DESCRIPTION SECTION

11 DESCRIPTION

Alemtuzumab is a recombinant humanized IgG1 kappa monoclonal antibody directed against the cell surface glycoprotein, CD52. Alemtuzumab has an approximate molecular weight of 150 kD. Alemtuzumab is produced in mammalian cell (Chinese hamster ovary) suspension culture in a nutrient medium containing neomycin. Neomycin is not detectable in the final product.

LEMTRADA (alemtuzumab) injection is a sterile, clear and colorless to slightly yellow, solution (pH 7.2 ± 0.2) for intravenous infusion.

Each 1 mL of solution contains 10 mg alemtuzumab, dibasic sodium phosphate (1.15 mg), disodium edetate dihydrate (0.0187 mg), polysorbate 80 (0.1 mg), potassium chloride (0.2 mg), potassium dihydrogen phosphate (0.2 mg), sodium chloride (8 mg), and Water for Injection, USP.

INDICATIONS & USAGE SECTION

Highlight: * LEMTRADA is a CD52-directed cytolytic monoclonal antibody indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, the use of LEMTRADA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS. (1.5)
Limitations of Use:
LEMTRADA is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile. (1.5)

1 INDICATIONS AND USAGE

LEMTRADA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, the use of LEMTRADA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS [see Warnings and Precautions (5)].

Limitations of Use

LEMTRADA is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile [see Warnings and Precautions (5)].

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Injection: 12 mg/1.2 mL (10 mg/mL) in a single-dose vial. (3)

3 DOSAGE FORMS AND STRENGTHS

Injection: 12 mg/1.2 mL (10 mg/mL) in a single-dose vial. LEMTRADA is a clear and colorless to slightly yellow solution that requires dilution prior to intravenous infusion.

CONTRAINDICATIONS SECTION

Highlight: * Known hypersensitivity or anaphylactic reactions to alemtuzumab or any of the excipients in LEMTRADA (4)

• Infection with Human Immunodeficiency Virus (4)
• Active infection (4)

4 CONTRAINDICATIONS

LEMTRADA is contraindicated in patients:

• with known hypersensitivity or anaphylactic reactions to alemtuzumab or any of the excipients in LEMTRADA
• who are infected with human immunodeficiency virus (HIV) because LEMTRADA causes prolonged reductions of CD4+ lymphocyte counts
• with active infection

BOXED WARNING SECTION

WARNING: AUTOIMMUNITY, INFUSION REACTIONS, STROKE, AND MALIGNANCIES

USE IN SPECIFIC POPULATIONS SECTION

Highlight: Pregnancy: May cause fetal harm. (8.1)

Women of childbearing potential should use effective contraception during and for 4 months after a course of treatment with LEMTRADA. (8.3)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of LEMTRADA in pregnant women. LEMTRADA was embryolethal in pregnant huCD52 transgenic mice when administered during organogenesis [see Animal data]. Auto-antibodies may develop after administration of LEMTRADA. Placental transfer of anti-thyroid antibodies resulting in neonatal Graves' disease has been reported.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

There is a pregnancy surveillance program for LEMTRADA. If LEMTRADA exposure occurs during pregnancy, healthcare providers and patients are encouraged to report pregnancies by calling 1-800-745-4447, option 2.

Clinical Considerations

LEMTRADA induces persistent thyroid disorders [see Warnings and Precautions (5.8)]. Untreated hypothyroidism in pregnant women increases the risk for miscarriage and may have effects on the fetus including mental retardation and dwarfism. In mothers with Graves' disease, maternal thyroid stimulating hormone receptor antibodies can be transferred to a developing fetus and can cause neonatal Graves' disease. In a patient who developed Graves' disease after treatment with alemtuzumab, placental transfer of anti-thyrotropin receptor antibodies resulted in neonatal Graves' disease with thyroid storm in her infant who was born 1 year after alemtuzumab dosing [see Warnings and Precautions (5.1)].

Data

Animal data

When LEMTRADA was administered to pregnant huCD52 transgenic mice during organogenesis (gestation days [GD] 6–10 or GD 11–15) at doses of 3 or 10 mg/kg IV, no teratogenic effects were observed. However, there was an increase in embryolethality (increased postimplantation loss and the number of dams with all fetuses dead or resorbed) in pregnant animals dosed during GD 11–15. In a separate study in pregnant huCD52 transgenic mice, administration of LEMTRADA during organogenesis (GD 6–10 or GD 11–15) at doses of 3 or 10 mg/kg IV, decreases in B- and T-lymphocyte populations were observed in the offspring at both doses tested.

In pregnant huCD52 transgenic mice administered LEMTRADA at doses of 3 or 10 mg/kg/day IV throughout gestation and lactation, there was an increase in pup deaths during the lactation period at 10 mg/kg. Decreases in T- and B-lymphocyte populations and in antibody response were observed in offspring at both doses tested.

8.2 Lactation

Risk Summary

There are no data on the presence of alemtuzumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Alemtuzumab was detected in the milk of lactating huCD52 transgenic mice administered LEMTRADA [see Animal data].

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LEMTRADA and any potential adverse effects on the breastfed child from LEMTRADA or from the underlying maternal conditions.

Data

Animal data

Alemtuzumab was detected in the milk of lactating huCD52 transgenic mice following intravenous administration of LEMTRADA at a dose of 10 mg/kg on postpartum days 8–12. Serum levels of alemtuzumab were similar in lactating mice and offspring on postpartum Day 13 and were associated with evidence of pharmacological activity (decrease in lymphocyte counts) in the offspring.

8.3 Females and Males of Reproductive Potential

Contraception

Before initiation of LEMTRADA treatment, women of childbearing potential should be counselled on the potential for a serious risk to the fetus. To avoid in utero exposure to LEMTRADA, 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 [see Use in Specific Populations (8.1)].

Infertility

In huCD52 transgenic mice, administration of LEMTRADA prior to and during the mating period resulted in adverse effects on sperm parameters in males and reduced number of corpora lutea and implantations in females [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients less than 17 years of age have not been established. Use of LEMTRADA is not recommended in pediatric patients due to the risks of autoimmunity, infusion reactions, and stroke, and because it may increase the risk of malignancies (thyroid, melanoma, lymphoproliferative disorders, and lymphoma) [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4)].

8.5 Geriatric Use

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

ADVERSE REACTIONS SECTION

Highlight: Most common adverse reactions (incidence ≥10% and > interferon beta-1a): rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticaria, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-745-4447, option 2 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch**.**

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

• Autoimmunity [see Boxed Warning and Warnings and Precautions (5.1)]
• Infusion Reactions [see Boxed Warning and Warnings and Precautions (5.2)]
• Stroke and Cervicocephalic Arterial Dissection [see Warnings and Precautions (5.3)]
• Malignancies [see Warnings and Precautions (5.4)]
• Immune Thrombocytopenia [see Warnings and Precautions (5.6)]
• Glomerular Nephropathies Including Anti-glomerular Basement Membrane Disease [see Warnings and Precautions (5.7)]
• Thyroid Disorders [see Warnings and Precautions (5.8)]
• Other Autoimmune Cytopenias [see Warnings and Precautions (5.9)]
• Autoimmune Hepatitis [see Warnings and Precautions (5.10)]
• Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.11)]
• Adult Onset Still's Disease [see Warnings and Precautions (5.12)]
• Thrombotic Thrombocytopenic Purpura (TTP) [see Warnings and Precautions (5.13)]
• Autoimmune Encephalitis (AIE) [see Warnings and Precautions (5.14)]
• Acquired Hemophilia A [see Warnings and Precautions (5.15)]
• Infections [see Warnings and Precautions (5.16)]
• Progressive Multifocal Leukoencephalopathy (PML) [see Warnings and Precautions (5.17)]
• Acute Acalculous Cholecystitis [see Warnings and Precautions (5.18)]
• Pneumonitis [see Warnings and Precautions (5.19)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In controlled clinical trials (Study 1 and Study 2), a total of 811 patients with relapsing forms of MS received LEMTRADA. The population was 18 to 55 years of age, 65% were female, and 92% were Caucasian. A total of 811 patients received 1 course of therapy, and 789 patients received a second course of therapy at 12 months. The overall follow-up in the controlled trials was equivalent to 1622 patient years.

In MS clinical studies (controlled and open-label extension), overall, a total of 1217 patients received LEMTRADA. Approximately 60% of patients received a total of 2 treatment courses and approximately 24% of patients received a total of 3 treatment courses; others received a total of 4 or more treatment courses, although data beyond 3 treatment courses are limited. The overall follow-up was 6858 person-years. Patients had a median of 6 years of follow-up from the first LEMTRADA dose, with approximately 14% having at least 7 years of follow-up.

Most Common Adverse Reactions

In controlled clinical trials, the most common adverse reactions with LEMTRADA (in at least 10% of patients and more frequently than in interferon beta-1a) were rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticaria, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting.

Table 1 lists adverse reactions occurring in ≥5% of LEMTRADA-treated patients in Study 1 and 2 and at the same or at a higher rate than interferon beta-1a.

6.2 Lymphopenia

Nearly all (99.9%) patients treated with LEMTRADA in MS clinical trials experienced lymphopenia. The lowest lymphocyte counts occurred approximately by 1 month after each course of treatment. The mean lymphocyte count at 1 month after LEMTRADA treatment was 0.25 × 109 L (range 0.02–2.30 × 109 L) and 0.32 (0.02–1.81 × 109 L) for treatment courses 1 and 2, respectively. Total lymphocyte counts increased to reach the lower limit of normal in approximately 40% of patients by 6 months after each LEMTRADA treatment course and approximately 80% of patients by 12 months after each course [see Clinical Pharmacology (12.2)].

6.3 Suicidal Behavior or Ideation

In clinical studies, 0.6% of patients in both the LEMTRADA and interferon beta-1a groups had events of attempted suicide or suicidal ideation. There were no completed suicides in either clinical study treatment group. Suicidal behavior or ideation occurred in patients with or without a history of a psychiatric or thyroid disorder. Advise patients to report immediately any symptoms of depression or suicidal ideation to the prescribing physician.

6.4 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The incidence of antibodies is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including inhibitory antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to LEMTRADA with the incidence of antibodies to other products may be misleading.

Using an enzyme-linked immunosorbent assay (ELISA) and a competitive binding assay, anti-alemtuzumab binding antibodies were detected in 62%, 67%, and 29% of LEMTRADA-treated patients, at months 1, 3, and 12 (Course 1) as well as 83%, 83%, and 75% of LEMTRADA-treated patients at months 13, 15, and 24 (Course 2). Samples that tested positive for binding antibodies were further evaluated for evidence of in vitro inhibition using a flow cytometry assay. Neutralizing antibodies were detected in 87%, 46%, and 5% of positive binding antibody patients at months 1, 3, and 12 (Course 1) as well as 94%, 88%, and 42% of positive binding antibody patients at months 13, 15, and 24 (Course 2). Anti-alemtuzumab antibodies were associated with decreased alemtuzumab concentration during Course 2, but not Course 1. Through 2 treatment courses, there was no evidence from clinical trials that the presence of binding or inhibitory anti-alemtuzumab antibodies had a significant effect on clinical outcomes, total lymphocyte count, or adverse events. High titer anti- alemtuzumab antibodies, which were observed in 13 patients, were associated with incomplete lymphocyte depletion following a third or fourth treatment course, but there was no clear effect of anti-alemtuzumab antibodies on the clinical efficacy or safety profile of LEMTRADA.

6.5 Postmarketing Experience

The following adverse reactions have been identified during post approval use of alemtuzumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Postmarketing Experience with LEMTRADA

Blood and Lymphatic System Disorders: Acquired hemophilia A [see Warnings and Precautions (5.15)], neutropenia, thrombocytopenia [see Warnings and Precautions (5.2)], thrombotic thrombocytopenic purpura [see Warnings and Precautions (5.13)]

Cerebrovascular Disorders: Stroke, including hemorrhagic and ischemic stroke and cervicocephalic arterial dissection [see Warnings and Precautions (5.3)]

Gastrointestinal System Disorders: Cholecystitis, including acalculous cholecystitis and acute acalculous cholecystitis [see Warnings and Precautions (5.18)]

Hepatobiliary Disorders: Autoimmune hepatitis [see Warnings and Precautions (5.10)], viral hepatitis [see Warnings and Precautions (5.16)]

Infections and Infestations: Opportunistic infections [see Warnings and Precautions (5.16)], Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.17)]

Immune System Disorders: Autoimmune hepatitis, vasculitis, Guillain-Barré syndrome [see Warnings and Precautions (5.1)], hemophagocytic lymphohistiocytosis [see Warnings and Precautions (5.11)], sarcoidosis

Musculoskeletal and Connective Tissue Disorders: Adult Onset Still's Disease [see Warnings and Precautions (5.12)]

Nervous System Disorders: Autoimmune encephalitis [see Warnings and Precautions (5.14)], myasthenia gravis, Lambert-Eaton myasthenic syndrome

Pulmonary System Disorders: Pulmonary alveolar hemorrhage [see Warnings and Precautions (5.2)]

Skin and Subcutaneous Tissue Disorders: Alopecia

Postmarketing Experience with CAMPATH

CAMPATH is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) and is generally administered at higher and more frequent doses (e.g., 30 mg) than recommended in the treatment of MS.

Cardiac Disorders: Congestive heart failure, cardiomyopathy, and decreased ejection fraction in non-MS patients previously treated with potentially cardiotoxic agents.

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

The efficacy of LEMTRADA was demonstrated in two studies (Study 1 and 2) that evaluated LEMTRADA 12 mg in patients with relapsing-remitting multiple sclerosis (RRMS). LEMTRADA was administered by intravenous infusion once daily over a 5-day course, followed one year later by intravenous infusion once daily over a 3-day course. Both studies included patients who had experienced at least 2 relapses during the 2 years prior to trial entry and at least 1 relapse during the year prior to trial entry. Neurological examinations were performed every 12 weeks and at the time of suspected relapse. Magnetic resonance imaging (MRI) evaluations were performed annually.

Study 1

Study 1 was a 2-year randomized, open-label, rater-blinded, active comparator (interferon beta-1a 44 micrograms administered subcutaneously three times a week) controlled study in patients with RRMS. Patients entering Study 1 had Expanded Disability Status Scale (EDSS) scores of 5 or less and had to have experienced at least one relapse while on interferon beta or glatiramer acetate therapy.

Patients were randomized to receive LEMTRADA (n=426) or interferon beta-1a (n=202). At baseline, the mean age was 35 years, the mean disease duration was 4.5 years, and the mean EDSS score was 2.7.

The clinical outcome measures were the annualized relapse rate (ARR) over 2 years and the time to confirmed disability progression. Confirmed disability progression was defined as at least a 1 point increase above baseline EDSS (1.5 point increase for patients with baseline EDSS of 0) sustained for 6 months. The MRI outcome measure was the change in T2 lesion volume.

The annualized relapse rate was significantly lower in patients treated with LEMTRADA than in patients who received interferon beta-1a. Time to onset of 6-month confirmed disability progression was significantly delayed with LEMTRADA treatment compared to interferon beta-1a. There was no significant difference between the treatment groups for the change in T2 lesion volume. The results of Study 1 are shown in Table 2 and Figure 1.

Figure 1: Time to 6-month Confirmed Disability Progression (Study 1)

Study 2

Study 2 was a 2-year randomized, open-label, rater-blinded, active comparator (interferon beta-1a 44 micrograms administered subcutaneously three times a week) controlled study in patients with RRMS. Patients entering Study 2 had EDSS scores of 3 or less and no prior treatment for multiple sclerosis.

Patients were randomized to receive LEMTRADA (n=376) or interferon beta-1a (n=187). At baseline, the mean age was 33 years, the mean disease duration was 2 years, and the mean EDSS score was 2.

The clinical outcome measures were the annualized relapse rate (ARR) over 2 years and the time to confirmed disability progression, as defined in Study 1. The MRI outcome measure was the change in T2 lesion volume.

The annualized relapse rate was significantly lower in patients treated with LEMTRADA than in patients who received interferon beta-1a. There was no significant difference between the treatment groups for the time to confirmed disability progression and for the primary MRI endpoint (change in T2 lesion volume). The results for Study 2 are shown in Table 3.

OVERDOSAGE SECTION

10 OVERDOSAGE

Two MS patients experienced serious reactions (headache, rash, and either hypotension or sinus tachycardia) after a single accidental infusion up to 60 mg of LEMTRADA. Doses of LEMTRADA greater than those recommended may increase the intensity and/or duration of infusion reactions or its immune effects. There is no known antidote for alemtuzumab overdosage.

INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Autoimmunity

• Advise patients to contact their healthcare provider promptly if they experience any symptoms of potential autoimmune disease. Give examples of important symptoms such as bleeding, easy bruising, petechiae, purpura, hematuria, edema, jaundice, or hemoptysis [see Warnings and Precautions (5.1)].
• Advise patients of the importance of monthly blood and urine tests for 48 months following the last course of LEMTRADA to monitor for signs of autoimmunity because early detection and prompt treatment can help prevent serious and potentially fatal outcomes associated with these events. Advise patients that monitoring may need to continue past 48 months if they have signs or symptoms of autoimmunity.
• Advise patients that LEMTRADA may cause hyperthyroid or hypothyroid disorders.
• Advise patients to contact their healthcare provider if they experience symptoms reflective of a potential thyroid disorder such as unexplained weight loss or gain, fast heartbeat or palpitations, nervousness, worsening tiredness, eye swelling, constipation, or feeling cold.
• Advise women of childbearing potential of the risks of pregnancy with concomitant thyroid disease. Advise women of childbearing potential to discuss pregnancy planning with their doctor.
• Cases of autoimmune hepatitis have been reported in patients treated with LEMTRADA. Advise patients to contact their healthcare provider right away if they develop signs or symptoms suggestive of hepatic dysfunction such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine, or bleeding or bruising more easily than normal.
• Advise patients to contact their healthcare provider if they experience symptoms of acquired hemophilia A such as spontaneous bruising, nose bleeds, painful or swollen joints, other types of bleeding, or bleeding from a cut that may take longer than usual to stop.
• Advise patients that cases of autoimmune encephalitis can occur after receiving LEMTRADA. This condition may include symptoms such as behavior and psychiatric changes, movement disorders, short-term memory loss or seizures, as well as other symptoms that may resemble an MS relapse.

Infusion Reactions

• Advise patients that infusion reactions can occur at the time of infusion or after they leave the infusion center [see Warnings and Precautions (5.2)].
• Instruct the patient to remain at the infusion center for at least 2 hours after each LEMTRADA infusion, or longer at the discretion of the healthcare provider. Advise patients that symptoms of infusion reactions may occur after they leave the infusion center and to report these symptoms to their healthcare provider.
• Advise patients that their healthcare provider will monitor vital signs, including blood pressure, before and during the infusion and to contact their healthcare provider promptly if they experience infusion reactions, which include swelling in the mouth or throat, difficulty breathing, weakness, abnormal heart rate (fast, slow, or irregular), chest pain, rash, facial drooping, sudden severe headache, weakness on one side of the body, difficulty with speech, or neck pain.
• Instruct patients that there have also been reports of rare but serious infusion reactions, including bleeding in the lung, chest tightness/pain or discomfort, heart attack, and stroke or tears in blood vessels supplying the brain, which should be reported to your healthcare provider.
• Advise patients that 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.

Stroke and Cervicocephalic Arterial Dissection

• Educate patients on the symptoms and instruct patients to seek immediate medical attention if symptoms of stroke or cervicocephalic arterial dissection occur (e.g., neck pain, weakness on one side, facial droop, difficulty with speech, sudden severe headache) [see Warnings and Precautions (5.3)].

Malignancies

• Advise patients that LEMTRADA may increase their risk of malignancies including thyroid cancer and melanoma [see Warnings and Precautions (5.4)].
• Advise patients to report symptoms of thyroid cancer, including a new lump or swelling in the neck, pain in the front of the neck, hoarseness or other voice changes that do not go away, trouble swallowing or breathing, or a constant cough not due to a cold.
• Advise patients that they should have baseline and yearly skin examinations.

LEMTRADA REMS Program

• LEMTRADA is available only through a restricted program called the LEMTRADA REMS Program [see Warnings and Precautions (5.5)]. Inform the patient of the following notable requirements:
  • Patients and providers must be enrolled in the program.
  • Patients must comply with the ongoing monitoring requirements.
  • Patients must report any side effects or symptoms to their doctor.
• LEMTRADA is available only at certified infusion centers participating in the program. Therefore, provide patients with information on the LEMTRADA REMS Program in order to locate an infusion center.
• Advise patients to read the LEMTRADA REMS material for patients, LEMTRADA Treatment and Infusion Reactions Patient Guide.
• Instruct patients to carry the LEMTRADA REMS Patient Safety Information Card with them in case of an emergency.

Hemophagocytic Lymphohistiocytosis

• Inform patients that treatment with LEMTRADA may increase the risk of a type of excessive immune activation (hemophagocytic lymphohistiocytosis), which can be fatal, particularly if not diagnosed and treated early.
• Advise patients to contact their healthcare provider immediately if they experience symptoms such as fever, swollen glands, skin rash, or new neurologic symptoms such as mental status changes, ataxia, or seizures.
• In cases reported with LEMTRADA, symptoms occurred within approximately thirteen months to thirty-three months following the initiation of treatment.

Adult Onset Still's Disease (AOSD)

• Inform patients that AOSD is a rare condition that has the potential to cause multi-organ inflammation with several symptoms such as fever >39°C or 102.2°F lasting more than 1 week, pain, stiffness with or without swelling in multiple joints, and/or a skin rash [see Warnings and Precautions (5.12)].
• Instruct patients if they experience a combination of these symptoms to contact their healthcare provider immediately.

Thrombotic Thrombocytopenic Purpura

• Inform patients that there have been reports of TTP in patients treated with LEMTRADA and that this is a potentially life-threatening condition [see Warnings and Precautions (5.13)].
• Instruct patients to get prompt medical attention if they experience symptoms of TTP such as fever, fatigue, pallor, purpura, jaundice, tachycardia, dyspnea, hematuria, dark-colored urine, decreased urine volume, abdominal pain, nausea, vomiting, or new neurological symptoms such as confusion, altered mental status, vision or speech changes, or seizures.

Infections

• Advise patients to contact their healthcare provider if they develop symptoms of serious infection such as fatigue, fever, or swollen glands [see Warnings and Precautions (5.16)].
• Advise patients to complete any necessary immunizations at least 6 weeks prior to treatment with LEMTRADA [see Dosage and Administration (2.1)]. Advise patients that they should talk to their healthcare provider before taking any vaccine after recent treatment with LEMTRADA [see Warnings and Precautions (5.16)].
• Advise patients to avoid or adequately heat foods that are potential sources of Listeria monocytogenes prior to receiving LEMTRADA and if they have had a recent course of LEMTRADA. The duration of increased risk for Listeria infection after LEMTRADA administration is not known. Inform patients that Listeria infection can lead to significant complications or death [see Warnings and Precautions (5.16)].
• Advise patients to take their prescribed medication for herpes prophylaxis as directed by their healthcare provider [see Warnings and Precautions (5.16)].
• Advise patients that yearly HPV screening is recommended [see Warnings and Precautions (5.16)].

Progressive Multifocal Leukoencephalopathy

• Inform patients that progressive multifocal leukoencephalopathy (PML) has occurred in a patient who received LEMTRADA. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that 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 [see Warnings and Precautions (5.17)].

Acute Acalculous Cholecystitis

• Advise patients to report symptoms of acute acalculous cholecystitis. These include abdominal pain, abdominal tenderness, fever, nausea, and vomiting [see Warnings and Precautions (5.18)].

Pneumonitis

• Advise patients that pneumonitis has been reported in patients treated with LEMTRADA [see Warnings and Precautions (5.19)]. Advise patients to report symptoms of lung disease such as shortness of breath, cough, wheezing, chest pain or tightness, and hemoptysis.

Concomitant Use of CAMPATH

• Advise patients that alemtuzumab is the same drug as CAMPATH for use in B-CLL. Patients should inform their healthcare provider if they have taken CAMPATH [see Warnings and Precautions (5.20)].

Fetal Risk

• Inform patients that LEMTRADA may cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise women of childbearing age of the need for effective contraception during LEMTRADA treatment and for 4 months after a treatment course of LEMTRADA. Advise the patient that if she should nevertheless become pregnant, she should immediately inform her physician.
• Advise patients exposed to LEMTRADA during pregnancy that there is a pregnancy safety surveillance program that monitors pregnancy outcomes [see Use in Specific Populations (8.1)]. If exposure occurs during pregnancy, healthcare providers and patients are encouraged to report pregnancies by calling 1-800-745-4447, option 2.

SPL MEDGUIDE SECTION

**Serious autoimmune problems.** Some people receiving LEMTRADA develop a condition where the immune cells in your body attack other cells or organs in the body (autoimmunity) which can be serious and may cause death. Serious autoimmune problems may include:

**Serious infusion reactions.** LEMTRADA can cause serious infusion reactions that may cause death. Serious infusion reactions may happen while you receive, or up to 24 hours or longer after you receive LEMTRADA.  

**Stroke and tears in your arteries that supply blood to your brain (carotid and vertebral arteries).** Some people have had serious and sometimes deadly strokes and tears in their carotid or vertebral arteries within 3 days of receiving LEMTRADA. Get help right away if you have any of the following symptoms that may be signs of a stroke or tears in your carotid or vertebral arteries:

**Certain cancers.** Receiving LEMTRADA may increase your chance of getting some kinds of cancers, including thyroid cancer, skin cancer (melanoma), and blood cancers called lymphoproliferative disorders and lymphoma. Call your healthcare provider if you have the following symptoms that may be a sign of thyroid cancer:

excessive sweating

unexplained weight loss

fast heartbeat

eye swelling

nervousness

unexplained weight gain

feeling cold

worsening tiredness

constipation

SPL UNCLASSIFIED SECTION

Manufactured and distributed by:
Genzyme Corporation
Cambridge, MA 02141
A SANOFI COMPANY
US License Number: 1596

LEMTRADA and CAMPATH are registered trademarks of Genzyme Corporation. ©2024 Genzyme Corporation.