Lemtrada

Overdose

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.

Contraindications

LEMTRADA is contraindicated in patients who are infected with Human Immunodeficiency Virus (HIV) because LEMTRADA causes prolonged reductions of CD4+ lymphocyte counts.

Undesirable effects

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

• Autoimmunity
• Infusion Reactions
• Malignancies
• Immune Thrombocytopenia
• Glomerular Nephropathies
• Thyroid Disorders
• Other Autoimmune Cytopenias
• Infections
• Acute Acalculous Cholecystitis
• Pneumonitis

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. 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, with an additional 3411 person-years of follow-up in an open-label extension study. The population was 18-55 years of age, 65% were female, and 92% were Caucasian.

In 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.

Table 1: Adverse Reactions in the Pooled 2-Year Active-Controlled Studies in Patients with Relapsing-Remitting Multiple Sclerosis

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 x 109 L (range 0.02-2.30 x 109 L) and 0.32 (0.02-1.81 x 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.

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.

As with all therapeutic proteins, there is potential for immunogenicity. 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, 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, 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. 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.

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.

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.

Gastrointestinal System Disorders: Acute acalculous cholecystitis.

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.

Therapeutic indications

LEMTRADA is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS). 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.

Pharmacodynamic properties

LEMTRADA depletes circulating T and B lymphocytes after each treatment course. In clinical trials, the lowest cell counts occurred 1 month after a course of treatment at the time of the first post-treatment blood count. Lymphocyte counts then increased over time: B cell counts usually recovered within 6 months; T cell counts increased more slowly and usually remained below baseline 12 months after treatment. Approximately 60% of patients had total lymphocyte counts below the lower limit of normal 6 months after each treatment course and 20% had counts below the lower limit of normal after 12 months.

Reconstitution of the lymphocyte population varies for the different lymphocyte subtypes. At Month 1 in clinical trials, the mean CD4+ lymphocyte count was 40 cells per microliter, and, at Month 12, 270 cells per microliter. At 30 months, approximately half of patients had CD4+ lymphocyte counts that remained below the lower limit of normal.

In a study of 53 MS patients, alemtuzumab 12 mg per day for 5 days caused no changes in the QTc interval greater than 20 ms. An average 22 to 26 beats-per-minute increase in heart rate was observed for at least 2 hours after the first but not subsequent infusions.

Pharmacokinetic properties

The pharmacokinetics of LEMTRADA were evaluated in a total of 148 patients with relapsing forms of MS who received 12 mg/day on 5 consecutive days, followed by 12 mg/day on 3 consecutive days 12 months following the first treatment course.

Serum concentrations increased with each consecutive dose within a treatment course, with the highest observed concentrations occurring following the last infusion of a treatment course. The mean maximum concentration was 3014 ng/mL on Day 5 of the first treatment course, and 2276 ng/mL on Day 3 of the second treatment course.

LEMTRADA is largely confined to the blood and interstitial space with a central volume of distribution of 14.1 L.

The elimination half-life was approximately 2 weeks and was comparable between courses. The serum concentrations were generally undetectable (<60 ng/mL) within approximately 30 days following each treatment course.

Date of revision of the text

Fertility, pregnancy and lactation

There are no adequate and well-controlled studies in pregnant women. LEMTRADA was embryolethal in pregnant huCD52 transgenic mice when administered during organogenesis. Auto-antibodies may develop after administration of LEMTRADA. Placental transfer of antithyroid antibodies resulting in neonatal Graves' disease has been reported. LEMTRADA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 post-implantation 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 lymphocytes and T-lymphocyte populations were observed in the offspring at both doses tested. The effects of LEMTRADA, administered during organogenesis, on postnatal development have not been adequately assessed.

To avoid in utero exposure to LEMTRADA, 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.

LEMTRADA induces persistent thyroid disorders. 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.

Qualitative and quantitative composition

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

Each LEMTRADA carton (NDC: 58468-0200-1) contains 1 single-use vial that delivers 12 mg/1.2 mL (10 mg/mL). The vial stopper is not made with natural rubber latex.

LEMTRADA is a sterile, clear and colorless to slightly yellow solution for infusion, containing no antimicrobial preservatives.

Store LEMTRADA vials at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Store in original carton to protect from light.

Manufactured and distributed by: Genzyme Corporation 500 Kendall Street Cambridge, MA 02142. Revised: Dec 2017

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Treatment with LEMTRADA can result in the formation of autoantibodies and increase the risk of serious autoimmune mediated conditions. In clinical studies, LEMTRADA-treated patients experienced thyroid disorders (34%), immune thrombocytopenia (2%), and glomerular nephropathies (0.3%). Autoimmune hemolytic anemia and autoimmune pancytopenia , undifferentiated connective tissue disorders, and acquired hemophilia A (anti-Factor VIII antibodies) each occurred in 0.2% of patients. Rheumatoid arthritis, type I diabetes, vitiligo, and retinal pigment epitheliopathy occurred in 0.1% of patients.

During postmarketing use, additional autoimmune events including Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy have been reported in the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL), as well as other disorders, generally at higher and more frequent doses than recommended in MS. An oncology patient treated with alemtuzumab had fatal transfusion-associated graft-versus-host disease.

Autoantibodies may be transferred from the mother to the fetus during pregnancy. A case of transplacental transfer of anti-thyrotropin receptor antibodies resulting in neonatal Graves' disease occurred after alemtuzumab treatment in the mother.

LEMTRADA may increase the risk of other autoimmune conditions because of the broad range of autoantibody formation with LEMTRADA.

Monitor complete blood counts with differential, serum creatinine levels, and urinalysis with urine cell counts before starting treatment and then at monthly intervals for 48 months after the last dose of LEMTRADA to allow for early detection and treatment of autoimmune adverse reactions. After 48 months, testing should be performed based on clinical findings suggestive of autoimmunity.

LEMTRADA is available only through a restricted program under a REMS.

LEMTRADA causes cytokine release syndrome resulting in infusion reactions, some of which may be serious and life threatening. In clinical studies, 92% of LEMTRADA-treated patients experienced infusion reactions. In some patients, infusion reactions were reported more than 24 hours after LEMTRADA infusion. Serious reactions occurred in 3% of patients and included anaphylaxis in 2 patients (including anaphylactic shock), angioedema, bronchospasm, hypotension, chest pain, bradycardia, tachycardia (including atrial fibrillation), transient neurologic symptoms, hypertension, headache, pyrexia, and rash. Other infusion reactions included nausea, urticaria, pruritus, insomnia, chills, flushing, fatigue, dyspnea, pulmonary infiltrates, dysgeusia, dyspepsia, dizziness, and pain. In clinical studies, 0.6% of patients with infusion reactions received epinephrine or atropine.

During postmarketing use, other serious and sometimes fatal infusion reactions included hypoxia, syncope, acute respiratory distress syndrome, respiratory arrest, myocardial infarction, acute cardiac insufficiency, and cardiac arrest have been reported in the treatment of patients with B-CLL, as well as other disorders, generally at higher and more frequent doses than recommended in MS.

Premedicate patients with corticosteroids immediately prior to LEMTRADA infusion for the first 3 days of each treatment course. In clinical studies, patients received 1,000 mg of methylprednisolone for the first 3 days of each LEMTRADA treatment course. Consider pretreatment with antihistamines and/or antipyretics prior to LEMTRADA administration. Infusion reactions may occur despite pretreatment.

Consider additional monitoring in patients with medical conditions which predispose them to cardiovascular or pulmonary compromise.

LEMTRADA can only be administered in certified healthcare settings that have on-site access to equipment and personnel trained to manage infusion reactions (including anaphylaxis and cardiac and respiratory emergencies).

LEMTRADA is available only through a restricted program under a REMS.

LEMTRADA may increase the risk of thyroid cancer. In controlled clinical studies, 3 of 919 (0.3%) LEMTRADA-treated patients developed thyroid cancer, compared to none in the interferon beta-1a–treated group. However, screening for thyroid cancer was performed more frequently in the LEMTRADA-treated group, because of the higher incidence of autoimmune thyroid disorders in those patients. Two additional cases of thyroid cancer in LEMTRADA-treated patients occurred in uncontrolled studies.

Patients and healthcare providers should monitor for symptoms of thyroid cancer including a new lump or swelling in the neck, pain in the front of the neck, persistent hoarseness or other voice changes, trouble swallowing or breathing, or a constant cough not due to an upper respiratory tract infection.

LEMTRADA may increase the risk of melanoma. In uncontrolled studies, 4 of 1486 (0.3%) LEMTRADA-treated patients developed melanoma or melanoma in situ. One of those patients had evidence of locally advanced disease.

Perform baseline and yearly skin examinations to monitor for melanoma in patients receiving LEMTRADA.

Cases of lymphoproliferative disorders and lymphoma have occurred in LEMTRADA-treated patients with MS, including a MALT lymphoma, Castleman's Disease, and a fatality following treatment of non-Epstein Barr Virus–associated Burkitt's lymphoma. There are postmarketing reports of Epstein Barr Virus–associated lymphoproliferative disorders in non-MS patients.

Because LEMTRADA is an immunomodulatory therapy, caution should also be exercised in initiating LEMTRADA in patients with preexisting or ongoing malignancies.

LEMTRADA is available only through a restricted program under a REMS.

LEMTRADA is available only through a restricted program under a REMS called the LEMTRADA REMS Program because of the risks of autoimmunity, infusion reactions, and malignancies.

Notable requirements of the LEMTRADA REMS Program include the following:

• Prescribers must be certified with the program by enrolling and completing training.
• Patients must enroll in the program and comply with ongoing monitoring requirements.
• Pharmacies must be certified with the program and must only dispense to certified healthcare facilities that are authorized to receive LEMTRADA.
• Healthcare facilities must enroll in the program and verify that patients are authorized before infusing LEMTRADA. Healthcare facilities must have on-site access to equipment and personnel trained to manage infusion reactions.

Further information, including a list of qualified healthcare facilities, is available at 1-855-6766326.

Immune thrombocytopenia (ITP) occurred in 2% of LEMTRADA-treated patients in clinical studies in MS.

In a controlled clinical study in patients with MS, one LEMTRADA-treated patient developed ITP that went unrecognized prior to the implementation of monthly blood monitoring requirements, and died from intracerebral hemorrhage. Nadir platelet counts ≤20,000 cells per microliter as a result of ITP occurred in 2% of all LEMTRADA-treated patients in clinical studies in MS. Anti-platelet antibodies did not precede ITP onset. ITP has been diagnosed more than 3 years after the last LEMTRADA dose.

Symptoms of ITP include easy bruising, petechiae, spontaneous mucocutaneous bleeding (e.g., epistaxis, hemoptysis), and heavier than normal or irregular menstrual bleeding. Hemoptysis may also be indicative of anti-glomerular basement membrane (GBM) disease , and an appropriate differential diagnosis has to be undertaken. Remind the patient to remain vigilant for symptoms they may experience and to seek immediate medical help if they have any concerns.

Obtain complete blood counts (CBCs) with differential prior to initiation of treatment and at monthly intervals thereafter until 48 months after the last infusion. After this period of time, testing should be performed based on clinical findings suggestive of ITP. If ITP is suspected, a complete blood count should be obtained immediately. If ITP onset is confirmed, promptly initiate appropriate medical intervention.

Glomerular nephropathies occurred in 0.3% of LEMTRADA-treated patients in MS clinical studies. There were 3 cases of membranous glomerulonephritis and 2 cases of anti-glomerular basement membrane (anti-GBM) disease. There are published and postmarketing cases of MS patients treated with alemtuzumab who developed anti-GBM disease and subsequently developed end-stage renal disease requiring renal transplantation. Cases of anti-GBM disease have been diagnosed up to 40 months after the last dose of LEMTRADA. Urgent evaluation and treatment is required because anti-GBM disease can lead to renal failure requiring dialysis or transplantation and can be life-threatening if left untreated.

Clinical manifestations of nephropathy may include elevated serum creatinine levels, hematuria, or proteinuria. Alveolar hemorrhage manifested as hemoptysis is a common component of anti-GBM disease but did not occur in clinical studies.

Obtain serum creatinine levels and urinalysis with cell counts 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 nephropathies.

If clinically significant changes from baseline in serum creatinine, unexplained hematuria, or proteinuria are observed, perform further evaluation for nephropathies. Early detection and treatment of nephropathies may decrease the risk of poor outcomes.

Autoimmune thyroid disorders occurred in 34% of LEMTRADA-treated patients in clinical studies. Newly diagnosed thyroid disorders occurred throughout the uncontrolled clinical study follow-up period, more than 7 years after the first LEMTRADA dose. Autoimmune thyroid disorders included Graves' disease, hyperthyroidism and hypothyroidism. Graves' ophthalmopathy with decreased vision, eye pain, and exophthalmos occurred in 1% of LEMTRADA-treated patients. Two patients required surgical orbital decompression. Serious thyroid events occurred in about 2% of LEMTRADA-treated patients in clinical studies and included cardiac and psychiatric events associated with thyroid disease. Of all LEMTRADA-treated patients, 3% underwent thyroidectomy.

Thyroid disease poses special risks in women who are pregnant.

Obtain thyroid function tests, such as TSH levels, prior to initiation of treatment and every 3 months thereafter until 48 months after the last infusion. Continue to test thyroid function after 48 months if clinically indicated.

In patients with ongoing thyroid disorder, LEMTRADA should be administered only if the potential benefit justifies the potential risks.

Autoimmune cytopenias such as neutropenia (0.1%), hemolytic anemia (0.2%), and pancytopenia (0.2%) occurred in LEMTRADA-treated patients in clinical studies in MS. In cases of autoimmune hemolytic anemia, patients tested positive for direct antiglobulin antibodies, and nadir hemoglobin levels ranged from 2.9-8.6 g/dL. Symptoms of autoimmune hemolytic anemia include weakness, chest pain, jaundice, dark urine, and tachycardia. One LEMTRADA-treated patient with autoimmune pancytopenia died from sepsis.

During postmarketing use, additional autoimmune cytopenias including fatal autoimmune hemolytic anemia and aplastic anemia have been reported in the treatment of patients with BCLL, as well as other disorders, generally at higher and more frequent doses than recommended in MS.

Use CBC results to monitor for cytopenias. Prompt medical intervention is indicated if a cytopenia is confirmed.

Infections occurred in 71% of LEMTRADA-treated patients compared to 53% of patients treated with interferon beta-1a in controlled clinical studies in MS up to 2 years in duration. Infections that occurred more often in LEMTRADA-treated patients than interferon beta-1a patients included nasopharyngitis, urinary tract infection, upper respiratory tract infection, sinusitis, herpetic infections, influenza, and bronchitis. Serious infections occurred in 3% of patients treated with LEMTRADA as compared to 1% of patients treated with interferon beta-1a. Serious infections in the LEMTRADA group included: appendicitis, gastroenteritis, pneumonia, herpes zoster, and tooth infection.

Do not administer live viral vaccines following a course of LEMTRADA. Patients treated with LEMTRADA have altered immunity and may be at increased risk of infection following administration of live viral vaccines.

Consider delaying LEMTRADA administration in patients with active infection until the infection is fully controlled.

Concomitant use of LEMTRADA with antineoplastic or immunosuppressive therapies could increase the risk of immunosuppression.

In controlled clinical studies, 16% of LEMTRADA-treated patients developed a herpes viral infection compared to 3% of interferon beta-1a patients. These events included oral herpes (8.8%), herpes zoster (4.2%), herpes simplex (1.8%), and genital herpes (1.3%). Serious herpetic infections in LEMTRADA-treated patients included primary varicella (0.1%), herpes zoster (0.2%), and herpes meningitis (0.1%). Administer antiviral agents for herpetic prophylaxis at appropriate suppressive dosing regimens. Administer antiviral prophylaxis for herpetic viral infections starting on the first day of each treatment course and continue for a minimum of two months following treatment with LEMTRADA or until the CD4+ lymphocyte count is ≥200 cells per microliter, whichever occurs later.

Cervical human papilloma virus (HPV) infection, including cervical dysplasia, occurred in 2% of LEMTRADA-treated patients. Annual HPV screening is recommended for female patients.

Tuberculosis occurred in patients treated with LEMTRADA and interferon beta-1a in controlled clinical studies. Active and latent tuberculosis cases occurred in 0.3% of LEMTRADA-treated patients, most often in endemic regions. Perform tuberculosis screening according to local guidelines prior to initiation of LEMTRADA. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with LEMTRADA.

Fungal infections, especially oral and vaginal candidiasis, occurred more commonly in LEMTRADA-treated patients (12%) than in patients treated with interferon beta-1a (3%) in controlled clinical studies in MS.

Listeria monocytogenes infections (e.g., meningitis, encephalitis, sepsis, and gastroenteritis), including fatal cases of Listeria meningoencephalitis, have occurred in LEMTRADA-treated patients. Listeria infections have occurred as early as 3 days after treatment and up to 8 months after the last LEMTRADA dose. The duration of increased risk for Listeria infection after LEMTRADA treatment is unknown.

Advise patients to avoid or adequately heat foods that are potential sources of Listeria monocytogenes (e.g., deli meat, dairy products made with unpasteurized milk, soft cheeses, or undercooked meat, seafood, or poultry). Initiate these Listeria precautions prior to starting LEMTRADA treatment. The incubation period for Listeria monocytogenes ranges from 3 to 70 days. In most cases, signs and symptoms of invasive listeriosis start within 1 month of exposure to Listeria monocytogenes. Symptoms of Listeria infection include fever, chills, diarrhea, nausea, vomiting, headache, pains in joints and muscles, neck stiffness, difficulty walking, mental status changes, coma, and other neurologic changes. As is the case with many infections, treatment cannot always prevent mortality and morbidity related to Listeria infections. Therefore, advise patients to watch for symptoms of Listeria infection and seek prompt medical help if symptoms occur.

During postmarketing use, serious and sometimes fatal viral, bacterial, protozoan, and fungal infections, including some due to reactivation of latent infections, have been reported in the treatment of patients with B-CLL, as well as other disorders, generally at higher and more frequent doses than recommended in MS.

No data are available on the association of LEMTRADA with Hepatitis B virus (HBV) or Hepatitis C virus (HCV) reactivation because patients with evidence of active or chronic infections were excluded from the clinical studies. Consider screening patients at high risk of HBV and/or HCV infection before initiation of LEMTRADA and exercise caution 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.

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 postmarketing 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. Some 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 is associated with high morbidity and mortality rates if not diagnosed early and treated. If acute acalculous cholecystitis is suspected, evaluate and treat promptly.

In clinical studies, 6 of 1217 (0.5%) LEMTRADA-treated patients had pneumonitis of varying severity. Cases of hypersensitivity pneumonitis and pneumonitis with fibrosis occurred in clinical studies. Patients should be advised to report symptoms of pneumonitis, which include shortness of breath, cough, wheezing, chest pain or tightness, and hemoptysis.

LEMTRADA contains the same active ingredient (alemtuzumab) found in CAMPATH®. If LEMTRADA is considered for use in a patient who has previously received CAMPATH, exercise increased vigilance for additive and long-lasting effects on the immune system.

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

• 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.
• 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, 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.

• Advise patients that infusion reactions can occur after they leave the infusion center.
• Instruct the patient to remain at the infusion center for 2 hours after each LEMTRADA infusion, or longer at the discretion of the physician. Advise patients that symptoms of infusion reactions may occur after they leave the infusion center and to report these symptoms to their doctor.
• Advise patients 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, and rash.

• Advise patients that LEMTRADA may increase their risk of malignancies including thyroid cancer and melanoma.
• 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 is available only through a restricted program called the LEMTRADA REMS Program. 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, What You Need to Know About LEMTRADA Treatment: A Patient Guide and What You Need to Know About LEMTRADA Treatment and Infusion Reactions: A Patient Guide.
• Instruct patients to carry the LEMTRADA REMS Patient Safety Information Card with them in case of an emergency.

• Advise patients to contact their healthcare provider if they develop symptoms of serious infection such as fever or swollen glands.
• Advise patients to complete any necessary immunizations at least 6 weeks prior to treatment with LEMTRADA. Advise patients that they should talk to their healthcare provider before taking any vaccine after recent treatment with LEMTRADA.
• Advise patients to take their prescribed medication for herpes prophylaxis as directed by their healthcare provider.
• Advise patients that yearly HPV screening is recommended.
• 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..

• Advise patients to report symptoms of acute acalculous cholecystitis. These include abdominal pain, abdominal tenderness, fever, nausea, and vomiting

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

• 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.

Studies to assess the carcinogenic or genotoxic potential of LEMTRADA have not been conducted.

When LEMTRADA (3 or 10 mg/kg IV) was administered to huCD52 transgenic male mice on 5 consecutive days prior to cohabitation with untreated wild-type females, no effect on fertility or reproductive performance was observed. However, adverse effects on sperm parameters (including abnormal morphology [detached /no head] and reduced total count and motility) were observed at both doses tested.

When LEMTRADA (3 or 10 mg/kg IV) was administered to huCD52 transgenic female mice for 5 consecutive days prior to cohabitation with untreated wild-type males, there was a decrease in the average number of corpora lutea and implantation sites and an increase in post-implantation loss, resulting in fewer viable embryos at the higher dose tested.

There are no adequate and well-controlled studies in pregnant women. LEMTRADA was embryolethal in pregnant huCD52 transgenic mice when administered during organogenesis. Auto-antibodies may develop after administration of LEMTRADA. Placental transfer of antithyroid antibodies resulting in neonatal Graves' disease has been reported. LEMTRADA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 post-implantation 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 lymphocytes and T-lymphocyte populations were observed in the offspring at both doses tested. The effects of LEMTRADA, administered during organogenesis, on postnatal development have not been adequately assessed.

To avoid in utero exposure to LEMTRADA, 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.

LEMTRADA induces persistent thyroid disorders. 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.

Alemtuzumab was detected in the milk of lactating mice administered 10 mg/kg LEMTRADA on Days 8 through 12 postpartum. Serum levels of alemtuzumab were similar in lactating mice and offspring on Day 13 postpartum, and were associated with evidence of pharmacological activity (decrease in lymphocyte counts) in the offspring.

It is not known whether alemtuzumab is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from LEMTRADA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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 because it may increase the risk of malignancies (thyroid, melanoma, lymphoproliferative disorders, and lymphoma).

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

Dosage (Posology) and method of administration

The recommended dosage of LEMTRADA is 12 mg/day administered by intravenous infusion for 2 treatment 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.

Baseline laboratory tests are required prior to treatment with LEMTRADA. In addition, prior to starting treatment with LEMTRADA :

• complete any necessary immunizations at least 6 weeks prior to treatment
• determine whether patients have a history of varicella or have been vaccinated for varicella zoster virus (VZV). If not, test the patient for antibodies to VZV and consider vaccination for those who are antibody-negative. Postpone treatment with LEMTRADA until 6 weeks after VZV vaccination.
• perform tuberculosis screening according to local guidelines
• instruct patients to avoid potential sources of Listeria monocytogenes

Premedicate patients with high dose corticosteroids (1,000 mg methylprednisolone or equivalent) immediately prior to LEMTRADA infusion and for the first 3 days of each treatment course.

Administer anti-viral prophylaxis for herpetic viral infections starting on the first day of each treatment course and continue for a minimum of two months following treatment with LEMTRADA or until the CD4+ lymphocyte count is ≥200 cells per microliter, whichever occurs later.

Follow the steps below to prepare the diluted solution of LEMTRADA for intravenous infusion:

• Inspect LEMTRADA visually for particulate matter and discoloration prior to administration. Do not use if particulate matter is present or the solution is discolored. Do not freeze or shake vials prior to use.
• Withdraw 1.2 mL of LEMTRADA from the vial into a syringe using aseptic technique and inject into a 100 mL bag of sterile 0.9% Sodium Chloride, USP or 5% Dextrose in Water, USP.
• Gently invert the bag to mix the solution. Ensure the sterility of the prepared solution, because it contains no antimicrobial preservatives. Each vial is for single use only.

Prior to administration, protect diluted LEMTRADA solution from light and store for as long as 8 hours either at room temperature 15°C to 25°C (59°F to 77°F) or keep refrigerated at conditions 2°C to 8°C (36°F to 46°F).

Infuse LEMTRADA over 4 hours starting within 8 hours after dilution. Extend the duration of the infusion if clinically indicated.

Administer LEMTRADA in a setting in which equipment and personnel to appropriately manage anaphylaxis or serious infusion reactions are available.

Do not add or simultaneously infuse other drug substances through the same intravenous line. Do not administer as an intravenous push or bolus.

Monitor vital signs before the infusion and periodically during the infusion. Provide appropriate symptomatic treatment for infusion reactions as needed. Consider immediate discontinuation of the intravenous infusion if severe infusion reactions occur.

Observe patients for infusion reactions during and for at least 2 hours after each LEMTRADA infusion. Consider longer periods of observation if clinically indicated. Inform patients that they should report symptoms that occur during and after each infusion because they may indicate a need for prompt medical intervention.

Conduct the following laboratory tests at baseline and at periodic intervals for 48 months following the last treatment course of LEMTRADA in order to monitor for early signs of potentially serious adverse effects:

• Complete blood count (CBC) 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 thyroid stimulating hormone (TSH) level (prior to treatment initiation and every 3 months thereafter)

Conduct baseline and yearly skin exams to monitor for melanoma.

Interaction with other medicinal products and other forms of interaction

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

• Autoimmunity
• Infusion Reactions
• Malignancies
• Immune Thrombocytopenia
• Glomerular Nephropathies
• Thyroid Disorders
• Other Autoimmune Cytopenias
• Infections
• Acute Acalculous Cholecystitis
• Pneumonitis

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. 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, with an additional 3411 person-years of follow-up in an open-label extension study. The population was 18-55 years of age, 65% were female, and 92% were Caucasian.

In 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.

Table 1: Adverse Reactions in the Pooled 2-Year Active-Controlled Studies in Patients with Relapsing-Remitting Multiple Sclerosis

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 x 109 L (range 0.02-2.30 x 109 L) and 0.32 (0.02-1.81 x 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.

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.

As with all therapeutic proteins, there is potential for immunogenicity. 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, 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, 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. 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.

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.

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.

Gastrointestinal System Disorders: Acute acalculous cholecystitis.

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.

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