Highlights

This article describes the drug label information for alemtuzumab injection, solution, concentrate marketed as Lemtrada®. For the formulation of alemtuzumab marketed as Campath®, marketed for the treatment of B-cell chronic lymphocytic leukemia, see the DAILYMED database.

See Patient counseling information and medication guide available in the DAILYMED drug label information.

Boxed warning

Indications and usage

Alemtuzumab is indicated for the treatment of relapsing forms of multiple sclerosis, including relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, the use of alemtuzumab should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of multiple sclerosis.

Limitations of use. Alemtuzumab is not recommended for use in patients with clinically isolated syndrome because of its safety profile.

Dosage and administration

Testing and procedures before treatment

Baseline laboratory tests are required before treatment with alemtuzumab. In addition, before starting treatment with alemtuzumab:

Recommended premedication and concomitant medication

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

Herpes prophylaxis. Administer antiviral prophylaxis for herpetic viral infections starting on the first day of each treatment course and continue for a minimum of 2 months following treatment with alemtuzumab or until the CD4+ lymphocyte count is at least 200 cells per microliter, whichever occurs later.

Recommended dosage

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.

Preparation instructions

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

Prior to administration, protect diluted alemtuzumab solution from light and store for as long as 8 hours 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).

Infusion instructions

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

Administer alemtuzumab 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.

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 alemtuzumab 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.

Laboratory testing and monitoring to assess safety

Measure the urine protein-to-creatinine ratio before initiation of treatment. Conduct the following laboratory tests at baseline and at periodic intervals until 48 months after the last treatment course of alemtuzumab in order to monitor for early signs of potentially serious adverse effects.

Conduct baseline and yearly skin exams to monitor for melanoma.

Dosage forms and strengths

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

Contraindications

Alemtuzumab is contraindicated in patients:

Warnings and precautions

Autoimmunity

Treatment with alemtuzumab 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 alemtuzumab-treated patients, which are described in separate warnings:

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 alemtuzumab-treated patients.

In the postmarketing setting, cases of autoimmune hepatitis, hemophagocytic lymphohistiocytosis, adult-onset Still disease, thrombotic thrombocytopenic purpura, autoimmune encephalitis, immune-mediated colitis, 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 multiple sclerosis.

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.

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

Measure the urine protein-to-creatinine ratio before 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 alemtuzumab 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.

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

Infusion reactions

Alemtuzumab causes cytokine release syndrome, resulting in infusion reactions, some of which may be serious and life-threatening. In clinical studies, 92% of alemtuzumab-treated patients experienced infusion reactions. In some patients, infusion reactions were reported more than 24 hours after alemtuzumab infusion. Serious reactions occurred in 3% of patients and included anaphylaxis in two 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 (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, the time to onset was within 1 to 3 days of alemtuzumab 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 alemtuzumab 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 (eg, 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 multiple sclerosis.

Premedicate patients with corticosteroids immediately before alemtuzumab 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 alemtuzumab treatment course. Consider pretreatment with antihistamines and/or antipyretics before alemtuzumab administration. Infusion reactions may occur despite pretreatment.

Consider additional monitoring in patients with medical conditions that predispose them to cardiovascular or pulmonary compromise. Physicians should alert patients that an infusion reaction could occur within 48 hours of infusion.

Alemtuzumab 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).

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

Stroke 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 alemtuzumab administration, with most cases occurring within 1 day.

Cervicocephalic arterial dissection. In the postmarketing setting, cases of cervicocephalic (eg, vertebral, carotid) arterial dissection involving multiple arteries have been reported within 3 days of alemtuzumab 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

Thyroid cancer. Alemtuzumab may increase the risk of thyroid cancer. In controlled clinical studies, three of 919 (0.3%) alemtuzumab-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 alemtuzumab-treated group, because of the higher incidence of autoimmune thyroid disorders in those patients. Two additional cases of thyroid cancer in alemtuzumab-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. Alemtuzumab may increase the risk of melanoma. In multiple sclerosis clinical studies (controlled and open-label extension), five of 1486 (0.3%) alemtuzumab-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 alemtuzumab.

Lymphoproliferative disorders and lymphoma. Cases of lymphoproliferative disorders and lymphoma have occurred in alemtuzumab-treated patients with multiple sclerosis, including a MALT lymphoma, Castleman 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 patients without multiple sclerosis.

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

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

Alemtuzumab REMS program

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

Notable requirements of the alemtuzumab REMS Program include the following:

Further information, including a list of qualified healthcare facilities, is available at 1-855-676-6326.

Immune thrombocytopenia

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

In a controlled clinical study in patients with multiple sclerosis, one alemtuzumab-treated patient developed ITP that went unrecognized before 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 alemtuzumab-treated patients in clinical studies in multiple sclerosis. Antiplatelet antibodies did not precede ITP onset. ITP has been diagnosed more than 3 years after the last alemtuzumab 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 with differential before 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, initiate appropriate medical intervention promptly.

Glomerular nephropathies, including antiglomerular basement membrane disease

Glomerular nephropathies occurred in 0.3% of patients treated with alemtuzumab in multiple sclerosis clinical studies. There were three cases of membranous glomerulonephritis and two cases of anti-glomerular basement membrane (anti-GBM) disease.

In postmarketing cases, some alemtuzumab-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 alemtuzumab.

Symptoms of nephropathy may include edema, hematuria, a 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 before 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 a urine protein-to-creatinine ratio greater than 200 mg/g, an 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. Early detection and treatment of nephropathies may decrease the risk of poor outcomes.

Thyroid disorders

Thyroid endocrine disorders, including autoimmune thyroid disorders, occurred in 36.8% of alemtuzumab-treated patients in multiple sclerosis 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 alemtuzumab dose. Autoimmune thyroid disorders include Graves disease, hyperthyroidism, hypothyroidism, autoimmune thyroiditis, and goiter. Graves disease ophthalmopathy with decreased vision, eye pain, and exophthalmos occurred in 2% of alemtuzumab-treated patients. Seven patients required surgical orbital decompression. Serious thyroid events occurred in about 5.2% of alemtuzumab-treated patients in clinical studies and included cardiac and psychiatric events associated with thyroid disease. Of all alemtuzumab-treated patients, 3.8% underwent thyroidectomy.

Thyroid disease poses special risks in women who are pregnant.

Obtain thyroid function tests, such as TSH levels, before 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, alemtuzumab should be administered only if the potential benefit justifies the potential risks.

Other autoimmune cytopenias

Autoimmune cytopenias such as neutropenia (0.1%), hemolytic anemia (0.3%), and pancytopenia (0.2%) occurred in alemtuzumab-treated patients in multiple sclerosis 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 to 8.6 g/dL. Symptoms of autoimmune hemolytic anemia include weakness, chest pain, jaundice, dark urine, and tachycardia. One alemtuzumab-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 multiple sclerosis.

Use complete blood count 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 alemtuzumab 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 alemtuzumab, as appropriate.

Prior to starting treatment with alemtuzumab, obtain serum transaminases (alanine aminotransferase and aspartate aminotransferase) 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 has occurred in patients taking alemtuzumab. Hemophagocytic lymphohistiocytosis 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 (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. In cases of hemophagocytic lymphohistiocytosis reported with alemtuzumab, 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 the mean or range of latency for hemophagocytic lymphohistiocytosis, symptoms have been reported to occur within approximately thirteen months to 33 months following the initiation of treatment. Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of hemophagocytic lymphohistiocytosis should be considered. Alemtuzumab should be discontinued if an alternate etiology for the signs or symptoms cannot be established.

Adult-onset Still disease

During postmarketing use, adult-onset Still disease has been reported in patients treated with alemtuzumab. Adult-onset Still disease is a rare inflammatory condition that requires urgent evaluation and treatment. Patients with adult-onset Still disease 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 adult-onset Still disease should be evaluated immediately, and alemtuzumab should be discontinued if an alternate etiology for the signs or symptoms cannot be established.

Thrombotic thrombocytopenic purpura

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

Autoimmune encephalitis

During postmarketing use, cases of autoimmune encephalitis have been reported in patients treated with alemtuzumab. Autoimmune encephalitis can present with a variety of clinical manifestations, including subacute onset of memory impairment, altered mental status, psychiatric symptoms, neurologic findings, and seizures. Alemtuzumab should be discontinued if autoimmune encephalitis is confirmed by the presence of neural autoantibodies or if 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. 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.

Immune-mediated colitis

Immune-mediated colitis, which can present as a severe and acute-onset form of colitis, has been reported in patients receiving alemtuzumab 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 alemtuzumab 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 alemtuzumab is a monophasic disorder or whether recurrent flares (as are seen in patients with inflammatory bowel disease) will occur.

Infections

Infections occurred in 71% of alemtuzumab-treated patients compared to 53% of patients treated with interferon beta-1a in controlled clinical studies in multiple sclerosis, up to 2 years in duration. Infections that occurred more often in alemtuzumab-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 alemtuzumab as compared to 1% of patients treated with interferon beta-1a. Serious infections in the alemtuzumab group included: appendicitis, gastroenteritis, pneumonia, herpes zoster, and tooth infection.

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

Alemtuzumab administration is contraindicated in patients with active infection.

Concomitant use of alemtuzumab 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 alemtuzumab, 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 alemtuzumab-treated patients. Listeria infections have occurred as early as 3 days after treatment and up to 8 months after the last alemtuzumab dose. The duration of increased risk for Listeria infection after alemtuzumab treatment is unknown.

Advise patients to avoid or adequately heat foods that are potential sources of Listeria monocytogenes (eg, deli meat, dairy products made with unpasteurized milk, soft cheeses, or undercooked meat, seafood, or poultry). Initiate these Listeria precautions before starting alemtuzumab 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.

Herpes viral infections. In controlled clinical studies, 16% of alemtuzumab-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 alemtuzumab-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 2 months following treatment with alemtuzumab or until the CD4+ lymphocyte count is ≥200 cells per microliter, whichever occurs later.

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

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

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

Infections in patients without multiple sclerosis. 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 multiple sclerosis.

Hepatitis. No data are available on the association of alemtuzumab 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 or HCV infection before initiation of alemtuzumab and exercise caution in prescribing alemtuzumab to patients identified as carriers of HBV 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

Progressive multifocal leukoencephalopathy (PML) has occurred in a patient with multiple sclerosis treated with alemtuzumab. PML is an opportunistic viral infection of the brain caused by the JC virus that typically only occurs in patients who are immunocompromised and that usually leads to death or severe disability. PML was diagnosed 2 months after the second course of alemtuzumab. The patient had previously received multiple multiple sclerosis therapies, but had not received other drugs for treatment of multiple sclerosis for more than 1 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. 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 alemtuzumab 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 JC virus DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other multiple sclerosis 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 multiple sclerosis 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 multiple sclerosis treatment or due to differences in the disease in these patients.

Acute acalculous cholecystitis

Alemtuzumab may increase the risk of acute acalculous cholecystitis. In controlled clinical studies, 0.2% of alemtuzumab-treated multiple sclerosis 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 alemtuzumab-treated patients. Time to onset of symptoms ranged from less than 24 hours to 2 months after alemtuzumab 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.

Pneumonitis

In clinical studies, six of 1217 (0.5%) alemtuzumab-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 the same active ingredient

Alemtuzumab contains the same active ingredient (alemtuzumab) found in Campath®. If alemtuzumab 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.

Adverse reactions

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

Clinical trials experience

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

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

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

Most common adverse reactions. In controlled clinical trials, the most common adverse reactions with alemtuzumab (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 alemtuzumab-treated patients in Studies 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

Lymphopenia

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

Suicidal behavior or ideation

In clinical studies, 0.6% of patients in both the alemtuzumab 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.

Immunogenicity

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

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

Postmarketing experience

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

Postmarketing experience with alemtuzumab.

Blood and lymphatic system disorders. Acquired hemophilia A, neutropenia, thrombocytopenia, thrombotic thrombocytopenic purpura

Cerebrovascular disorders. Stroke, including hemorrhagic and ischemic stroke, and cervicocephalic arterial dissection

Gastrointestinal system disorders. Cholecystitis, including acalculous cholecystitis and acute acalculous cholecystitis, and immune-mediated colitis

Hepatobiliary disorders. Autoimmune hepatitis, viral hepatitis

Infections and infestations. Opportunistic infections, Progressive multifocal leukoencephalopathy

Immune system disorders. Autoimmune hepatitis, vasculitis, Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis, sarcoidosis

Musculoskeletal and connective tissue disorders. Adult-onset Still disease

Nervous system disorders. Autoimmune encephalitis, myasthenia gravis, Lambert-Eaton myasthenic syndrome

Pulmonary system disorders. Pulmonary alveolar hemorrhage

Skin and subcutaneous tissue disorders. Alopecia

Postmarketing experience with Campath®. Campath is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) and is generally administered at higher and more frequent doses (eg, 30 mg) than recommended in the treatment of multiple sclerosis.

Cardiac disorders. Congestive heart failure, cardiomyopathy, and decreased ejection fraction in patients without multiple sclerosis previously treated with potentially cardiotoxic agents.

Use in specific populations

Pregnancy

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

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

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

Clinical considerations. Alemtuzumab induces persistent thyroid disorders. Untreated hypothyroidism in pregnant women increases the risk for miscarriage and may have effects on the fetus, including intellectual disability 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.

Data.

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

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

Lactation

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

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

Data.

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

Females and males of reproductive potential

Contraception. Before initiation of alemtuzumab treatment, women of childbearing potential should be counselled on the potential for a serious risk to the fetus. To avoid in utero exposure to Alemtuzumab, women of childbearing potential should use effective contraceptive measures when receiving a course of treatment with alemtuzumab and for 4 months following that course of treatment.

Infertility. In huCD52 transgenic mice, administration of alemtuzumab before and during the mating period resulted in adverse effects on sperm parameters in males and reduced number of corpora lutea and implantations in females.

Pediatric use

Safety and effectiveness in pediatric patients younger than 17 years of age have not been established. Use of alemtuzumab is not recommended in pediatric patients due to the risks of autoimmunity, infusion reactions, and stroke, and because it may increase the risk of malignancies (thyroid, melanoma, lymphoproliferative disorders, and lymphoma).

Geriatric use

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

Overdosage

Two patients with multiple sclerosis experienced serious reactions (headache, rash, and either hypotension or sinus tachycardia) after a single accidental infusion of up to 60 mg of alemtuzumab. Doses of alemtuzumab 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.

Description

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

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

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

Clinical pharmacology

Mechanism of action

The precise mechanism by which alemtuzumab exerts its therapeutic effects in multiple sclerosis is unknown but is presumed to involve binding to CD52, a cell surface antigen present on T and B lymphocytes, and on natural killer cells, monocytes, and macrophages. Following cell surface binding to T and B lymphocytes, alemtuzumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.

Pharmacodynamics

Effects of alemtuzumab on the lymphocyte population. Alemtuzumab 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 the patients had CD4+ lymphocyte counts that remained below the lower limit of normal.

Cardiac electrophysiology. In a study of 53 patients with multiple sclerosis, 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.

Pharmacokinetics

The pharmacokinetics of alemtuzumab were evaluated in a total of 148 patients with relapsing forms of multiple sclerosis 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.

Absorption. 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.

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

Elimination. 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.

Specific populations. Age, race, or gender had no effect on the pharmacokinetics of alemtuzumab.

Nonclinical toxicology

Carcinogenesis, mutagenesis, and impairment of fertility

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

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

Clinical studies

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

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

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

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

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

Table 2. Clinical and MRI Results of Study 1

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

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

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

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

Table 3. Clinical and MRI Results of Study 2

How supplied/storage and handling

How supplied

Alemtuzumab (alemtuzumab) injection is a sterile, clear, and colorless to slightly yellow solution for intravenous infusion, containing no antimicrobial preservatives.

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

Storage and handling

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

Patient counseling information

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

Autoimmunity.

Infusion reactions.

Stroke and cervicocephalic arterial dissection.

Malignancies.

Alemtuzumab REMS program.

Hemophagocytic lymphohistiocytosis.

Adult-onset Still disease.

Thrombotic thrombocytopenic purpura.

Immune-mediated colitis.

Infections.

Progressive multifocal leukoencephalopathy.

Acute acalculous cholecystitis.

Pneumonitis.

Concomitant use of Campath®.

Fetal risk.

Medication guide

See the Medication guide section of the DAILYMED drug label information.

Acknowledgement

This article was excerpted from U.S. FDA Drug Labeling information available on the DailyMed website.