Consumer medicine information

Lemtrada

Alemtuzumab

BRAND INFORMATION

Brand name

Lemtrada

Active ingredient

Alemtuzumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lemtrada.

What is in this leaflet

This leaflet answers some common questions about Lemtrada.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Lemtrada against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What Lemtrada is used for

Lemtrada contains the active substance alemtuzumab and is used to treat relapsing forms of multiple sclerosis (MS) in adults with active disease who are not stable on current therapy.

Lemtrada slows down the progression of physical disability in people with relapsing forms of MS and decreases the number of flare-ups (relapses).

In MS your immune system mistakenly attacks the protective layer (myelin) around the nerve fibres of your brain and spinal cord, causing inflammation.

Lemtrada works on your immune system so that it may reduce the impact of the disease on your nervous system.

Your doctor, however, may have prescribed Lemtrada for another purpose.

Ask your doctor if you have any questions about why it has been prescribed for you. This medicine is only available with a doctor's prescription.

Lemtrada is not intended to be used in children and adolescents as it has not been studied in MS patiens below 18 years old.

Before you take Lemtrada

Before treatment your doctor should have discussed the risks and benefits of Lemtrada and the need for you to commit to 48-months of follow-up after the last infusion of Lemtrada

When you must not take Lemtrada

Do not take Lemtrada if you:

  • have an allergy to alemtuzumab (the active ingredient) or proteins of mouse origin, or any of the ingredients listed at the end of this leaflet.

Symptoms that may indicate an allergic reaction include

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

These symptoms may also occur as a non-allergic reaction to Lemtrada infusion. Tell your doctor if you are experiencing these symptoms.

Lemtrada should not be used after the expiry date (exp) printed on the pack.

Lemtrada should not be used if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor, nurse or pharmacist if you have:

  • allergies to any of the ingredients listed at the end of this leaflet
  • received a vaccination in the last 6 weeks
  • if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby
  • bleeding, thyroid or kidney problems
  • a recent history of infection
  • a malignancy (cancer)
  • had a positive HIV, Hepatitis B or C blood test
  • received an organ transplant
  • taken or are taking other medicines to reduce the function of your immune system
  • other illness in addition to your Multiple Sclerosis.

Important Information

Talk to your doctor before Lemtrada is given. After having a course of treatment you may be at risk of developing autoimmune conditions (see below) or experiencing serious infections. It is important you understand these risks and how to monitor for them. You will be given a Patient Wallet Card and Patient Guide with further information. It is important you keep the Patient Wallet Card with you during treatment and for 4 years after your last infusion, because side effects may occur many years after treatment. If you have medical treatment,even if not for your MS, show the Patient Wallet Card to your doctor.

Autoimmune conditions

Treatment with Lemtrada may increase the risk for autoimmune conditions. These are conditions where your immune system mistakenly attacks certain cells of your body. Information about some specific conditions is provided below.

These autoimmune conditions can occur many years after treatment with Lemtrada.

You will need to have a blood test and a urine test before starting treatment and every month until 4 years after your last Lemtrada infusion even if you are feeling well and your MS symptoms are under control. In addition there are certain signs and symptoms that you should look out for yourself. Details are described under Side Effects. More helpful information about these conditions and testing for them can be found in the Lemtrada Patient Guide.

Immune Thrombocytopenic Purpura

Approximately 2% of patients may develop an autoimmune bleeding disorder called Immune Thrombocytopenic Purpura (ITP). This must be diagnosed and treated promptly, as otherwise the effects can be serious or even fatal. ITP can cause bleeding (that may be hard to stop) and/or easy bruising, and/or small scattered spots on your skin that are red, pink or purple.

Your blood will be checked before starting your treatment with Lemtrada, and every month after your initial treatment course until 4 years after your last infusion. This should allow a problem to be detected early and treatment to begin right away. Your doctor will explain symptoms for you to look out for so that you can seek urgent medical help if you experience them.

Kidney Disease (such as anti-GBM disease)

Approximately 1 in 250 patients have experienced autoimmune related problems with their kidneys, such as anti-glomerular basement membrane disease (anti-GBM disease). If untreated it can cause kidney failure requiring dialysis or transplantation, and may lead to death. Your blood and urine will be checked before starting your treatment with Lemtrada, and every month after your initial treatment course until 4 years after your last infusion. This should allow a problem to be detected early and treatment to begin right away.

Thyroid Disorders

More than a third of patients have experienced an autoimmune disorder of the thyroid gland affecting its ability to make or control hormones that are important for your metabolism. This can result in many different symptoms such as excessive sweating, unexplained weight loss, eye swelling, nervousness, or fast heartbeat. Let your doctor know if you experience any such symptoms. If you develop a thyroid disorder, in most cases you will need to be treated for the rest of your life with medication to control your thyroid disorder, or in some cases your thyroid may have to be removed. Your blood will be checked before starting your treatment with Lemtrada, and every 3 months after your initial treatment course until 4 years after your last infusion.

Should you develop a thyroid disorder, it is very important that you are properly treated for it, especially if you become pregnant after using Lemtrada. Having an untreated thyroid disorder could harm your unborn baby, or harm your baby after birth.

Liver inflammation

Some patients have developed liver inflammation after receiving Lemtrada. If you develop one or more of the following symptoms report this to your doctor: nausea, vomiting, abdominal pain, fatigue, loss of appetite, yellow skin or yeses, dark urine, or bleeding or bruising more easily than normal.

Other autoimmune conditions

Uncommonly patients have experienced autoimmune conditions with the red blood cells or white blood cells. This can be diagnosed from the blood tests that you will be having after Lemtrada treatment. If you develop one of these conditions your doctor will take appropriate measures to treat it.

Summary of recommended testing for autoimmune conditions

Blood Test - Before treatment starts and every month until 4 years after your last Lemtrada infusion

Urine Test - Before treatment starts and every month until 4 years after your last Lemtrada infusion

Infusion reactions

Most patients treated with Lemtrada will experience side-effects at the time of the infusion or within 24 hours after the infusion. All of these reactions are described in the Side Effects section of this leaflet.

Most infusion reactions are mild but some serious reactions are possible such as change in heart rate, headache, low blood pressure, nausea, chest discomfort, fever or hives. Allergic reactions are possible.

In order to try to reduce these effects, your doctor will give you medication (corticosteroids) prior to the first 3 infusions of a treatment course. Other treatments to limit these reactions can also be given before the infusion or when you experience symptoms. In addition, you will be observed during the infusion and after the infusion has been completed. In case of serious reactions, it is possible that the infusion may be slowed down or even stopped.

Other serious reactions occurring shortly after Lemtrada infusion

Some patients have had serious or life-threatening reactions after LEMTRADA infusion, including bleeding in the lung, heart attack, stroke or tears in blood vessels supplying the brain. Reactions may occur following any of the doses during the treatment course.

In the majority of cases reactions occurred within 1-3 days of the infusion. Your doctor will monitor vital signs, including blood pressure, before and during the infusion.

Get help right away if you have any of the following symptoms: trouble breathing, chest pain, facial drooping, sudden severe headache, weakness on one side of the body, difficulty with speech or neck pain.

Haemophagocytic lymphohistiocytosis

Treatment with Lemtrada may increase the risk of excessive activation of white blood cells associated with inflammation (haemophagocytic lymphohistiocytosis), which can be fatal if not diagnosed and treated early.

If you experience multiple symptoms such as fever, swollen glands, bruising, or skin rash, contact your doctor immediately

Infections

Patients treated with Lemtrada may be at a higher risk for getting a serious infection. If you are suffering from an infection before the initiation of your Lemtrada treatment, your doctor will consider delaying the treatment until the infection is under control or resolved.

Most infections seen in clinical trials were mild to moderate and most often included airway infections such as colds, bronchitis and sinus infections, cystitis, cold sores, or influenza (flu). However serious infections like appendicitis, gastric flu, pneumonia, chicken pox or shingles and tooth infection have also occurred.

If you have had a herpes infection (e.g. a cold sore) in the past it is possible that this will flare up after treatment with Lemtrada, or you could develop a herpes infection for the first time. It is recommended that your doctor prescribes treatment with a medicine against infections like this, which should be taken during the days that you receive infusions, and for one month following the infusion, in order to reduce the chance of developing a herpes infection.

In addition, infections which can result in abnormalities of the cervix (the neck of the womb) are possible. Therefore it is recommended that all female patients have annual screening performed, such as a pap smear. Your doctor will explain to you what testing will be done to you.

Patients who receive Lemtrada have an increased chance of getting an infection caused by the bacteria, Listeria. Avoid foods that may be a source for Listeria (for example, deli or processed meats, unpasteurized milk and cheese products, or undercooked meat, seafood or poultry) or make sure that the food you eat which may contain Listeria is heated well if you receive treatment with Lemtrada.

You may be tested for tuberculosis according to your doctor's decision.

Fungal (yeast) infections of the mouth (oral thrush), and vagina (vaginal thrush) have also been seen.

If you are a carrier of hepatitis B or hepatitis C infection (these affect the liver), extra caution is needed before you receive Lemtrada treatment as it is unknown if treatment could lead to activation of the hepatitis infection which could subsequently damage your liver.

Inflammation of the gallbladder

Lemtrada may increase your chance of getting inflammation of the gallbladder. This may be a serious medical condition that can be life threatening. You should report to your doctor if you have symptoms such as stomach pain or discomfort, fever, nausea or vomiting.

Previously diagnosed cancer

If you have been diagnosed with cancer in the past, please inform your doctor about it.

Vaccines

It is unknown if Lemtrada has an impact on your ability to raise a response to a vaccine. If you have not completed the standard required vaccinations, your doctor will consider whether you should have them before your Lemtrada treatment. In particular, your doctor will consider vaccinating you against chicken-pox if you have never had it. Any vaccination will need to be completed at least 6 weeks prior to starting a Lemtrada treatment course.

After your treatment course with Lemtrada, consult your healthcare provider if you require vaccination. Your healthcare provider will determine if it is safe for you to do so. You must not receive certain types of vaccines (live viral vaccines) if you have recently received Lemtrada.

Pregnancy and breast-feeding

Woman of childbearing potential should use effective contraceptive methods during treatment with Lemtrada and for 4 months after each course of treatment.

If you become pregnant after treatment with Lemtrada and experience thyroid problems during pregnancy, extra caution is needed. The thyroid problems could be harmful to the baby.

It is unknown if Lemtrada can be transferred to a baby through breast milk, but there could be a risk. You should not breast-feed during each course of treatment with Lemtrada and for 4 months after each treatment course.

Taking other medicines

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines (including vaccinations).

Besides Lemtrada, there are other treatments (including those for MS, or to treat other conditions) which could affect your immune system and so could affect your ability to fight infections. If you have used another MS treatment in the past, your doctor may ask you to stop the other medicine in advance of starting treatment with Lemtrada.

How Lemtrada is given

How it is given

Lemtrada will be given to you as an infusion into a vein. Each infusion will take approximately 4 hours.

How often is it given

The initial treatment you will receive will consist of one infusion (12mg) per day on 5 days (course 1) and one infusion (12mg) per day for 3 days one year later (course 2). There is no Lemtrada treatment between the two courses.

Some patients, if they have symptoms or signs of MS disease activity after the initial two courses may receive one or two additional treatment courses. In case you need an additional treatment course you will receive one infusion per day for three days administered at least a year after the prior treatment.

Once you have received Lemtrada, you will need to undergo regular tests to ensure that any potential side-effects can be diagnosed and treated promptly. Monitoring must continue for 4 years after the last infusion.

If you receive too much (overdose)

As Lemtrada is given to you under the supervision of a doctor or nurse, it is very unlikely that you will receive too much. However, if you experience any unexpected or worrying side effects after being given Lemtrada tell your doctor, pharmacist or nurse as soon as possible.

While you are taking Lemtrada

Things you must do

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking Lemtrada.

Woman of childbearing potential should use effective contraceptive methods during treatment with Lemtrada and for 4 months after each course of treatment.

Things to be careful of

Lemtrada does not directly affect your ability to drive or use machines. However you may experience a side-effect during the treatment course which could make this unsafe, for example dizziness. If affected, stop these activities until the side-effect resolves.

Side Effects

Tell your doctor, pharmacist or nurse as soon as possible if you do not feel well while you are taking Lemtrada.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

There have been reports of a rare, serious brain infection called PML (progressive multifocal leucoencephalopathy) in patients receiving some medicines for MS. PML can cause severe disability or even death. Symptoms of PML can be similar to those of MS.

Tell your partner or carer about your Lemtrada treatment, especially if you have received other medicines to treat MS before. They might notice symptoms that you do not, such as changes in movement or behaviour, that your doctor may need to investigate further.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • trouble breathing
  • chest pain
  • Pressure, tightness, pain, or a squeezing or aching sensation in your chest or arms that may spread to your neck, jaw or back.
  • lightheadedness or sudden dizziness
  • drooping of the skin on your face
  • sudden weakness or numbness on one side of the body
  • sudden difficulty with speech or blurred vision
  • neck pain.
  • sudden severe headache
  • pain in your scalp, face or neck
  • eye pain
  • pulsing sound in the ear

If any of the following happen after you have been given Lemtrada tell your doctor or nurse immediately. If you cannot reach your doctor or nurse you must seek immediate medical attention:

  • small scattered spots on your skin that are red, pink or purple
  • any bleeding that is heavier than usual or harder to stop than expected, easy bruising
  • blood in the urine, coughing up blood and swelling in your legs or feet
  • stomach pain or discomfort, fever, nausea or vomiting.

If any of the following happen after you have been given Lemtrada tell your doctor or nurse soon so that they are treated promptly

  • signs of infection such as fever and/or chills, swollen glands, mouth or skin ulcers, abscesses, or wounds that take along time to heal
  • excessive sweating, unexplained weight loss, eye swelling, nervousness, fast heartbeat
  • unexplained weight gain, feeling cold, worsening tiredness, new constipation

Tell your doctor, pharmacist or nurse if you notice any of the following and they worry you.

  • side effects that can happen during, or within 24 hours, of the infusion including: headache, rash, fever, feeling sick, hives, itching, reddening of the face and neck, feeling tired
  • change in heart rate, indigestion, chills, chest pain, dizziness, strange taste, difficulty sleeping, difficulty breathing or shortness of breath, rash
  • muscular or joint pain, sore mouth or gums, feeling weak, vomiting, diarrhoea, stomach pain, gastric flu, heartburn, trembling, burning or prickling sensation
  • swelling of arms or legs, prolonged or irregular menstruation, red skin, excessive sweating, nose bleeds and bruising

Refer to your Lemtrada patient guide for further information

After using Lemtrada

Storage

Lemtrada is stored in the pharmacy or clinic at 2-8°C.

Disposal

The Doctor, Nurse or Pharmacist will dispose of any unused Lemtrada

Product description

What Lemtrada looks like

Lemtrada is a clear colourless to yellowish solution.

Ingredients

Active ingredients:

Each vial of Lemtrada contains 10mg/mL of alemtuzumab

Inactive ingredients:

  • Sodium chloride
  • Dibasic sodium phosphate
  • Potassium chloride
  • Monobasic potassium phosphate
  • Polysorbate 80
  • Disodium edetate
  • Water for injections

Name and Address of Australian Sponsor

sanofi-aventis australia pty ltd
Talavera Corporate Centre -
Building D
12-24 Talavera Road
Macquarie Park NSW 2113
Australia

Name and Address of New Zealand Sponsor

sanofi-aventis new zealand pty ltd
56 Cawley St
Ellerslie
Auckland, New Zealand

AUST R number

AUST R 200941

Date of preparation

This leaflet was prepared in January 2020

lem-ccdsv13-cmiv9-20jan20

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Lemtrada

Active ingredient

Alemtuzumab

Schedule

S4

 

1 Name of Medicine

Alemtuzumab (rch).

6.7 Physicochemical Properties

Alemtuzumab (rch) is a Y-shaped molecule consisting of two 24 kilodalton (kD) light polypeptide chains (L-C) and two 49 kD heavy polypeptide chains (H-C) linked together by 2 interdisulfide (L-C)-(H-C) bridges and two interdisulfide (H-C)-(H-C) bridges. Each molecule also contains a total of 12 intrachain disulfide bridges and an asparagine residue in each heavy chain that is amenable to glycosylation.

Chemical structure.


CAS number.

Not applicable.

2 Qualitative and Quantitative Composition

Each 1.0 mL of concentrate solution contains 10 mg alemtuzumab (rch). See Section 6.1 List of Excipients.

3 Pharmaceutical Form

Alemtuzumab (rch) is a recombinant DNA derived humanised monoclonal antibody directed against the 21-28 kD cell surface glycoprotein, CD52. Alemtuzumab (rch) is an IgG1 kappa antibody with human variable framework and constant regions, and complementarity-determining regions from a murine monoclonal antibody. The antibody has an approximate molecular weight of 150 kD. Alemtuzumab (rch) is produced in mammalian cell (Chinese hamster ovary) suspension culture in a nutrient medium. Alemtuzumab (rch) is a sterile, clear, colourless to slightly yellow, injection concentrate with pH 7.0-7.4. It is intended for dilution prior to infusion.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Alemtuzumab binds to CD52, a cell surface antigen present at high levels on T and B 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 through antibody dependent cellular cytolysis and complement mediated lysis following cell surface binding to T and B lymphocytes.
The mechanism by which alemtuzumab exerts its therapeutic effects in MS is unknown, but may involve immunomodulation through the depletion and repopulation of lymphocytes. Research suggests that the potential immunomodulatory effects in MS may include alterations in the number, proportions, and properties of some lymphocyte subsets post-treatment.
Alemtuzumab depletes circulating T and B lymphocytes after each treatment course with the lowest observed values occurring at the first post-treatment assessment, which was as early as 2 days after the end of the first treatment cycle in a Phase 2 study. Lymphocytes repopulate over time (Figure 1). B cells recover to normal within 6 months for > 90% of patients.
T lymphocyte counts rise more slowly towards normal, and 10-70% (depending on cell type) return to baseline by 12 months post-treatment. Approximately 40% of patients had total lymphocyte counts reaching the lower limit of normal (LLN) by 6 months after each treatment course, and approximately 80% of patients had total lymphocyte counts reaching the LLN by 12 months after each treatment course.
Neutrophils, monocytes, eosinophils, basophils, and natural killer cells are only transiently affected by alemtuzumab.

Clinical trials.

The safety and efficacy of Lemtrada were evaluated in 3 randomised, rater-blinded, active comparator clinical trials and one uncontrolled, rater-blinded extension study in patients with MS.
Studies 1 and 2 (CAMMS323 and CAMMS324) enrolled patients with active MS who had experienced at least 2 clinical episodes during the prior 2 years. Neurological examinations were performed every 12 weeks and at times of suspected relapse. MRI evaluations were performed annually. Patients were followed for 2 years. In both studies, patients were randomised to receive Lemtrada 12 mg/day IV infusion administered once per day on 5 days at Month 0 and on 3 days at Month 12 (the 12 mg group) or interferon beta-1a (IFNB-1a) 44 microgram SC injection administered 3 times per week. Study 2 also included an exploratory dose arm for Lemtrada 24 mg/day administered once per day on 5 days at Month 0 and on 3 days at Month 12 (the 24 mg group). The primary outcome measures for Studies 1 and 2 were the annualised relapse rate (ARR) over 2 years and the time to onset of confirmed disability worsening (CDW) [CDW is the currently preferred terminology during the study the endpoint was called sustained accumulation of disability or SAD], defined as an increase of at least 1 point on the expanded disability status scale (EDSS) from a baseline EDSS score ≥ 1.0 (1.5 point increase for patients with baseline EDSS of 0) that was sustained for 6 months.
Study 1 (CAMMS323) included patients with RRMS with an EDSS from 0-3.0 with N = 376 in the Lemtrada 12 mg group and N = 187 in the IFNB-1a group. Mean age was 33 years, mean disease duration was 2 years and mean EDSS score was 2.0 at baseline. Patients had not received prior therapy for MS at study entry.
The ARR was significantly reduced by 55% in patients treated with Lemtrada as compared to SC IFNB-1a at 2 years. There was no statistically significant difference between the treatment groups in the 6 month sustained accumulation of disability; at 2 years 8% of Lemtrada treated patients had a sustained increase in EDSS score as compared to 11% of IFNB-1a patients, results are shown in Table 3.
Study 2 (CAMMS324) included patients with RRMS with an EDSS from 0-5 with N = 426 in the Lemtrada 12 mg group and N = 202 in the IFNB-1a group. Mean age was 35 years, mean disease duration was 4.5 years, and mean EDSS score was 2.7 at baseline. Prior to enrolling, patients experienced at least 1 relapse during treatment with beta interferon or glatiramer acetate after having been on therapy with drug for at least 6 months. At baseline, the mean duration of exposure to prior MS therapies (≥ 1 drug used) was 35 months in the Lemtrada 12 mg group; 29% had received ≥ 2 prior MS therapies.
The RR was significantly reduced by 49% in patients in the Lemtrada 12 mg group as compared to SC IFNB-1a over 2 years. In addition, treatment with Lemtrada significantly reduced by 42% the risk of 6-month SAD versus SC IFNB-1a over 2 years; 13% of Lemtrada-treated patients had a sustained increase in EDSS score as compared to 21% of IFNB-1a patients (absolute difference 8.42%). The mean EDSS score in patients treated with Lemtrada was significantly reduced over 2 years, (indicating improvement), compared to the mean EDSS score from baseline for patients treated with SC IFNB-1a. Compared with IFNB-1a-treated patients, Lemtrada-treated patients were 2.6 times more likely to achieve a confirmed disability improvement (CDI) [CDI is the currently preferred terminology, during the study, CDI was referred to as "sustained reduction in disability"]. The secondary variable percent change from baseline in MRI-T2-hyperintense lesion volume at Year 2 showed no significant different between treatments. Effects on tertiary MRI measures are shown in Table 3.
Results are shown in Table 3 and Figure 2.
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 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 on 5 days at Month 0 and on 3 days at Month 12 or SC IFNB-1a 44 microgram (N = 107) administered 3 times per week for 3 years. Twenty-four patients received a third course of Lemtrada treatment at 12 mg/day for 3 days at Month 24.
At 3 years, the ARR was significantly reduced by 70% in patients in the Lemtrada 12 mg group who had received 2 courses of therapy as compared to SC IFNB-1a. In addition, treatment with Lemtrada significantly reduced by 70% the risk of 6 month CDW versus IFNB-1a.

Long term efficacy data.

Study 4 provides efficacy data for up to 6 years from entry into studies 1 and 2. Of patients treated with Lemtrada 12 mg in studies 1 and 2, 91.8% entered Study 4.
In Study 4, 40% of the patients initially treated with Lemtrada 12 mg/day in Study 1 or 2 received additional courses upon documented evidence of MS disease activity (relapse and/or MRI) and the treating physician's decision to retreat. Relapse was defined as:
a) Have, within the previous year, experienced ≥ 1 protocol-defined relapse. Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination. Symptoms must be attributable to MS, last at least 48 hours, be present at normal body temperature, and be preceded by at least 1 month (30 days) of clinical stability.
b) Have, within the previous year or since their last on-study MRI, accumulated ≥ 2 unique lesions on brain or spinal cord MRIs comprised of any combination of the following: gadolinium-enhancing lesion(s) (usually ≥ 3 mm in any dimension); new or enlarging MRI T2 lesions (usually ≥ 3 mm in any dimension, or ≥ 3 mm increase).
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.
377 patients received only 2 treatment courses of Lemtrada in prior studies and no further Lemtrada or other disease-modifying treatment in this extension study, having not met the criteria for relapse. In this 2-course subgroup 63/377 (16.7%) patients experienced CDW either in the 2 years of the initial study or in the 4 subsequent years compared with 110/321 (34.3%) patients who required additional treatment courses.
For patients who were retreated, the mean (SD) time to meeting retreatment criteria was 2.4(1.34) years prior to course 3 and 2.1(1.13) years prior to course 4.
Table 4 represents the key clinical and MRI outcome in Study 4 (year 0-6) for Lemtrada treated patients in Studies 1 and 2.

Additional as needed treatment.

Relapse rate and MRI activity and mean EDSS score all improved in the year both following a third or fourth Lemtrada treatment course when compared with outcomes in the preceding year (Table 4).
These data demonstrate that patients with MS disease activity following a prior Lemtrada treatment course can achieve clinical improvement on clinical and MRI measures (reduced ARR, decreased lesions and stabilisation of disability) after additional Lemtrada treatment courses.
The benefits and risks of 5 or more treatment courses have not been fully established, but results suggest that the safety profile does not 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 evaluated for evidence of in vitro inhibition using a flow cytometry assay. Patients in 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 90% of these patients testing positive also for antibodies that inhibited alemtuzumab binding in vitro. Patients who developed anti-alemtuzumab antibodies did so by 15 months from initial exposure. Through 2 treatment courses 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. 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 antibody 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.

5.2 Pharmacokinetic Properties

The pharmacokinetics of alemtuzumab were evaluated in a total of 216 patients with RRMS who received IV infusions of either 12 mg/day or 24 mg/day for 5 consecutive days (Course 1), followed by 3 consecutive days 12 months following the initial treatment course (Course 2). 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 Cmax of 3014 nanogram/mL on Day 5 of the initial treatment course, and 2276 nanogram/mL on Day 3 of the second treatment course. The alpha half-life approximated 2 days and was comparable between courses leading to low or undetectable serum concentrations within approximately 30 days following each treatment course.
The population pharmacokinetics of alemtuzumab were best described by a linear, 2 compartment model. Systemic clearance decreased with lymphocyte count due to loss of CD52 antigen in the periphery; however, the decrease from Course 1 to Course 2 was less than 20%. The central volume of distribution was proportional to body weight, and approximated extracellular fluid volume (14.1 L), suggesting that Lemtrada is largely confined to the blood and interstitial space.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

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

4 Clinical Particulars

4.1 Therapeutic Indications

Lemtrada is indicated for the treatment of relapsing forms of multiple sclerosis (MS) for patients with active disease defined by clinical or imaging features to slow the accumulation of physical disability and reduce the frequency of clinical relapses.

4.3 Contraindications

Lemtrada is contraindicated in: hypersensitivity or anaphylactic reactions to alemtuzumab, to murine proteins or to any of the excipients; 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.
Lemtrada has not been administered for treatment of MS concomitantly with other disease modifying MS 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 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). There are limited data for use of other disease modifying therapies after Lemtrada.
Patients treated with Lemtrada must be given the Consumer Medicines Information, the Patient Wallet Card and the Patient Guide. Before treatment, patients must 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 including immune thrombocytopenic purpura (ITP), thyroid disorders or, uncommonly, nephropathies (e.g. anti-glomerular basement membrane disease) and autoimmune hepatitis (AIH).

Immune thrombocytopenic purpura.

Serious events of ITP have been observed in 12 (1%) of patients treated with alemtuzumab 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 up to 12 years follow up (cumulative annualised rate 0.0028 events/patient/year).
ITP onset has generally occurred between 14 and 36 months after first alemtuzumab exposure (range 3.7 to 40.7 months).
Full blood counts (FBC) 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 FBC should be obtained immediately.
If ITP onset is confirmed, appropriate medical intervention should be promptly initiated, including 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 alemtuzumab 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 6.1 years (maximum 12 years) of follow up and generally occurred within 39 months following last administration of alemtuzumab. 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.
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 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 alemtuzumab following the occurrence of nephropathies is unknown.

Thyroid disorders.

Endocrine disorders including autoimmune thyroid disorders have been observed in an estimated 36.8% of patients treated with alemtuzumab 12 mg in clinical trials in MS with a median of 6.1 years (maximum 12 years) of follow-up from the first alemtuzumab 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 Graves' disease (also known as Basedow's 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.
Thyroid function tests, such as thyroid stimulating hormone (TSH) levels, should be obtained prior to initiation of treatment and every 3 months thereafter until 48 months after 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 Fertility, Pregnancy and Lactation, Use in pregnancy).

Cytopenias.

Suspected autoimmune cytopenias such as neutropenia, haemolytic anaemia, and pancytopenia have been reported uncommonly in patients in clinical trials in MS. Neutropenia was commonly reported in both treatment groups in clinical trials (IFNB-1a 4.0% vs. 1.8% Lemtrada 12 mg). FBC 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).

Autoimmune hepatitis causing clinically significant liver injury, including acute liver failure requiring transplant, has been reported in patients treated with Lemtrada in the postmarketing 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.

Infusion associated reactions.

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 clinical trials in MS experienced mild to moderate 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, urticarial, pruritus, insomnia, chills, flushing, fatigue, dyspnoea, dysgeusia, chest discomfort, generalised rash, tachycardia, bradycardia, dyspepsia, dizziness, and pain. Serious reactions occurred in 3% of patients and included cases of headache, pyrexia, urticarial, tachycardia atrial fibrillation, nausea, chest discomfort, and hypotension. In addition, anaphylaxis has been reported rarely. During postmarketing use, cases of pulmonary alveolar haemorrhage , myocardial ischaemia, myocardial infarction, stroke (including ischemic and hemorrhagic stroke), and cervicocephalic (e.g. vertebral, carotid) arterial dissection 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 1-3 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.
It is recommended that patients be premedicated with corticosteroids immediately prior to the initiation of the Lemtrada infusion on the first 3 days of any treatment course to ameliorate the effects of infusion reactions. In clinical trials patients were pretreated with 1,000 mg of methylprednisolone on the first 3 days of each Lemtrada treatment course. Pretreatment with antihistamines and/or antipyretics prior to Lemtrada administration may also be considered.
Most patients in controlled clinical trials received antihistamines and/or antipyretics before at least 1 Lemtrada infusion. IARs may occur in patients despite pretreatment. Physicians should be aware of the patient's cardiac history as infusion-associated reactions can include cardiac symptoms such as tachycardia. Observation for infusion reactions is recommended during and for 2 hours after each Lemtrada infusion. Physicians should alert patients that an IAR could occur within 48 hours of infusion. Monitor vital signs before the infusion and periodically during the 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 IV infusion should be considered.
Within the clinical trials, anaphylaxis or serious reactions that necessitated treatment discontinuation were very rare. Facilities for the management of anaphylaxis or serious reactions should be available.

Infections.

Infections occurred in 71% of patients treated with alemtuzumab 12 mg as compared to 53% of patients treated with Rebif (interferon beta-1a [IFNB-1a]) 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 alemtuzumab-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 alemtuzumab as compared to 1.0% of patients treated with IFNB-1a in controlled clinical trials in MS. Serious infections in the alemtuzumab group included: appendicitis, gastroenteritis, pneumonia, herpes zoster, and tooth infection. Infections were generally of typical duration and resolved following conventional medical treatment.
The cumulative annualised rate of infection was 0.99 through a median of 6.1 years (maximum 12 years) of follow-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, have occurred more often in patients treated with alemtuzumab 12 mg (0.4%) 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 alemtuzumab 12 mg (2%). It is recommended that HPV screening, such as a cervical smear, be completed annually for female patients.
Tuberculosis has been reported for patients treated with alemtuzumab and IFNB-1a in controlled clinical trials. Active and latent tuberculosis have been reported in 0.3% of the patients treated with alemtuzumab, most often in endemic regions. Tuberculosis screening should be done according to local guidelines prior to initiation of alemtuzumab.
Listeria meningitis has been reported in Lemtrada-treated patients. Cases of listeria meningitis occurred within 1 month of alemtuzumab dosing. The duration of increased risk for listeria meningitis is unclear. Unless treated, listeria infection can lead to significant morbidity or mortality. Patients should avoid or adequately heat foods that are potential sources of Listeria monocytogenes.
Superficial fungal infections, especially oral and vaginal candidiasis, occurred more commonly in alemtuzumab-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.
Lemtrada has not been administered for treatment of MS concomitantly with 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 alemtuzumab 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.
Cytomegalovirus infections have been reported in Lemtrada-treated patients with concomitant corticosteroid use. Most cases occurred within 2 months of alemtuzumab dosing. In symptomatic patients, clinical assessment should be performed for CMV infection during and for at least two months following each Lemtrada treatment course.

Progressive multifocal leukoencephalopathy (PML).

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
No case of PML has been reported in clinical studies of alemtuzumab in patients with multiple sclerosis. PML has been reported in the postmarketing setting in patients with other risk factors, specifically prior treatment with MS products associated with PML.
MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI, including prior to initiation of Lemtrada, for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Following discontinuation of another MS medication associated with PML, lower PML-related mortality and morbidity have been reported in patients who were initially asymptomatic at diagnosis compared to patients who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.

Pneumonitis.

Pneumonitis has been reported in Lemtrada treated patients. Most cases occurred within the first month after treatment with Lemtrada. Patients should be advised to report symptoms of pneumonitis, which may include shortness of breath, cough, wheezing, chest pain or tightness and haemoptysis.

Haemophagocytic lymphohistiocytosis (HLH).

During postmarketing use, HLH has been reported in patients treated with Lemtrada. HLH is a life-threatening syndrome of pathologic immune activation characterised by clinical signs and symptoms of extreme systemic inflammation. It is associated with high mortality rates if not recognised early and treated. Symptoms have been reported to occur within a few months to four years following the initiation of treatment. Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered.

Cervicocephalic arterial dissection and stroke.

In the postmarketing setting, serious and life-threatening stroke (including ischaemic and haemorrhagic stroke) has been reported within one week of Lemtrada administration, with most cases occurring within 3 days of Lemtrada infusion. Cervicocephalic arterial dissections involving multiple arteries ((e.g. vertebral, carotid) were reported in some cases.
Educate patients on the symptoms of stroke and cervicocephalic (e.g., carotid, vertebral) arterial dissection. Instruct patients to seek immediate medical attention if symptoms of stroke or cervicocephalic arterial dissection occur.

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 patients treated with interferon beta-1a. During post-marketing use, additional cases of acute acalculous cholecystitis have been reported in Lemtrada-treated patients. Time to onset of symptoms ranged from less than 24 hours to 2 months after Lemtrada infusion. Typical risk or predisposing factors such as concurrent critical illness were often not reported. Abnormal ultrasound or computed tomography was used to support the diagnosis of acute acalculous cholecystitis in some cases. Most patients were treated conservatively with antibiotics and recovered without surgical intervention, whereas others underwent cholecystectomy.
Symptoms of acute acalculous cholecystitis include abdominal pain, abdominal tenderness, fever, nausea, and vomiting. Leukocytosis and abnormal liver enzymes are also commonly observed. Acute acalculous cholecystitis is a condition that may be associated with high morbidity and mortality rates if not diagnosed early and treated. If acute acalculous cholecystitis is suspected, evaluate and treat promptly.

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.
In clinical trials of up to 24 months duration no increase in the incidence of malignancy was seen in patients given alemtuzumab compared with interferon β-1a. Additionally, over all available follow-up for alemtuzumab treated patients (up to 9 years) the annualised rate of malignancy was within the range of the background population. The most common malignancies reported in patients given alemtuzumab were thyroid cancer (5 patients), breast cancer (5 patients) and basal cell carcinoma (4 patients), which are among the most frequent cancers reported for white, young adults.
Clinical trial data to 6 years has not indicated an increased risk of malignancy greater than the general MS population is associated with use of Lemtrada. Regular routine surveillance for malignancies is recommended.

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 alemtuzumab treatment has not been formally studied in controlled clinical trials in MS. Live vaccines 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 drug, 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, postpone treatment with Lemtrada 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.
FBC with differential (prior to treatment initiation and at monthly intervals thereafter).
Serum creatinine levels (prior to treatment initiation and at monthly intervals thereafter).
Urinalysis with urine cell counts (prior to treatment initiation and at monthly intervals thereafter).
A test of thyroid function, such as TSH level (prior to treatment initiation and every 3 months thereafter).

Information from the post-marketing use of alemtuzumab in B-cell chronic lymphocytic leukaemia and other disorders.

Alemtuzumab (also known commercially as MabCampath) was first approved in 2006 for use in B-CLL. The following adverse reactions were identified during post-approval 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.

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.

Use in hepatic impairment.

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

Use in renal impairment.

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

Use in the elderly.

Clinical studies of Lemtrada did not include sufficient numbers of patients aged 55 and over to determine whether they respond differently than younger patients.

Paediatric use.

The safety and efficacy of alemtuzumab in MS patients below the age of 18 years of age has not yet been established.

Effects on laboratory tests.

It is not known whether alemtuzumab interferes with any routine clinical laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug interaction studies have been conducted with alemtuzumab 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.
Lemtrada is administered parenterally; therefore interactions with food and drink are unlikely.
In the absence of compatibility studies, alemtuzumab should not be mixed with other medicinal products. Do not add or simultaneously infuse other medicinal products through the same intravenous line.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In male transgenic mice, intravenous administration of alemtuzumab at doses of 3 and up to 10 mg/kg/day for 5 consecutive days (respective plasma AUC exposure 4 and 12 times clinical exposure at the MRHD) had no effect on fertility or reproductive performance. Effects on sperm were observed, with a significant increase in abnormal (detached head/no head) sperm; (respective incidences of 11%, 15%, 17% in control 3 and 10 mg/kg dose groups; a no-effect dose was not determined. The clinical significance of these effects is unknown.
In female transgenic mice treated intravenously with alemtuzumab for 5 consecutive days, the numbers of corpora lutea and implantation sites were significantly reduced at 10 mg/kg/day (plasma AUC 8 times clinical exposure at the MRHD); the no-effect dose was 3 mg/kg/day (3 times clinical exposure). Other mating and fertility parameters were unaffected at these doses.
(Category B3)
There are no adequate and well-controlled studies 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. It is not known whether Lemtrada can cause foetal harm when administered to pregnant women or whether it can affect reproductive capacity.
Alemtuzumab crosses the placenta in transgenic mice. Intravenous administration of alemtuzumab to pregnant mice during late organogenesis at a dose of 10 mg/kg/day for 5 consecutive days (plasma AUC exposure 4 times clinical exposure at the MRHD) was associated with an increased number of dams with all conceptuses dead or resorbed, along with a concomitant reduction in the number of dams with viable foetuses. There was no external, soft tissue or skeletal malformations or variations. There was evidence for reductions in lymphocytic counts and altered lymphocyte subpopulations in offspring at 3 weeks postpartum was observed following alemtuzumab treatment of mice during early or late gestation at doses of 3 mg/kg/day or greater for 5 consecutive days (plasma AUC similar to clinical exposure at the MRHD); a no-effect dose was not determined. The relevance to humans of reproductive toxicity findings in transgenic mice is unknown.
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.
Thyroid disease (see Section 4.4 Special Warnings and Precautions for Use, 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.
It is not known whether alemtuzumab is excreted in human milk. Because immunoglobulins are excreted in milk, caution should be exercised when alemtuzumab is administered to a nursing woman. Breast feeding should be discontinued during each course of treatment with alemtuzumab and for 4 months following the last infusion of each treatment course.
Alemtuzumab was detected in the milk and offspring of lactating female transgenic mice administered intravenous alemtuzumab 10 mg/kg/day for 5 consecutive days postpartum. There was evidence for reductions in lymphocytic counts, along with a reduced IgM antibody response in offspring at about 9 weeks postpartum following this treatment; a no-effect dose was not determined. Cognitive, physical, and sexual development of pups exposed to alemtuzumab during lactation were not affected. The relevance to humans of reproductive toxicity findings in transgenic mice is unknown.

4.8 Adverse Effects (Undesirable Effects)

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 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.
The most important adverse reactions are autoimmunity (ITP, thyroid disorders, nephropathies, cytopenias), IARs, and infections (see Section 4.4 Special Warnings and Precautions for Use).
The most common adverse reactions with alemtuzumab (in ≥ 20% of patients) were rash, headache, and pyrexia.

Tabulated list of adverse reactions.

The tables are based on pooled safety data on all alemtuzumab 12 mg-treated patients during studies 1 and 2 (Table 1) and all available follow up in clinical trials (Table 2).
Study 1 and Study 2 were 2-year active-controlled trials in MS patients treated with alemtuzumab 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 microgram 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 (CAMMS0309) was an open label uncontrolled extension study to evaluate the long term safety and efficacy (4 additional years) of Lemtrada in patients from Study 1 and 2.
Table 1 and Table 2 lists adverse reactions occurring in ≥ 5% of patients, listed by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT).

Safety profile in long-term follow up.

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 3-6 as compared to years 1 and 2. The rate of thyroid adverse reactions was highest in year three and declined thereafter.

Post-marketing experience.

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.
The following adverse reactions were identified during post-approval use of alemtuzumab for the treatment of relapsing forms of multiple sclerosis (MS): (For additional information see Section 4.4 Special Warnings and Precautions for Use).

Nervous system disorders.

Stroke, including haemorrhagic and ischaemic.

Vascular disorders.

Cervicocephalic arterial dissection (including cases with multiple arterial dissections).

Hepatobiliary disorders.

Cases of cholecystitis including acalculous cholecystitis and acute acalculous cholecystitis have been reported with Lemtrada. Autoimmune hepatitis.

Infections and infestations.

Cytomegalovirus infections have been reported in Lemtrada- treated patients with concomitant corticosteroid use.

Respiratory, thoracic and mediastinal disorders.

Pulmonary alveolar haemorrhage.

Blood and lymphatic system disorders.

Haemophagocytic lymphohistiocytosis, cases of severe (including fatal) neutropenia.

Cardiac disorders.

Myocardial infarction and myocardial ischaemia.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Lemtrada treatment should be initiated and supervised by a neurologist. Specialists and equipment required for the timely diagnosis and management of serious adverse reactions, especially autoimmune conditions and infections, should be available.
Facilities for the management of hypersensitivity and/or anaphylactic reactions should be available.
Patients treated with Lemtrada must be given the Patient Wallet Card and Patient Guide and be informed about the risks of Lemtrada.
The recommended dose of Lemtrada is 12 mg/day administered by IV infusion for 2 or more treatment courses.

Initial treatment of two 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 course(s).

Additional treatment with a third or fourth course: 12 mg/day on 3 consecutive days (36 mg total dose) administrated at least 12 months after the prior treatment course (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Follow-up of patients.

The therapy is recommended as an initial treatment of 2 courses with safety follow-up of patients from initiation of the first treatment course and until 48 months after the last infusion of the second treatment course. If an additional course is administered, continue safety follow-up until 48 months after the last infusion.

Recommended concomitant medication.

Patients should be premedicated with corticosteroids immediately prior to Lemtrada administration on the first 3 days of any treatment course. In clinical trials, patients were pretreated with 1000 mg methylprednisolone on the first 3 days of each Lemtrada treatment course. 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 Section 4.4 Special Warnings and Precautions for Use, Infections). In clinical trials, patients were administered aciclovir 200 mg BID or equivalent.

Patients with renal or hepatic impairment.

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

Elderly population.

Clinical studies of Lemtrada did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.

Paediatric population.

The safety and efficacy of alemtuzumab in MS patients below the age of 18 years of age has not yet been established.

Administration.

Lemtrada should be administered by IV infusion over a period of approximately 4 hours.
Lemtrada vials should be inspected for particulate matter and discoloration prior to administration. Do not use if particulate matter is present or the solution is discoloured.
For IV administration, withdraw 1.2 mL of Lemtrada from the vial and inject into 100 mL sterile 0.9% sodium chloride or 5% dextrose/glucose in water. Gently invert the bag to mix the solution.
Lemtrada contains no antimicrobial preservatives and therefore care should be taken to ensure the sterility of the prepared solution. Product is for single use in one patient only.
To reduce microbiological hazard, use as soon as practical after preparation. Lemtrada diluted product may be stored for not more than 6 hours at room temperature (15° to 25°C) or for not more than 8 hours at refrigerated conditions (2° to 8°C). Protect from light. Partially used, unused, or damaged drug vials should be disposed of in accordance with local requirements.
There are no known incompatibilities between Lemtrada and PVC infusion bags, or PVC or polyethylene lined PVC administration sets or low protein binding filters.

4.7 Effects on Ability to Drive and Use Machines

No studies of the effect of Lemtrada on the ability to drive and handle machines have been performed.

4.9 Overdose

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 Lemtrada overdosage. Treatment consists of drug discontinuation and supportive therapy.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

8.0 mg sodium chloride, 1.15 mg dibasic sodium phosphate, 0.2 mg potassium chloride, 0.2 mg monobasic potassium phosphate, 0.1 mg polysorbate 80, 0.0187 mg disodium edetate, and water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Lemtrada vials should be stored at 2° to 8°C. Do not freeze or shake. Protect from light.

6.5 Nature and Contents of Container

Lemtrada is provided as a sterile, clear, colourless to slightly yellow concentrate solution for infusion with pH 7.0-7.4, containing no antimicrobial preservatives. It is supplied in a clear, single use, 2 mL glass vial, with a latex-free stopper. Each 2 mL Lemtrada vial is filled to deliver 1.2 mL of 10 mg/mL solution (12 mg alemtuzumab).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes