Lemtrada

Autoimmunity (see Boxed Warnings).

• In clinical studies (controlled and open-label extension), Lemtrada-treated patients experienced thyroid disorders (36.8%), immune thrombocytopenia (2%), and glomerular nephropathies (0.3%). Vitiligo and autoimmune hemolytic anemia occurred in 0.3% of patients. Autoimmune pancytopenia, undifferentiated connective tissue disorders, and type 1 diabetes each occurred in 0.2% of patients. Rheumatoid arthritis, retinal pigment epitheliopathy, and acquired hemophilia A (anti-Factor VIII antibodies) occurred in 0.1% of patients. During postmarketing use, cases of vasculitis, autoimmune hepatitis, Guillain-Barré syndrome, thrombotic thrombocytopenic purpura, and autoimmune encephalitis 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. 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.

Infusion Reactions (see Boxed Warnings).

• 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.
• During postmarketing use, cases of pulmonary alveolar hemorrhage, myocardial ischemia, myocardial infarction, stroke (including ischemic and hemorrhagic stroke), and cervicocephalic (eg, 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. 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.
• 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.

Stroke and Cervicocephalic Arterial Dissection (see Boxed Warnings).

• In the postmarketing setting, cases of cervicocephalic (eg, 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 (eg, carotid, vertebral) arterial dissection. Instruct patients to seek immediate medical attention if symptoms of stroke or cervicocephalic arterial dissection occur.

Malignancies (see Boxed Warnings).

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.
• 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 openlabel 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. 

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 (eg, 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 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.
• 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 (eg, hemoptysis, exertional dyspnea) warrant immediate evaluation. 

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.
• 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.

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

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 (eg, 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

• 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.
• Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms (eg, 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. 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.

Adult 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.

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.

Autoimmune 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. 

Acquired 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.

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.

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 (eg, 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. 

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.

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.

Progressive 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.
• 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.

Acute Acalculous Cholecystitis

• Lemtrada may increase the risk of acute acalculous cholecystitis. In controlled clinical studies, 0.2% of Lemtrada-treated MS patients developed acute acalculous cholecystitis, compared to 0% of patients treated with interferon beta-1a. During 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.
• Symptoms of acute acalculous cholecystitis include abdominal pain, abdominal tenderness, fever, nausea, and vomiting. Leukocytosis and abnormal liver enzymes are also commonly observed. If acute acalculous cholecystitis is suspected, evaluate and treat promptly.

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.

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.