may occur. Acoagulopathy panel including aPTT must be obtained in all patients that present with such symptoms. In caseof a prolonged aPTT patient should be referred to a haematologist. Educate patients on the signs andsymptoms of acquired haemophilia A and to seek immediate medical attention, if any of these symptoms areobserved.

Development of TTP has been reported in patients treated with LEMTRADA during post-marketing use,including a fatal case. TTP is a serious condition that requires urgent evaluation and prompt treatment, andcan develop several months after last LEMTRADA infusion. TTP may be characterized bythrombocytopenia, microangiopathic hemolytic anemia, neurological symptoms, fever and renal impairment.

Autoimmune Encephalitis

Cases of autoimmune encephalitis have been reported in patients treated with LEMTRADA. Autoimmuneencephalitis is characterized by subacute onset (with rapid progression over months) of memory impairment,altered mental status or psychiatric symptoms, generally in combination with new onset focal neurologicalfindings and seizures. Patients with suspected autoimmune encephalitis should have neuroimaging (MRI),

EEG, lumbar puncture and serologic testing for appropriate biomarkers (e.g. neural autoantibodies) toconfirm diagnosis and exclude alternative etiologies.

Immune Thrombocytopenic Purpura (ITP)

Serious events of ITP have been observed in 12 (1%) patients treated in controlled clinical trials in MS(corresponding to an annualised rate 4.7 events/1000 patient years). An additional 12 serious events of ITPhas been observed through a median of 6.1 years (maximum 12 years) of follow-up (cumulative annualisedrate of 2.8 events/1000 patient years). One patient developed ITP that went unrecognised prior toimplementation of monthly blood monitoring requirements and died from intracerebral haemorrhage. In79.5% of cases, ITP onset occurred within 4 years after first exposure. However, in some cases ITPdeveloped years later. Symptoms of ITP could include (but are not limited to) easy bruising, petechiae,spontaneous mucocutaneous bleeding (e.g., epistaxis, haemoptysis), heavier than normal or irregularmenstrual bleeding. Haemoptysis may also be indicative of anti-GBM disease (see below), and anappropriate differential diagnosis has to be undertaken. Remind the patient to remain vigilant for symptomsthey may experience and to seek immediate medical help if they have any concerns.

Complete blood counts with differential should be obtained prior to initiation of treatment and at monthlyintervals thereafter until at least 48 months after the last infusion. After this period of time, testing should beperformed based on clinical findings suggestive of ITP. If ITP is suspected a complete blood count should beobtained immediately.

If ITP onset is confirmed, appropriate medical intervention should be promptly initiated, includingimmediate referral to a specialist. Data from clinical trials in MS has shown that adherence to the bloodmonitoring requirements and education relative to signs and symptoms of ITP has led to early detection andtreatment of ITP with most cases responding to first-line medical therapy.

Nephropathies

Nephropathies, including anti-glomerular basement membrane (anti-GBM) disease, have been observed in6 (0.4%) patients in clinical trials in MS through a median of 6.1 years (maximum 12 years) of follow-upand generally occurred within 39 months following the last administration of LEMTRADA. In clinical trials,there were 2 cases of anti-GBM disease. Both cases were serious, were identified early through clinical andlaboratory monitoring, and had a positive outcome after treatment.

Clinical manifestations of nephropathy may include elevation in serum creatinine, haematuria, and/orproteinuria. While not observed in clinical trials, alveolar haemorrhage manifested as haemoptysis may occurwith anti-GBM disease. Haemoptysis may also be indicative of ITP or acquired haemophilia A (see above),and an appropriate differential diagnosis has to be undertaken. The patient should be reminded to remainvigilant for symptoms they may experience and to seek immediate medical help if they have any concerns.

Anti-GBM disease may lead to renal failure requiring dialysis and/or transplantation if not treated rapidlyand can be life-threatening if left untreated.

Serum creatinine levels should be obtained prior to initiation of treatment and at monthly intervals thereafteruntil at least 48 months after the last infusion. Urinalysis with microscopy should be obtained prior toinitiation and at monthly intervals thereafter until at least 48 months after the last infusion. The observationof clinically significant changes from baseline in serum creatinine, unexplained haematuria, and/orproteinuria, should prompt further evaluation for nephropathies including immediate referral to a specialist.

Early detection and treatment of nephropathies may decrease the risk of poor outcomes. After this period oftime, testing should be performed based on clinical findings suggestive of nephropathies.

Thyroid disorders

Thyroid endocrine disorders including autoimmune thyroid disorders have been observed in 36.8% ofpatients treated with LEMTRADA 12 mg in clinical trials in MS with a median of 6.1 years (maximum12 years) of follow- up from the first LEMTRADA exposure. The incidence of thyroid events was higher inpatients with a medical history of thyroid disorders both in the LEMTRADA and interferon beta 1a (IFNB-1a) treatment groups. Observed autoimmune thyroid disorders included hyperthyroidism or hypothyroidism.

Most events were mild to moderate in severity. Serious endocrine events occurred in 4.4% of patients, with

Basedow’s disease (also known as Graves’ disease), hyperthyroidism, hypothyroidism, autoimmunethyroiditis, and goitre occurring in more than 1 patient. Most thyroid events were managed with conventionalmedical therapy however some patients required surgical intervention. In the post-marketing setting severalpatients who developed biopsy proven AIH had previously developed autoimmune thyroid disorders.

Thyroid function tests, such as thyroid stimulating hormone levels, should be obtained prior to initiation oftreatment and every 3 months thereafter until 48 months following the last infusion. After this period of timetesting should be performed based on clinical findings suggestive of thyroid dysfunction or in case ofpregnancy.

Thyroid disease poses special risks in women who are pregnant (see section 4.6).

In clinical trials, 74% of patients with positive anti-thyroid peroxidase (anti-TPO) antibodies at baselinedeveloped a thyroid event compared with 38% of patients with a baseline negative status. The vast majority(approximately 80%) of patients who presented with a thyroid event after treatment were anti-TPO antibodynegative at baseline. Therefore, regardless of pretreatment anti-TPO antibody status patients may develop athyroid adverse reaction and must have all tests periodically performed as described above.

Cytopenias

Suspected autoimmune cytopenias such as neutropenia, haemolytic anaemia and pancytopenia have beeninfrequently reported in clinical trials in MS. Complete blood count results (see above under ITP) should beused to monitor for cytopenias, including neutropenia. If a cytopenia is confirmed, appropriate medicalintervention should be promptly initiated, including referral to a specialist.

Autoimmune hepatitis and hepatic injury

Cases of autoimmune hepatitis (including fatal cases and cases requiring liver transplantation) and hepaticinjury related to infections have been reported in patients treated with LEMTRADA (see section 4.3). Liverfunction tests should be performed before initial treatment and at monthly intervals until at least 48 monthsafter the last infusion. Patients should be informed about the risk of autoimmune hepatitis, hepatic injury andrelated symptoms.

Haemophagocytic lymphohistiocytosis (HLH)

During post-marketing use, HLH (including fatal cases) has been reported in patients treated with

LEMTRADA. HLH is a life-threatening syndrome of pathologic immune activation characterized by clinicalsigns and symptoms of extreme systemic inflammation. HLH is characterized by fever, hepatomegaly andcytopenias. It is associated with high mortality rates if not recognized early and treated. Symptoms have beenreported to occur within a few months to four years following the initiation of treatment. Patients should beinformed about symptoms of HLH and time to onset. Patients who develop early manifestations ofpathologic immune activation should be evaluated immediately, and a diagnosis of HLH should beconsidered.

Infusion-associated Reactions (IARs)

In clinical trials, infusion associated reactions (IARs) were defined as any adverse event occurring during orwithin 24 hours of LEMTRADA infusion. The majority of these may be due to cytokine release duringinfusion. Most patients treated with LEMTRADA in clinical trials in MS experienced mild to moderate IARsduring and/or up to 24 hours after LEMTRADA 12 mg administration. The incidence of IARs was higher incourse 1 than in subsequent courses. Through all available follow-up, including patients who receivedadditional treatment courses, the most common IARs included headache, rash, pyrexia, nausea, urticaria,pruritus, insomnia, chills, flushing, fatigue, dyspnoea, dysgeusia, chest discomfort, generalised rash,tachycardia, bradycardia, dyspepsia, dizziness, and pain. Serious reactions occurred in 3% of patients andincluded cases of headache, pyrexia, urticaria, tachycardia, atrial fibrillation, nausea, chest discomfort, andhypotension. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of infusionassociated reactions, but would tend to be more severe or potentially life-threatening. Reactions attributed toanaphylaxis have been reported rarely in contrast to infusion associated reactions.

It is recommended that patients be premedicated to ameliorate the effects of infusion reactions (see section4.2).

Most patients in controlled clinical trials received antihistamines and/or antipyretics before at least one

LEMTRADA infusion. IARs may occur in patients despite pretreatment. Observation for infusion reactionsis recommended during and for at least 2 hours after LEMTRADA infusion. Extended observation time(hospitalization) should be considered, as appropriate. If severe infusion reactions occur, the intravenousinfusion should be discontinued immediately. Resources for the management of anaphylaxis or seriousreactions (see below) should be available.

Adult Onset Still’s disease (AOSD)

During postmarketing use, Adult Onset Still’s Disease (AOSD) has been reported in patients treated with

LEMTRADA. AOSD is a rare inflammatory condition that requires urgent evaluation and treatment. Patientswith AOSD may have a combination of the following signs and symptoms: fever, arthritis, rash andleukocytosis in the absence of infections, malignancies, and other rheumatic conditions. Considerinterruption or discontinuation of treatment with LEMTRADA if an alternate etiology for the signs orsymptoms cannot be established.

Other serious reactions temporally associated with LEMTRADA infusion

During post-marketing use, rare, serious, sometimes fatal and unpredictable adverse events from variousorgan systems have been reported. In the majority of cases time to onset was within 1-3 days of the

LEMTRADA infusion. Reactions have occurred following any of the doses and also after course number 2.

Patients should be informed about the signs and symptoms and on the time to onset of the events. Patientsshould be advised to seek immediate medical attention if any of these symptoms occur and be informed onthe potential for delayed onset.

Haemorrhagic stroke

Several of the patient reported were below 50 years of age and had no history of hypertension, bleedingdisorders or concomitant anticoagulants or platelet inhibitors. In some patients there was increased bloodpressure from baseline before the haemorrhage.

Myocardial ischaemia and myocardial infarction

Several of the patients reported were below 40 years of age and had no risk factors for ischemic heartdisease. It was noted that in some of the patients, blood pressure and /or heart rate was temporarily abnormalduring the infusion.

Dissection of the cervicocephalic arteries

Cases of cervicocephalic arterial dissections, including multiple dissections, have been reported both withinthe first days after the LEMTRADA infusion or later on within the first month after the infusion.

Pulmonary alveolar haemorrhage

Reported cases of temporally associated events were not related to anti-GBM disease (Goodpasteurssyndrome).

The reported thrombocytopenia occurred within the first days after the infusion (unlike ITP). It was oftenself-limiting and relatively mild, although severity and outcome was unknown in many cases.

Pericarditis

Rare cases of pericarditis, pericardial effusion and other pericardial events have been reported, both as partof acute infusion reaction and with later onset.

Pneumonitis

Pneumonitis has been reported in patients who received LEMTRADA infusions. Most cases occurred withinthe first month after treatment with LEMTRADA. Patients should be advised to report symptoms ofpneumonitis, which may include shortness of breath, cough, wheezing, chest pain or tightness andhemoptysis.

Infusion instructions to reduce serious reactions temporally associated with LEMTRADA infusion

* Pre-infusion evaluations:

o Obtain a baseline ECG and vital signs, including heart rate and blood pressure measurement.

o Perform laboratory tests (complete blood count with differential, serum transaminases,serum creatinine, test of thyroid function and urinanalysis with microscopy).

* During infusion:

o Perform continuous/frequent (at least every hour) monitoring of heart rate, blood pressureand overall clinical status of the patients▪ Discontinue the infusion

* In case of a severe adverse event

* If the patient shows clinical symptoms suggesting development of a seriousadverse event associated with the infusion (myocardial ischemia,hemorrhagic stroke, cervico-cephalic arterial dissection or pulmonaryalveolar haemorrhage

* Post-infusion:

o Observation for infusion reactions is recommended for a minimum of 2 hours after

LEMTRADA infusion. Patients with clinical symptoms suggesting development of a seriousadverse event temporally associated with the infusion (myocardial ischemia, haemorrhagicstroke, cervico-cephalic arterial dissection or pulmonary alveolar haemorrhage) should beclosely monitored until complete resolution of the symptoms. The observation time shouldbe extended (hospitalisation) as appropriate. The patients should be educated on the potentialfor delayed onset of infusion associated reactions and instructed to report symptoms andseek appropriate medical care.

o Platelet count should be obtained immediately after infusion on Days 3 and 5 of the firstinfusion course, as well as immediately after infusion on Day 3 of any subsequent course.

Clinically significant thrombocytopenia needs to be followed until resolution. Referral to ahaematologist for management should be considered.

Infections occurred in 71% of patients treated with LEMTRADA 12 mg as compared to 53% of patientstreated with subcutaneous interferon beta-1a [IFNB 1a](44mcg 3-times weekly) in controlled clinical trials in

MS up to 2 years in duration and were predominantly mild to moderate in severity. Infections that occurredmore often in LEMTRADA -treated patients than IFNB 1a patients included nasopharyngitis, urinary tractinfection, upper respiratory tract infection, sinusitis, oral herpes, influenza, and bronchitis. Serious infectionsoccurred in 2.7% of patients treated with LEMTRADA as compared to 1% of patients treated with IFNB-1ain controlled clinical trials in MS. Serious infections in the LEMTRADA group included: appendicitis,gastroenteritis, pneumonia, herpes zoster, and tooth infection. Infections were generally of typical durationand resolved following conventional medical treatment.

The cumulative annualised rate of infections was 0.99 through a median of 6.1 years (maximum 12 years) offollow-up from the first LEMTRADA exposure, as compared to 1.27 in controlled clinical trials.

Serious varicella zoster virus infections, including primary varicella and varicella zoster re-activation, haveoccurred more often in patients treated with LEMTRADA 12 mg (0.4%) in clinical trials as compared to

IFNB-1a (0%). Cervical human papilloma virus (HPV) infection, including cervical dysplasia and anogenitalwarts, has also been reported in patients treated with LEMTRADA 12 mg (2%). It is recommended that HPVscreening be completed annually for female patients.

Cytomegalovirus infections (CMV) including cases of CMV reactivation have been reported in

LEMTRADA-treated patients. Most cases occurred within 2 months of alemtuzumab dosing. Beforeinitiation of therapy, evaluation of immune serostatus could be considered according to local guidelines.

Epstein-Barr virus (EBV) infection, including reactivation and severe and sometimes fatal EBV hepatitiscases, has been reported in LEMTRADA-treated patients.

Tuberculosis has been reported for patients treated with LEMTRADA and IFNB-1a in controlled clinicaltrials. Active and latent tuberculosis, including a few cases of disseminated tuberculosis, have been reportedin 0.3% of the patients treated with LEMTRADA, most often in endemic regions. Before initiation oftherapy, all patients must be evaluated for both active or inactive (“latent”) tuberculosis infection, accordingto local guidelines.

Listeriosis/Listeria meningitis has been reported in LEMTRADA treated patients, generally within onemonth of LEMTRADA infusion. To reduce the risk of infection, patients receiving LEMTRADA shouldavoid ingestion of uncooked or undercooked meats, soft cheeses and unpasteurized dairy products two weeksprior to, during, and for at least one month after LEMTRADA infusion.

Superficial fungal infections, especially oral and vaginal candidiasis, occurred more commonly in

LEMTRADA -treated patients (12%) than in patients treated with IFNB-1a (3%) in controlled clinical trialsin MS.

Initiation of treatment with LEMTRADA should be delayed in patients with severe active infection untilresolution. Patients receiving LEMTRADA should be instructed to report symptoms of infections to aphysician.

Prophylaxis with an oral anti-herpes agent should be initiated starting on the first day of LEMTRADAtreatment and continuing for a minimum of 1 month following each course of treatment. In clinical trialspatients were administered cyclovir 200 mg twice a day or equivalent.

LEMTRADA has not been administered for treatment of MS concomitantly with or following antineoplasticor immunosuppressive therapies. As with other immunomodulating therapies, potential combined effects onthe patient’s immune system should be taken into account when considering administration of LEMTRADA.

Concomitant use of LEMTRADA with any of these therapies could increase the risk of immunosuppression.

No data are available on the association of LEMTRADA with Hepatitis B virus (HBV) or Hepatitis C virus(HCV) reactivation as patients with evidence of active or chronic infections were excluded from clinicaltrials. Screening patients at high risk of HBV and/or HCV infection before initiation of LEMTRADA shouldbe considered and caution should be exercised in prescribing LEMTRADA to patients identified as carriersof HBV and/or HCV as these patients may be at risk of irreversible liver damage relative to a potential virusreactivation as a consequence of their pre-existing status.

Rare cases of PML (including fatal), have been reported in MS patients after treatment with alemtuzumab.

Patients treated with alemtuzumab must be monitored for any signs that may be suggestive of PML. Riskfactors of special importance include previous immunosuppressive treatment, in particular other MStreatments with known risk of causing PML.

MRI findings may be apparent before clinical signs or symptoms. Prior to initiation and readministration ofalemtuzumab treatment, MRI scan should be made and evaluated for signs that are consistent with PML.

Further evaluation, including cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurologicalassessments should be performed as appropriate. The physician should be particularly alert to symptomssuggestive of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms).

Patients should also be advised to inform their relatives or caregivers about their treatment, since they maynotice symptoms that the patient is not aware of. PML should be considered as a differential diagnosis in any

MS patient taking alemtuzumab presenting with neurological symptoms and/or new brain lesions in MRI.

If a diagnosis of PML has been made, treatment with alemtuzumab should not be started or restarted.

Acute acalculous cholecystitis

LEMTRADA may increase the risk of acute acalculous cholecystitis. In controlled clinical studies, 0.2% of

LEMTRADA-treated MS patients developed acute acalculous cholecystitis, compared to 0% of patientstreated with IFNB-1a. During post-marketing use, additional cases of acute acalculous cholecystitis havebeen reported in LEMTRADA-treated patients. Time to onset of symptoms ranged from less than 24 hours to2 months after LEMTRADA infusion. Most patients were treated conservatively with antibiotics andrecovered without surgical intervention, whereas others underwent cholecystectomy. Symptoms of acuteacalculous cholecystitis include abdominal pain, abdominal tenderness, fever, nausea, and vomiting. Acuteacalculous cholecystitis is a condition that may be associated with high morbidity and mortality rates if notdiagnosed early and treated. If acute acalculous cholecystitis is suspected, evaluate and treat promptly.

As with other immunomodulatory therapies, caution should be exercised in initiating LEMTRADA therapyin patients with pre-existing and/or an on-going malignancy. It is not currently known if LEMTRADAconfers a higher risk for developing thyroid malignancies, since thyroid autoimmunity may itself be a riskfactor for thyroid malignancies.

Placental transfer and potential pharmacologic activity of LEMTRADA were observed in mice duringgestation and following delivery. Women of childbearing potential should use effective contraceptivemeasures during treatment and for 4 months following a course of LEMTRADA treatment (see section 4.6).

Vaccines

It is recommended that patients have completed local immunisation requirements at least 6 weeks prior totreatment with LEMTRADA. The ability to generate an immune response to any vaccine following

LEMTRADA treatment has not been studied.

The safety of immunisation with live viral vaccines following a course of LEMTRADA treatment has notbeen formally studied in controlled clinical trials in MS and should not be administered to MS patients whohave recently received a course of LEMTRADA.

Varicella zoster virus antibody testing/vaccination

As for any immune modulating medicinal product, before initiating a course of LEMTRADA treatment,patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) shouldbe tested for antibodies to VZV. VZV vaccination of antibody-negative patients should be considered priorto treatment initiation with LEMTRADA. To allow for the full effect of the VZV vaccination to occur,treatment with LEMTRADA should be postponed for 6 weeks following vaccination.

Recommended laboratory tests for monitoring patients

Clinical examination and laboratory tests should be conducted at periodic intervals until at least 48 monthsfollowing the last treatment course of LEMTRADA in order to monitor for early signs of autoimmunediseases:

* Complete blood count with differential, serum transaminases and serum creatinine levels (prior totreatment initiation and at monthly intervals thereafter).

* Urinalysis with microscopy (prior to treatment initiation and at monthly intervals thereafter)

* A test of thyroid function, such as thyroid stimulating hormone level (prior to treatment initiation andevery 3 months thereafter).

Information from use of alemtuzumab prior to the marketing authorisation of LEMTRADA outside ofcompany-sponsored studies

The following adverse reactions were identified prior to registration of LEMTRADA during use ofalemtuzumab for the treatment of B-cell chronic lymphocytic leukaemia (B-CLL), as well as for thetreatment of other disorders, generally at higher and more frequent doses (e.g. 30 mg) than thatrecommended in the treatment of MS. Because these reactions are reported voluntarily from a population ofuncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationshipto alemtuzumab exposure.

Autoimmune disease

Autoimmune events reported in alemtuzumab-treated patients include neutropenia, haemolytic anaemia(including a fatal case), acquired haemophilia, anti-GBM disease, and thyroid disease. Serious andsometimes fatal autoimmune phenomena including autoimmune haemolytic anaemia, autoimmunethrombocytopenia, aplastic anaemia, Guillain-Barré syndrome, and chronic inflammatory demyelinatingpolyradiculoneuropathy have been reported in alemtuzumab-treated non-MS patients. A positive Coombstest has been reported in an alemtuzumab-treated oncology patient. A fatal event of transfusion associatedgraft versus host disease has been reported in an alemtuzumab-treated oncology patient.

Serious and sometimes fatal IARs including bronchospasm, hypoxia, syncope, pulmonary infiltrates, acuterespiratory distress syndrome , respiratory arrest, myocardial infarction, arrhythmias, acute cardiacinsufficiency, and cardiac arrest have been observed in non-MS patients treated with alemtuzumab at higherand more frequent doses than used in MS. Severe anaphylaxis and other hypersensitivity reactions, includinganaphylactic shock and angioedema have also been reported.

Serious and sometimes fatal viral, bacterial, protozoan, and fungal infections, including those due toreactivation of latent infections, have been reported in non-MS patients treated with alemtuzumab at higherand more frequent doses than used in MS.

Severe bleeding reactions have been reported in non-MS patients.

Congestive heart failure, cardiomyopathy, and decreased ejection fraction have been reported inalemtuzumab-treated non-MS patients previously treated with potentially cardiotoxic agents.

Epstein-Barr Virus-associated lymphoproliferative disorders

Epstein-Barr Virus-associated lymphoproliferative disorders have been observed outside company-sponsoredstudies.

LEMTRADA contains sodium and potassium

This medicine contains less than 1 mmol potassium (39 mg) per infusion, i.e. it is essentially ‘potassium-free’.

This medicine contains less than 1 mmol sodium (23 mg) per infusion, i.e. it is essentially ‘sodium- free’.

No formal drug interaction studies have been conducted with LEMTRADA using the recommended dose inpatients with MS. In a controlled clinical trial in MS patients recently treated with beta interferon andglatiramer acetate were required to discontinue treatment 28 days before initiating treatment with

LEMTRADA.

Serum concentrations were low or undetectable within approximately 30 days following each treatmentcourse. Therefore, women of childbearing potential have to use effective contraception when receiving acourse of treatment with LEMTRADA and up to 4 months after each course of treatment.

There is a limited amount of data from the use of alemtuzumab in pregnant women. LEMTRADA should beadministered during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Human IgG is known to cross the placental barrier; alemtuzumab may cross the placental barrier as well andthus potentially pose a risk to the foetus. Animal studies have shown reproductive toxicity (see section 5.3).

It is not known whether alemtuzumab can cause foetal harm when administered to pregnant women orwhether it can affect reproductive capacity.

Thyroid disease (see section 4.4 Thyroid Disorders) poses special risks in women who are pregnant. Withouttreatment of hypothyroidism during pregnancy, there is an increased risk for miscarriage and foetal effectssuch as mental retardation and dwarfism. In mothers with Graves’ disease, maternal thyroid stimulatinghormone receptor antibodies can be transferred to a developing foetus and can cause transient neonatal

Graves’ disease.

Alemtuzumab was detected in the milk and offspring of lactating female mice.

It is unknown whether alemtuzumab is excreted in human milk. A risk to the suckling newborn/infant cannotbe excluded. Therefore, breast-feeding should be discontinued during each course of treatment with

LEMTRADA and for 4 months following the last infusion of each treatment course. However, benefits ofconferred immunity through breast-milk may outweigh the risks of potential exposure to alemtuzumab forthe suckling newborn/infant.

There are no adequate clinical safety data on the effect of LEMTRADA on fertility. In a sub-study in 13male LEMTRADA-treated patients (treated with either 12 mg or 24 mg), there was no evidence of aspermia,azoospermia, consistently depressed sperm count, motility disorders or an increase in sperm morphologicalabnormalities.

CD52 is known to be present in human and rodent reproductive tissues. Animal data have shown effects onfertility in humanised mice (see section 5.3), however a potential impact on human fertility during the periodof exposure is unknown based on the available data.

LEMTRADA has minor influence on the ability to drive and use machines. Most patients experience IARswhich occur during or within 24 hours after treatment with LEMTRADA. Some of the IARs (e.g. dizziness)could temporarily impact the patient's ability to drive or use machines and caution should be exercised untilthese are resolved.

Summary of the safety profile in clinical studies

A total of 1,486 patients treated with LEMTRADA (12 mg or 24 mg) constituted the safety population in apooled analysis of MS clinical studies with a median follow-up of 6.1 years (maximum 12 years), resultingin 8,635 patient-years of safety follow-up.

The most important adverse reactions are autoimmunity (ITP, thyroid disorders, nephropathies, cytopenias),

IARs, and infections. These are described in section 4.4.

The most common adverse reactions with LEMTRADA (in ≥20% of patients) were rash, headache, pyrexia,and respiratory tract infections.

The table below is based on the pooled safety data on all LEMTRADA 12 mg-treated patients during allavailable follow up in clinical trials. Adverse reactions are listed by Medical Dictionary for Regulatory

Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT). Frequencies are definedaccording to the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimatedfrom the available data). Within each frequency grouping, adverse reactions have been presented in order ofdecreasing seriousness.

Table 1: Adverse reactions in study 1, 2, 3 and 4 observed in LEMTRADA 12 mg treated patients andpost-marketing surveillance

System Organ Very Common Common Uncommon Rare Not known

Class

Infections and Upper respiratory Herpes zoster Onychomycosis, Listeriosis/linfestations tract infection, infections2, lower gingivitis, fungal isteriaurinary tract respiratory tract skin infection, meningitis,infection, herpes infections, tonsillitis, acute Epstein-virus infection,1 gastroenteritis, sinusitis, Barr virusoral candidiasis, cellulitis, (EBV)vulvovaginal tuberculosis, infectioncandidiasis, cytomegalovirus (includinginfluenza, ear infection reactivationinfection, )pneumonia,vaginal infection,tooth infection

Neoplasms Skin papillomabenign,malignant andunspecified (incl.

cysts and polyps)

Blood and Lymphopenia, Lymphadenopath Pancytopenia, Haemophagocyticlymphatic system leukopenia, y, immune haemolytic lymphohistiocytosisdisorders including thrombocytopeni anaemia, (HLH), thromboticneutropenia c purpura, acquired thrombocytopenicthrombocytopeni haemophilia A purpura (TTP)a, anaemiahaematocritdecreased,leukocytosis

Immune system Cytokine release Sarcoidosisdisorders syndrome*,hypersensitivityincludinganaphylaxis*

Endocrine Basedow’s Autoimmunedisorders disease, thyroiditishyperthyrodisim, includinghypothyroidism thyroiditissubacute, goitre,anti-thyroidantibody positive

Metabolism and Decreasednutrition appetitedisorders

Psychiatric Insomnia*,disorders anxiety,depression

Nervous system Headache* MS relapse, Sensory Haemorrhadisorders dizziness*, disturbance, gichypoaesthesia, hyperaesthesia, stroke**,paraesthesia, tension headache, cervicoceph

System Organ Very Common Common Uncommon Rare Not known

Class

Infections and Upper respiratory Herpes zoster Onychomycosis, Listeriosis/linfestations tract infection, infections2, lower gingivitis, fungal isteriaurinary tract respiratory tract skin infection, meningitis,infection, herpes infections, tonsillitis, acute Epstein-virus infection,1 gastroenteritis, sinusitis, Barr virusoral candidiasis, cellulitis, (EBV)vulvovaginal tuberculosis, infectioncandidiasis, cytomegalovirus (includinginfluenza, ear infection reactivationinfection, )pneumonia,vaginal infection,tooth infectiontremor, autoimmune alic arterialdysgeusia*, encephalitis dissection*migraine* *

Eye disorders Conjunctivitis, Diplopiaendocrineophthalmopathy,vision blurred

Ear and labyrinth Vertigo Ear paindisorders

Cardiac disorders Tachycardia* Bradycardia*, Atrial Myocardialpalpitations* fibrillation* ischaemia*

*,myocardialinfarction**

Vascular Flushing* Hypotension*,disorders hypertension*

Respiratory, Dyspnoea*, Throat Pulmonarythoracic and cough, epistaxis, tightness*, throat alveolarmediastinal hiccups, irritation, haemorrhagdisorders oropharyngeal pneumonitis e**pain, asthma

Gastrointestinal Nausea* Abdominal pain, Constipation,disorders vomiting, gastro-diarrhoea oesophagealdyspepsia*, reflux disease,stomatitis gingivalbleeding, drymouth,dysphagia,gastrointestinaldisorder,haematochezia

Hepatobiliary Aspartate Cholecystitis Autoimmundisorders aminotransferase including e hepatitis,increased, acalculous Hepatitisalanine cholecystitis and (associatedaminotransferase acute acalculous with EBVincrease cholecystitis infection)

System Organ Very Common Common Uncommon Rare Not known

Class

Infections and Upper respiratory Herpes zoster Onychomycosis, Listeriosis/linfestations tract infection, infections2, lower gingivitis, fungal isteriaurinary tract respiratory tract skin infection, meningitis,infection, herpes infections, tonsillitis, acute Epstein-virus infection,1 gastroenteritis, sinusitis, Barr virusoral candidiasis, cellulitis, (EBV)vulvovaginal tuberculosis, infectioncandidiasis, cytomegalovirus (includinginfluenza, ear infection reactivationinfection, )pneumonia,vaginal infection,tooth infection

Skin and Urticaria*, rash*, Erythema*, Blister, nightsubcutaneous pruritus*, ecchymosis, sweats, swellingtissue disorders generalised rash* alopecia, face, eczema,hyperhidrosis, vitiligo, alopeciaacne, skin lesion, areatadermatitis

Musculoskeletal Myalgia, muscle Musculoskeletal Adult Onsetand connective weakness, stiffness, limb Still’stissue disorders arthralgia, back discomfort Diseasepain, pain in (AOSD)extremity,muscle spasms,neck pain,musculoskeletalpain

Renal and Proteinuria, Nephrolithiasis,urinary disorders haematuria ketonuria,nephropathiesincluding anti-

GBM disease

Reproductive Menorrhagia, Cervicalsystem and breast menstruation dysplasia,disorders irregular amenorrhoea

General disorders Pyrexia*, Chestand fatigue*, chills* discomfort*,administration pain*, oedemasite conditions peripheral,asthenia,influenza-likeillness, malaise,infusion site pain

Investigations Blood creatinine Weightincreased decreased,weight increased,red blood cellcount decreased,bacterial testpositive, bloodglucoseincreased, mean

System Organ Very Common Common Uncommon Rare Not known

Class

Infections and Upper respiratory Herpes zoster Onychomycosis, Listeriosis/linfestations tract infection, infections2, lower gingivitis, fungal isteriaurinary tract respiratory tract skin infection, meningitis,infection, herpes infections, tonsillitis, acute Epstein-virus infection,1 gastroenteritis, sinusitis, Barr virusoral candidiasis, cellulitis, (EBV)vulvovaginal tuberculosis, infectioncandidiasis, cytomegalovirus (includinginfluenza, ear infection reactivationinfection, )pneumonia,vaginal infection,tooth infectioncell volumeincrease

Injury, poisoning Contusion,and procedural infusion relatedcomplications reaction1 Herpes virus infections include PTs: Oral herpes, Herpes simplex, Genital herpes, Herpes virus infection,

Genital herpes simplex, Herpes dermatitis, Ophthalmic herpes simplex, Herpes simplex serology positive.2 Herpes zoster infections include PTs: Herpes zoster, Herpes zoster cutaneous disseminated, Ophthalmicherpes zoster, Herpes ophthalmic, Herpes zoster infection neurological, Herpes zoster meningitis.

Terms marked with asterisk (*) in Table 1 include adverse reactions reported as Infusion Associated

Reactions.

Terms marked with two asterisks (**) in Table 1 include adverse reactions observed in the post marketingsetting which have occurred in the majority of cases with time to onset within 1-3 days of LEMTRADAinfusion, following any of the doses during the treatment course.

Cases of severe (including fatal) neutropenia have been reported within 2 months of LEMTRADA infusion.

Safety profile in long-term follow-up

The type of adverse reactions including seriousness and severity observed in LEMTRADA treatment groupsthrough all available follow-up including patients who received additional treatment courses were similar tothose in the active-controlled studies. The incidence of IARs was higher in course 1 than in subsequentcourses.

In patients continuing from controlled clinical studies and who did not receive any additional LEMTRADAafter the initial 2 treatment courses, the rate (events per person-year) of most adverse reactions wascomparable to or reduced in years 3-6 as compared to years 1 and 2. The rate of thyroid adverse reactionswas highest in year three and declined thereafter.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

In controlled clinical trials two MS patients accidentally received up to 60 mg LEMTRADA (i.e. total dosefor initial treatment course) in a single infusion and experienced serious reactions (headache, rash, and eitherhypotension or sinus tachycardia). Doses of LEMTRADA greater than those tested in clinical studies mayincrease the intensity and/or duration of infusion-associated adverse reactions or its immune effects.

There is no known antidote for alemtuzumab over dosage. Treatment consists of discontinuation of themedicinal product and supportive therapy.

Pharmacotherapeutic group: Immunosuppressants, Monoclonal antibodies, ATC code: L04AG06

Alemtuzumab, is a recombinant DNA-derived humanised monoclonal antibody directed against the21-28 kD cell surface glycoprotein CD52. Alemtuzumab is an IgG1 kappa antibody with human variableframework and constant regions, and complementary-determining regions from a murine (rat) monoclonalantibody. The antibody has an approximate molecular weight of 150 kD.

Alemtuzumab binds to CD52, a cell surface antigen present at high levels on T (CD3+) and B (CD19+)lymphocytes, and at lower levels on natural killer cells, monocytes, and macrophages. There is little or no

CD52 detected on neutrophils, plasma cells, or bone marrow stem cells. Alemtuzumab acts throughantibody-dependent cellular cytolysis and complement-mediated lysis following cell surface binding to Tand B lymphocytes.

The mechanism by which LEMTRADA exerts its therapeutic effects in MS is not fully elucidated. However,research suggests immunomodulatory effects through the depletion and repopulation of lymphocytes,including:

- Alterations in the number, proportions, and properties of some lymphocyte subsets post-treatment

- Increased representation of regulatory T cell subsets

- Increased representation of memory T- and B-lymphocytes

- Transient effects on components of innate immunity (i.e., neutrophils, macrophages, NK cells)

The reduction in the level of circulating B and T cells by LEMTRADA and subsequent repopulation, mayreduce the potential for relapse, which ultimately delays disease progression.

LEMTRADA depletes circulating T and B lymphocytes after each treatment course with the lowest observedvalues occurring 1 month after a course of treatment (the earliest post-treatment time point in phase 3studies). Lymphocytes repopulate over time with B-cell recovery usually completed within 6 months. CD3+and CD4+ lymphocyte counts rise more slowly towards normal, but generally do not return to baseline by12-months post-treatment. Approximately 40% of patients had total lymphocyte counts reaching the lowerlimit of normal (LLN) by 6 months after each treatment course, and approximately 80% of patients had totallymphocyte counts reaching the LLN by 12 months after each course.

Neutrophils, monocytes, eosinophils, basophils, and natural killer cells are only transiently affected by

LEMTRADA.

The safety and efficacy of alemtuzumab in MS were evaluated in 3 randomised, rater-blinded, active-comparator clinical trials and 1 uncontrolled, rater-blinded extension study in patients with RRMS.

Study design/demographics for Studies 1, 2, 3 and 4 are shown in Table 2

Table 2: Study Design and Baseline Characteristics for Studies 1, 2, 3 and 4

Study 1 Study 2 Study 3

CAMMS323 CAMMS32400507

Study name CAMMS223(CARE-MS I) (CARE-MS II)

Controlled,

Controlled, randomised, Controlled, randomised, rater and

Study design randomised, rater-rater-blinded dose-blindedblinded

Disease history Patients with active

MS, defined as at least

Patients with active MS, defined as at least 2 relapses 2 relapses within thewithin the prior 2 years. prior 2 years and 1 ormore contrast-enhancing lesions

Duration 2 years 3 years‡

Patients with inadequate response Treatment- naïve

Study population Treatment-naïve patientsto prior therapy* patients

Baseline characteristics

Mean Age (years) 33 35 32

Mean/Median Disease2.0/1.6 years 4.5/3.8 years 1.5/1.3 yearsduration

Mean duration of prior MS

None 36 months Nonetherapy (≥1 drug used)% receiving ≥2 prior MS

Not applicable 28% Not applicabletherapies

Mean EDSS score at2.0 2.7 1.9baseline

Study 4

Study name CAMMS03409

Study design Uncontrolled, rater-blinded extension study

Study population Patients who participated in CAMMS223, CAMMS323, or CAMMS32400507(see baseline characteristics above)

Duration of extension 4 years

* Defined as patients having experienced at least 1 relapse during treatment with beta interferon orglatiramer acetate after having been on therapy with medicinal product for at least 6 months.‡ Study primary endpoint was scored at 3 years. Additional follow-up provided data through a median of4.8 years (maximum 6.7).

Results for Studies 1 and 2 are shown in Table 3.

Table 3: Key Clinical and MRI Endpoints from Studies 1 and 2

Study 1 Study 2

CAMMS323 CAMMS32400507

Study name(CARE-MS I) (CARE-MS II)

LEMTRADA SC IFNB-1a LEMTRADA SC IFNB-1a12 mg (N=187) 12 mg (N=202)

Clinical endpoints (N=376) (N=426)

Relapse Rate1

Annualised Relapse rate (ARR) 0.18 0.39 0.26 0.52(95% CI) (0.13, 0.23) (0.29, 0.53) (0.21, 0.33) (0.41, 0.66)

Rate ratio (95% CI) 0.45 (0.32, 0.63) 0.51 (0.39, 0.65)

Risk reduction 54.9 49.4(p<0.0001) (p<0.0001)

Disability1(Confirmed Disability Worsening [CDW] 2

Patients with 6-month CDW 8.0% 11.1% 12.7% 21.1%(95% CI) (5.7, 11.2) (7.3, 16.7) (9.9, 16.3) (15.9, 27.7)

Hazard ratio (95% CI) 0.70 (0.40, 1.23) 0.58 (0.38, 0.87)(p=0.22) (p=0.0084)

Patients who are relapse free at Year 2 77.6% 58.7% 65.4% 46.7(95% CI) (72.9, 81.6) (51.1, 65.5) (60.6, 69.7) (39.5, 53.5)(p<0.0001) (p<0.0001)

Change from Baseline in EDSS at Year 23(95% CI) -0.14 (-0.25, - -0.14 (-0.29, -0.17 (-0.29, - 0.24 (0.07,0.02) 0.01) 0.05) 0.41)(p=0.42) (p<0.0001)

MRI Endpoints (0-2 years)

Median % change in MRI-T2 lesion volume -9.3 (-19.6, - -6.5 (-20.7, 2.5) -1.3 -1.20.2) (p=0.14)(p=0.31)

Patients with new or enlarging T2 lesions 48.5% 57.6% 46.2% 67.9%through Year 2 (p=0.035) (p<0.0001)

Patients with Gadolinium enhancing lesions 15.4% 27.0% 18.5% 34.2%through Year 2 (p=0.001) (p<0.0001)

Patients with new T1 hypointense lesions 24.0% 31.4% 19.9% 38.0%through Year 2 (p=0.055) (p<0.0001)

Median % Change in Brain Parenchymal -0.867 -1.488 -0.615 -0.810

Fraction (p<0.0001) (p=0.012)1 Co-primary endpoints: ARR & CDW. The study was declared successful if at least one of the two co-primary endpoints was met.

2 CDW was defined as an increase of at least 1 point on the expanded disability status scale (EDSS) from abaseline EDSS score ≥1.0 (1.5 point increase for patients with baseline EDSS of 0) that was sustained for6 months.

3 Estimated using a mixed model for repeated measures.

Figure 1: Time to 6 Month Confirmed Disability Worsening in Study 2

HR: 0.58p-value: 0.0084

Alemtuzumab20 SC IFNB-1a0 3 6 9 12 15 18 21 24

Follow-up month

Relapse severity

In alignment with the effect on relapse rate, supportive analyses from Study 1 (CAMMS323) showed that

LEMTRADA 12 mg/day led to significantly fewer LEMTRADA -treated patients experiencing severerelapses (61% reduction, p=0.0056) and signficantly fewer relapses that led to steroid treatment (58%reduction, p<0.0001) compared to IFNB-1a.

Supportive analyses from Study 2 (CAMMS32400507) showed that LEMTRADA 12 mg/day led tosignificantly fewer LEMTRADA -treated patients experiencing severe relapses (48% reduction, p=0.0121),and significantly fewer relapses that led to steroid treatment (56% reduction, p<0.0001) or to hospitalization(55% reduction, p=0.0045) compared to IFNB-1a.

Confirmed disability improvement (CDI)

Time to onset of CDI was defined as a decrease of at least one point on the EDSS from a baseline EDSSscore ≥ 2 that was sustained for at least 6 months. CDI is a measure for sustained disability improvement.

29% of patients treated with LEMTRADA reached CDI in Study 2, while only 13% of subcutaneous IFNB-1a treated patients reached this endpoint. The difference was statistically significant (p=0.0002).

Study 3 (phase 2 study CAMMS223) evaluated the safety and efficacy of LEMTRADA in patients with

RRMS over the course of 3 years. Patients had an EDSS from 0-3.0, at least 2 clinical episodes of MS in theprior 2 years, and ≥1 gadolinium-enhancing lesion at study entry. Patients had not received prior therapy for

MS. Patients were treated with LEMTRADA 12 mg/day (N=108) or 24 mg/day (N=108) administered onceper day for 5 days at month 0 and for 3 days at month 12 or subcutaneous IFNB-1a 44 µg (N=107)administered 3 times per week for 3 years. Forty-six patients received a third course of LEMTRADAtreatment at 12 mg/day or 24 mg/day for 3 days at month 24.

At 3 years, LEMTRADA reduced the risk of 6-month CDW by 76% (hazard ratio 0.24 [95% CI: 0.110,0.545], p<0.0006) and reduced the ARR by 67% (rate ratio 0.33 [95% CI: 0.196, 0.552], p<0.0001) ascompared to subcutaneous IFNB-1a. LEMTRADA 12 mg/day led to significantly lower EDSS scores(improved compared to baseline) through 2 years of follow up, compared with IFNB-1a (p<0.0001).

Percentage of Patients with CDW

In the subgroup of RRMS patients with 2 or more relapses in the prior year and at least 1 Gd-enhanced T1lesion at baseline, the annualised relapse rate was 0.26 (95% CI: 0.20, 0.34) in the Lemtrada treated group (n= 205) and 0.51 (95% CI: 0.40, 0.64) in the IFNB-1a group (n = 102) (p<0.0001). This analysis includes datafrom Phase 3 studies only (CAMMS324 and CAMMS323) due to differences in the MRI acquisitionalgorithms between the Phase 2 and Phase 3 studies. These results were obtained from a post hoc analysisand should be interpreted cautiously.

Long-term efficacy data

Study 4, was a Phase 3, multicenter, open-label, rater-blinded, efficacy and safety extension study forpatients with RRMS who participated in Study 1, 2, or 3 (prior phase 3 and 2 studies) to assess long-termefficacy and safety of LEMTRADA. The study provides efficacy and safety through a median of 6 yearsfrom entry into Studies 1 and 2. Patients in the extension study (Study 4) were eligible to receive additionalas-needed LEMTRADA treatment course(s) upon documentation of resumed disease activity, defined as theoccurrence of ≥1 MS relapse and/or ≥2 new or enlarging brain or spinal lesions on magnetic resonanceimaging (MRI). Additional course(s) of LEMTRADA were administered at 12 mg/day for 3 consecutivedays (36 mg total dose) at least 12 months after the prior treatment course.

91.8% of the patients treated with LEMTRADA 12 mg in Studies 1 and 2 entered Study 4. 82.7% of thesepatients completed the study. Approximately half (51.2%) of patients initially treated with LEMTRADA12 mg/day in Study 1 or 2 who enrolled in Study 4, received only the initial 2 courses of LEMTRADA andno other disease modifying treatment throughout 6 years of follow-up.

46.6% of the patients initially treated with LEMTRADA 12 mg/day in Study 1 or 2 received additionalcourses upon documented evidence of MS disease activity (relapse and/or MRI) and the treating physician’sdecision to retreat. No characteristics at study entry identified patients who would later receive one or moreadditional courses.

Through 6 years from initial LEMTRADA treatment, patients continuing in follow-up showed rates of MSrelapse, brain lesion formation on MRI, and brain volume loss consistent with LEMTRADA’s treatmenteffects during Studies 1 and 2 as well as predominantly stable or improved disability scores. Includingfollow-up in Study 4, patients originally treated with LEMTRADA in Studies 1 and 2, respectively, had

ARRs 0.17 and 0.23, CDW was seen in 22.3% and 29.7%, while 32.7% and 42.5% achieved CDI. In eachyear of Study 4, patients from both studies continued to show a low risk of forming new T2 (27.4% to33.2%) or gadolinium-enhancing lesions (9.4% to 13.5%), and the median annual percent change in brainparenchymal fraction ranged from 0.19% to -0.09%.

Among patients who received one or two additional LEMTRADA treatment courses, improvements wereseen in relapse rate, MRI activity and mean disability scores following a first or second LEMTRADAretreatment (Courses 3 and 4) when compared with outcomes in the preceding year. For these patients, the

ARR declined from 0.79 in the year prior to Course 3 to 0.18 one year after, and the mean EDSS score from2.89 to 2.69. The percentage of patients with new or enlarging T2 lesions declined from 50.8% the year priorto Course 3 to 35.9% one year after, and new gadolinium-enhancing lesions from 32.2% to 11.9%. Similarimprovements in ARR, mean EDSS score, and T2 and gadolinium-enhancing lesions were seen after Course4 when compared with the prior year. These improvements were subsequently maintained, but no firmconclusions can be made with regards to the longer-term efficacy (e.g. 3 and 4 years after additionaltreatment courses) because many patients completed the study before reaching these time points.

The benefits and risks of 5 or more treatment courses have not been established.

As with all therapeutic proteins, there is potential for immunogenicity. Data reflect the percentage of patientswhose test results were considered positive for antibodies to alemtuzumab using an enzyme-linkedimmunosorbent assay (ELISA) and confirmed by a competitive binding assay. Positive samples were furtherevaluated for evidence of in vitro inhibition using a flow cytometry assay. Patients in clinical trials in MShad serum samples collected 1, 3, and 12 months after each treatment course for determination of anti-alemtuzumab antibodies. Approximately 85% of patients receiving LEMTRADA tested positive for anti-alemtuzumab antibodies during the study, with ≥90% of these patients testing positive also for antibodiesthat inhibited alemtuzumab binding in vitro. Patients who developed anti-alemtuzumab antibodies did so by15 months from initial exposure. Through 2 treatment courses, there was no association of the presence ofanti-alemtuzumab or inhibitory anti-alemtuzumab antibodies with a reduction in efficacy, change inpharmacodynamics, or the occurrence of adverse reactions, including infusion associated reactions. Hightiter anti-alemtuzumab antibodies observed in some patients were associated with incomplete lymphocytedepletion following a third or fourth treatment course, but there was no clear impact of anti-alemtuzumabantibodies on the clinical efficacy or safety profile of LEMTRADA.

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 influencedby several factors including assay methodology, sample handling, timing of sample collection, concomitantmedicines, 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.

The European Medicines Agency has waived the obligation to submit the results of studies withalemtuzumab in children from birth to less than 10 years in treatment of multiple sclerosis (see section 4.2for information on paediatric use).

The European Medicines Agency has deferred the obligation to submit the results of studies with

LEMTRADA in one or more subsets of the paediatric population in RRMS (see section 4.2 for informationon paediatric use).

The pharmacokinetics of alemtuzumab were evaluated in a total of 216 patients with RRMS who receivedintravenous infusions of either 12 mg/day or 24 mg/day on 5 consecutive days, followed by 3 consecutivedays 12 months following the initial treatment course. Serum concentrations increased with each consecutivedose within a treatment course, with the highest observed concentrations occurring following the lastinfusion of a treatment course. Administration of 12 mg/day resulted in a mean Cmax of 3014 ng/ml on day 5of the initial treatment course, and 2276 ng/ml on day 3 of the second treatment course. The alpha half-lifeapproximated 4-5 days and was comparable between courses leading to low or undetectable serumconcentrations within approximately 30 days following each treatment course.

Alemtuzumab is a protein for which the expected metabolic pathway is degradation to small peptides andindividual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies havenot been conducted.

Conclusions cannot be made with available data on the effect of race and gender on the pharmacokinetics ofalemtuzumab. The pharmacokinetics of alemtuzumab in RRMS has not been studied in patients aged 55years and older.

Carcinogenesis and mutagenesis

There have been no studies to assess the carcinogenic or mutagenic potential of alemtuzumab.

Fertility and reproduction

Treatment with intravenous alemtuzumab at doses up to 10 mg/kg/day, administered for 5 consecutive days(AUC of 7.1 times the human exposure at the recommended daily dose) had no effect on fertility andreproductive performance in male huCD52 transgenic mice. The number of normal sperm was significantlyreduced (<10%) relative to controls and the percent abnormal sperm (detached heads or no heads) weresignificantly increased (up to 3%). However, these changes did not affect fertility and were thereforeconsidered to be non-adverse.

In female mice dosed with intravenous alemtuzumab up to 10 mg/kg/day (AUC of 4.7 times the humanexposure at the recommended daily dose) for 5 consecutive days prior to cohabitation with wild-type malemice, the average number of corpora lutea and implantation sites per mouse were significantly reduced ascompared to vehicle treated animals. Reduced gestational weight gain relative to the vehicle controls wasobserved in pregnant mice dosed with 10 mg/kg/day.

A reproductive toxicity study in pregnant mice exposed to intravenous doses of alemtuzumab up to10 mg/kg/day (AUC 2.4 times the human exposure at the recommended dose of 12 mg/day) for5 consecutive days during gestation resulted in significant increases in the number of dams with allconceptuses dead or resorbed, along with a concomitant reduction in the number of dams with viablefoetuses. There were no external, soft tissue, or skeletal malformations or variations observed at doses up to10 mg/kg/day.

Placental transfer and potential pharmacologic activity of alemtuzumab were observed during gestation andfollowing delivery in mice. In studies in mice, alterations in lymphocyte counts were observed in pupsexposed to alemtuzumab during gestation at doses of 3 mg/kg/day for 5 consecutive days (AUC 0.6 times thehuman exposure at the recommended dose of 12 mg/day). Cognitive, physical, and sexual development ofpups exposed to alemtuzumab during lactation were not affected at doses up to 10 mg/kg/day alemtuzumab.

Disodium phosphate dihydrate (E339)

Disodium edetate dihydrate

Potassium chloride (E508)

Potassium dihydrogen phosphate (E340)

Polysorbate 80 (E433)

Sodium chloride

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts except those mentioned in section 6.6.

Concentrate4 years

Chemical and physical in-use stability has been demonstrated for 8 hours at 2°C - 8°C.

From a microbiological point of view, it is recommended that the product should be used immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the user andshould not be longer than 8 hours at 2°C - 8°C, under protection from light.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

LEMTRADA is supplied in a clear, 2 ml glass vial, with a butyl rubber stopper and aluminium seal with aplastic flip-off cap.

Pack size: carton with 1 vial.

The vial contents should be inspected for particulate matter and discoloration prior to administration. Do notuse if particulate matter is present or the concentrate is discoloured.

Do not shake the vials prior to use.

For intravenous administration, withdraw 1.2 ml of LEMTRADA from the vial into a syringe using aseptictechnique. Inject into 100 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose (5%)solution for infusion. This medicinal product must not be diluted with other solvents. The bag should beinverted gently to mix the solution.

Care should be taken to ensure the sterility of the prepared solution. It is recommended that the dilutedproduct be administered immediately. Each vial is intended for single use only.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Sanofi Belgium

Leonardo Da Vincilaan 19

B-1831 Diegem

Belgium

EU/1/13/869/001

Date of first authorisation: 12 September 2013

Date of latest renewal: 2 July 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.