Lemtrada 12 mg/1.2 mL Concentrate for solution for infusion

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

• Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy (DMT), or
• Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.

Posology

The recommended dose of LEMTRADA is 12 mg/day administered by intravenous (IV) infusion for 2 or more treatment courses.

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 months after the first treatment course.

Additional as needed treatment courses:

• 12 mg/day on 3 consecutive days (36 mg total dose) administered at least 12 months after the prior treatment course.

Missed doses should not be given on the same day as a scheduled dose. Administer LEMTRADA in a setting in which equipment and personnel are available to appropriately manage anaphylaxis, serious infusion reactions, myocardial ischaemia, myocardial infarction and cerebrovascular adverse reactions.

Pre-treatment

Patients should be premedicated with corticosteroids immediately prior to LEMTRADA administration for 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. Pre-treatment 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.

Special populations

Elderly population

Clinical studies of LEMTRADA did not include sufficient numbers of patients aged over 65 years old to determine 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 paediatric MS patients below the age of 18 years have not been established.

Method of administration

Route of administration: intravenous (IV) infusion. LEMTRADA must be diluted before infusion. The diluted solution should be administered by IV infusion over a period of approximately 4 hours. For instructions on the dilution of LEMTRADA before administration, see section 6.6.

Special handling conditions

LEMTRADA vials should be inspected for particulate matter and discolouration prior to administration. Do not use if particulate matter is present or the solution is discoloured. Do not freeze or shake vials prior to use. Protect from light.

LEMTRADA is contraindicated in:

• Patients with known Type 1 hypersensitivity or anaphylactic reactions to alemtuzumab or any of the ingredients of the formulation (see section 6.1).
• Patients who are infected with human immunodeficiency virus (HIV).
• Patients with severe active infection.
• 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 or on concomitant anti-coagulant therapy.

Before treatment, patients must receive educational information and be informed about the risks and benefits, and the need to commit to follow up from treatment initiation until 48 months after the last infusion of the second LEMTRADA treatment course. If an additional course is administered, continue safety follow-up until 48 months after the last infusion. Remind the patient to remain vigilant for symptoms they may experience and to seek immediate medical help if they have any concerns.

Autoimmunity

Treatment with LEMTRADA may result in the formation of autoantibodies and increase the risk of autoimmune-mediated conditions, which may be serious and life-threatening. Reported autoimmune conditions include thyroid disorders, immune thrombocytopenic purpura (ITP), or, rarely, nephropathies (e.g. anti-glomerular basement membrane disease), autoimmune hepatitis (AIH), acquired haemophilia A, thrombotic thrombocytopenic purpura (TTP) and autoimmune encephalitis. In the post-marketing setting, patients developing multiple autoimmune disorders after LEMTRADA treatment have been observed. Patients who develop autoimmunity should be assessed for other autoimmune-mediated conditions. Patients and medical practitioners should be made aware of the potential later onset of autoimmune disorders after the 48 months monitoring period.

Acquired haemophilia A

Cases of acquired haemophilia A (anti-factor VIII antibodies) have been reported in both clinical trial and post-marketing setting. Patients typically present with spontaneous subcutaneous haematomas and extensive bruising although haematuria, epistaxis, gastrointestinal or other types of bleeding may occur. A coagulopathy panel including aPTT must be obtained in all patients who present with such symptoms. Patients should be informed about the signs and symptoms of acquired haemophilia A and advised to seek immediate medical attention if any of these symptoms occur.

Immune thrombocytopenic purpura (ITP)

Serious events of ITP have been observed in 12 (1 %) patients treated with LEMTRADA in controlled clinical trials in MS (corresponding to an annualised rate 0,0047 events/patient/year). In a controlled clinical trial in patients with MS, 1 patient developed ITP that went unrecognised prior to the implementation of monthly blood monitoring requirements and died from intracerebral haemorrhage. An additional 12 serious events of ITP have been observed through a median of 6,1 years (maximum 12 years) of follow-up (cumulative annualised rate 0,0028 events/patient/year). ITP onset has generally occurred between 14 and 36 months after first LEMTRADA exposure. Complete blood counts (CBC) with differential should be obtained prior to initiation of treatment and at monthly intervals thereafter until 48 months after the last infusion. If ITP is suspected a CBC 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 have 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 re-treatment with LEMTRADA following the occurrence of ITP is unknown.

Nephropathies

Nephropathies, including anti-glomerular basement membrane (anti-GBM) disease, have been observed in 6 (0,4 %) patients in clinical trials in MS through a median of 6,1 years (maximum 12 years) of follow-up 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 as a component of anti-GBM disease. 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. The patient should be reminded to remain vigilant for symptoms they may experience and to seek immediate medical help if they have any concerns. Serum creatinine levels and urinalysis with cell counts should be obtained prior to initiation of treatment 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 evaluation for nephropathies, including immediate referral to a specialist. Early detection and treatment of nephropathies may decrease the risk of poor outcomes. The potential risk associated with re-treatment with LEMTRADA following the occurrence of nephropathies is unknown.

Thyroid disorders

Thyroid endocrine disorders including autoimmune thyroid disorders have been observed in an estimated 36,8 % of patients treated with LEMTRADA 12 mg in clinical trials in MS with a median of 6,1 years (maximum 12 years) of follow-up from the first LEMTRADA exposure. 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 Basedowu2019s disease (also known as Gravesu2019 disease), hyperthyroidism, hypothyroidism, autoimmune thyroiditis, and goitre 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 adverse events were permitted to receive re-treatment with LEMTRADA. Approximately 5 % of patients from the total study population developed a thyroid adverse event during the year following the initial treatment course of alemtuzumab and were re-treated. The majority of those patients did not experience a worsening in severity of thyroid disorders. Thyroid function tests (TFTs), such as thyroid stimulating hormone (TSH) 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 or in case of pregnancy. Thyroid disease poses special risks in women who are pregnant (see section 4.6).

Cytopenias

Suspected autoimmune cytopenias such as neutropenia, haemolytic anaemia and pancytopenia have been infrequently reported in patients in clinical trials in MS. CBC results should be used to monitor for cytopenias. If a cytopenia is confirmed, appropriate medical intervention should be promptly initiated, including referral to a specialist.

Autoimmune hepatitis (AIH)

Cases of autoimmune hepatitis (including fatal cases and cases requiring liver transplantation) causing clinically significant liver injury, including acute liver failure requiring transplant, have been reported in patients treated with LEMTRADA in the post-marketing setting. If a patient develops clinical signs, including unexplained liver enzyme elevations or symptoms suggestive of hepatic dysfunction (e.g. unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with LEMTRADA, as appropriate. Liver function tests should be performed before initial treatment and at monthly intervals until at least 48 months after the last infusion. Patients should be informed about the risk of autoimmune hepatitis, hepatic injury and related symptoms.

Thrombotic thrombocytopenic purpura (TTP)

During post-marketing use, TTP, which can be fatal, has been reported in patients treated with LEMTRADA. TTP is a serious condition that requires urgent evaluation and treatment. TTP may be characterised by thrombocytopenia, microangiopathic haemolytic anaemia, neurological sequelae, fever and renal impairment. It is associated with high morbidity and mortality rates if not recognised and treated early.

Autoimmune encephalitis

Cases of autoimmune encephalitis during post-marketing use have been reported in patients treated with LEMTRADA. Autoimmune encephalitis is confirmed by the presence of neural autoantibodies as well as a variety of clinical manifestations like subacute onset of memory impairment, altered mental status, psychiatric symptoms, neurological findings and seizures.

Infusion-associated reactions (lARs)

In clinical trials, infusion-associated reactions (IARs) were defined as any adverse event occurring during or within 24 hours of LEMTRADA infusion. Most patients treated with LEMTRADA in controlled clinical trials in MS experienced IARs during and/or up to 24 hours after LEMTRADA 12 mg administration. The incidence of IARs was higher in course 1 than in subsequent courses. Through all available follow-up, including patients who received additional 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 including cases of headache, pyrexia, urticaria, tachycardia, atrial fibrillation, nausea, chest discomfort and hypotension. In addition, anaphylaxis has been reported. During post-marketing use, serious, sometimes fatal and unpredictable adverse events from various organ systems have been reported. Cases of pulmonary alveolar haemorrhage, myocardial ischaemia, myocardial infarction, stroke (including ischaemic and haemorrhagic stroke), cervicocephalic (e.g. vertebral, carotid) arterial dissection, and thrombocytopenia have been reported. Reactions may occur following any of the doses during the treatment course. In the majority of cases, time to onset was within 1 u2013 3 days of LEMTRADA infusion. Patients should be informed about the signs and symptoms and advised to seek immediate medical attention if any of these symptoms occur.

No formal 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.

Safety in pregnancy and lactation has not been established.

Pregnancy

There are no adequate and well-controlled studies of LEMTRADA in pregnant women. LEMTRADA should not be administered during pregnancy. 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 fetus. It is not known whether alemtuzumab can cause fetal harm when administered to pregnant women or whether it can affect reproductive capacity. Women of childbearing potential should use effective contraceptive measures when receiving a course of treatment with LEMTRADA and for 4 months following that course of treatment.

Thyroid disease (see section 4.4) poses special risks in women who are pregnant. Without treatment of hypothyroidism during pregnancy, there is an increased risk for miscarriage and fetal effects such as mental retardation and dwarfism. In mothers with Gravesu2019 disease, maternal thyroid stimulating hormone receptor antibodies can be transferred to a developing fetus and can cause transient neonatal Gravesu2019 disease.

Breastfeeding

LEMTRADA was detected in the milk and offspring of lactating female mice administered 10 mg/kg for 5 consecutive days postpartum. Breastfeeding should be discontinued during each course of treatment with LEMTRADA and for 4 months following the last infusion of each treatment course.

No studies of the effect of LEMTRADA on the ability to drive and use machines have been performed.

A total of 1 486 patients treated with LEMTRADA (12 mg or 24 mg) constituted the safety population in a pooled analysis of MS clinical studies with a median follow-up of 6,1 years (maximum 12 years), resulting in 8 635 patient-years of safety follow-up. Study 1 and Study 2 were 2-year active-controlled trials in RRMS patients treated with LEMTRADA 12 mg/day on 5 consecutive days at study entry and on 3 consecutive days at Study Month 12, or subcutaneous (SC) IFNB-1a 44 u03bcg 3 times per week. Study 3 (CAMMS223) evaluated the safety and efficacy of LEMTRADA in patients with RRMS over the course of 3 years. Study 4 (CAMMS03409) was an uncontrolled extension study to evaluate the long-term safety and efficacy (4 additional years) of LEMTRADA in patients from Studies 1, 2 or 3. As the number of courses increases, data from fewer patients and shorter-term follow-up are available.

Table 1 lists adverse reactions occurring in u2265 5 % of LEMTRADA -treated patients (12 mg/day) through complete follow-up by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT).

Table 1: Side effects in Study 1, 2, 3 and 4 observed in u2265 5 % of LEMTRADA 12 mg treated patients

The type of adverse events including seriousness and severity observed in LEMTRADA treatment groups through all available follow-up, including patients who received additional treatment courses were similar to those in the active-controlled studies. In patients continuing from controlled clinical studies and who did not receive any additional LEMTRADA after the initial 2 treatment courses, the rate (events per person-year) of most adverse reactions was comparable to or reduced in years 3 u2013 6 as compared to years 1 and 2. The rate of thyroid adverse reactions was highest in year three and declined thereafter.

Immunogenicity

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 evaluated 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. Through 2 treatment courses, there was no apparent 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. High titre anti-alemtuzumab antibodies observed in some patients were associated with incomplete lymphocyte depletion following a third or fourth treatment course but there was no clear impact of anti-alemtuzumab antibodies on the clinical efficacy or safety profile of LEMTRADA. The incidence of antibodies is highly dependent on the sensitivity and specificity of the assay.

Two MS patients accidentally received up to 60 mg LEMTRADA (i.e. total dose for initial treatment course) in a single infusion and experienced serious reactions (headache, rash, and either hypotension or sinus tachycardia). Doses of LEMTRADA greater than those tested in clinical studies may increase the intensity and/or duration of infusion-associated adverse reactions or its immune effects. There is no known antidote for alemtuzumab overdosage. Treatment consists of discontinuation of LEMTRADA and supportive therapy.