Alemtuzumab (Multiple Sclerosis) (Monograph)
Drug class: Immunomodulatory Agents
ATC class: L01XC04
Chemical name: Disulfide with human-rat monoclonal CAMPATH-1H light chain, anti-(human CD52 (antigen)) (human-rat monoclonal CAMPATH-1H, γ1-chain), immunoglobulin G1 dimer
Molecular formula: C6468H10066N1732O2005S40
CAS number: 216503-57-0
Risk Evaluation and Mitigation Strategy (REMS):
FDA approved a REMS for alemtuzumab to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of alemtuzumab and consists of the following: communication plan, elements to assure safe use, and implementation system. See https://www.accessdata.fda.gov/scripts/cder/rems/. (Also see Restricted Distribution Program under Dosage and Administration: General.)
Alemtuzumab, a recombinant DNA-derived humanized anti-CD52 monoclonal antibody, has immunomodulatory and disease-modifying activity in multiple sclerosis (MS); the drug also is an antineoplastic agent.
Uses for Alemtuzumab (Multiple Sclerosis)
Alemtuzumab is used for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting disease and active secondary progressive disease. Because of substantial risks associated with the drug (e.g., autoimmune disorders, infusion reactions, malignancy), alemtuzumab generally is reserved for patients who have had an inadequate response to 2 or more MS therapies. Because of its safety profile, alemtuzumab is not recommended for use in patients with clinically isolated syndrome. (See Cautions.)
Alemtuzumab is one of several disease-modifying therapies used in the management of relapsing forms of MS. Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing magnetic resonance imaging (MRI) lesions, and disability progression; results of placebo-controlled studies indicate that treatment with a disease-modifying agent can reduce the frequency of MS attacks by 28–68%. The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with relapsing forms of MS who have had recent relapses and/or MRI activity; these experts state that the benefits versus risks (e.g., adverse effects or burden of taking a long-term medication) of treatment in patients who have not had relapses in 2 or more years and do not have active MRI lesions are not known. Because CNS damage occurs early and continues throughout the course of MS, other clinicians recommend that disease-modifying therapy be initiated as soon as possible following diagnosis and continued indefinitely unless there is a clear lack of benefit, adverse effects are intolerable, the patient is unable to adhere to the recommended treatment regimen, or a more appropriate treatment becomes available. Clinicians should consider the adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate disease-modifying therapy.
Efficacy and safety of alemtuzumab for the management of relapsing forms of MS were principally demonstrated in 2 randomized, open-label, evaluator-blinded studies (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis [CARE-MS] I and II) that compared alemtuzumab with a standard drug used in the treatment of MS (interferon beta-1a). In these studies, alemtuzumab was more effective than interferon beta-1a in reducing clinical relapse rates; however, a substantial effect of alemtuzumab on progression of disability was demonstrated in only one of the studies.
The studies included patients with relapsing forms of MS who had at least 2 relapses in the previous 2 years and at least 1 relapse in the prior year. Patients enrolled in the CARE-MS I study were treatment-naive and patients in the CARE-MS II study had failed previous therapy with interferon beta or glatiramer acetate therapy; mean Expanded Disability Status Scale (EDSS) scores at baseline were comparable between the studies (2 and 2.7, respectively). Alemtuzumab was administered by IV infusion at a dosage of 12 mg once daily for 2 treatment courses (initial 5-day course, followed 1 year later by a 3-day course) and interferon beta-1a was administered subcutaneously at a dosage of 44 mcg 3 times weekly after initial dosage titration. Neurologic examinations were performed every 12 weeks and at the time of suspected relapse, and MRI scans were performed annually. The primary efficacy end points of the studies were the annualized relapse rate over 2 years and time to confirmed disability progression (defined as an increase from baseline of at least 1 EDSS point [or 1.5 points for patients with baseline EDSS of 0] sustained over 6 months).
In both studies, alemtuzumab substantially reduced the annualized relapse rate compared with interferon beta-1a therapy (relative reductions of 49–55%). At 2 years, more patients receiving alemtuzumab were relapse-free than those receiving interferon beta-1a (78 versus 59% in the CARE-MS I study, and 65 versus 47% in the CARE-MS II study). However, alemtuzumab was more effective than interferon beta-1a therapy in reducing time to disability progression in only the CARE-MS II study in previously treated patients; in this study, 13% of patients in the alemtuzumab group experienced disability progression compared with 21% of those in the interferon beta-1a group at 2 years. In the CARE-MS I study, the proportion of patients with disability progression at 2 years was similar between the alemtuzumab and interferon beta-1a treatment groups (8 and 11%, respectively). With regard to MRI outcomes, no substantial difference in T2 lesion volume was observed between patients who received alemtuzumab and those who received interferon beta-1a in these studies.
Following completion of the CARE-MS I and CARE-MS II studies, the majority of patients were entered into extension studies in which they could receive additional 3-day courses of alemtuzumab at intervals of at least 1 year if there was any evidence of disease relapse. Results after 5 years of follow-up demonstrated continued efficacy of alemtuzumab on clinical disease and MRI outcomes without the need for retreatment in most patients. Long-term (approximately 5–8 years) data from other studies evaluating the use of alemtuzumab in patients with relapsing forms of MS further demonstrate the durable effects of alemtuzumab after 2 courses of therapy. Although these findings indicate that retreatment generally is not necessary in most patients receiving alemtuzumab, long-term monitoring is required because of the serious risks associated with the drug. (See Cautions.)
Alemtuzumab (Multiple Sclerosis) Dosage and Administration
Alemtuzumab should be administered only in settings where adequate monitoring can be performed and appropriate medical support is available for the management of anaphylaxis or serious infusion reactions. (See Infusion Reactions under Warnings/Precautions: Warnings, in Cautions.)
Because alemtuzumab can cause potentially serious adverse effects, appropriate laboratory tests and clinical evaluations (e.g., dermatologic examinations) should be performed prior to, during, and following a course of alemtuzumab therapy at recommended intervals. Urine protein-to-creatinine ratio should be measured at baseline. A complete blood count (CBC) with differential, serum creatinine concentration, and urinalysis with cell counts should be obtained prior to initiating therapy and at monthly intervals thereafter. Thyroid function tests should be conducted prior to initiating therapy and every 3 months thereafter. In addition, serum aminotransferase and total bilirubin concentrations should be determined prior to initiation of therapy and periodically thereafter. (See Cautions.)
To reduce the incidence and/or severity of infusion-related reactions, patients should be premedicated with a high-dose corticosteroid (e.g., methylprednisolone 1 g or equivalent) immediately prior to the alemtuzumab infusion for the first 3 days of each treatment course. In addition, premedication with antihistamines and/or antipyretics may be considered. Patients should be monitored for infusion reactions during and for at least 2 hours after each infusion. Longer periods of observation may be considered if clinically indicated. Vital signs also should be monitored prior to and periodically during each infusion. (See Infusion Reactions under Warnings/Precautions: Warnings, in Cautions.)
Because alemtuzumab therapy has been associated with the development of herpes virus infections, antiviral prophylaxis is recommended; the prophylactic regimen should be initiated on the first day of each alemtuzumab treatment course and continued for at least 2 months following completion of the course or until the CD4+ lymphocyte count is at least 200/mm3, whichever occurs later. (See Infectious Complications under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Before initiating alemtuzumab therapy, patients without a history of varicella infection or varicella vaccination should be tested for antibodies to varicella zoster virus; vaccination of antibody-negative patients should be considered prior to initiating alemtuzumab therapy. Patients should complete any necessary immunizations, including varicella vaccination, at least 6 weeks prior to alemtuzumab therapy. In addition, patients should be screened for tuberculosis according to local guidelines.
Restricted Distribution Program
Because of the risks of autoimmunity, infusion reactions, and malignancies (see Cautions: Warnings/Precautions), alemtuzumab (Lemtrada) is available only through a restricted distribution program called the Lemtrada Risk Evaluation and Mitigation Strategy (REMS) Program.
Additional information about the Lemtrada REMS Program is available at 855-676-6326 or [Web].
Alemtuzumab is administered by IV infusion over 4 hours (or longer if clinically indicated). The drug should not be administered by rapid IV injection, such as IV push or bolus. For the treatment of MS, alemtuzumab is usually administered over 2 treatment courses (initial 5-day course, followed by a 3-day course 12 months later).
Alemtuzumab injection concentrate should be stored at 2–8°C in the original carton and protected from light. The vials should not be frozen or shaken. The drug should be inspected visually for particulate matter and discoloration prior to dilution and administration, and should be discarded if visible particles and/or discoloration are present; solutions of the drug should be clear and colorless to slightly yellow. Each vial is intended for single use only because the drug contains no preservatives.
Prior to administration, the commercially available injection concentrate must be diluted by adding 1.2 mL of alemtuzumab 10 mg/mL to an infusion bag containing 100 mL of 0.9% sodium chloride or 5% dextrose injection; the bag should be inverted gently to mix the solution. The drug should be administered within 8 hours of dilution; if not used immediately, the diluted solution may be stored at room temperature (15–25°C) or under refrigeration (2–8°C) for up to 8 hours and protected from light.
Alemtuzumab should not be admixed or administered simultaneously in the same IV line with other drugs.
The recommended adult dosage of alemtuzumab for the management of relapsing forms of multiple sclerosis (MS) in the first treatment course is 12 mg daily by IV infusion for 5 consecutive days (total dose of 60 mg), followed 12 months later by a second treatment course consisting of 12 mg daily for 3 consecutive days (total dose of 36 mg).
In clinical studies, 2 courses of treatment generally were sufficient to maintain clinical benefits. However, if needed, subsequent treatment courses of 12 mg daily on 3 consecutive days (total dose of 36 mg) may be administered at least 12 months after the last dose of any prior treatment courses.
No special population dosage recommendations at this time.
Cautions for Alemtuzumab (Multiple Sclerosis)
Alemtuzumab is contraindicated in patients with human immunodeficiency virus (HIV) infection because the drug can cause prolonged reductions in CD4+ T-cell counts. (See Description.)
Alemtuzumab therapy may result in the formation of autoantibodies, which can increase the risk of serious, and sometimes fatal, autoimmune disorders. Thyroid disorders (see Thyroid Disorders under Warnings/Precautions: Warnings, in Cautions), immune thrombocytopenia (see Idiopathic Thrombocytopenic Purpura under Warnings/Precautions: Warnings, in Cautions), and anti-glomerular basement membrane disease (see Glomerular Nephropathy under Warnings/Precautions: Warnings, in Cautions) are among the serious autoimmune conditions that have occurred in patients receiving alemtuzumab for the treatment of multiple sclerosis (MS). Thyroid disorders were the most commonly reported autoimmune condition, occurring in about 34% of alemtuzumab-treated patients in clinical studies. Other autoimmune conditions that were reported at a lower incidence (0.1–0.3%) include autoimmune hemolytic anemia, autoimmune pancytopenia (see Other Autoimmune Cytopenias under Warnings/Precautions: Warnings, in Cautions), undifferentiated connective tissue disorders, acquired hemophilia A (anti-factor VIII antibodies), rheumatoid arthritis, type 1 diabetes mellitus, vitiligo, and retinal pigment epitheliopathy. Vasculitis, autoimmune hepatitis, and Guillain-Barré syndrome also have been reported during postmarketing experience with alemtuzumab for the treatment of MS. Chronic inflammatory demyelinating polyradiculoneuropathy and fatal transfusion-associated graft versus host disease have been reported during postmarketing experience in patients receiving alemtuzumab for B-cell chronic lymphocytic leukemia (B-CLL) or other disorders. A case of neonatal Graves' disease, which resulted from transplacental transfer of antithyrotropin receptor antibodies after maternal treatment with alemtuzumab, also has been reported. (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)
Careful patient monitoring, including appropriate laboratory testing, is required during and following completion of alemtuzumab therapy to allow for early detection and treatment of such autoimmune-related adverse effects. (See Dosage and Administration: General.) Long-term monitoring is recommended because these events have been reported to occur months or years after the drug is discontinued. For additional information on specific monitoring requirements, see individual warnings section in Cautions.
Idiopathic Thrombocytopenic Purpura
Idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura) has been reported in 2% of alemtuzumab-treated patients in clinical studies of patients with MS. Several cases occurred in a phase 2 study, which led to temporary suspension of dosing until monthly monitoring requirements were implemented; one patient died from intracranial hemorrhage after developing ITP. In controlled clinical trials in patients with MS, nadir platelet counts of 20,000/mm3 or less as a result of ITP were observed in 2% of all patients receiving alemtuzumab; antiplatelet antibodies did not precede the onset of ITP. Cases of ITP have been diagnosed more than 3 years after discontinuance of alemtuzumab therapy.
A complete blood cell count (CBC) including differential should be obtained prior to initiation of alemtuzumab therapy and monthly thereafter until 48 months after the last infusion. After this time, testing should be performed based on clinical findings suggestive of ITP. Clinical manifestations of ITP include easy bruising, petechiae, spontaneous mucocutaneous bleeding (e.g., epistaxis, hemoptysis), and heavier than normal or irregular menstrual bleeding. Because hemoptysis also may be indicative of anti-glomerular basement membrane disease, differential diagnosis is required. (See Glomerular Nephropathy under Warnings/Precautions: Warnings, in Cautions.) If ITP is suspected, a CBC should be obtained immediately, and if confirmed, appropriate medical therapy should be promptly initiated.
Other Autoimmune Cytopenias
Other autoimmune cytopenias such as neutropenia, hemolytic anemia, and pancytopenia also have been reported in patients receiving alemtuzumab at an incidence of about 0.1–0.3% in clinical trials. At least one patient who developed autoimmune pancytopenia died as a result of sepsis. Patients who experienced autoimmune hemolytic anemia in these studies tested positive for direct antiglobulin antibodies, with nadir hemoglobin concentrations of 2.9–8.6 g/dL. Cases of fatal autoimmune hemolytic anemia and aplastic anemia also have been reported during postmarketing experience in patients receiving alemtuzumab for the treatment of B-CLL or other disorders, generally at higher and more frequent doses than those used in the treatment of MS.
Patients should be monitored closely for the development of autoimmune cytopenias with routine CBCs and clinical observation. (See Idiopathic Thrombocytopenic Purpura under Warnings/Precautions: Warnings, in Cautions.) Manifestations of autoimmune hemolytic anemia include weakness, chest pain, jaundice, dark urine, and tachycardia. If a cytopenia is confirmed, appropriate medical treatment should be promptly initiated.
Autoimmune hepatitis resulting in serious liver injury (e.g., acute liver failure requiring transplant) has been reported in MS patients receiving alemtuzumab during postmarketing experience.
Patients should be monitored closely for the development of autoimmune hepatitis with routine determinations of serum aminotransferase (ALT and AST) and total bilirubin concentrations at baseline and periodically thereafter until 48 months after the last dose. If a patient develops any manifestations suggestive of hepatic dysfunction (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine), serum aminotransferase and total bilirubin concentrations should be measured immediately, and alemtuzumab therapy should be interrupted or discontinued as necessary.
Autoimmune renal conditions such as membranous glomerulonephritis and anti-glomerular basement membrane disease have been reported in MS patients receiving alemtuzumab; glomerular nephropathies occurred in 0.3% of alemtuzumab-treated patients in clinical trials and additional cases have been reported during postmarketing experience. Anti-glomerular basement membrane disease can result in end-stage renal disease requiring dialysis or renal transplantation, and can be life-threatening if untreated. Cases of anti-glomerular basement membrane disease have been diagnosed up to 40 months after discontinuance of alemtuzumab therapy. Clinical manifestations of nephropathy may include edema, hematuria, changes in urine color, decreased urine output, fatigue, dyspnea, and hemoptysis. Alveolar hemorrhage manifesting as hemoptysis is a common component of anti-glomerular basement membrane disease that has been reported during postmarketing experience.
Urine protein-to-creatinine ratio should be measured prior to initiating therapy with alemtuzumab. In addition, serum creatinine concentrations and urinalysis with cell counts should be performed prior to initiation of alemtuzumab therapy and monthly thereafter until 48 months after the last infusion. After this time, testing should be performed based on clinical findings suggestive of nephropathy. If there is any evidence of nephropathy based on changes in urine protein-to-creatinine ratio, serum creatinine concentration, unexplained hematuria, or clinical symptoms (e.g., proteinuria), patients should be further evaluated. Early detection and treatment may decrease the risk of poor outcomes.
Autoimmune thyroid disorders, including Graves' disease, Graves' ophthalmopathy, hyperthyroidism, hypothyroidism, autoimmune thyroiditis, and goiter, were reported in approximately 37% of patients receiving alemtuzumab for the treatment of MS in clinical studies; serious thyroid events, including associated cardiac and psychiatric abnormalities, occurred in about 5% of patients. In some cases, surgical intervention (e.g., thyroidectomy, surgical orbital decompression) was required. Thyroid disorders have been diagnosed more than 7 years after initiation of alemtuzumab therapy.
Baseline thyroid function tests (e.g., thyroid-stimulating hormone [TSH] concentrations) should be performed prior to initiation of alemtuzumab therapy and every 3 months thereafter until 48 months after completion of therapy. After 48 months, monitoring should continue if clinically indicated. In patients with preexisting thyroid disorders, alemtuzumab should be used only if the potential benefits outweigh the potential risks.
Cytokine release syndrome can occur following administration of alemtuzumab, potentially causing infusion reactions. Serious, sometimes fatal, infusion-related reactions have occurred in patients receiving alemtuzumab; such reactions have included anaphylaxis, angioedema, bronchospasm, hypotension, chest pain, bradycardia, tachycardia, atrial fibrillation, transient neurologic symptoms, hypertension, headache, pyrexia, and rash. Other possible manifestations include nausea, urticaria, pruritus, insomnia, chills, flushing, fatigue, dyspnea, pulmonary infiltrates, dysgeusia, dyspepsia, dizziness, and pain.
In clinical studies of alemtuzumab for the management of MS, infusion reactions were reported in 92% of patients who received the drug; a serious reaction occurred in 3% of such patients, in some cases requiring treatment with epinephrine or atropine. Infusion-related reactions have been reported to occur more than 24 hours after alemtuzumab infusion. Cases of pulmonary alveolar hemorrhage and myocardial ischemia have been reported with an onset within 48 hours of the alemtuzumab infusion. Cases of severe (including fatal) neutropenia have occurred within 2 months of alemtuzumab infusion; some of the cases resolved following granulocyte colony-stimulating factor therapy. Platelet counts also have been reported in association with alemtuzumab infusions during postmarketing experience. Other serious infusion-related reactions (e.g., hypoxia, syncope, acute respiratory distress syndrome, respiratory arrest, myocardial infarction, acute cardiac insufficiency, cardiac arrest) have been reported during postmarketing experience in patients receiving alemtuzumab for B-CLL or other disorders.
Alemtuzumab must be administered in a setting with appropriate equipment and personnel trained in the management of serious infusion reactions, including anaphylaxis. Patients should receive appropriate premedication with corticosteroids, antihistamines, and/or antipyretics. (See Dosage and Administration: General.) Patients should be monitored for infusion reactions during and for at least 2 hours after each infusion at the healthcare facility where the drug is being administered. Additional monitoring should be considered for patients with predisposing conditions for cardiovascular or pulmonary compromise. Patients should be advised that infusion reactions can occur during or within 48 hours of the infusion. (See Advice to Patients.) If a severe infusion reaction occurs, immediate discontinuance of the alemtuzumab infusion should be considered and appropriate supportive treatment instituted.
Alemtuzumab may increase the risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders. Caution is advised when initiating alemtuzumab in patients with a history of or ongoing malignancy.
Thyroid cancer and melanoma (or melanoma in situ) were reported in several patients who received alemtuzumab for the treatment of MS in controlled and uncontrolled studies. Lymphoproliferative disorders and lymphoma, including cases of mucosa-associated lymphoid tissue (MALT) lymphoma, Castleman's disease, and fatal non-Epstein-Barr virus-associated Burkitt lymphoma also have been reported in MS patients who received the drug. In addition, Epstein-Barr virus-associated lymphoproliferative disorders have been reported in patients receiving alemtuzumab for non-MS indications during postmarketing experience.
Patients should be monitored for symptoms of thyroid cancer (e.g., new lump or swelling in the neck, pain in the front of the neck, persistent hoarseness or other voice changes, trouble swallowing or breathing, constant cough not due to upper respiratory tract infection) during alemtuzumab therapy. In addition, baseline and annual dermatologic examinations should be performed to monitor for melanoma. (See Advice to Patients.)
Serious and life-threatening stroke (ischemic and hemorrhagic) has been reported during postmarketing experience in MS patients receiving alemtuzumab; such events occurred within 3 days of receiving the drug, with most cases occurring within 1 day. Postmarketing cases of cervicocephalic (e.g., carotid, vertebral) arterial dissection involving multiple arteries also have been reported with alemtuzumab. Patients should be instructed to monitor for these cerebrovascular complications during alemtuzumab therapy. (See Advice to Patients.)
Other Warnings and Precautions
Serious, sometimes fatal, infections can occur in patients receiving alemtuzumab. Infections were reported in 71% of patients receiving alemtuzumab in controlled clinical trials of patients with MS. Infections that occurred more often in alemtuzumab-treated patients than those who received interferon beta-1a included nasopharyngitis, urinary tract infection, upper respiratory tract infection, sinusitis, herpes infections, influenza, and bronchitis. Fungal infections, particularly oral and vaginal candidiasis, also occurred more frequently with alemtuzumab than interferon beta-1a therapy (12 versus 3%). In controlled clinical trials, herpes infection occurred in 16% of patients receiving alemtuzumab (oral herpes [8.8%], herpes zoster [4.2%], herpes simplex [1.8%], genital herpes [1.3%]) and cervical human papillomavirus (HPV) infection, including cervical dysplasia, occurred in 2% of patients receiving the drug. Other serious infections that have occurred in patients receiving alemtuzumab in clinical studies include Listeria meningitis, appendicitis, gastroenteritis, pneumonia, and tooth infection. Serious and sometimes fatal opportunistic infections (e.g., aspergillosis, coccidioidomycosis, histoplasmosis, pneumocystis jirovecii pneumonia, nocardiosis, cytomegalovirus infections) have been reported during postmarketing experience with alemtuzumab in MS patients receiving the drug. In addition, there have been postmarketing reports of serious, sometimes fatal, viral, bacterial, protozoan, and fungal infections, including some due to reactivation of latent infections, in patients receiving alemtuzumab for the treatment of B-CLL or other disorders.
In patients with active infection, a delay in alemtuzumab therapy should be considered until the infection is controlled. Patients should be advised to monitor for symptoms of Listeria infection and to avoid or adequately heat foods that are potential sources of Listeria monocytogenes. (See Advice to Patients.) The duration of increased risk for Listeria infection is unknown; clinical experience indicates that these infections may occur as early as 3 days after treatment to up to 8 months after the last dose is administered. Other precautions that should be taken to minimize or prevent the risk of infection include herpes prophylaxis during and after alemtuzumab therapy and annual HPV screening in women who have received alemtuzumab therapy. (See Dosage and Administration: General.)
Because tuberculosis (both active and latent) has been reported in patients receiving alemtuzumab, patients should be screened and treated (if necessary) for tuberculosis infection prior to initiating the drug.
The effect of alemtuzumab on the risk of reactivation of hepatitis B virus (HBV) or hepatitis C virus (HCV) is not known. Because of the potential risk of liver damage due to viral hepatitis reactivation, the manufacturer recommends that patients at high risk of HBV or HCV infection be screened prior to initiation of alemtuzumab therapy; caution should be exercised if the drug is administered to patients identified as carriers of HBV or HCV.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain caused by the JC virus, has been reported in at least one MS patient receiving alemtuzumab. In the reported case, PML was diagnosed 2 months after the second course of alemtuzumab treatment. Patients who are immunocompromised are at increased risk of PML; however, this patient was not receiving any other immunosuppressive or immunomodulatory drugs concurrently and had no other immunocompromising conditions, but had a history of prior use of other MS drugs (not including natalizumab). The patient's condition improved with mild residual neurologic sequelae.
Symptoms typically associated with PML are diverse, progress over a period of days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, vision disturbances, and changes in thinking, memory, orientation, or personality. MRI signs of PML may be apparent before clinical manifestations develop. Therefore, MRI monitoring for signs consistent with PML may be helpful. Any suspicious MRI findings should prompt further investigation to allow for an early diagnosis of PML. At the first sign or symptom suggestive of PML, alemtuzumab therapy should be withheld and an appropriate diagnostic evaluation should be performed. (See Advice to Patients.)
Acute Acalculous Cholecystitis
Acute acalculous cholecystitis has been reported in MS patients receiving alemtuzumab in clinical studies and during postmarketing experience. The onset of symptoms ranged from less than 24 hours to 2 months after administration of the drug. While some patients recovered with conservative treatment (e.g., antibiotic therapy), others required cholecystectomy.
Signs and symptoms of acute acalculous cholecystitis include abdominal pain or tenderness, fever, nausea, vomiting, leukocytosis, and liver enzyme abnormalities. Prompt evaluation and treatment are required in patients who develop the condition to avoid substantial morbidity and mortality.
Pneumonitis, including hypersensitivity pneumonitis and pneumonitis with fibrosis, occurred in 0.5% of patients receiving alemtuzumab for the treatment of MS in clinical studies. Manifestations of pneumonitis include dyspnea, cough, wheezing, chest pain or tightness, and hemoptysis.
Other Alemtuzumab Preparations
Alemtuzumab (Lemtrada) for the treatment of MS contains the same active ingredient as alemtuzumab (Campath) for the treatment of B-CLL; increased monitoring for additive, long-term effects may be necessary in patients receiving Lemtrada who have previously received Campath.
In clinical studies of alemtuzumab in patients with MS, attempted suicide or suicidal ideation was reported in a similar percentage (0.6%) of patients in both the alemtuzumab and interferon beta-1a treatment groups. Patients should be advised to report any symptoms of depression or suicidal ideation to their clinician.
As with all therapeutic proteins, there is a potential for immunogenicity with alemtuzumab therapy. In clinical studies, anti-alemtuzumab antibodies were detected in up to 67 and 83% of patients receiving the drug following the first and second courses of therapy, respectively; among patients who tested positive for antibodies, the rate of detection of neutralizing antibodies ranged from about 5 to 94% at various time points during therapy. Anti-alemtuzumab antibodies were associated with decreased drug concentrations during the second, but not first, course of therapy. The presence of neutralizing or non-neutralizing antibodies did not appear to substantially affect clinical outcomes, total lymphocyte counts, or adverse events through the first 2 treatment courses; however, following additional treatment courses, high-titer antibodies were associated with incomplete lymphocyte depletion in a few patients.
There are no adequate data in pregnant women to determine whether there are any developmental risks associated with alemtuzumab. Animal reproductive studies have not shown any evidence of teratogenicity; however, embryolethality was observed.
The manufacturer states that women of childbearing potential should use effective contraceptive measures during and for 4 months following a course of alemtuzumab therapy. A pregnancy registry has been established to monitor pregnancy outcomes of women exposed to alemtuzumab during pregnancy; clinicians are encouraged to register patients by calling 866-758-2990.
Alemtuzumab therapy may induce autoimmune thyroid disorders, which can increase the risk of complications in pregnant women. (See Thyroid Disorders under Warnings/Precautions: Warnings, in Cautions.) Untreated hypothyroidism in pregnant women can increase the risk of miscarriage and may have adverse effects on the fetus, including mental retardation and dwarfism.
Because autoantibodies can cross the placenta, placental transfer of antithyrotropin receptor antibodies may occur in pregnant women who develop Graves' disease following alemtuzumab therapy. At least one case of neonatal Graves' disease with thyroid storm was reported as a result of such placental transfer. (See Autoimmunity under Warnings/Precautions: Warnings, in Cautions.)
Alemtuzumab is distributed into milk in animals. It is not known whether the drug is distributed into human milk.
The effects of alemtuzumab on nursing infants or on milk production are not known. The known benefits of breast-feeding should be considered along with the woman's clinical need for alemtuzumab and any potential adverse effects of the drug or disease on the breast-fed infant.
Safety and efficacy of alemtuzumab have not been established in pediatric patients younger than 17 years of age. Use of the drug is not recommended in pediatric patients because of the potential for serious adverse effects (e.g., autoimmunity, infusion reactions, stroke, malignancies).
Clinical studies of alemtuzumab for the management of MS did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger patients.
The pharmacokinetics of alemtuzumab have not been studied in patients with hepatic impairment.
The pharmacokinetics of alemtuzumab have not been studied in patients with renal impairment.
Common Adverse Effects
Adverse effects reported in 10% or more of patients receiving alemtuzumab and with an incidence greater than interferon beta-1a in clinical studies include rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes virus infection, urticaria, pruritus, thyroid disorders, fungal infection, arthralgia, extremity pain, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting.
There is a potential for increased immunosuppression and risk of infection with concomitant use of antineoplastic agents.
There is a potential for increased immunosuppression and risk of infection with concomitant use of immunosuppressive agents.
Because of the immunosuppressive effects of alemtuzumab, live virus vaccines should not be administered following a course of alemtuzumab therapy.
Alemtuzumab, a recombinant DNA-derived humanized anti-CD52 monoclonal antibody, has immunomodulatory and disease-modifying activity in multiple sclerosis (MS). Alemtuzumab is an IgG1 kappa immunoglobulin containing human framework (i.e., variable and constant regions) and murine complementarity-determining regions. The drug binds specifically to antigen CD52, a glycoprotein expressed at high levels on the surface of B and T cells, and at lower levels on monocytes, macrophages, and natural killer (NK) cells. Binding of alemtuzumab to antigen CD52 triggers a host immune response consisting of antibody-dependent cell-mediated cytolysis (ADCC) and complement-dependent cytolysis (CDC), ultimately resulting in depletion of circulating B and T cells.
Although the exact mechanism of action of alemtuzumab in patients with MS has not been fully elucidated, the depletion and repopulation of B and T cells is thought to result in the drug's immunomodulatory effects. Following a course of alemtuzumab therapy, nadir lymphocyte counts occur at approximately 1 month and then increase over time. B-cell counts usually recover within 6 months while T-cell counts increase more slowly and usually remain below baseline levels 12 months after treatment. In clinical studies, mean CD4+ T-cell count was 40/mm3 at 1 month and increased to 270/mm3 at 12 months after alemtuzumab treatment; approximately half of the patients had CD4+ counts below the lower limit of normal 30 months after treatment.
Following administration of the recommended 2-course regimen of alemtuzumab, serum concentrations of the drug increase with each consecutive dose within a treatment course. Metabolism of the drug is thought to be mediated by proteolytic degradation. The elimination half-life of alemtuzumab is approximately 2 weeks in patients with MS. Serum alemtuzumab concentrations generally are undetectable within approximately 30 days after each treatment course. The pharmacokinetics of alemtuzumab are not affected by age, race, or gender.
Advice to Patients
Importance of patients reading the manufacturer's patient information (medication guide) prior to each treatment course.
Importance of advising patients that alemtuzumab (Lemtrada) is available only through a restricted distribution program called the Lemtrada REMS Program. Inform patients of the requirements of the program and provide them with information on how to locate a certified infusion site. Advise patients to read the Lemtrada REMS educational materials and to carry the Patient Safety Information Card with them in case of an emergency.
Risk of developing autoimmune diseases such as idiopathic thrombocytopenic purpura (ITP) and anti-glomerular basement membrane disease. Importance of monthly monitoring of blood cell counts and urine tests during and for at least 48 months after completion of therapy. Advise patients to immediately report any manifestations of potential autoimmunity (e.g., bleeding, easy bruising, petechiae, purpura, hematuria, edema, jaundice, hemoptysis) to their clinician.
Risk of infusion-related reactions; importance of informing patients that they will need to be monitored at the healthcare facility (e.g., infusion center) for at least 2 hours after each infusion. Advise patients that infusion-related reactions may occur after they leave the infusion center and to immediately contact their clinician if they experience any manifestations of such a reaction (e.g., swelling of the mouth or throat, difficulty breathing, weakness, abnormal heart rate, chest pain, rash).
Risk of autoimmune hepatitis; instruct patients to immediately contact their clinician if they develop any signs or symptoms of possible hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine, easy bruising or bleeding).
Risk of stroke and cervicocephalic (e.g., carotid, vertebral) arterial dissection; educate patients on possible symptoms (e.g., neck pain, unilateral facial weakness, facial droop, speech difficulty, sudden severe headache) and to seek immediate medical attention if any such symptoms occur.
Risk of malignancies such as thyroid cancer and melanoma. Advise patients to report any symptoms of thyroid cancer such as a new lump or swelling in the neck, pain in the front of the neck, persistent hoarseness or other voice changes, difficulty swallowing or breathing, or constant cough not due to upper respiratory tract infection. Importance of annual skin examinations to monitor for melanoma.
Risk of thyroid disorders (e.g., hyperthyroidism, hypothyroidism). Importance of advising patients to inform their clinician if they experience any manifestations of potential thyroid problems (e.g., unexplained weight loss or gain, rapid heart rate or palpitations, eye swelling, constipation, feeling cold).
Risk of infections. Importance of advising patients to immediately contact their clinician if they develop any signs or symptoms of infection (e.g., fever, swollen glands). Importance of adhering to prescribed herpes virus prophylaxis regimens. Importance of advising 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, undercooked meat, seafood, or poultry) and to seek immediate medical attention if any symptoms of Listeria infection (e.g., fever, chills, diarrhea, nausea, vomiting, headache, pain in joints and muscles, neck stiffness, difficulty walking, mental status changes, coma, other neurologic changes) occur. Listeria precautions should be initiated prior to beginning alemtuzumab therapy. The incubation period for L. monocytogenes ranges from 3 to 70 days; in most cases, signs and symptoms of invasive listeriosis start within one month of exposure to L. monocytogenes. Importance of advising female patients that annual HPV screening is recommended.
Importance of informing patients that progressive multifocal leukoencephalopathy (PML) has occurred in a patient with MS receiving alemtuzumab and that the condition usually leads to death or severe disability over weeks or months. Importance of advising patients to inform their clinician if they develop any symptoms suggestive of PML (e.g., progressive weakness on one side of body; clumsiness of limbs; vision disturbance; changes in thinking, memory, or orientation leading to confusion and personality changes).
Advise patients to report any symptoms suggestive of acute acalculous cholecystitis (e.g., abdominal pain or tenderness, fever, nausea, vomiting).
Importance of advising patients to complete any necessary vaccinations at least 6 weeks prior to the start of alemtuzumab therapy and to consult with their clinician prior to receiving any vaccination after recent use of alemtuzumab.
Risk of pneumonitis; advise patients to report any symptoms such as shortness of breath, cough, wheezing, chest pain or tightness, or hemoptysis.
Advise patients that alemtuzumab (Lemtrada) for the treatment of multiple sclerosis (MS) contains the same active ingredient as alemtuzumab (Campath) for the treatment of B-cell chronic lymphocytic leukemia (B-CLL); patients receiving Lemtrada should inform their clinician if they have previously received Campath.
Risk of fetal harm. Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise women of childbearing potential of the need for effective contraception during and for 4 months after each course of alemtuzumab therapy. Advise patients of the existence of a pregnancy registry for Lemtrada.
Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Alemtuzumab (Lemtrada) is available only through a restricted distribution program (Lemtrada REMS Program). (See Restricted Distribution Program under Dosage and Administration: General.)
For injection concentrate, for IV infusion
10 mg/mL (12 mg)
AHFS DI Essentials™. © Copyright 2024, Selected Revisions May 4, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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