Lemtrada

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

• 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)]

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

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, 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)

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
  [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 list of qualified healthcare facilities, is available at 1-855-676-6326.

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

Obtain complete blood counts (CBCs) with differential prior to initiation of treatment and at monthly intervals thereafter until 48 months after the last infusion

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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.

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.

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.