1. Name of the medicinal product
LEMTRADA 12mg concentrate for solution for infusion
2. Qualitative and quantitative composition
Each vial contains 12mg alemtuzumab in 1.2ml (10mg/ml).
Alemtuzumab is a monoclonal antibody produced in mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium by recombinant DNA technology.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Concentrate for solution for infusion (sterile concentrate).
A clear, colourless to slightly yellow concentrate with pH 7.0 - 7.4.
4. Clinical particulars
4.1 Therapeutic indications
LEMTRADA is indicated for adult patients with relapsing remitting multiple sclerosis (RRMS) with active disease defined by clinical or imaging features (see sections 4.4 and 5.1).
4.2 Posology and method of administration
LEMTRADA treatment should be initiated and supervised by a neurologist experienced in the treatment of patients with MS. Specialists and equipment required for the timely diagnosis and management of the most frequent adverse reactions, especially autoimmune conditions and infections, should be available.
Resources for the management of hypersensitivity and/or anaphylactic reactions should be available.
Patients treated with LEMTRADA must be given the Patient Alert Card and Patient Guide and be informed about the risks of LEMTRADA (see also package leaflet).
Posology
The recommended dose of LEMTRADA is 12 mg/day administered by intravenous infusion for 2 treatment courses.
• Initial treatment course: 12 mg/day for 5 consecutive days (60 mg total dose)
• Second treatment course: 12 mg/day for 3 consecutive days (36 mg total dose) administered 12 months after the initial treatment course.
Missed doses should not be given on the same day as a scheduled dose.
Follow-up of patients
The therapy is recommended as 2 treatment courses (see posology) with safety follow-up of patients from initiation of treatment and until 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 each of the first 3 days of any treatment course. In clinical trials, patients were pre-treated with 1,000 mg methylprednisolone for the first 3 days of each LEMTRADA treatment course.
Additionally, pretreatment with antihistamines and/or antipyretics prior to LEMTRADA administration may also be considered.
Oral prophylaxis for herpes infection should be administered to all patients starting on the first day of each treatment course and continuing for a minimum of 1 month following treatment with LEMTRADA (see also under 'Infections' in section 4.4). In clinical trials, patients were administered aciclovir 200 mg twice a day or equivalent.
Elderly
Clinical studies did not include any patients aged over 55 years old. It has not been determined whether they respond differently than younger patients.
Renal or hepatic impairment
LEMTRADA has not been studied in patients with renal or hepatic impairment.
Paediatric population
The safety and efficacy of LEMTRADA in children with MS aged 0 to 18 years have not yet been established. There is no relevant use of alemtuzumab in children aged from birth to less than 10 years for the treatment of multiple sclerosis. No data are available.
Method of administration
LEMTRADA must be diluted before infusion. The diluted solution should be administered by intravenous infusion over a period of approximately 4 hours.
For instructions on dilution of the medicinal product before administration, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1.
Human Immunodeficiency Virus (HIV) infection.
4.4 Special warnings and precautions for use
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 to 48-months of follow-up after the last infusion of LEMTRADA.
Autoimmunity
Treatment may result in the formation of autoantibodies and increase the risk of autoimmune mediated conditions including immune thrombocytopenic purpura (ITP), thyroid disorders or, rarely, nephropathies (e.g. anti-glomerular basement membrane disease). Caution should be exercised in patients with previous autoimmune conditions other than MS, although available data suggests there is no worsening of pre-existing autoimmune conditions after alemtuzumab treatment.
Immune Thrombocytopenic Purpura (ITP)
Serious events of ITP have been observed in approximately 1% of patients treated in controlled clinical trials in MS. In a controlled clinical trial in patients with MS, one patient developed ITP that went unrecognised prior to implementation of monthly blood monitoring requirements and died from intracerebral haemorrhage. ITP onset has generally occurred between 14 and 36 months after first exposure. Symptoms of ITP could include (but are not limited to) easy bruising, petechiae, spontaneous mucocutaneous bleeding (e.g., epistaxis, haemoptysis), heavier than normal or irregular menstrual bleeding. Haemoptysis may also be indicative of anti-GBM disease (see below), and an appropriate differential diagnosis has to be undertaken. Remind the patient to remain vigilant for symptoms they 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 monthly intervals thereafter until 48 months after the last infusion. After this period of time, testing should be performed based on clinical findings suggestive of ITP. If ITP is suspected a complete blood count should be obtained immediately.
If ITP onset is confirmed, appropriate medical intervention should be promptly initiated, including immediate referral to a specialist. Data from clinical trials in MS has shown that adherence to the blood monitoring requirements and education relative to signs and symptoms of ITP has led to early detection and treatment of ITP with most cases responding to first-line medical therapy.
The potential risk associated with retreatment with LEMTRADA following the occurrence of ITP is unknown.
Nephropathies
Nephropathies, including anti-glomerular basement membrane (anti-GBM) disease, have been observed in 0.3% of patients in clinical trials in MS and 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 and laboratory monitoring, and had a positive outcome after treatment.
Clinical manifestations of nephropathy may include elevation in serum creatinine, haematuria, and/or proteinuria. While not observed in clinical trials, alveolar haemorrhage manifested as haemoptysis may occur with anti-GBM disease. Haemoptysis may also be indicative of ITP (see above), and an appropriate differential diagnosis has to be undertaken. The patient should be reminded to remain vigilant 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 rapidly and can be life-threatening if left untreated.
Serum creatinine levels should be obtained prior to initiation of treatment and at monthly intervals thereafter until 48 months after the last infusion. Urinalysis with microscopy should be obtained prior to initiation and at monthly intervals thereafter until 48 months after the last infusion. The observation of clinically significant changes from baseline in serum creatinine, unexplained haematuria, and/or proteinuria, should prompt further eva luation for nephropathies including immediate referral to a specialist. Early detection and treatment of nephropathies may decrease the risk of poor outcomes. After this period of time, testing should be performed based on clinical findings suggestive of nephropathies.
The potential risk associated with retreatment with LEMTRADA following the occurrence of nephropathies is unknown.
Thyroid disorders
Autoimmune thyroid disorders have been observed in an estimated 36% of patients treated with LEMTRADA 12 mg in clinical trials in MS through 48 months following first LEMTRADA exposure. The incidence of thyroid events was higher in patients with a medical history of thyroid disorders both in the LEMTRADA and interferon beta 1a (IFNB-1a) treatment groups. In patients with ongoing thyroid disorder LEMTRADA should be administered if the potential benefit justifies the potential risks. Observed autoimmune thyroid disorders included hyperthyroidism or hypothyroidism. Most events were mild to moderate in severity. Prior to authorisation, serious events occurred in <1% of patients, with only Basedow's disease (also known as Graves' disease), hyperthyroidism, and hypothyroidism occurring in more than 1 patient. Most thyroid events were managed with conventional medical therapy however some patients required surgical intervention. In clinical trials, patients who developed thyroid events were permitted to receive re-treatment with LEMTRADA. Although experience is limited, patients who were re-treated generally did not experience a worsening in severity of thyroid disorders. Further treatment with LEMTRADA should be considered on an individual basis taking into account the clinical condition of the respective patient.
Thyroid function tests, such as thyroid stimulating hormone levels, should be obtained prior to initiation of treatment and every 3 months thereafter until 48 months following the last infusion. After this period of time testing should be performed based on clinical findings suggestive of thyroid dysfunction.
Thyroid disease poses special risks in women who are pregnant (see section 4.6).
In clinical trials, a patient's anti-thyroid peroxidase (anti-TPO) antibody status prior to treatment was not indicative for the development of a thyroid related adverse event. Half the patients who tested positive at baseline, and a quarter of patients who tested negative at baseline for anti-TPO antibodies developed a thyroid event. The vast majority (approximately 80%) of patients who presented with a thyroid event after treatment were anti-TPO antibody negative at baseline. Therefore, regardless of pretreatment anti-TPO antibody status patients may develop a thyroid adverse reaction and must have all tests periodically performed as described above.
Cytopenias
Suspected autoimmune cytopenias such as neutropenia, haemolytic anaemia and pancytopenia have been infrequently reported in clinical trials in MS. Complete blood count results (see above under ITP) should be used to monitor for cytopenias. If a cytopenia is confirmed, appropriate medical intervention should be promptly initiated, including referral to a specialist.
Infusion-associated Reactions (IARs)
In controlled clinical trials, infusion associated reactions (IARs) were defined as any adverse event occurring during or within 24 hours of LEMTRADA infusion. The majority of these may be due to cytokine release during infusion. Most patients treated with LEMTRADA in controlled clinical trials in MS experienced mild to moderate IARs during and/or up to 24 hours after LEMTRADA 12 mg administration, which often included headache, rash, pyrexia, nausea, urticaria, pruritus, insomnia, chills, flushing, fatigue, dyspnoea, dysgeusia, chest discomfort, generalised rash, tachycardia, dyspepsia, dizziness, and pain. Serious reactions occurred in 3% of patients including cases of pyrexia, urticaria, atrial fibrillation, nausea, chest discomfort, and hypotension. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of infusion associated reactions, but would tend to be more severe or potentially life-threatening. Reactions attributed to anaphylaxis 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 section 4.2). 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 reactions is recommended during and for 2 hours after LEMTRADA infusion. If an IAR occurs, provide the appropriate symptomatic treatment, as needed. If the infusion is not well tolerated, the infusion duration may be extended. If severe infusion reactions occur, immediate discontinuation of the intravenous infusion should be considered. Within the clinical trials, anaphylaxis or serious reactions that necessitated treatment discontinuation were very rare.
Physicians should be aware of the patient's cardiac history as infusion-associated reactions can include cardiac symptoms such as tachycardia.
Resources for the management of anaphylaxis or serious reactions should be available.
Infections
Infections occurred in 71% of patients treated with LEMTRADA 12 mg as compared to 53% of patients treated 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 occurred more often in LEMTRADA -treated patients than IFNB 1a patients included nasopharyngitis, urinary tract infection, upper respiratory tract infection, sinusitis, oral herpes, influenza, and bronchitis. Serious infections occurred in 2.7% of patients treated with LEMTRADA as compared to 1% of patients treated with IFNB-1a in 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 duration and resolved following conventional medical treatment.
Serious varicella zoster virus infections, including primary varicella and varicella zoster re-activation, have occurred more often in patients treated with LEMTRADA 12 mg (0.3%) in clinical trials as compared to IFNB-1a (0%). Cervical human papilloma virus (HPV) infection, including cervical dysplasia, has also been reported in patients treated with LEMTRADA 12 mg (2%). It is recommended that HPV screening be completed annually for female patients.
Tuberculosis has been reported for patients treated with LEMTRADA and IFNB-1a in controlled clinical trials. Active and latent tuberculosis have been reported in 0.3% of the patients treated with LEMTRADA, most often in endemic regions. Before initiation of therapy, all patients must be eva luated for both active or inactive (“latent”) tuberculosis infection, according to local guidelines.
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 trials in MS.
Physicians should consider delaying initiation of LEMTRADA administration in patients with active infection until the infection is fully controlled.
Prophylaxis with an oral anti-herpes agent should be initiated starting on the first day of LEMTRADA treatment and continuing for a minimum of 1 month following each course of treatment. In clinical trials patients were administered aciclovir 200 mg twice a day or equivalent.
LEMTRADA has not been administered for treatment of MS concomitantly with or following antineoplastic or immunosuppressive therapies. As with other immunomodulating therapies, potential combined effects on the 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 clinical trials. Screening patients at high risk of HBV and/or HCV infection before initiation of LEMTRADA should be considered and caution should be exercised in prescribing LEMTRADA to patients identified as carriers of HBV and/or HCV as these patients may be at risk of irreversible liver damage relative to a potential virus reactivation as a consequence of their pre-existing status.
Malignancy
As with other immunomodulatory therapies, caution should be exercised in initiating LEMTRADA therapy in patients with pre-existing and/or an on-going malignancy. It is not currently known if alemtuzumab confers a higher risk for developing thyroid malignancies, since thyroid autoimmunity may itself be a risk factor for thyroid malignancies.
Contraception
Placental transfer and potential pharmacologic activity of LEMTRADA were observed in mice during gestation and following delivery. Women of childbearing potential should use effective contraceptive measures 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 to treatment 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 not been formally studied in controlled clinical trials in MS and should not be administered to MS patients who have 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) should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients should be considered prior to 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
Laboratory tests should be conducted at periodic intervals for 48 months following the last treatment course of LEMTRADA in order to monitor for early signs of autoimmune disease:
• Complete blood count 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 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 and every 3 months thereafter)
After this period of time, any clinical findings suggestive of nephropathies or thyroid dysfunction will require further testing.
Information from use of alemtuzumab prior to the marketing authorisation of LEMTRADA outside of company-sponsored studies
The following adverse reactions were identified prior to registration of LEMTRADA during use of alemtuzumab for the treatment of B-cell chronic lymphocytic leukaemia (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 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 and sometimes fatal autoimmune phenomena including autoimmune haemolytic anaemia, autoimmune thrombocytopenia, aplastic anaemia, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyradiculoneuropathy have been reported in alemtuzumab-treated non-MS patients. A positive Coombs test has been reported in an alemtuzumab-treated oncology patient. A fatal event of transfusion associated graft versus host disease has been reported in an alemtuzumab-treated oncology patient.
Infusion-associated reactions
Serious and sometimes fatal IARs including bronchospasm, hypoxia, syncope, pulmonary infiltrates, acute respiratory distress syndrome , respiratory arrest, myocardial infarction, arrhythmias, acute cardiac insufficiency, and cardiac arrest have been observed in non-MS patients treated with alemtuzumab at higher and more frequent doses than used in MS. Severe anaphylaxis and other hypersensitivity reactions, including anaphylactic shock and angioedema have also been reported.
Infections and infestations
Serious and sometimes fatal viral, bacterial, protozoan, and fungal infections, including those due to reactivation of latent infections, have been reported in non-MS patients treated with alemtuzumab at higher and more frequent doses than used in MS. Progressive multifocal leukoencephalopathy (PML) has been reported in patients with B-CLL with or without treatment with alemtuzumab. The frequency of PML in B-CLL patients treated with alemtuzumab is no greater than the background frequency.
Blood and lymphatic system disorders
Severe bleeding reactions have been reported in non-MS patients.
Cardiac disorders
Congestive heart failure, cardiomyopathy, and decreased ejection fraction have been reported in alemtuzumab-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-sponsored studies.
4.5 Interaction with other medicinal products and other forms of interaction
No formal drug interaction studies have been conducted with LEMTRADA using the recommended dose in patients with MS. In a controlled clinical trial in MS patients recently treated with beta interferon and glatiramer acetate were required to discontinue treatment 28 days before initiating treatment with LEMTRADA.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Serum concentrations were low or undetectable within approximately 30 days following each treatment course. Therefore, women of child bearing potential should use effective contraceptive measures when receiving a course of treatment with LEMTRADA and for 4 months following that course of treatment.
Pregnancy
There is a limited amount of data from the use of LEMTRADA in pregnant women. LEMTRADA should be administered 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 and thus 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 or whether it can affect reproductive capacity.
Thyroid disease (see section 4.4 Thyroid Disorders) poses special risks in women who are pregnant. Without treatment of hypothyroidism during pregnancy, there is an increased risk for miscarriage and foetal effects such as mental retardation and dwarfism. In mothers with Graves' disease, maternal thyroid stimulating hormone receptor antibodies can be transferred to a developing foetus and can cause transient neonatal Graves' disease.
Breast-feeding
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 breastfed child cannot be 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 of conferred immunity through breast-milk may outweigh the risks of potential exposure to alemtuzumab for the breastfed child.
Fertility
There are no adequate clinical safety data on the effect of LEMTRADA on fertility. In a sub-study in 13 male alemtuzumab-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 morphological abnormalities.
CD52 is known to be present in human and rodent reproductive tissues. Animal data have shown effects on fertility in humanised mice (see section 5.3), however a potential impact on human fertility during the period of exposure is unknown based on the available data.
4.7 Effects on ability to drive and use machines
No studies on the effects of LEMTRADA on the ability to drive and use machines have been performed.
Most patients experience IARs which 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 until these are resolved.
4.8 Undesirable effects
Summary of the safety profile
A total of 1,188 patients with relapsing remitting MS (RRMS) treated with LEMTRADA (12 mg or 24 mg) constituted the safety population in a pooled analysis of controlled clinical studies resulting in 2,363 patient-years of safety follow-up and a median follow-up of 24 months.
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) are rash, headache, pyrexia, and respiratory tract infections.
Tabulated list of adverse reactions
The table below is based on the pooled safety data up to 24 months from RRMS patients treated with LEMTRADA 12 mg/day for 5 consecutive days at study entry and for 3 consecutive days at Study Month 12. Adverse reactions occurring in ≥0.5% of patients are listed by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT). Frequencies are defined according to the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100).Within each frequency grouping, adverse reactions have been presented in order of decreasing seriousness.
Table 1: Adverse reactions in study 1, 2, and 3 observed in ≥0.5% of LEMTRADA 12 mg treated patients
 

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 severe relapses (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 to significantly 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.
Sustained reduction of disability (SRD)
Time to onset of SRD was defined as a decrease of at least one point on the EDSS from a baseline EDSS score ≥ 2 that was sustained for at least 6 months. SRD is a measure for sustained disability improvement. 29% of patients treated with LEMTRADA reached SRD in study 2, while only 13% of subcutaneous IFNB-1a treated patiets reached this endpoint. The difference was statistically significant (p=0.0002).
Study 3 (phase 2 study CAMMS223) eva luated the safety and efficacy of LEMTRADA in patients with RRMS over the course of 5 years. Patients had an EDSS from 0-3.0, at least 2 clinical episodes of MS in the prior 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 once per 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 LEMTRADA treatment at 12 mg/day or 24/mg day for 3 days at Month 24.
At 3 years, LEMTRADA reduced the risk of 6-month SAD 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) as compared to subcutaneous IFNB-1a. Alemtuzumab 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).
At 5 years, LEMTRADA reduced the risk of SAD by 69% (hazard ratio 0.31 [95% CI: 0.161, 0.598], p=0.0005) and reduced the ARR by 66% (rate ratio 0.34 [95% CI: 0.202, 0.569], p<0.0001) as compared to subcutaneous IFNB-1a.
In open-label follow-up of LEMTRADA clinical trials, some patients received additional “as needed” treatment with LEMTRADA upon documented evidence of resumed MS disease activity. The additional course(s) of LEMTRADA were administered at 12 mg/day for 3 consecutive days (36 mg total dose) at least 12 months after the prior treatment course. The benefits and risks of >2 treatment courses have not been fully established, but results suggest that the safety profile does not appear to change with additional courses. If additional treatment courses are to be given they must be administered at least 12 months after the prior course.
Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. Data reflect the percentage of patients whose test results were considered positive for antibodies to alemtuzumab using an enzyme-linked immunosorbent assay (ELISA) and confirmed by a competitive binding assay. Positive samples were further eva luated for evidence of in vitro inhibition using a flow cytometry assay. Patients in controlled clinical trials in MS had 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 92% of these patients testing positive also for antibodies that inhibited LEMTRADA binding in vitro. Patients who developed anti-alemtuzumab antibodies did so by 15 months from initial exposure. There was no association of the presence of anti-alemtuzumab or inhibitory anti-alemtuzumab antibodies with a reduction in efficacy, change in pharmacodynamics, or the occurrence of adverse reactions, including infusion associated reactions.
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.
Paediatric population.
The European Medicines Agency has waived the obligation to submit the results of studies with alemtuzumab in children from birth to less than 10 years in treatment of multiple sclerosis (see section 4.2 for 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 information on paediatric use).
5.2 Pharmacokinetic properties
The pharmacokinetics of LEMTRADA were eva luated in a total of 216 patients with RRMS who received intravenous infusions of either 12 mg/day or 24 mg/day for 5 consecutive days, followed by 3 consecutive days 12 months following the initial treatment course. 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. Administration of 12 mg/day resulted in a mean Cmax of 3014 ng/ml on Day 5 of the initial treatment course, and 2276 ng/ml on Day 3 of the second treatment course. The alpha half-life approximated 4-5 days and was comparable between courses leading to low or undetectable serum concentrations within approximately 30 days following each treatment course.
Alemtuzumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies have not been conducted.
Conclusions cannot be made with available data on the effect of race and gender on the pharmacokinetics of LEMTRADA. The pharmacokinetics of LEMTRADA has not been studied in patients aged 55 years and older.
5.3 Preclinical safety data
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 and reproductive performance in male huCD52 transgenic mice. The number of normal sperm was significantly reduced (<10%) relative to controls and the percent abnormal sperm (detached heads or no heads) were significantly increased (up to 3%). However, these changes did not affect fertility and were therefore considered to be non-adverse.
In female mice dosed with intravenous alemtuzumab up to 10 mg/kg/day (AUC of 4.7 times the human exposure at the recommended daily dose) for 5 consecutive days prior to cohabitation with wild-type male mice, the average number of corpora lutea and implantation sites per mouse were significantly reduced as compared to vehicle treated animals. Reduced gestational weight gain relative to the vehicle controls was observed in pregnant mice dosed with 10 mg/kg/day.
A reproductive toxicity study in pregnant mice exposed to intravenous doses of alemtuzumab up to 10 mg/kg/day (AUC 2.4 times the human exposure at the recommended dose of 12 mg/day) for 5 consecutive days during gestation resulted in significant increases in the number of dams with all conceptuses dead or resorbed, along with a concomitant reduction in the number of dams with viable foetuses. There were no external, soft tissue, or skeletal malformations or variations observed at doses up to 10 mg/kg/day.
Placental transfer and potential pharmacologic activity of alemtuzumab were observed during gestation and following delivery in mice. In studies in mice, alterations in lymphocyte counts were observed in pups exposed to alemtuzumab during gestation at doses of 3 mg/kg/day for 5 consecutive days (AUC 0.6 times the human exposure at the recommended dose of 12 mg/day). Cognitive, physical, and sexual development of pups exposed to alemtuzumab during lactation were not affected at doses up to 10 mg/kg/day alemtuzumab.
6. Pharmaceutical particulars
6.1 List of excipients
Disodium phosphate dihydrate (E339)
Disodium edetate dihydrate
Potassium chloride (E508)
Potassium dihydrogen phosphate (E340)
Polysorbate 80 (E433)
Sodium chloride
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Concentrate
3 years
Diluted solution
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 not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 8 hours at 2°C - 8°C, under protection from light.
6.4 Special precautions for storage
Concentrate
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.
6.5 Nature and contents of container
LEMTRADA is supplied in a clear, 2 ml glass vial, with a butyl rubber stopper and aluminium seal with a plastic flip-off cap.
Pack size: carton with 1 vial.
6.6 Special precautions for disposal and other handling
The vial contents should be inspected for particulate matter and discoloration prior to administration. Do not use 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 aseptic technique. 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 be inverted gently to mix the solution.
LEMTRADA contains no antimicrobial preservatives and, therefore, care should be taken to ensure the sterility of the prepared solution. It is recommended that the diluted product 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 local requirements.
7. Marketing authorisation holder
Genzyme Therapeutics Ltd
4620 Kingsgate
Cascade Way
Oxford Business Park South
Oxford
OX4 2SU
United Kingdom
8. Marketing authorisation number(s)
EU/1/13/869/001
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 12 September 2013
10. Date of revision of the text
12/2013
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.