LEMTRADA Dailymed

Recent Major Changes Section

Warnings and Precautions (5.1, 5.16)

5/2024

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)].

• 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)

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)].

2 Dosage And Administration

• Baseline laboratory tests are required prior to treatment. (2.1)
• Administer LEMTRADA by intravenous infusion over 4 hours for 2 or more treatment courses: Initial treatment of 2 courses:
  • First course: 12 mg/day on 5 consecutive days. (2.3)
  • Second course: 12 mg/day on 3 consecutive days 12 months after first treatment course. (2.3)
  Subsequent treatment courses of 12 mg per day on 3 consecutive days (36 mg total dose) may be administered, as needed, at least 12 months after the last dose of any prior treatment course. (2.3)
• Premedicate with corticosteroids prior to LEMTRADA infusion for the first 3 days of each treatment course. (2.2)
• Administer antiviral agents for herpetic prophylaxis starting on the first day of LEMTRADA dosing and continuing for a minimum of two months after completion of LEMTRADA dosing or until CD4+ lymphocyte count is more than 200 cells per microliter, whichever occurs later. (2.2)
• Must be diluted prior to administration. (2.4)

2.1 Testing and Procedures Prior to Treatment

Baseline laboratory tests are required prior to treatment with LEMTRADA [seeDosage and Administration (2.6)]. In addition, prior to starting treatment with LEMTRADA [seeWarnings and Precautions (5.15)]:

• 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.

2.2 Recommended Premedication and Concomitant Medication

Corticosteroids

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 [see Warnings and Precautions (5.2)].

Herpes Prophylaxis

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 at least 200 cells per microliter, whichever occurs later [see Warnings and Precautions (5.15)].

2.3Recommended Dosage

• 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.

Following the second treatment course, subsequent treatment courses of 12 mg per day on 3 consecutive days (36 mg total dose) may be administered, as needed, at least 12 months after the last dose of any prior treatment courses.

2.4 Preparation Instructions

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).

2.5 Infusion Instructions

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, serious infusion reactions, myocardial ischemia, myocardial infarction, and cerebrovascular and respiratory adverse reactions are available [see Warnings and Precautions (5.2)].

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

Obtain a baseline ECG. 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 [see Warnings and Precautions (5.2)].

2.6 Laboratory Testing and Monitoring to Assess Safety

Measure the urine protein to creatinine ratio prior to initiation of treatment. Conduct the following laboratory tests at baseline and at periodic intervals until 48 months after 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)
• Serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and total bilirubin levels (prior to treatment initiation and periodically thereafter)

Conduct baseline and yearly skin exams to monitor for melanoma [see Warnings and Precautions (5.4)].

• Immune Thrombocytopenia: Obtain complete blood counts (CBCs) with differential prior to initiation of treatment and at monthly intervals thereafter until 48 months after the last infusion. (5.6)
• Glomerular Nephropathies: Obtain serum creatinine levels, urinalysis with cell counts and urine protein to creatinine ratio prior to initiation of treatment. Monitor serum creatinine levels and urinalysis with cell counts at monthly intervals thereafter until 48 months after the last infusion. (5.7)
• Thyroid Disorders: Obtain thyroid function tests prior to initiation of treatment and every 3 months until 48 months after the last infusion. (5.8)
• Other Autoimmune Cytopenias: Monitor CBCs monthly until 48 months after the last infusion. (2.6, 5.9)
• Autoimmune Hepatitis: If signs of hepatic dysfunction occur, promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment. (5.10)
• Hemophagocytic Lymphohistiocytosis: Consider this diagnosis and evaluate patients immediately if they develop signs or symptoms of systemic inflammation. Discontinue LEMTRADA if an alternative etiology is not established. (5.11)
• Adult Onset Still's Disease (AOSD): If a patient develops AOSD, they require prompt evaluation and treatment. (5.12)
• Thrombotic Thrombocytopenic Purpura (TTP): Evaluate patients immediately if they develop clinical symptoms or laboratory findings consistent with TTP. Discontinue LEMTRADA if TTP is confirmed or if an alternative etiology is not established. (5.13)
• Autoimmune Encephalitis (AIE): Evaluate patients if they develop signs and symptoms suggestive of AIE, such as subacute onset of memory impairment, altered mental status, psychiatric symptoms, neurological findings, and seizures. (5.14)
• Acquired Hemophilia A: Obtain a coagulopathy panel including aPTT in patients who present with signs such as spontaneous subcutaneous hematomas, extensive bruising, hematuria, epistaxis, or gastrointestinal or other types of bleeding. (5.15)
• Immune-Mediated Colitis: Immune-mediated colitis has been reported in the postmarketing setting. Monitor patients for new or persistent diarrhea or other gastrointestinal symptoms, and evaluate promptly if colitis is suspected. (5.16)
• Infections: Administration is contraindicated in patients with active infection. Do not administer live viral vaccines following a course of LEMTRADA. (4, 5.17)
• Progressive Multifocal Leukoencephalopathy (PML): Withhold LEMTRADA at the first sign or symptom suggestive of PML. (5.18)

5.1 Autoimmunity

Treatment with LEMTRADA can result in the formation of autoantibodies and increase the risk of serious autoimmune conditions, which may be life threatening.

In clinical studies (controlled and open-label extension), the following serious autoimmune conditions were reported in LEMTRADA-treated patients, which are described in separate warnings:

• thyroid disorders (36.8%) [see Warnings and Precautions (5.8)]
• immune thrombocytopenia (2%) [see Warnings and Precautions (5.6)]
• glomerular nephropathies (0.3%) [see Warnings and Precautions 5.7]
• autoimmune hemolytic anemia (0.3%), autoimmune pancytopenia (0.2%), and autoimmune neutropenia (0.1%) [see Warnings and Precautions (5.9)]
• acquired hemophilia A (anti-Factor VIII antibodies) (0.1%) [see Warnings and Precautions (5.15)]

In clinical studies (controlled and open-label extension), vitiligo (0.3%), undifferentiated connective tissue disorders (0.2%), type 1 diabetes (0.2%), rheumatoid arthritis (0.1%), and retinal pigment epitheliopathy (0.1%) were also reported in LEMTRADA-treated patients.

In the postmarketing setting, cases of 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 [see Warnings and Precautions (5.13)], autoimmune encephalitis [see Warnings and Precautions (5.14)], immune-mediated colitis [see Warnings and Precautions (5.16)], Guillain-Barré syndrome, and vasculitis have been reported.

Chronic inflammatory demyelinating polyradiculoneuropathy has been reported in the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL), as well as other autoimmune disorders, generally at higher and more frequent doses than recommended in MS.

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 [see Use in Specific Populations (8.1)].

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

Measure the urine protein to creatinine ratio prior to initiation of treatment. Monitor complete blood counts with differential, serum creatinine levels, and urinalysis with urine cell counts before starting treatment and then at monthly intervals until 48 months after the last dose of LEMTRADA to allow for early detection and treatment of autoimmune adverse reactions [see Dosage and Administration (2.6)]. 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 [see Warnings and Precautions (5.5)].

5.2 Infusion Reactions

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, cases of pulmonary alveolar hemorrhage, myocardial ischemia, 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 to 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. Cases of severe (including fatal) neutropenia have been reported within 2 months of LEMTRADA infusion; some cases resolved with receiving granulocyte-colony stimulating factor treatment. Mild to moderate decreases in platelet counts, starting at the time of alemtuzumab infusion and often resolving without treatment, have been reported. Other serious and sometimes fatal infusion reactions (e.g., hypoxia, syncope, acute respiratory distress syndrome, respiratory arrest, myocardial infarction, acute cardiac insufficiency, 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. Physicians should alert patients that an infusion reaction could occur within 48 hours of infusion.

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, cerebrovascular, cardiac and respiratory emergencies) [see Dosage and Administration (2.5)].

LEMTRADA is available only through a restricted program under a REMS [see Warnings and Precautions (5.5)].

5.3Stroke and Cervicocephalic Arterial Dissection

Stroke

In the postmarketing setting, serious and life-threatening stroke (including ischemic and hemorrhagic stroke) has been reported within 3 days of LEMTRADA administration, with most cases occurring within 1 day.

Cervicocephalic Arterial Dissection

In the postmarketing setting, cases of cervicocephalic (e.g., vertebral, carotid) arterial dissection involving multiple arteries have been reported within 3 days of LEMTRADA administration. Ischemic stroke was reported in one of these 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.

5.4 Malignancies

Thyroid Cancer

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.

Melanoma

LEMTRADA may increase the risk of melanoma. In MS clinical studies (controlled and open-label extension), 5 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.

Lymphoproliferative Disorders and Lymphoma

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 [see Warnings and Precautions (5.5)].

5.5 LEMTRADA REMS Program

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 [see Warnings and Precautions (5.1, 5.2, 5.4)].

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 [see Dosage and Administration (2.6)].
• 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 ul of qualified healthcare facilities, is available at 1-855-676-6326.

5.6 Immune Thrombocytopenia

Immune thrombocytopenia (ITP) occurred in 2% of LEMTRADA-treated patients in MS clinical studies (controlled and open-label extension).

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 [see Warnings and Precautions (5.7)], 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 [see Dosage and Administration (2.6)]. 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.

5.7Glomerular Nephropathies Including Anti-glomerular Basement Membrane Disease

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.

In postmarketing cases, some LEMTRADA-treated patients with anti-GBM disease developed end-stage renal disease requiring dialysis or renal transplantation. Urgent evaluation and treatment are required because early treatment can improve the preservation of renal function. Anti-GBM disease can be life-threatening if left untreated. Alveolar hemorrhage, manifested as hemoptysis, is a common component of anti-GBM disease and has been reported in postmarketing cases. Cases of anti-GBM disease have been diagnosed up to 40 months after the last dose of LEMTRADA.

Symptoms of nephropathy may include edema, hematuria, change in urine color, decreased urine output, fatigue, dyspnea, and hemoptysis. Patients and caregivers should be instructed to seek medical advice if they have concerns.

Obtain serum creatinine levels, urinalysis with cell counts, and urine protein to creatinine ratio prior to initiation of treatment. Obtain serum creatinine levels and urinalysis with cell counts 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.

For urine dipstick results of 1+ protein or greater, measure the urine protein to creatinine ratio. For urine protein to creatinine ratio greater than 200 mg/g, increase in serum creatinine greater than 30%, or unexplained hematuria, perform further evaluation for nephropathies. Increased serum creatinine with hematuria or signs of pulmonary involvement of anti-GBM disease (e.g., hemoptysis, exertional dyspnea) warrant immediate evaluation. Early detection and treatment of nephropathies may decrease the risk of poor outcomes.

5.8 Thyroid Disorders

Thyroid endocrine disorders, including autoimmune thyroid disorders, occurred in 36.8% of LEMTRADA-treated patients in MS clinical studies (controlled and open-label extension). 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, hypothyroidism, autoimmune thyroiditis, and goiter. Graves' ophthalmopathy with decreased vision, eye pain, and exophthalmos occurred in 2% of LEMTRADA-treated patients. Seven patients required surgical orbital decompression. Serious thyroid events occurred in about 5.2% of LEMTRADA-treated patients in clinical studies and included cardiac and psychiatric events associated with thyroid disease. Of all LEMTRADA-treated patients, 3.8% underwent thyroidectomy.

Thyroid disease poses special risks in women who are pregnant [see Use in Specific Populations (8.1)].

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 or in case of pregnancy.

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

5.9 Other Autoimmune Cytopenias

Autoimmune cytopenias such as neutropenia (0.1%), hemolytic anemia (0.3%), and pancytopenia (0.2%) occurred in LEMTRADA-treated patients in MS clinical studies (controlled and open-label extension). 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 B-CLL, as well as other disorders, generally at higher and more frequent doses of alemtuzumab than recommended in MS.

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

5.10 Autoimmune Hepatitis

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.

Prior to starting treatment with LEMTRADA, obtain serum transaminases (ALT and AST) and total bilirubin levels. Obtain transaminase levels and total bilirubin levels at periodic intervals until 48 months after the last dose.

5.11Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) has occurred in patients taking LEMTRADA. HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. It is associated with high mortality rates if not recognized early and treated. Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms (e.g., mental status changes, ataxia, or seizures), cytopenias, high serum ferritin, hypertriglyceridemia, and liver function and coagulation abnormalities. Hemophagocytosis may be seen on histologic examination of bone marrow, spleen, or lymph nodes. In cases of HLH reported with LEMTRADA, most patients presented with fever, elevated ferritin, transaminitis, hypertriglyceridemia, and all patients required hospitalization. Although the small number of cases limits the ability to draw conclusions pertaining to mean or range of latency for HLH, symptoms have been reported to occur within approximately thirteen months to thirty-three months 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. LEMTRADA should be discontinued if an alternate etiology for the signs or symptoms cannot be established.

5.12Adult Onset Still's Disease (AOSD)

During postmarketing use, Adult Onset Still's Disease (AOSD) has been reported in patients treated with LEMTRADA. AOSD is a rare inflammatory condition that requires urgent evaluation and treatment. Patients with AOSD may have a combination of the following signs and symptoms: fever, arthritis, rash, and leukocytosis in the absence of infections, malignancies, and other rheumatic conditions. Patients with manifestations of AOSD should be evaluated immediately and LEMTRADA should be discontinued if an alternate etiology for the signs or symptoms cannot be established.

5.13 Thrombotic Thrombocytopenic Purpura (TTP)

TTP has been reported in patients treated with LEMTRADA. TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurological sequelae, fever, and renal impairment. TTP is associated with high morbidity and mortality rates if not recognized and treated early. LEMTRADA should be discontinued if TTP is confirmed or an alternate etiology for the signs or symptoms cannot be established.

5.14Autoimmune Encephalitis (AIE)

During postmarketing use, cases of AIE have been reported in patients treated with LEMTRADA. AIE can present with a variety of clinical manifestations, including subacute onset of memory impairment, altered mental status, psychiatric symptoms, neurological findings, and seizures. LEMTRADA should be discontinued if AIE is confirmed by the presence of neural autoantibodies or an alternate etiology cannot be established.

5.15Acquired Hemophilia A

Cases of acquired hemophilia A (anti-Factor VIII antibodies) have been reported in both the clinical trial and postmarketing settings. Patients typically present with spontaneous subcutaneous hematomas and extensive bruising, although hematuria, epistaxis, gastrointestinal, or other types of bleeding may occur. Obtain a coagulopathy panel including aPTT in patients who present with such symptoms. Patients should be informed about the signs and symptoms of acquired hemophilia A and advised to seek immediate medical attention if any of these symptoms occur.

5.16Immune-Mediated Colitis

Immune-mediated colitis, which can present as a severe and acute-onset form of colitis, has been reported in patients receiving LEMTRADA in the postmarketing setting. Some cases of colitis were serious, requiring hospitalization. Systemic corticosteroids were required in some of these patients. The time from treatment initiation to onset of symptoms in these cases ranged from a few months to years.

Monitor patients for immune-mediated colitis during and after LEMTRADA treatment, and evaluate promptly if signs and symptoms that may indicate immune-mediated colitis, such as new or persistent diarrhea or other gastrointestinal signs and symptoms, occur.

It is unknown whether immune-mediated colitis in patients treated with LEMTRADA is a monophasic disorder, or whether recurrent flares (as are seen in patients with inflammatory bowel disease) will occur.

5.17 Infections

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.

LEMTRADA administration is contraindicated in patients with active infection [see Contraindications (4)].

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

Opportunistic Infections

In the postmarketing setting, serious, sometimes fatal, opportunistic infections have been reported in patients taking LEMTRADA, including aspergillosis, coccidioidomycosis, histoplasmosis, Pneumocystis jirovecii pneumonia, nocardiosis, Epstein-Barr virus, and cytomegalovirus infections.

Listeria Monocytogenes Infections

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 uleriosis 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.

Herpes Viral Infections

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 [see Dosage and Administration (2.2)].

Human Papilloma Virus

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

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

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.

Infections in Non-MS Patients

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.

Hepatitis

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.

5.18Progressive Multifocal Leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) has occurred in a patient with MS treated with LEMTRADA. 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. PML was diagnosed two months after the second course of LEMTRADA. The patient had previously received multiple MS therapies, but had not received other drugs for treatment of MS for more than one year. The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was not taking any immunosuppressive or immunomodulatory medications concomitantly. After the diagnosis of PML, the patient developed immune reconstitution inflammatory syndrome (IRIS). The patient's condition improved, but mild residual neurologic sequelae remained at last follow-up.

At the first sign or symptom suggestive of PML, withhold LEMTRADA and perform an appropriate diagnostic evaluation. 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.

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 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.

5.19Acute 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 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 was 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.

5.20 Pneumonitis

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 may include shortness of breath, cough, wheezing, chest pain or tightness, and hemoptysis.

5.21 Drug Products with Same Active Ingredient

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.