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  • CLASSES

    Antineoplastic Monoclonal Antibodies Targeting CD52
    CD52 Antigen Inhibitors
    MS Agents

    BOXED WARNING

    Fungal infection, hepatitis B exacerbation, herpes infection, infection, tuberculosis, varicella, viral infection

    Due to severe lymphopenia, opportunistic infections (e.g., bacterial, protozoan, viral, and fungal infection) or reactivation of latent infections may occur in some patients. Patients with a history of varicella, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of prior infections when treated with alemtuzumab. Monitor chronic lymphocytic leukemia patients for signs and symptoms of Epstein-Barr virus (EBV) infection; hold alemtuzumab therapy for EPV reactivation or severe infection. In patients with multiple sclerosis (MS), alemtuzumab is contraindicated during an active infection. Herpes prophylaxis is recommended beginning on the first day of each treatment course and continuing for a minimum of 2 months following treatment or until the CD4 count is 200 cells/mcL or more, whichever occurs later. Consider serology screening for patients at high risk of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections before treatment, as there may be a potential risk for hepatitis B exacerbation or HCV exacerbation due to HBV or HCV reactivation. Before alemtuzumab use in patients treated for MS, screen for tuberculosis according to local guidelines, and treat any patients with positive screens before the start of alemtuzumab therapy. In CLL patients, withhold alemtuzumab for serious infections and during antiviral treatment for CMV infection or confirmed CMV viremia, which is defined as polymerase chain reaction positive CMV in at least 2 consecutive samples obtained 1 week apart. Prophylaxis against Pneumocystis jirovecii pneumonia (PCP) and herpes infection has been shown to decrease, but not eliminate, the occurrence of these infections. Prophylactic antibiotics are recommended upon the initiation of therapy and for a minimum of 2 months after the last dose of alemtuzumab or until the CD4 counts are 200 cells/mcL or more, whichever occurs later. The prophylactic regimens used during CLL clinical trials were sulfamethoxazole; trimethoprim DS twice daily 3 times per week and famciclovir 250 mg twice daily (or equivalent). The median time to recovery of CD4 counts to 200 cells/mcL or more was 2 months; however, full recovery (to baseline) of CD4 and CD8 counts may take more than 12 months. Additionally, initiate precautions against Listeria infection before alemtuzumab treatment; the incubation period for Listeria monocytogenes ranges from 3 to 70 days. In most cases, symptoms of invasive listeriosis appear within 1 month of exposure. Advise all patients to avoid or adequately heat foods that are potential sources of Listeria monocytogenes (e.g., deli meat, dairy products made with unpasteurized milk, soft cheeses, or undercooked meat, seafood, or poultry), to watch for symptoms of Listeria infection, and to seek prompt medical attention if symptoms do occur. Initiate these Listeria precautions before starting alemtuzumab treatment. Symptoms of Listeria infection include fever, chills, diarrhea, nausea, vomiting, headache, joint and muscle pains, neck stiffness, difficulty walking, mental status changes, coma, and other neurological changes. Cervical human papillomavirus (HPV) infection has also been reported; annual HPV screening for female patients is recommended.[27942] [58461]

    Autoimmune disease, bone marrow suppression, glomerulonephritis, hepatitis, human immunodeficiency virus (HIV) infection, immune thrombocytopenic purpura (ITP), immunosuppression, leukopenia, thyroid disease

    Alemtuzumab may be inappropriate for patients with immunosuppression. Close monitoring of hematologic parameters is recommended during alemtuzumab treatment because of moderate-to-severe bone marrow suppression anemia, leukopenia, neutropenia, and thrombocytopenia. Serious and, in rare cases, fatal pancytopenia/marrow hypoplasia, aplastic anemia, and autoimmune disease [e.g., immune thrombocytopenic purpura (ITP), hemolytic anemia, anti-glomerular basement membrane disease, membranous glomerulonephritis, and autoimmune thyroid disease such as Graves' disease, hyperthyroidism, hypothyroidism, autoimmune thyroiditis, goiter, and autoimmune hepatitis requiring liver transplant] have occurred during alemtuzumab therapy.[27942] [58461] When alemtuzumab is used for multiple sclerosis (i.e., Lemtrada), the drug is contraindicated in patients with human immunodeficiency virus (HIV) infection as prolonged reductions of CD4+ lymphocyte counts occur with alemtuzumab therapy.[58461] In patients with chronic lymphocytic leukemia (CLL), weekly or more frequent monitoring depending upon the severity of hematologic toxicity is recommended; monitor CD4+ counts for a minimum of 2 months following therapy or until CD4+ counts are 200 cells/microliter or more; dosage reduction or discontinuation may be required. Do not exceed recommended dosages; dosages greater than 30 mg/dose or more than 90 mg/week were associated with a higher incidence of pancytopenia in CLL patients.[27942] Because of the potential for graft-versus-host disease (GVHD) in severely lymphopenic patients, it is recommended to irradiate any blood products administered before the patient has recovered from lymphopenia.[27942] Prompt medical intervention is indicated if a cytopenia is confirmed. In patients with multiple sclerosis (MS), measure serum transaminases (ALT and AST) and total bilirubin concentrations before treatment and periodically until 48 months after the last dose. If a patient develops clinical signs of liver dysfunction, promptly assess liver function, and interrupt or discontinue treatment as appropriate. Measure urine protein to creatinine ratio before treatment initiation. Monitor the following before therapy initiation and monthly for 48 months after the last dose: CBC with differential (to detect cytopenias), serum creatinine, and urinalysis with urine cell counts. For urine dipstick results of 1+ protein or more, measure the urine protein creatinine ratio. For urine protein; creatinine ratios of 200 mg/gram or more, an increase in serum creatinine greater than 30%, or unexplained hematuria, perform further investigation for nephropathies. Monitor thyroid function tests (e.g., TSH) before treatment and every 3 months thereafter until 48 months after the last dose. After that, monitor TSH, if needed, based on clinical findings suggestive of autoimmune disease or in the case that a patient becomes pregnant. Symptoms of ITP include easy bruising, petechiae, spontaneous mucocutaneous bleeding (e.g., epistaxis, hemoptysis), and heavy or irregular menstrual bleeding. Hemoptysis may also be indicative of anti-glomerular basement membrane (GBM) disease. Symptoms of nephropathy may include edema, hematuria, change in urine color, decreased urine output, fatigue, dyspnea, and hemoptysis. Immediately evaluate signs of pulmonary involvement, anti-GBM disease (e.g., hemoptysis and exertional dyspnea), or increased serum creatinine with hematuria.[58461]

    Angina, cardiac disease, coronary artery disease, hypotension, infusion-related reactions, requires a specialized care setting

    Alemtuzumab requires a specialized care setting that has on-site access to equipment and personnel trained to manage potentially serious infusion-related reactions. To prevent potentially fatal infusion-related reactions in patients with chronic lymphocytic leukemia (CLL), alemtuzumab should be started at a low dose with gradual dose escalation to the effective dose and premedication with acetaminophen and diphenhydramine should be given. Patients with multiple sclerosis (MS) should be premedicated with high dose corticosteroids (i.e., methylprednisolone 1,000 mg or equivalent) immediately prior to infusion for the first 3 days of each treatment course; concomitant use of antihistamines and/or antipyretics may be considered. Obtain a baseline ECG before infusion in all MS patients. Carefully monitor vital signs before, during, and for 2 hours after infusions in all patients, especially those with conditions that predispose them to cardiovascular or pulmonary compromise. Careful monitoring of blood pressure for hypotension and for hypotensive symptoms is recommended, especially in patients with ischemic cardiac disease (i.e., angina, coronary artery disease) and in patients receiving antihypertensive therapy. 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. Consider immediate discontinuation of the intravenous infusion if severe infusion reactions occur. In patients with CLL, withhold alemtuzumab for Grade 3 or 4 infusion reactions; if therapy is interrupted for 7 days or more, alemtuzumab should be reinstituted with gradual dose escalation. Infusion-related reactions that have been reported during use have included anaphylaxis (including anaphylactic shock), angioedema, bronchospasm, hypotension, chest pain, bradycardia, tachycardia (including atrial fibrillation), transient neurologic symptoms, hypertension, headache, pyrexia, and rash. Other infusion-related reactions reported included nausea, urticaria, pruritus, insomnia, chills, flushing, fatigue, dyspnea, pulmonary infiltrates, dysgeusia, dyspepsia, dizziness, and pain. During postmarketing use, other serious and sometimes fatal infusion reactions included hypoxia, syncope, acute respiratory distress syndrome, respiratory arrest, myocardial infarction, acute cardiac insufficiency, and cardiac arrest. Institute medical management (e.g., glucocorticoids, epinephrine, etc.) for infusion reactions as needed.

    Stroke

    Monitor patients for signs and symptoms of stroke or arterial dissection within the head and neck during treatment with alemtuzumab. Rare, but serious and life-threatening cases of hemorrhagic and ischemic stroke and tears in the lining of arteries of the head and neck (arterial dissection) have been observed in patients with multiple sclerosis, most often within 1 day of receiving treatment, although cases have also been reported to occur a few (3) days after treatment. Although individual risk factors were fully assessed in all cases, the occurrence of these events within 1 day of administration suggests an association with alemtuzumab administration. The etiology of these adverse events is unclear; however, incidents occurred during the same time frame as cytokine release syndrome, a known systemic inflammatory response syndrome that can occur after alemtuzumab administration. Advise patients to seek immediate medical attention if they experience symptoms of an ischemic or hemorrhagic stroke or cervicocephalic arterial dissection. The diagnosis is often complicated because early symptoms such as a headache and neck pain are not specific. [63789]

    New primary malignancy

    Alemtuzumab, when given in patients with mulitple sclerosis, may increase the risk of developing a new primary malignancy such as thyroid cancer, melanoma, lymphoproliferative disorders, and lymphoma. Monitor patients for symptoms of thyroid cancer such as lump or swelling in the neck, pain in front of the neck, persistent hoarseness or other voice changes, trouble swallowing or breathing, or persistent cough not related to a respiratory infection. Baseline and yearly skin examinations should be performed to assess for melanoma or other skin cancer. Use caution when treating patients with pre-existing or ongoing malignancies.

    DEA CLASS

    Rx

    DESCRIPTION

    Humanized monoclonal antibody against the CD52 antigen
    One product, Lemtrada, is used for relapsing forms of multiple sclerosis (MS) but is reserved for those with inadequate response to 2 or more drugs due to risk for serious side effects
    The product used for B-cell chronic lymphocytic leukemia, Campath, is only available through a restricted access distribution program

    COMMON BRAND NAMES

    LEMTRADA

    HOW SUPPLIED

    LEMTRADA Intravenous Inj Sol: 1mL, 10mg

    DOSAGE & INDICATIONS

    For the treatment of chronic lymphocytic leukemia (CLL) (B-cell).
    NOTE: Alemtuzumab has been designated an orphan drug by the FDA for chronic lymphocytic leukemia (CLL).
    For the treatment of previously untreated CLL as a single agent.
    Intravenous dosage
    Adults

    Initially, 3 mg IV over 2 hours once daily. Withhold alemtuzumab for grade 3 or 4 infusion reactions. When the 3 mg dose is tolerated (infusion reactions are grade 2 or less), escalate the daily dose to 10 mg IV once daily and continue until infusion reactions are grade 2 or less, then start the maintenance dose of 30 mg IV given 3 times weekly on alternate days (i.e., Monday, Wednesday, Friday); the total therapy duration including dose escalation is 12 weeks. In most patients, the dose escalation to 30 mg can be done in 3—7 days. Gradual dose escalation to the maintenance dosage is required at treatment initiation and after therapy interruption for 7 or more days; start at a dose of 3 mg. Single doses > 30 mg or cumulative weekly doses of > 90 mg should not be given because of an increased incidence of pancytopenia. Adjust dose based on hematologic toxicity (see Dosage Adjustments). Withhold alemtuzumab during serious infection or other serious adverse reactions until resolution. In a phase III trial, 297 patients with previously untreated CLL with progressive disease that required therapy were randomized to receive alemtuzumab or chlorambucil. Progression-free survival (14.6 months vs. 11.7 months, p < 0.0001) and the overall response rate (83% vs. 55%, p < 0.0001) were significantly better in the alemtuzumab arm. In addition, a complete response was achieved by 24% of patients in the alemtuzumab arm compared to 2% of patients in the chlorambucil arm (p < 0.0001).

    Subcutaneous dosage†
    Adults

    Initially, 3 mg subcutaneously on day 1. If tolerated, escalate the dose to 10 mg subcutaneously on day 3 and then to the target dose of 30 mg subcutaneously on day 5. In the event of local skin erythema or edema, escalate the dose over a period of 1 to 2 weeks. Administer the maintenance dose of 30 mg subcutaneously 3 times weekly on alternate days (i.e., Monday, Wednesday, Friday) for a maximum of 18 weeks. In clinical trials, treatment was held in patients achieving a complete remission or developing progressive disease. If treatment was interrupted for more than 7 days, the dose was reinitiated at 3 or 10 mg. Dosage adjustments may be necessary based on hematologic toxicity, although not specified in clinical trials. Alemtuzumab therapy may need to be suspended during serious adverse reactions until resolution. In a phase II trial, 38 patients with previously untreated CLL received alemtuzumab subcutaneously matched to 75 historical control patients. The overall response rate in the alemtuzumab arm was 87% compared to a 56% response rate among historical controls. All patients received allopurinol (300 mg/day) for the first 4 weeks; cotrimoxazole, valacyclovir, and fluconazole were given during alemtuzumab treatment and for 8 weeks after completion.

    For the treatment of previously treated CLL as a single agent.
    Intravenous dosage
    Adults

    Initially, 3 mg IV over 2 hours once daily. Withhold alemtuzumab for grade 3 or 4 infusion reactions. When the 3 mg dose is tolerated (infusion reactions are grade 2 or less), escalate the daily dose to 10 mg IV once daily and continue until infusion reactions are grade 2 or less, then start the maintenance dose of 30 mg IV given 3 times weekly on alternate days (i.e., Monday, Wednesday, Friday); the total therapy duration including dose escalation is 12 weeks. In most patients, the dose escalation to 30 mg can be done in 3—7 days. Gradual dose escalation to the maintenance dosage is required at treatment initiation and after therapy interruption for 7 or more days; start at a dose of 3 mg. Single doses > 30 mg or cumulative weekly doses of > 90 mg should not be given because of an increased incidence of pancytopenia. Adjust dose based on hematologic toxicity (see Dosage Adjustments). Withhold alemtuzumab during serious infection or other serious adverse reactions until resolution. In 3 open-label single-arm studies of 149 CLL patients who had previously received chemotherapy, complete response rates of 0—2% and partial response rates of 21—31% were observed with alemtuzumab.

    Subcutaneous dosage†
    Adults

    Multiple dosage regimens have been studied. In a clinical trial of 103 patients with fludarabine-refractory CLL, 57 patients received alemtuzumab subcutaneously. Patients received a dose escalation of alemtuzumab 3 mg subcutaneously on day 1, then 10 mg subcutaneously on day 2, and then the target dose of 30 mg subcutaneously on day 3. Patients then received alemtuzumab 30 mg subcutaneously 3 times weekly (i.e., Monday, Wednesday, Friday) for a minimum of 4 weeks up to a maximum of 12 weeks. In patients receiving alemtuzumab subcutaneously, the overall response rate was 34% and overall survival was 19.1 months. Another clinical trial in 49 patients with refractory CLL studied low-dose alemtuzumab. Patients received alemtuzumab 3 mg subcutaneously on day 1, then 10 mg subcutaneously on day 3. Alemtuzumab 10 mg subcutaneously was then given 3 times weekly for a maximum of 18 weeks (maximum cumulative dose: 544 mg). The overall response rate was 53%, including a 60% response rate in patients with the unfavorable 17p deletion.

    For the treatment of relapsed or refractory CLL in combination with rituximab†.
    Intravenous dosage
    Adults

    Multiple regimens have been studied. In a phase II trial, 48 patients with relapsed or refractory lymphoid malignancies (32 patients with CLL) were given alemtuzumab in combination with rituximab. Alemtuzumab was dose escalated over 3 consecutive days in week 1 (3 mg IV over 2 hours on day 1, 10 mg IV on day 2, 30 mg IV on day 3, and withheld for grade 3 or 4 infusion reactions), then administered at 30 mg IV on days 3 and 5 of weeks 2—4. Rituximab 375 mg/m2 IV was given weekly on day 1 for 4 consecutive weeks (first dose divided as 100 mg/m2 IV on day 1, then 275 mg/m2 IV on day 2 in patients with WBC count > 50,000 cells/mm3. Patients could receive a second 4-week cycle depending on response and toxicities. All patients received prophylactic trimethoprim/sulfamethoxazole and valacyclovir during treatment and for 2 months after completion. Combination therapy provided an overall response rate of 63% in patients with CLL. In another clinical trial, 40 patients with previously treated CLL received continuous IV infusion alemtuzumab (15 mg/day IV over 24 hours on days 2—7), followed by subcutaneous alemtuzumab (30 mg subcutaneously on days 3 and 5 in weeks 2—4), in combination with rituximab (375 mg/m2 IV on day 1 of week 1, then 500 mg/m2 IV on day 1 of weeks 2—4). The primary endpoint, overall response rate, was 53% (CR 18%, nodular PR 10%, PR 25%), and the median time-to-treatment failure was 6 months. The median overall survival in patients with a major response (CR or nodular PR) was 62 months compared to 28 months in patients with a PR or no response (p = 0.01).

    For the treatment of relapsed or refractory CLL in combination with fludarabine†.
    Intravenous dosage
    Adults

    30 mg IV on days 1—3 in combination with fludarabine 30 mg/m2 IV over 30 minutes on days 1—3 repeated every 28 days for up to 6 cycles has been studied in a randomized, phase III trial. Alemtuzumab was titrated to 30 mg on the first cycle of treatment as follows: 3 mg IV over 2 hours on day 1, 10 mg IV over 2 hours on day 2, 30 mg IV over 2 hours on day 3. The same dose was repeated daily if grade 3 or 4 infusion-related toxicity occurred until it was well tolerated (grade 2 or lower toxicity) with appropriate premedication; a maximum of 14 days was allowed for titration to 30 mg. After escalation, fludarabine was administered first followed by alemtuzumab IV over 4—6 hours on the first day of each cycle and over 2 hours on days 2 and 3. All patients received acetaminophen and an antihistamine 30 minute prior to each alemtuzumab infusion and hydrocortisone 100 mg IV (or equivalent) prior to each alemtuzumab infusion during the dose escalation phase and then on day 1 of each subsequent cycles. Patients also received prophylaxis with co-trimoxazole (or equivalent) and famciclovir starting at the beginning of therapy and continuing until CD4 counts were at least 200 cells/microliter.

    For the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting disease and active secondary progressive disease.
    Intravenous dosage
    Adults

    Regimen consists of 2 treatment courses as follows: 12 mg IV infusion over 4 hours daily on 5 consecutive days (total dose of 60 mg) for a first treatment course. Follow 12 months later with 12 mg IV infusion over 4 hours daily for 3 consecutive days (total dose of 36 mg) for a second treatment course. Subsequent treatment courses of 12 mg IV daily for 3 consecutive days may be given at least 12 months after the last dose of any prior treatment course.[58461] Because of its safety profile, the use of alemtuzumab is not recommended in patients with clinically isolated syndrome (CIS) and should generally be reserved for those with an inadequate response to 2 or more other multiple sclerosis drug therapies.

    For the treatment of T-cell prolymphocytic leukemia (PLL)†.
    Intravenous infusion
    Adults

    30 mg IV 3 times per week has been studied; alemtuzumab was usually titrated up to a 30 mg dose (3 mg, 10 mg, and 30 mg on 3 consecutive days). In a phase II study of 18 patients, alemtuzumab for up to 12 weeks led to a complete response in 8 patients and a partial response in 2 patients; 5 patients still had a complete response at 9 months, 10 months, 11 months, 12 months, and 15 months. Patients had advanced or refractory disease; most had received multiple previous therapies (median of 3), and the median time from diagnosis was 7 years. In another trial of 38 patients, most of whom had been treated with other agents, 23 had a complete response and 6 had a partial response to alemtuzumab. If tolerated, the alemtuzumab dose was titrated to 30 mg IV 3 times weekly, although some patients who failed to respond to a 30 mg dose got daily alemtuzumab, and 5 patients got an 80 mg dose; a response was induced in 2 patients. The median dose received was 508 mg (range, 50—1325 mg) over a median of 35 days (range, 2—82 days). The median time from alemtuzumab discontinuation to relapse was 7 months (range, 4—45 months). In a retrospective analysis of 76 patients with T-PLL (72 previously treated, 4 treatment naive), alemtuzumab produced a 51% objective response rate. The median time to progression was 4.5 months and the median overall survival was 7.5 months.

    For the treatment of relapsed or refractory cutaneous T-cell lymphoma (CTCL)†, including mycosis fungoides† and Sezary syndrome†.
    Intravenous infusion
    Adults

    30 mg IV 3 times weekly has been studied. Of 50 patients with advanced, low-grade NHL who had relapsed after chemotherapy or were resistant to chemotherapy, 2 had a complete remission and 8 had a partial remission with alemtuzumab 30 mg IV 3 times weekly for up to 12 weeks. Both patients with a complete remission and 2 of the 8 patients with a partial remission had mycosis fungoides. In another trial, 30 mg IV 3 times weekly for up to 12 weeks in 22 patients with advanced mycosis fungoides/Sezary syndrome led to a complete response in 7 and a partial response in 5 patients. Of note, 8 of 10 patients who had received 1—2 previous regimens had either a complete or partial response whereas only 4 of 12 patients who had received 3 or more prior regimens had the outcome. In a trial of 19 heavily pretreated patients with erythrodermic MF/SS, alemtuzumab (3 mg IV day 1, 10 mg IV day 3, 30 mg IV day 5; week 1) 30 mg IV 3 times weekly for 12 weeks produced an objective response rate of 84% (CR 47%, PR 37%). The median overall survival was 41 months.

    For stem cell transplant preparation† and graft-versus-host disease (GVHD) prophylaxis† in combination with fludarabine and melphalan in nonmyeloablative allogeneic hematopoietic stem cell transplantation (SCT) in patients with hematologic malignancies.
    Intravenous dosage
    Adults

    20 mg/day IV (over 8 hours) on days -8 and -4 in combination with fludarabine (30 mg/m2 IV on days -7 to -3) and melphalan (140 mg/m2 IV on day -2) has been studied. In a retrospective comparison of 2 prospectively studied conditioning regimens, alemtuzumab in combination with fludarabine, melphalan, and cyclosporine for GVHD prophylaxis was compared to fludarabine/melphalan alone with GVHD prophylaxis including cyclosporine and methotrexate. Patients receiving alemtuzumab had a higher incidence of cytomegalovirus reactivation (85% vs. 24%) and a significantly lower incidence of acute GVHD (21.7% vs 45.1%) and chronic GVHD (5% vs. 66.7%) as compared to those receiving fludarabine/melphalan/cyclosporine/methotrexate. In addition, patients receiving alemtuzumab often required donor lymphocyte infusions (DLI) to achieve similar tumor control; however, the incidence of GVHD was not significantly increased after DLI. There were no significant differences in event-free or overall survival between the 2 groups. These results are consistent with a similarly designed study. In another study of 43 evaluable patients, alemtuzumab/fludarabine/melphalan produced durable engraftment in 42/43 patients with no Grade III or IV acute GVHD events. Subsequent to these studies, a feasibility trial of fludarabine/melphalan conditioning with alemtuzumab on day -1 was conducted in an attempt to reduce the delay in immune reconstitution and rate of infectious complications observed with alemtuzumab given on 5 days during conditioning. Study arms included alemtuzumab 20 mg IV (day -1), 30 mg IV (day -1), 40 mg IV (20 mg IV days -2 and -1), and 60 mg IV (30 mg IV days -2 and -1). Alemtuzumab 30 mg IV on day -1 produced similar clinical outcomes as higher doses with better lymphocyte recovery at 1 year.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Treatment of chronic lymphocytic leukemia (Campath): Single doses > 30 mg IV or cumulative weekly doses > 90 mg IV are not recommended.
    Treatment of relapsing multiple sclerosis (Lemtrada): 12 mg/dose IV.

    Geriatric

    Treatment of chronic lymphocytic leukemia (Campath): Single doses > 30 mg IV or cumulative weekly doses > 90 mg IV are not recommended.
    Treatment of relapsing multiple sclerosis (Lemtrada): 12 mg/dose IV.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Emetic Risk
    Moderate
    Administer routine antiemetic prophylaxis prior to treatment.

    Injectable Administration

    For intravenous infusion use only. Dilute drug prior to administration.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The solution is clear and colorless to slightly yellow.
     
    General Information:
    Administer in a setting in which equipment and personnel to appropriately manage anaphylaxis or serious infusion reactions are available. Administration can cause serious, sometimes fatal, infusion-related reactions. Carefully monitor the patient during the infusion.
    Patients with CLL should be premedicated 30 minutes before the first dose, dose-escalation, and as needed with diphenhydramine (50 mg) and acetaminophen (500 to 1,000 mg) to decrease the incidence of infusion-related reactions.
    Patients with multiple sclerosis should be premedicated with high dose corticosteroids (i.e., methylprednisolone 1,000 mg or equivalent) immediately prior to infusion for the first 3 days of each treatment course; concomitant use of antihistamines and/or antipyretics may be considered.
    Patients should receive anti-infective prophylaxis to minimize the risk of opportunistic infections.
    In chronic lymphocytic leukemia patients, sulfamethoxazole; trimethoprim DS twice daily 3 times per week or the equivalent for Pneumocystis jiroveci pneumonia (PCP) prophylaxis and famciclovir 250 mg twice daily or the equivalent for herpetic prophylaxis are recommended.
    In multiple sclerosis patients, anti-viral prophylaxis for herpetic viral infections should be given on the first day of each treatment course.
    Continue prophylaxis for 2 months or more following treatment or until the CD4 count is 200 cells/mcL or more, whichever occurs later.

    Intravenous Administration

    Only administer as an intravenous (IV) infusion; do NOT administer as an IV push or bolus dose.
    Do not add or simultaneously infuse other drugs through the same intravenous line.
    No incompatibilities with polyvinylchloride (PVC) bags or PVC or polyethylene lined PVC administration sets have been observed.
    Storage: Use within 8 hours after dilution. Solutions may be stored at room temperature (15 to 25 degrees C) or refrigerated (2 to 8 degrees C). Protect solutions from light.
     
    Campath administration:
    Preparation of infusion prior to IV administration:
    Do not shake vial prior to use. Vials are preservative-free are intended for single-use only. Discard any drug not used to prepare an infusion dose.
    Withdraw the appropriate dose from the vial.
    Inject the dose into 100 mL 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
    Gently invert the bag to mix the solution.
    Intravenous infusion:
    Monitor vital signs before the infusion and periodically during the infusion. Provide appropriate symptomatic treatment for infusion reactions as needed.
    Withhold alemtuzumab administration if a grade 3 or 4 infusion reaction occurs.
    Infuse over 2 hours.
    Observe patients for infusion reactions during and for at least 2 hours after each infusion.
    Inform patients that they should report symptoms that occur during and after each infusion because they may indicate a need for prompt medical intervention.
     
    Lemtrada administration:
    Preparation of infusion prior to IV administration:
    Do not shake vial prior to use. Vials are preservative-free are intended for single-use only. Discard any drug not used to prepare an infusion dose.
    Withdraw 12 mg (1.2 mL) from the vial.
    Inject the dose in 100 mL 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
    Gently invert the bag to mix the solution.
    Intravenous infusion:
    Monitor vital signs before the infusion and periodically during the infusion. Provide appropriate symptomatic treatment for infusion reactions as needed.
    Consider immediate discontinuation if a severe infusion reaction occurs.
    Infuse over 4 hours. Infusion duration may be extended if clinically indicated.
    Observe patients for infusion reactions during and for at least 2 hours after each infusion.
    Inform patients that they should report symptoms that occur during and after each infusion because they may indicate a need for prompt medical intervention.

    Subcutaneous Administration

    NOTE: Alemtuzumab is not FDA-approved for subcutaneous administration.
    No dilution is necessary. Withdraw the desired amount of alemtuzumab 30 mg/mL solution for injection into a syringe.
    Injection site skin reactions occur commonly with subcutaneous administration. Rotation of the injection site may be indicated.
    Inject subcutaneously taking care not to inject intradermally.

    STORAGE

    Campath:
    - Do not freeze
    - Protect from direct sunlight
    - Refrigerate (between 36 and 46 degrees F)
    LEMTRADA:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Store diluted product in accordance with package insert instructions
    - Store in refrigerator at 2 to 8 degrees C (36 to 46 degrees F)
    - Store in the original carton to protect from light

    CONTRAINDICATIONS / PRECAUTIONS

    Hamster protein hypersensitivity

    Alemtuzumab is contraindicated in patients with alemtuzumab hypersensitivity or hypersensitivity to any of the components. Use with caution in patients with a hamster protein hypersensitivity. Alemtuzumab is produced in mammalian cell (Chinese hamster ovary) suspension culture in a nutrient medium containing neomycin, but neomycin is not detectable in the final products.

    Fungal infection, hepatitis B exacerbation, herpes infection, infection, tuberculosis, varicella, viral infection

    Due to severe lymphopenia, opportunistic infections (e.g., bacterial, protozoan, viral, and fungal infection) or reactivation of latent infections may occur in some patients. Patients with a history of varicella, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of prior infections when treated with alemtuzumab. Monitor chronic lymphocytic leukemia patients for signs and symptoms of Epstein-Barr virus (EBV) infection; hold alemtuzumab therapy for EPV reactivation or severe infection. In patients with multiple sclerosis (MS), alemtuzumab is contraindicated during an active infection. Herpes prophylaxis is recommended beginning on the first day of each treatment course and continuing for a minimum of 2 months following treatment or until the CD4 count is 200 cells/mcL or more, whichever occurs later. Consider serology screening for patients at high risk of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections before treatment, as there may be a potential risk for hepatitis B exacerbation or HCV exacerbation due to HBV or HCV reactivation. Before alemtuzumab use in patients treated for MS, screen for tuberculosis according to local guidelines, and treat any patients with positive screens before the start of alemtuzumab therapy. In CLL patients, withhold alemtuzumab for serious infections and during antiviral treatment for CMV infection or confirmed CMV viremia, which is defined as polymerase chain reaction positive CMV in at least 2 consecutive samples obtained 1 week apart. Prophylaxis against Pneumocystis jirovecii pneumonia (PCP) and herpes infection has been shown to decrease, but not eliminate, the occurrence of these infections. Prophylactic antibiotics are recommended upon the initiation of therapy and for a minimum of 2 months after the last dose of alemtuzumab or until the CD4 counts are 200 cells/mcL or more, whichever occurs later. The prophylactic regimens used during CLL clinical trials were sulfamethoxazole; trimethoprim DS twice daily 3 times per week and famciclovir 250 mg twice daily (or equivalent). The median time to recovery of CD4 counts to 200 cells/mcL or more was 2 months; however, full recovery (to baseline) of CD4 and CD8 counts may take more than 12 months. Additionally, initiate precautions against Listeria infection before alemtuzumab treatment; the incubation period for Listeria monocytogenes ranges from 3 to 70 days. In most cases, symptoms of invasive listeriosis appear within 1 month of exposure. Advise all patients to avoid or adequately heat foods that are potential sources of Listeria monocytogenes (e.g., deli meat, dairy products made with unpasteurized milk, soft cheeses, or undercooked meat, seafood, or poultry), to watch for symptoms of Listeria infection, and to seek prompt medical attention if symptoms do occur. Initiate these Listeria precautions before starting alemtuzumab treatment. Symptoms of Listeria infection include fever, chills, diarrhea, nausea, vomiting, headache, joint and muscle pains, neck stiffness, difficulty walking, mental status changes, coma, and other neurological changes. Cervical human papillomavirus (HPV) infection has also been reported; annual HPV screening for female patients is recommended.[27942] [58461]

    Autoimmune disease, bone marrow suppression, glomerulonephritis, hepatitis, human immunodeficiency virus (HIV) infection, immune thrombocytopenic purpura (ITP), immunosuppression, leukopenia, thyroid disease

    Alemtuzumab may be inappropriate for patients with immunosuppression. Close monitoring of hematologic parameters is recommended during alemtuzumab treatment because of moderate-to-severe bone marrow suppression anemia, leukopenia, neutropenia, and thrombocytopenia. Serious and, in rare cases, fatal pancytopenia/marrow hypoplasia, aplastic anemia, and autoimmune disease [e.g., immune thrombocytopenic purpura (ITP), hemolytic anemia, anti-glomerular basement membrane disease, membranous glomerulonephritis, and autoimmune thyroid disease such as Graves' disease, hyperthyroidism, hypothyroidism, autoimmune thyroiditis, goiter, and autoimmune hepatitis requiring liver transplant] have occurred during alemtuzumab therapy.[27942] [58461] When alemtuzumab is used for multiple sclerosis (i.e., Lemtrada), the drug is contraindicated in patients with human immunodeficiency virus (HIV) infection as prolonged reductions of CD4+ lymphocyte counts occur with alemtuzumab therapy.[58461] In patients with chronic lymphocytic leukemia (CLL), weekly or more frequent monitoring depending upon the severity of hematologic toxicity is recommended; monitor CD4+ counts for a minimum of 2 months following therapy or until CD4+ counts are 200 cells/microliter or more; dosage reduction or discontinuation may be required. Do not exceed recommended dosages; dosages greater than 30 mg/dose or more than 90 mg/week were associated with a higher incidence of pancytopenia in CLL patients.[27942] Because of the potential for graft-versus-host disease (GVHD) in severely lymphopenic patients, it is recommended to irradiate any blood products administered before the patient has recovered from lymphopenia.[27942] Prompt medical intervention is indicated if a cytopenia is confirmed. In patients with multiple sclerosis (MS), measure serum transaminases (ALT and AST) and total bilirubin concentrations before treatment and periodically until 48 months after the last dose. If a patient develops clinical signs of liver dysfunction, promptly assess liver function, and interrupt or discontinue treatment as appropriate. Measure urine protein to creatinine ratio before treatment initiation. Monitor the following before therapy initiation and monthly for 48 months after the last dose: CBC with differential (to detect cytopenias), serum creatinine, and urinalysis with urine cell counts. For urine dipstick results of 1+ protein or more, measure the urine protein creatinine ratio. For urine protein; creatinine ratios of 200 mg/gram or more, an increase in serum creatinine greater than 30%, or unexplained hematuria, perform further investigation for nephropathies. Monitor thyroid function tests (e.g., TSH) before treatment and every 3 months thereafter until 48 months after the last dose. After that, monitor TSH, if needed, based on clinical findings suggestive of autoimmune disease or in the case that a patient becomes pregnant. Symptoms of ITP include easy bruising, petechiae, spontaneous mucocutaneous bleeding (e.g., epistaxis, hemoptysis), and heavy or irregular menstrual bleeding. Hemoptysis may also be indicative of anti-glomerular basement membrane (GBM) disease. Symptoms of nephropathy may include edema, hematuria, change in urine color, decreased urine output, fatigue, dyspnea, and hemoptysis. Immediately evaluate signs of pulmonary involvement, anti-GBM disease (e.g., hemoptysis and exertional dyspnea), or increased serum creatinine with hematuria.[58461]

    Angina, cardiac disease, coronary artery disease, hypotension, infusion-related reactions, requires a specialized care setting

    Alemtuzumab requires a specialized care setting that has on-site access to equipment and personnel trained to manage potentially serious infusion-related reactions. To prevent potentially fatal infusion-related reactions in patients with chronic lymphocytic leukemia (CLL), alemtuzumab should be started at a low dose with gradual dose escalation to the effective dose and premedication with acetaminophen and diphenhydramine should be given. Patients with multiple sclerosis (MS) should be premedicated with high dose corticosteroids (i.e., methylprednisolone 1,000 mg or equivalent) immediately prior to infusion for the first 3 days of each treatment course; concomitant use of antihistamines and/or antipyretics may be considered. Obtain a baseline ECG before infusion in all MS patients. Carefully monitor vital signs before, during, and for 2 hours after infusions in all patients, especially those with conditions that predispose them to cardiovascular or pulmonary compromise. Careful monitoring of blood pressure for hypotension and for hypotensive symptoms is recommended, especially in patients with ischemic cardiac disease (i.e., angina, coronary artery disease) and in patients receiving antihypertensive therapy. 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. Consider immediate discontinuation of the intravenous infusion if severe infusion reactions occur. In patients with CLL, withhold alemtuzumab for Grade 3 or 4 infusion reactions; if therapy is interrupted for 7 days or more, alemtuzumab should be reinstituted with gradual dose escalation. Infusion-related reactions that have been reported during use have included anaphylaxis (including anaphylactic shock), angioedema, bronchospasm, hypotension, chest pain, bradycardia, tachycardia (including atrial fibrillation), transient neurologic symptoms, hypertension, headache, pyrexia, and rash. Other infusion-related reactions reported included nausea, urticaria, pruritus, insomnia, chills, flushing, fatigue, dyspnea, pulmonary infiltrates, dysgeusia, dyspepsia, dizziness, and pain. During postmarketing use, other serious and sometimes fatal infusion reactions included hypoxia, syncope, acute respiratory distress syndrome, respiratory arrest, myocardial infarction, acute cardiac insufficiency, and cardiac arrest. Institute medical management (e.g., glucocorticoids, epinephrine, etc.) for infusion reactions as needed.

    Stroke

    Monitor patients for signs and symptoms of stroke or arterial dissection within the head and neck during treatment with alemtuzumab. Rare, but serious and life-threatening cases of hemorrhagic and ischemic stroke and tears in the lining of arteries of the head and neck (arterial dissection) have been observed in patients with multiple sclerosis, most often within 1 day of receiving treatment, although cases have also been reported to occur a few (3) days after treatment. Although individual risk factors were fully assessed in all cases, the occurrence of these events within 1 day of administration suggests an association with alemtuzumab administration. The etiology of these adverse events is unclear; however, incidents occurred during the same time frame as cytokine release syndrome, a known systemic inflammatory response syndrome that can occur after alemtuzumab administration. Advise patients to seek immediate medical attention if they experience symptoms of an ischemic or hemorrhagic stroke or cervicocephalic arterial dissection. The diagnosis is often complicated because early symptoms such as a headache and neck pain are not specific. [63789]

    Gallbladder disease

    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. Time to onset of symptoms ranged from less than 24 hours to 2 months after alemtuzumab infusion. Typical risk or predisposing factors such as pre-existing gallbladder disease or 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, 6 of 1,217 (0.5%) alemtuzumab-treated multiple sclerosis patients had pneumonitis of varying severity. Cases of hypersensitivity pneumonitis and pneumonitis with fibrosis occurred in clinical studies. Patients should be advised to report symptoms of pneumonitis, which include shortness of breath, cough, wheezing, chest pain or tightness, and hemoptysis.

    Depression, suicidal ideation

    In clinical studies, 0.6% of multiple sclerosis 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.

    New primary malignancy

    Alemtuzumab, when given in patients with mulitple sclerosis, may increase the risk of developing a new primary malignancy such as thyroid cancer, melanoma, lymphoproliferative disorders, and lymphoma. Monitor patients for symptoms of thyroid cancer such as lump or swelling in the neck, pain in front of the neck, persistent hoarseness or other voice changes, trouble swallowing or breathing, or persistent cough not related to a respiratory infection. Baseline and yearly skin examinations should be performed to assess for melanoma or other skin cancer. Use caution when treating patients with pre-existing or ongoing malignancies.

    Vaccination

    In patients with multiple sclerosis, complete any necessary immunizations at least 6 weeks prior to starting alemtuzumab treatment; do not administer live viral vaccines following a course of alemtuzumab. Determine if these patients have a history of varicella or have been vaccinated for varicella zoster virus (VZV); if not, test for antibodies to VZV and consider vaccination for those who are antibody negative. Vaccination with live virus vaccines is not recommended in patients with chronic lymphocytic leukemia who have recently received alemtuzumab therapy. Consider the risk and benefits of administering live or live-attenuated vaccines to infants exposed to alemtuzumab in utero; these infants may be more at risk for developing infections.

    Progressive multifocal leukoencephalopathy

    Progressive multifocal leukoencephalopathy (PML) has occurred in a patient with MS treated with alemtuzumab. As PML can be fatal, instruct patients to notify their healthcare provider immediately if they notice new or worsening neurological signs or symptoms such as ataxia, visual changes, or confusion. Similarly, suspect PML in any patient presenting with neurological symptoms; discontinue alemtuzumab at the first sign or symptom of PML and perform a clinical evaluation. Consider MRI monitoring for signs that may be consistent with PML. MRI findings suggestive of PML and detection of JC virus (JCV) DNA in the CSF in the absence of clinical signs and symptoms of PML have been reported in patients treated with other multiple sclerosis medications; many cases progressed to symptomatic PML. Promptly investigate any suspicious findings to allow for early diagnosis.

    Children, infants

    The safety and efficacy of alemtuzumab in adolescents, children, and infants with chronic lymphocytic leukemia have not been established. The safety and efficacy of alemtuzumab in multiple sclerosis patients less 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 because it may increase the risk of malignancies (e.g., thyroid, melanoma, lymphoproliferative disorders, and lymphoma).

    Neonates, pregnancy

    Alemtuzumab may cause fetal harm if administered during pregnancy, based on data from animal studies. Females of reproductive potential should avoid pregnancy during alemtuzumab therapy. Discuss the potential hazard to the fetus if alemtuzumab is used during pregnancy. Monoclonal antibodies may cross the placental membrane, especially during the third trimester. Auto-antibodies may develop with alemtuzumab therapy; placental transfer of anti-thyroid antibodies resulting in neonatal Graves disease has been reported. 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 a neonate born 1 year after maternal alemtuzumab therapy. Alemtuzumab-induced autoimmune thyroid disease poses special risks in women who are pregnant and potentially to neonates who were exposed in utero; untreated hypothyroidism in pregnant women increases the risk for miscarriage and may have effects on the fetus including mental retardation and dwarfism. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to alemtuzumab; information about the registry can be obtained at pregnancyregistries@syneoshealth.com or by calling 1-866-758-2990.

    Contraception requirements, infertility, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during alemtuzumab treatment. Women who become pregnant while receiving alemtuzumab should be apprised of the potential hazard to the fetus.  Female patients of reproductive potential with chronic lymphocytic leukemia require pregnancy testing prior to starting alemtuzumab. These women should use effective contraceptive measures during alemtuzumab therapy and for at least 3 months after the last dose. Female patients of reproductive potential with multiple sclerosis should use effective contraceptive measures during alemtuzumab therapy and for 4 months after the last dose. If a patient becomes pregnant during therapy, healthcare providers should register patients in the Lemtrada pregnancy exposure registry at 1-866-758-2990. There is a risk of infertility in male and female patients, based on data from animal studies; it is not known if fertility is reversible.[27942] [58461]

    Breast-feeding

    It is not known if alemtuzumab is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Alemtuzumab may be present in human breast milk, as human IgG is excreted in human milk.  Because there is a potential for adverse reactions (e.g., lymphopenia) in a nursing child from alemtuzumab, women with chronic lymphocytic leukemia should be advised against breast-feeding during alemtuzumab therapy and for at least 3 months after the last dose. In patients with multiple sclerosis, consider the developmental and health benefits of breast-feeding along with the mother's clinical need for alemtuzumab and any potential adverse effects on the breast-fed infant from alemtuzumab or the underlying maternal condition.[58461]

    ADVERSE REACTIONS

    Severe

    lymphopenia / Delayed / 97.0-99.9
    neutropenia / Delayed / 42.0-64.0
    thrombocytopenia / Delayed / 13.0-52.0
    anemia / Delayed / 13.0-38.0
    fever / Early / 10.0-35.0
    chills / Rapid / 3.0-35.0
    infection / Delayed / 5.0-21.0
    hypertension / Early / 5.0-5.0
    urticaria / Rapid / 2.0-2.0
    diarrhea / Early / 1.0-1.0
    headache / Early / 1.0-1.0
    hypotension / Rapid / 1.0-1.0
    rash / Early / 1.0-1.0
    suicidal ideation / Delayed / 0.6-0.6
    hemolytic anemia / Delayed / 0.3-0.3
    glomerulonephritis / Delayed / 0.3-0.3
    new primary malignancy / Delayed / 0.3-0.3
    pancytopenia / Delayed / 0.2-0.2
    cholecystitis / Delayed / 0.2-0.2
    bronchospasm / Rapid / 5.0
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    autoimmune disease / Delayed / Incidence not known
    red cell aplasia / Delayed / Incidence not known
    hemophagocytic lymphohistiocytosis / Delayed / Incidence not known
    progressive multifocal leukoencephalopathy / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    Still’s disease / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    heart failure / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    cardiac arrest / Early / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    stroke / Early / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    clotting factor deficiency / Delayed / Incidence not known
    coagulopathy / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    skin cancer / Delayed / Incidence not known
    lymphoma / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 1.9-94.0
    infusion-related reactions / Rapid / 10.0-92.0
    candidiasis / Delayed / 12.0-12.0
    sinus tachycardia / Rapid / 8.0-10.0
    hematuria / Delayed / 8.0-8.0
    myasthenia / Delayed / 0-7.0
    chest pain (unspecified) / Early / 7.0-7.0
    peripheral edema / Delayed / 5.0-5.0
    erythema / Early / 4.0-5.0
    vaginal bleeding / Delayed / 0-5.0
    cervical dysplasia / Delayed / 0-2.0
    pneumonitis / Delayed / 0.5-0.5
    hypothyroidism / Delayed / 10.0
    hyperthyroidism / Delayed / 10.0
    bleeding / Early / Incidence not known
    bone marrow suppression / Delayed / Incidence not known
    sarcoidosis / Delayed / Incidence not known
    hemoptysis / Delayed / Incidence not known
    wheezing / Rapid / Incidence not known
    depression / Delayed / Incidence not known
    hypoxia / Early / Incidence not known
    thyrotoxicosis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known

    Mild

    pharyngitis / Delayed / 25.0-25.0
    insomnia / Early / 10.0-16.0
    pruritus / Rapid / 14.0-14.0
    musculoskeletal pain / Early / 5.0-12.0
    arthralgia / Delayed / 0-12.0
    back pain / Delayed / 0-12.0
    abdominal pain / Early / 10.0-10.0
    paresthesias / Delayed / 10.0-10.0
    dizziness / Early / 10.0-10.0
    flushing / Rapid / 10.0-10.0
    cough / Delayed / 9.0-9.0
    influenza / Delayed / 8.0-8.0
    dyspepsia / Early / 8.0-8.0
    dysgeusia / Early / 8.0-8.0
    anxiety / Delayed / 7.0-8.0
    myalgia / Early / 0-6.0
    muscle cramps / Delayed / 0-6.0
    asthenia / Delayed / 5.0-5.0
    epistaxis / Delayed / 5.0-5.0
    tremor / Early / 3.0-3.0
    anorexia / Delayed / 5.0
    nausea / Early / 5.0
    vomiting / Early / 5.0
    dysesthesia / Delayed / 5.0
    fatigue / Early / 5.0
    purpura / Delayed / Incidence not known
    weakness / Early / Incidence not known
    syncope / Early / Incidence not known

    DRUG INTERACTIONS

    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Angiotensin II receptor antagonists: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Angiotensin-converting enzyme inhibitors: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Anifrolumab: (Major) Coadministration is not recommended. Anifrolumab has not been studied in combination with other biologic therapies including B-cell targeted therapies such as alemtuzumab. Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    Azelastine; Fluticasone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Beclomethasone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Beta-adrenergic blockers: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Betamethasone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Budesonide: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Budesonide; Formoterol: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Calcium-channel blockers: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Central-acting adrenergic agents: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Ciclesonide: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Cladribine: (Major) Concomitant use of cladribine with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Corticosteroids: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Cortisone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Deflazacort: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Dexamethasone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Dimethyl Fumarate: (Major) Concomitant use of dimethyl fumarate with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Diroximel Fumarate: (Major) Concomitant use of diroximel fumarate with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Doxazosin: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to immunosuppressant drugs like alemtuzumab. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Eplerenone: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Epoprostenol: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Fingolimod: (Major) Concomitant use of fingolimod with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Fludrocortisone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Flunisolide: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Fluticasone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Fluticasone; Salmeterol: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Fluticasone; Vilanterol: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Formoterol; Mometasone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Glatiramer: (Major) Concomitant use of glatiramer with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Hydrocortisone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Iloprost: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Interferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b; Ribavirin: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfacon-1: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Beta-1a: (Major) Concomitant use of interferon beta with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Interferon Beta-1b: (Major) Concomitant use of interferon beta with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Live Vaccines: (Contraindicated) Do not administer live vaccines to alemtuzumab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving alemtuzumab. At least 6 weeks before initiation of alemtuzumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Alemtuzumab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Loop diuretics: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Mecamylamine: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Methylprednisolone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Mitoxantrone: (Major) Concomitant use of mitoxantrone with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Mometasone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Natalizumab: (Major) Natalizumab should not be used in combination with alemtuzumab because of the potential for increased risk of progressive multifocal leukoencephalopathy and other serious infections. Ordinarily, multiple sclerosis patients receiving chronic immunomodulatory therapy should not be treated with natalizumab. No formal studies have studied the combination of alemtuzumab and natalizumab.
    Ocrelizumab: (Major) Ocrelizumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as alemtuzumab. Concomitant use of ocrelizumab with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Ofatumumab: (Moderate) Concomitant use of ofatumumab with alemtuzumab may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as alemtuzumab. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Ozanimod: (Major) Initiating treatment with ozanimod after alemtuzumab treatment is not recommended due to the characteristics and duration of the immunosuppressive effects of alemtuzumab.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
    Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon beta-1a: (Major) Concomitant use of peginterferon beta-1a with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Phenoxybenzamine: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Ponesimod: (Major) Initiating treatment with ponesimod after alemtuzumab treatment is not recommended due to the characteristics and duration of the immunosuppressive effects of alemtuzumab.
    Potassium-sparing diuretics: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Prazosin: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Prednisolone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Prednisone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Reserpine: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Ropeginterferon alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Siponimod: (Major) Initiating treatment with siponimod after alemtuzumab treatment is not recommended due to the characteristics and duration of the immunosuppresive effects of alemtuzumab.
    Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Terazosin: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Teriflunomide: (Major) Concomitant use of teriflunomide with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Thiazide diuretics: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Treprostinil: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Triamcinolone: (Moderate) Concomitant use of alemtuzumab with immunosuppressant doses of corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Vasodilators: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.

    PREGNANCY AND LACTATION

    Pregnancy

    Alemtuzumab may cause fetal harm if administered during pregnancy, based on data from animal studies. Females of reproductive potential should avoid pregnancy during alemtuzumab therapy. Discuss the potential hazard to the fetus if alemtuzumab is used during pregnancy. Monoclonal antibodies may cross the placental membrane, especially during the third trimester. Auto-antibodies may develop with alemtuzumab therapy; placental transfer of anti-thyroid antibodies resulting in neonatal Graves disease has been reported. 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 a neonate born 1 year after maternal alemtuzumab therapy. Alemtuzumab-induced autoimmune thyroid disease poses special risks in women who are pregnant and potentially to neonates who were exposed in utero; untreated hypothyroidism in pregnant women increases the risk for miscarriage and may have effects on the fetus including mental retardation and dwarfism. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to alemtuzumab; information about the registry can be obtained at pregnancyregistries@syneoshealth.com or by calling 1-866-758-2990.

    MECHANISM OF ACTION

    Alemtuzumab is a recombinant humanized IgG1 kappa monoclonal antibody directed against the cell surface glycoprotein, CD52, a cell surface antigen present on T and B lymphocytes, and on natural killer cells, monocytes, and macrophages.
    Effects in multiple sclerosis (MS): The precise mechanism by which alemtuzumab exerts its therapeutic effects in multiple sclerosis is unknown. However, the binding of the drug to CD52 and the effect on T lymphocytes is involved. Following cell surface binding to T and B lymphocytes, alemtuzumab results in antibody-dependent cellular cytolysis and complement-mediated lysis. The depletion of T and B cells is then followed by repletion of these cell lines over several months, which appears to have a beneficial effect on the immune system in MS patients. As immune reconstitution becomes more established, regulatory CD4+ T cells dominate the repopulated T cell population and are considered to be 1 of the factors contributing to long-term efficacy of alemtuzumab in MS. Clinical trials have demonstrated a dramatic effect on relapse rates as well as a positive effect on radiological disease outcomes and disability measures.
    Effects in leukemia: The precise mechanism by which alemtuzumab exerts its therapeutic effects in leukemia is unknown but is presumed to involve binding to CD52. Following cell surface binding to T and B lymphocytes, alemtuzumab results in antibody-dependent cellular cytolysis and complement-mediated lysis. As an unconjugated monoclonal antibody, alemtuzumab relies on the ability of the monoclonal antibody itself to kill the cell directly (e.g., induce an apoptotic signal) or to activate effector mechanisms such as complement or T-cells to attack the targeted cells. In comparison, conjugated antibodies rely on a toxic moiety to destroy the targeted cells and the monoclonal antibody serves as a vector. Only certain cell-surface antigens allow cell lysis via complement or cellular cytotoxicity mechanisms (i.e., natural killer (NK) cells or cytotoxic T-cells); CD52 allows for cell lysis via both cellular cytotoxicity and complement mediated cytotoxicity. Alemtuzumab is also associated with the release of tumor necrosis factor (TNF), interleukin-6, and interferon gamma. The sensitivity of lymphoid malignancies to anti-CD52 antibodies varies over 200-fold. T-cell prolymphocytic leukemia is very sensitive in vitro and in vivo. However, monocytes and monocytic leukemias are resistant to alemtuzumab in vivo despite expressing similar amounts of antigen.

    PHARMACOKINETICS

    Alemtuzumab is administered as an intravenous infusion or off-label as a subcutaneous injection. Distribution mainly occurs in the blood and interstitial space. The elimination half-life of alemtuzumab is approximately 2 weeks (Lemtrada) and 11 hours (range 2 to 32 hours) after a single 30 mg dose and 6 days (range 1 to 14 days) after 12 weeks of dosing (Campath).

    Intravenous Route

    Serum concentrations of alemtuzumab (Lemtrada) increased with each consecutive dose within a treatment course in 148 patients who received 12 mg/day for 5 consecutive days, followed by 12 mg/day on 3 consecutive days 12 months following the first treatment course. The highest observed concentrations occurred following the last infusion of a treatment course. Serum concentrations were undetectable within approximately 30 days following each treatment course. With repeated administration of alemtuzumab (Campath) according to the recommended dosing schedule over 12 weeks, systemic clearance decreased with repeated administration due to decreased receptor-mediated clearance (i.e., loss of CD52 receptors in the periphery).

    Subcutaneous Route

    In a study designed to assess alemtuzumab blood concentrations in patients after intravenous and subcutaneous administration, mean trough serum blood concentrations were found to be similar between the two arms (5.4 mcg/mL IV and subcutaneous). Accumulation of alemtuzumab in the blood (to an arbitrary threshold of 1 mcg/mL), took an average of 6 weeks longer with subcutaneous administration of alemtuzumab than with intravenous administration. The clinical implications of this are not known.