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Medizinisch geprüft von Oliinyk Elizabeth Ivanovna, Apotheke Zuletzt aktualisiert am 03.04.2022
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MabCampath ist zur Behandlung von Patienten mit rezidivierenden Formen der Multiplen Sklerose (MS) indiziert. Aufgrund seines Sicherheitsprofils sollte die Anwendung von MabCampath im Allgemeinen Patienten vorbehalten sein, die auf zwei oder mehr Medikamente, die für die Behandlung von MS angezeigt sind, nicht ausreichend angesprochen haben
Dosierungsinformationen
Die empfohlene Dosierung von MabCampath beträgt 12 mg / Tag, die durch intravenöse Infusion für 2 Behandlungszyklen verabreicht werden:
- Erster Behandlungskurs: 12 mg / Tag an 5 aufeinanderfolgenden Tagen (60 mg Gesamtdosis)
- Zweiter Behandlungsverlauf: 12 mg / Tag an 3 aufeinanderfolgenden Tagen (36 mg Gesamtdosis), 12 Monate nach dem ersten Behandlungsverlauf verabreicht.
Tests und Verfahren vor der Behandlung
Vor der Behandlung mit MabCampath sind Basislabortests erforderlich. Zusätzlich vor Beginn der Behandlung mit MabCampath :
- Führen Sie alle erforderlichen Impfungen mindestens 6 Wochen vor der Behandlung durch
- festzustellen, ob Patienten in der Vorgeschichte Varizellen hatten oder gegen das Varizellen-Zoster-Virus (VZV) geimpft wurden. Wenn nicht, testen Sie den Patienten auf Antikörper gegen VZV und erwägen Sie eine Impfung für diejenigen, die antikörpernegativ sind. Nachbehandlung mit MabCampath bis 6 Wochen nach VZV-Impfung.
- Führen Sie ein Tuberkulose-Screening gemäß den örtlichen Richtlinien durch
- Weisen Sie die Patienten an, mögliche Quellen für Listeria monocytogenes zu vermeiden
Empfohlene Prämedikation und begleitende Medikamente
Kortikosteroide
Prämedikamentöse Patienten mit hochdosierten Kortikosteroiden (1.000 mg Methylprednisolon oder gleichwertig) unmittelbar vor der MabCampath-Infusion und für die ersten 3 Tage jedes Behandlungsverlaufs.
Herpes-Prophylaxe
Verabreichen Sie die antivirale Prophylaxe für herpetische Virusinfektionen ab dem ersten Tag jedes Behandlungsverlaufs und fahren Sie nach der Behandlung mit MabCampath mindestens zwei Monate lang fort oder bis die CD4 + -Lymphozytenzahl ≥ 200 Zellen pro Mikroliter beträgt, je nachdem, was später auftritt.
Vorbereitungsanweisungen
Befolgen Sie die folgenden Schritte, um die verdünnte Lösung von MabCampath für die intravenöse Infusion vorzubereiten:
- Untersuchen Sie MabCampath vor der Verabreichung visuell auf Partikel und Verfärbungen. Nicht verwenden, wenn Partikel vorhanden sind oder die Lösung verfärbt ist. Frieren oder schütteln Sie die Fläschchen vor dem Gebrauch nicht.
- Ziehen Sie 1,2 ml MabCampath mit aseptischer Technik aus dem Fläschchen in eine Spritze und injizieren Sie sie in einen 100-ml-Beutel mit sterilem 0,9% Natriumchlorid, USP oder 5% Dextrose in Wasser, USP
- Drehen Sie den Beutel vorsichtig um, um die Lösung zu mischen. Stellen Sie die Sterilität der vorbereiteten Lösung sicher, da sie keine antimikrobiellen Konservierungsmittel enthält. Jede Durchstechflasche ist nur zum einmaligen Gebrauch bestimmt.
Schützen Sie vor der Verabreichung die verdünnte MabCampath-Lösung vor Licht und lagern Sie sie 8 Stunden lang entweder bei Raumtemperatur von 15 ° C bis 25 ° C (59 ° F bis 77 ° F) oder halten Sie sie bei Bedingungen von 2 ° C bis 8 ° C gekühlt ° C (36 ° F bis 46 ° F).
Infusionsanweisungen
Infundieren Sie MabCampath über 4 Stunden ab 8 Stunden nach der Verdünnung. Verlängern Sie die Infusionsdauer, wenn dies klinisch angezeigt ist.
Verabreichen Sie MabCampath in einer Umgebung, in der Geräte und Personal zur angemessenen Behandlung von Anaphylaxie oder schwerwiegenden Infusionsreaktionen verfügbar sind.
Fügen Sie keine anderen Arzneimittelsubstanzen hinzu oder infundieren Sie sie gleichzeitig über dieselbe intravenöse Linie. Nicht als intravenösen Stoß oder Bolus verabreichen.
Überwachen Sie die Vitalfunktionen vor der Infusion und regelmäßig während der Infusion. Bieten Sie bei Bedarf eine geeignete symptomatische Behandlung für Infusionsreaktionen an. Erwägen Sie ein sofortiges Absetzen der intravenösen Infusion, wenn schwere Infusionsreaktionen auftreten.
Beobachten Sie die Patienten während und mindestens 2 Stunden nach jeder MabCampath-Infusion auf Infusionsreaktionen. Betrachten Sie längere Beobachtungszeiten, wenn dies klinisch angezeigt ist. Informieren Sie die Patienten darüber, dass sie Symptome melden sollten, die während und nach jeder Infusion auftreten, da sie möglicherweise auf eine sofortige medizinische Intervention hinweisen.
Labortests und -überwachung zur Beurteilung der Sicherheit
Führen Sie die folgenden Labortests zu Studienbeginn und in regelmäßigen Abständen 48 Monate nach dem letzten Behandlungsverlauf von MabCampath durch, um frühzeitige Anzeichen potenziell schwerwiegender Nebenwirkungen zu überwachen:
- Vollständiges Blutbild (CBC) mit Differential (vor Beginn der Behandlung und danach in monatlichen Abständen)
- Serumkreatininspiegel (vor Beginn der Behandlung und danach in monatlichen Abständen)
- Urinanalyse mit Urinzellzahlen (vor Beginn der Behandlung und danach in monatlichen Abständen)
- Ein Test der Schilddrüsenfunktion, wie z. B. der Schilddrüsen-stimulierende Hormonspiegel (TSH) (vor Beginn der Behandlung und danach alle 3 Monate)
Führen Sie Basis- und jährliche Hautuntersuchungen durch, um das Melanom zu überwachen.
MabCampath ist bei Patienten, die mit dem Human Immunodeficiency Virus (HIV) infiziert sind, kontraindiziert, da MabCampath eine anhaltende Verringerung der CD4 + -Lymphozytenzahlen verursacht.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Autoimmunity
Treatment with MabCampath can result in the formation of autoantibodies and increase the risk of serious autoimmune mediated conditions. In clinical studies, MabCampath-treated patients experienced thyroid disorders (34%), immune thrombocytopenia (2%), and glomerular nephropathies (0.3%). Autoimmune hemolytic anemia and autoimmune pancytopenia , undifferentiated connective tissue disorders, and acquired hemophilia A (anti-Factor VIII antibodies) each occurred in 0.2% of patients. Rheumatoid arthritis, type I diabetes, vitiligo, and retinal pigment epitheliopathy occurred in 0.1% of patients.
During postmarketing use, additional autoimmune events including Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy have been reported in the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL), as well as other disorders, generally at higher and more frequent doses than recommended in MS. An oncology patient treated with alemtuzumab had fatal transfusion-associated graft-versus-host disease.
Autoantibodies may be transferred from the mother to the fetus during pregnancy. A case of transplacental transfer of anti-thyrotropin receptor antibodies resulting in neonatal Graves' disease occurred after alemtuzumab treatment in the mother.
MabCampath may increase the risk of other autoimmune conditions because of the broad range of autoantibody formation with MabCampath.
Monitor complete blood counts with differential, serum creatinine levels, and urinalysis with urine cell counts before starting treatment and then at monthly intervals for 48 months after the last dose of MabCampath to allow for early detection and treatment of autoimmune adverse reactions. After 48 months, testing should be performed based on clinical findings suggestive of autoimmunity.
MabCampath is available only through a restricted program under a REMS.
Infusion Reactions
MabCampath causes cytokine release syndrome resulting in infusion reactions, some of which may be serious and life threatening. In clinical studies, 92% of MabCampath-treated patients experienced infusion reactions. In some patients, infusion reactions were reported more than 24 hours after MabCampath infusion. Serious reactions occurred in 3% of patients and included anaphylaxis in 2 patients (including anaphylactic shock), angioedema, bronchospasm, hypotension, chest pain, bradycardia, tachycardia (including atrial fibrillation), transient neurologic symptoms, hypertension, headache, pyrexia, and rash. Other infusion reactions included nausea, urticaria, pruritus, insomnia, chills, flushing, fatigue, dyspnea, pulmonary infiltrates, dysgeusia, dyspepsia, dizziness, and pain. In clinical studies, 0.6% of patients with infusion reactions received epinephrine or atropine.
During postmarketing use, other serious and sometimes fatal infusion reactions included hypoxia, syncope, acute respiratory distress syndrome, respiratory arrest, myocardial infarction, acute cardiac insufficiency, and cardiac arrest have been reported in the treatment of patients with B-CLL, as well as other disorders, generally at higher and more frequent doses than recommended in MS.
Premedicate patients with corticosteroids immediately prior to MabCampath infusion for the first 3 days of each treatment course. In clinical studies, patients received 1,000 mg of methylprednisolone for the first 3 days of each MabCampath treatment course. Consider pretreatment with antihistamines and/or antipyretics prior to MabCampath administration. Infusion reactions may occur despite pretreatment.
Consider additional monitoring in patients with medical conditions which predispose them to cardiovascular or pulmonary compromise.
MabCampath can only be administered in certified healthcare settings that have on-site access to equipment and personnel trained to manage infusion reactions (including anaphylaxis and cardiac and respiratory emergencies).
MabCampath is available only through a restricted program under a REMS.
Malignancies
Thyroid Cancer
MabCampath may increase the risk of thyroid cancer. In controlled clinical studies, 3 of 919 (0.3%) MabCampath-treated patients developed thyroid cancer, compared to none in the interferon beta-1a–treated group. However, screening for thyroid cancer was performed more frequently in the MabCampath-treated group, because of the higher incidence of autoimmune thyroid disorders in those patients. Two additional cases of thyroid cancer in MabCampath-treated patients occurred in uncontrolled studies.
Patients and healthcare providers should monitor for symptoms of thyroid cancer including a new lump or swelling in the neck, pain in the front of the neck, persistent hoarseness or other voice changes, trouble swallowing or breathing, or a constant cough not due to an upper respiratory tract infection.
Melanoma
MabCampath may increase the risk of melanoma. In uncontrolled studies, 4 of 1486 (0.3%) MabCampath-treated patients developed melanoma or melanoma in situ. One of those patients had evidence of locally advanced disease.
Perform baseline and yearly skin examinations to monitor for melanoma in patients receiving MabCampath.
Lymphoproliferative Disorders And Lymphoma
Cases of lymphoproliferative disorders and lymphoma have occurred in MabCampath-treated patients with MS, including a MALT lymphoma, Castleman's Disease, and a fatality following treatment of non-Epstein Barr Virus–associated Burkitt's lymphoma. There are postmarketing reports of Epstein Barr Virus–associated lymphoproliferative disorders in non-MS patients.
Because MabCampath is an immunomodulatory therapy, caution should also be exercised in initiating MabCampath in patients with preexisting or ongoing malignancies.
MabCampath is available only through a restricted program under a REMS.
MabCampath REMS Program
MabCampath is available only through a restricted program under a REMS called the MabCampath REMS Program because of the risks of autoimmunity, infusion reactions, and malignancies.
Notable requirements of the MabCampath REMS Program include the following:
- Prescribers must be certified with the program by enrolling and completing training.
- Patients must enroll in the program and comply with ongoing monitoring requirements.
- Pharmacies must be certified with the program and must only dispense to certified healthcare facilities that are authorized to receive MabCampath.
- Healthcare facilities must enroll in the program and verify that patients are authorized before infusing MabCampath. Healthcare facilities must have on-site access to equipment and personnel trained to manage infusion reactions.
Further information, including a list of qualified healthcare facilities, is available at 1-855-6766326.
Immune Thrombocytopenia
Immune thrombocytopenia (ITP) occurred in 2% of MabCampath-treated patients in clinical studies in MS.
In a controlled clinical study in patients with MS, one MabCampath-treated patient developed ITP that went unrecognized prior to the implementation of monthly blood monitoring requirements, and died from intracerebral hemorrhage. Nadir platelet counts ≤20,000 cells per microliter as a result of ITP occurred in 2% of all MabCampath-treated patients in clinical studies in MS. Anti-platelet antibodies did not precede ITP onset. ITP has been diagnosed more than 3 years after the last MabCampath dose.
Symptoms of ITP include easy bruising, petechiae, spontaneous mucocutaneous bleeding (e.g., epistaxis, hemoptysis), and heavier than normal or irregular menstrual bleeding. Hemoptysis may also be indicative of anti-glomerular basement membrane (GBM) disease , and an appropriate differential diagnosis has to be undertaken. Remind the patient to remain vigilant for symptoms they may experience and to seek immediate medical help if they have any concerns.
Obtain complete blood counts (CBCs) with differential prior to initiation of treatment and at monthly intervals thereafter until 48 months after the last infusion. After this period of time, testing should be performed based on clinical findings suggestive of ITP. If ITP is suspected, a complete blood count should be obtained immediately. If ITP onset is confirmed, promptly initiate appropriate medical intervention.
Glomerular Nephropathies
Glomerular nephropathies occurred in 0.3% of MabCampath-treated patients in MS clinical studies. There were 3 cases of membranous glomerulonephritis and 2 cases of anti-glomerular basement membrane (anti-GBM) disease. There are published and postmarketing cases of MS patients treated with alemtuzumab who developed anti-GBM disease and subsequently developed end-stage renal disease requiring renal transplantation. Cases of anti-GBM disease have been diagnosed up to 40 months after the last dose of MabCampath. Urgent evaluation and treatment is required because anti-GBM disease can lead to renal failure requiring dialysis or transplantation and can be life-threatening if left untreated.
Clinical manifestations of nephropathy may include elevated serum creatinine levels, hematuria, or proteinuria. Alveolar hemorrhage manifested as hemoptysis is a common component of anti-GBM disease but did not occur in clinical studies.
Obtain serum creatinine levels and urinalysis with cell counts prior to initiation of treatment and at monthly intervals thereafter until 48 months after the last infusion. After this period of time, testing should be performed based on clinical findings suggestive of nephropathies.
If clinically significant changes from baseline in serum creatinine, unexplained hematuria, or proteinuria are observed, perform further evaluation for nephropathies. Early detection and treatment of nephropathies may decrease the risk of poor outcomes.
Thyroid Disorders
Autoimmune thyroid disorders occurred in 34% of MabCampath-treated patients in clinical studies. Newly diagnosed thyroid disorders occurred throughout the uncontrolled clinical study follow-up period, more than 7 years after the first MabCampath dose. Autoimmune thyroid disorders included Graves' disease, hyperthyroidism and hypothyroidism. Graves' ophthalmopathy with decreased vision, eye pain, and exophthalmos occurred in 1% of MabCampath-treated patients. Two patients required surgical orbital decompression. Serious thyroid events occurred in about 2% of MabCampath-treated patients in clinical studies and included cardiac and psychiatric events associated with thyroid disease. Of all MabCampath-treated patients, 3% underwent thyroidectomy.
Thyroid disease poses special risks in women who are pregnant.
Obtain thyroid function tests, such as TSH levels, prior to initiation of treatment and every 3 months thereafter until 48 months after the last infusion. Continue to test thyroid function after 48 months if clinically indicated.
In patients with ongoing thyroid disorder, MabCampath should be administered only if the potential benefit justifies the potential risks.
Other Autoimmune Cytopenias
Autoimmune cytopenias such as neutropenia (0.1%), hemolytic anemia (0.2%), and pancytopenia (0.2%) occurred in MabCampath-treated patients in clinical studies in MS. In cases of autoimmune hemolytic anemia, patients tested positive for direct antiglobulin antibodies, and nadir hemoglobin levels ranged from 2.9-8.6 g/dL. Symptoms of autoimmune hemolytic anemia include weakness, chest pain, jaundice, dark urine, and tachycardia. One MabCampath-treated patient with autoimmune pancytopenia died from sepsis.
During postmarketing use, additional autoimmune cytopenias including fatal autoimmune hemolytic anemia and aplastic anemia have been reported in the treatment of patients with BCLL, as well as other disorders, generally at higher and more frequent doses than recommended in MS.
Use CBC results to monitor for cytopenias. Prompt medical intervention is indicated if a cytopenia is confirmed.
Infections
Infections occurred in 71% of MabCampath-treated patients compared to 53% of patients treated with interferon beta-1a in controlled clinical studies in MS up to 2 years in duration. Infections that occurred more often in MabCampath-treated patients than interferon beta-1a patients included nasopharyngitis, urinary tract infection, upper respiratory tract infection, sinusitis, herpetic infections, influenza, and bronchitis. Serious infections occurred in 3% of patients treated with MabCampath as compared to 1% of patients treated with interferon beta-1a. Serious infections in the MabCampath group included: appendicitis, gastroenteritis, pneumonia, herpes zoster, and tooth infection.
Do not administer live viral vaccines following a course of MabCampath. Patients treated with MabCampath have altered immunity and may be at increased risk of infection following administration of live viral vaccines.
Consider delaying MabCampath administration in patients with active infection until the infection is fully controlled.
Concomitant use of MabCampath with antineoplastic or immunosuppressive therapies could increase the risk of immunosuppression.
Herpes Viral Infections
In controlled clinical studies, 16% of MabCampath-treated patients developed a herpes viral infection compared to 3% of interferon beta-1a patients. These events included oral herpes (8.8%), herpes zoster (4.2%), herpes simplex (1.8%), and genital herpes (1.3%). Serious herpetic infections in MabCampath-treated patients included primary varicella (0.1%), herpes zoster (0.2%), and herpes meningitis (0.1%). Administer antiviral agents for herpetic prophylaxis at appropriate suppressive dosing regimens. Administer antiviral prophylaxis for herpetic viral infections starting on the first day of each treatment course and continue for a minimum of two months following treatment with MabCampath or until the CD4+ lymphocyte count is ≥200 cells per microliter, whichever occurs later.
Human Papilloma Virus
Cervical human papilloma virus (HPV) infection, including cervical dysplasia, occurred in 2% of MabCampath-treated patients. Annual HPV screening is recommended for female patients.
Tuberculosis
Tuberculosis occurred in patients treated with MabCampath and interferon beta-1a in controlled clinical studies. Active and latent tuberculosis cases occurred in 0.3% of MabCampath-treated patients, most often in endemic regions. Perform tuberculosis screening according to local guidelines prior to initiation of MabCampath. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with MabCampath.
Fungal Infections
Fungal infections, especially oral and vaginal candidiasis, occurred more commonly in MabCampath-treated patients (12%) than in patients treated with interferon beta-1a (3%) in controlled clinical studies in MS.
Listeria Monocytogenes Infections
Listeria monocytogenes infections (e.g., meningitis, encephalitis, sepsis, and gastroenteritis), including fatal cases of Listeria meningoencephalitis, have occurred in MabCampath-treated patients. Listeria infections have occurred as early as 3 days after treatment and up to 8 months after the last MabCampath dose. The duration of increased risk for Listeria infection after MabCampath treatment is unknown.
Advise 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). Initiate these Listeria precautions prior to starting MabCampath treatment. The incubation period for Listeria monocytogenes ranges from 3 to 70 days. In most cases, signs and symptoms of invasive listeriosis start within 1 month of exposure to Listeria monocytogenes. Symptoms of Listeria infection include fever, chills, diarrhea, nausea, vomiting, headache, pains in joints and muscles, neck stiffness, difficulty walking, mental status changes, coma, and other neurologic changes. As is the case with many infections, treatment cannot always prevent mortality and morbidity related to Listeria infections. Therefore, advise patients to watch for symptoms of Listeria infection and seek prompt medical help if symptoms occur.
Infections In Non-MS Patients
During postmarketing use, serious and sometimes fatal viral, bacterial, protozoan, and fungal infections, including some due to reactivation of latent infections, have been reported in the treatment of patients with B-CLL, as well as other disorders, generally at higher and more frequent doses than recommended in MS.
Hepatitis
No data are available on the association of MabCampath with Hepatitis B virus (HBV) or Hepatitis C virus (HCV) reactivation because patients with evidence of active or chronic infections were excluded from the clinical studies. Consider screening patients at high risk of HBV and/or HCV infection before initiation of MabCampath and exercise caution in prescribing MabCampath to patients identified as carriers of HBV and/or HCV as these patients may be at risk of irreversible liver damage relative to a potential virus reactivation as a consequence of their pre-existing status.
Acute Acalculous Cholecystitis
MabCampath may increase the risk of acute acalculous cholecystitis. In controlled clinical studies, 0.2% of MabCampath-treated MS patients developed acute acalculous cholecystitis, compared to 0% of patients treated with interferon beta-1a. During postmarketing use, additional cases of acute acalculous cholecystitis have been reported in MabCampath-treated patients. Time to onset of symptoms ranged from less than 24 hours to 2 months after MabCampath infusion. Typical risk or predisposing factors such as concurrent critical illness were often not reported. Abnormal ultrasound or computed tomography was used to support the diagnosis of acute acalculous cholecystitis in some cases. Some patients were treated conservatively with antibiotics and recovered without surgical intervention, whereas others underwent cholecystectomy.
Symptoms of acute acalculous cholecystitis include abdominal pain, abdominal tenderness, fever, nausea, and vomiting. Leukocytosis and abnormal liver enzymes are also commonly observed. Acute acalculous cholecystitis is a condition that is associated with high morbidity and mortality rates if not diagnosed early and treated. If acute acalculous cholecystitis is suspected, evaluate and treat promptly.
Pneumonitis
In clinical studies, 6 of 1217 (0.5%) MabCampath-treated patients had pneumonitis of varying severity. Cases of hypersensitivity pneumonitis and pneumonitis with fibrosis occurred in clinical studies. Patients should be advised to report symptoms of pneumonitis, which include shortness of breath, cough, wheezing, chest pain or tightness, and hemoptysis.
Drug Products With Same Active Ingredient
MabCampath contains the same active ingredient (alemtuzumab) found in CAMPATH®. If MabCampath is considered for use in a patient who has previously received CAMPATH, exercise increased vigilance for additive and long-lasting effects on the immune system.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Autoimmunity
- Advise patients to contact their healthcare provider promptly if they experience any symptoms of potential autoimmune disease. Give examples of important symptoms such as bleeding, easy bruising, petechiae, purpura, hematuria, edema, jaundice, or hemoptysis.
- Advise patients of the importance of monthly blood and urine tests for 48 months following the last course of MabCampath to monitor for signs of autoimmunity because early detection and prompt treatment can help prevent serious and potentially fatal outcomes associated with these events. Advise patients that monitoring may need to continue past 48 months if they have signs or symptoms of autoimmunity.
- Advise patients that MabCampath may cause hyperthyroid or hypothyroid disorders.
- Advise women of childbearing potential of the risks of pregnancy with concomitant thyroid disease. Advise women of childbearing potential to discuss pregnancy planning with their doctor.
Infusion Reactions
- Advise patients that infusion reactions can occur after they leave the infusion center.
- Instruct the patient to remain at the infusion center for 2 hours after each MabCampath infusion, or longer at the discretion of the physician. Advise patients that symptoms of infusion reactions may occur after they leave the infusion center and to report these symptoms to their doctor.
- Advise patients to contact their healthcare provider promptly if they experience infusion reactions, which include swelling in the mouth or throat, difficulty breathing, weakness, abnormal heart rate (fast, slow, or irregular), chest pain, and rash.
Malignancies
- Advise patients that MabCampath may increase their risk of malignancies including thyroid cancer and melanoma.
- Advise patients to report symptoms of thyroid cancer, including a new lump or swelling in the neck, pain in the front of the neck, hoarseness or other voice changes that do not go away, trouble swallowing or breathing, or a constant cough not due to a cold.
- Advise patients that they should have baseline and yearly skin examinations.
MabCampath REMS Program
- MabCampath is available only through a restricted program called the MabCampath REMS Program. Inform the patient of the following notable requirements:
- Patients and providers must be enrolled in the program.
- Patients must comply with the ongoing monitoring requirements.
- Patients must report any side effects or symptoms to their doctor.
- MabCampath is available only at certified infusion centers participating in the program. Therefore, provide patients with information on the MabCampath REMS Program in order to locate an infusion center.
- Advise patients to read the MabCampath REMS material for patients, What You Need to Know About MabCampath Treatment: A Patient Guide and What You Need to Know About MabCampath Treatment and Infusion Reactions: A Patient Guide.
- Instruct patients to carry the MabCampath REMS Patient Safety Information Card with them in case of an emergency.
Infections
- Advise patients to contact their healthcare provider if they develop symptoms of serious infection such as fever or swollen glands.
- Advise patients to complete any necessary immunizations at least 6 weeks prior to treatment with MabCampath. Advise patients that they should talk to their healthcare provider before taking any vaccine after recent treatment with MabCampath.
- Advise patients to take their prescribed medication for herpes prophylaxis as directed by their healthcare provider.
- Advise patients that yearly HPV screening is recommended.
- Advise patients to avoid or adequately heat foods that are potential sources of Listeria monocytogenes prior to receiving MabCampath and if they have had a recent course of MabCampath. The duration of increased risk for Listeria infection after MabCampath administration is not known. Inform patients that Listeria infection can lead to significant complications or death..
Acute Acalculous Cholecystitis
- Advise patients to report symptoms of acute acalculous cholecystitis. These include abdominal pain, abdominal tenderness, fever, nausea, and vomiting
Pneumonitis
- Advise patients that pneumonitis has been reported in patients treated with MabCampath. Advise patients to report symptoms of lung disease such as shortness of breath, cough, wheezing, chest pain or tightness, and hemoptysis.
Concomitant Use Of Campath
- Advise patients that alemtuzumab is the same drug as Campath for use in B-CLL. Patients should inform their healthcare provider if they have taken Campath.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Studies to assess the carcinogenic or genotoxic potential of MabCampath have not been conducted.
When MabCampath (3 or 10 mg/kg IV) was administered to huCD52 transgenic male mice on 5 consecutive days prior to cohabitation with untreated wild-type females, no effect on fertility or reproductive performance was observed. However, adverse effects on sperm parameters (including abnormal morphology [detached /no head] and reduced total count and motility) were observed at both doses tested.
When MabCampath (3 or 10 mg/kg IV) was administered to huCD52 transgenic female mice for 5 consecutive days prior to cohabitation with untreated wild-type males, there was a decrease in the average number of corpora lutea and implantation sites and an increase in post-implantation loss, resulting in fewer viable embryos at the higher dose tested.
Use In Specific Populations
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. MabCampath was embryolethal in pregnant huCD52 transgenic mice when administered during organogenesis. Auto-antibodies may develop after administration of MabCampath. Placental transfer of antithyroid antibodies resulting in neonatal Graves' disease has been reported. MabCampath should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data
When MabCampath was administered to pregnant huCD52 transgenic mice during organogenesis (gestation days [GD] 6-10 or GD 11-15) at doses of 3 or 10 mg/kg IV, no teratogenic effects were observed. However, there was an increase in embryolethality (increased post-implantation loss and the number of dams with all fetuses dead or resorbed) in pregnant animals dosed during GD 11-15.
In a separate study in pregnant huCD52 transgenic mice, administration of MabCampath during organogenesis (GD 6-10 or GD 11-15) at doses of 3 or 10 mg/kg/IV, decreases in B lymphocytes and T-lymphocyte populations were observed in the offspring at both doses tested. The effects of MabCampath, administered during organogenesis, on postnatal development have not been adequately assessed.
Clinical Considerations
To avoid in utero exposure to MabCampath, women of child bearing potential should use effective contraceptive measures when receiving a course of treatment with MabCampath and for 4 months following that course of treatment.
MabCampath induces persistent thyroid disorders. Untreated hypothyroidism in pregnant women increases the risk for miscarriage and may have effects on the fetus including mental retardation and dwarfism. In mothers with Graves' disease, maternal thyroid stimulating hormone receptor antibodies can be transferred to a developing fetus and can cause neonatal Graves' disease. In a patient who developed Graves' disease after treatment with alemtuzumab, placental transfer of anti-thyrotropin receptor antibodies resulted in neonatal Graves' Disease with thyroid storm in her infant who was born 1 year after alemtuzumab dosing.
Nursing Mothers
Alemtuzumab was detected in the milk of lactating mice administered 10 mg/kg MabCampath on Days 8 through 12 postpartum. Serum levels of alemtuzumab were similar in lactating mice and offspring on Day 13 postpartum, and were associated with evidence of pharmacological activity (decrease in lymphocyte counts) in the offspring.
It is not known whether alemtuzumab is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from MabCampath, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients less than 17 years of age have not been established. Use of MabCampath is not recommended in pediatric patients due to the risks of autoimmunity, infusion reactions, and because it may increase the risk of malignancies (thyroid, melanoma, lymphoproliferative disorders, and lymphoma).
Geriatric Use
Clinical studies of MabCampath did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.
The following serious adverse reactions are described below and elsewhere in the labeling:
- Autoimmunity
- Infusion Reactions
- Malignancies
- Immune Thrombocytopenia
- Glomerular Nephropathies
- Thyroid Disorders
- Other Autoimmune Cytopenias
- Infections
- Acute Acalculous Cholecystitis
- Pneumonitis
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In controlled clinical trials (Study 1 and Study 2), a total of 811 patients with relapsing forms of MS received MabCampath. A total of 811 patients received 1 course of therapy, and 789 patients received a second course of therapy at 12 months. The overall follow-up in the controlled trials was equivalent to 1622 patient years, with an additional 3411 person-years of follow-up in an open-label extension study. The population was 18-55 years of age, 65% were female, and 92% were Caucasian.
Most Common Adverse Reactions
In clinical trials, the most common adverse reactions with MabCampath (in at least 10% of patients and more frequently than in interferon beta-1a) were rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticaria, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting.
Table 1 lists adverse reactions occurring in ≥5% of MabCampath-treated patients in Study 1 and 2 and at the same or at a higher rate than interferon beta-1a.
Table 1: Adverse Reactions in the Pooled 2-Year Active-Controlled Studies in Patients with Relapsing-Remitting Multiple Sclerosis
MabCampath (N=811) % | interferon beta-1a 44 mcg (N=389) % | |
Rash | 53 | 6 |
Headache | 52 | 23 |
Pyrexia | 29 | 9 |
Nasopharyngitis | 25 | 19 |
Nausea | 21 | 9 |
Urinary tract infection | 19 | 8 |
Fatigue | 18 | 13 |
Insomnia | 16 | 15 |
Upper respiratory tract infection | 16 | 13 |
Herpes viral infection | 16 | 3 |
Urticaria | 16 | 2 |
Pruritus | 14 | 2 |
Thyroid gland disorders | 13 | 3 |
Fungal infection | 13 | 4 |
Arthralgia | 12 | 9 |
Pain in extremity | 12 | 9 |
Back pain | 12 | 8 |
Diarrhea | 12 | 6 |
Sinusitis | 11 | 8 |
Oropharyngeal pain | 11 | 5 |
Paresthesia | 10 | 8 |
Dizziness | 10 | 5 |
Abdominal pain | 10 | 5 |
Flushing | 10 | 4 |
Vomiting | 10 | 3 |
Cough | 9 | 4 |
Chills | 9 | 3 |
Dysgeusia | 8 | 7 |
Influenza | 8 | 6 |
Dermatitis | 8 | 5 |
Dyspepsia | 8 | 4 |
Blood in urine | 8 | 3 |
Dyspnea | 8 | 1 |
Tachycardia | 8 | 1 |
Anxiety | 7 | 6 |
Muscular weakness | 7 | 6 |
Bronchitis | 7 | 4 |
Chest discomfort | 7 | 2 |
Muscle spasms | 6 | 5 |
Myalgia | 6 | 5 |
Decrease in CD4 lymphocytes | 6 | 2 |
Decrease in CD8 lymphocytes | 6 | 2 |
Asthenia | 5 | 4 |
Decrease in T-lymphocyte count | 5 | 3 |
Erythema | 5 | 2 |
Peripheral edema | 5 | 2 |
Epistaxis | 5 | 2 |
Neck Pain | 5 | 2 |
Abnormal uterine bleeding | 5 | 1 |
Lymphopenia
Nearly all (99.9%) patients treated with MabCampath in MS clinical trials experienced lymphopenia. The lowest lymphocyte counts occurred approximately by 1 month after each course of treatment. The mean lymphocyte count at 1 month after MabCampath treatment was 0.25 x 109 L (range 0.02-2.30 x 109 L) and 0.32 (0.02-1.81 x 109 L) for treatment courses 1 and 2, respectively. Total lymphocyte counts increased to reach the lower limit of normal in approximately 40% of patients by 6 months after each MabCampath treatment course and approximately 80% of patients by 12 months after each course.
Suicidal Behavior Or Ideation
In clinical studies, 0.6% of patients in both the MabCampath and interferon beta-1a groups had events of attempted suicide or suicidal ideation. There were no completed suicides in either clinical study treatment group. Suicidal behavior or ideation occurred in patients with or without a history of a psychiatric or thyroid disorder. Advise patients to report immediately any symptoms of depression or suicidal ideation to the prescribing physician.
Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. Using an enzyme-linked immunosorbent assay (ELISA) and a competitive binding assay, anti-alemtuzumab binding antibodies were detected in 62%, 67%, and 29% of MabCampath-treated patients, at months 1, 3, 12 (Course 1) as well as 83%, 83%, and 75% of MabCampath-treated patients at months 13, 15, and 24 (Course 2). Samples that tested positive for binding antibodies were further evaluated for evidence of in vitro inhibition using a flow cytometry assay. Neutralizing antibodies were detected in 87%, 46%, and 5% of positive binding antibody patients at months 1, 3, 12 (Course 1) as well as 94%, 88%, and 42% of positive binding antibody patients at months 13, 15, and 24 (Course 2). Anti-alemtuzumab antibodies were associated with decreased alemtuzumab concentration during Course 2 but not Course 1. There was no evidence from clinical trials that the presence of binding or inhibitory anti-alemtuzumab antibodies had a significant effect on clinical outcomes, total lymphocyte count, or adverse events.
The incidence of antibodies is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including inhibitory antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to MabCampath with the incidence of antibodies to other products may be misleading.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of alemtuzumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Postmarketing Experience With MabCampath
Gastrointestinal System Disorders: Acute acalculous cholecystitis.
Postmarketing Experience With CAMPATH
CAMPATH is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) and is generally administered at higher and more frequent doses (e.g., 30 mg) than recommended in the treatment of MS.
Cardiac Disorders: Congestive heart failure, cardiomyopathy, and decreased ejection fraction in non-MS patients previously treated with potentially cardiotoxic agents.
Two MS patients experienced serious reactions (headache, rash, and either hypotension or sinus tachycardia) after a single accidental infusion up to 60 mg of MabCampath. Doses of MabCampath greater than those recommended may increase the intensity and/or duration of infusion reactions or its immune effects. There is no known antidote for alemtuzumab overdosage.
Auswirkungen von MabCampath auf die Lymphozytenpopulation
MabCampath verbraucht nach jedem Behandlungsverlauf zirkulierende T- und B-Lymphozyten. In klinischen Studien traten die niedrigsten Zellzahlen 1 Monat nach einer Behandlung zum Zeitpunkt des ersten Blutbildes nach der Behandlung auf. Die Lymphozytenzahlen nahmen dann im Laufe der Zeit zu: Die B-Zellzahlen erholten sich normalerweise innerhalb von 6 Monaten; Die T-Zellzahlen nahmen langsamer zu und blieben normalerweise 12 Monate nach der Behandlung unter dem Ausgangswert. Ungefähr 60% der Patienten hatten 6 Monate nach jedem Behandlungsverlauf eine Gesamtlymphozytenzahl unterhalb der Untergrenze des Normalwerts und 20% hatten nach 12 Monaten eine Zählung unterhalb der Untergrenze des Normalwerts.
Die Rekonstitution der Lymphozytenpopulation variiert für die verschiedenen Lymphozyten-Subtypen. In klinischen Studien betrug die mittlere CD4 + -Lymphozytenzahl im ersten Monat 40 Zellen pro Mikroliter und im 12. Monat 270 Zellen pro Mikroliter. Nach 30 Monaten hatte ungefähr die Hälfte der Patienten CD4 + -Lymphozytenzahlen, die unter der Untergrenze des Normalwerts blieben.
Herzelektrophysiologie
In einer Studie mit 53 MS-Patienten verursachte Alemtuzumab 12 mg pro Tag über 5 Tage keine Änderungen des QTc-Intervalls von mehr als 20 ms. Ein durchschnittlicher Anstieg der Herzfrequenz um 22 bis 26 Schläge pro Minute wurde mindestens 2 Stunden nach der ersten, jedoch nicht nach der anschließenden Infusion beobachtet.
Die Pharmakokinetik von MabCampath wurde bei insgesamt 148 Patienten mit rezidivierenden MS-Formen untersucht, die an 5 aufeinanderfolgenden Tagen 12 mg / Tag erhielten, gefolgt von 12 mg / Tag an 3 aufeinanderfolgenden Tagen 12 Monate nach dem ersten Behandlungsverlauf.
Absorption
Die Serumkonzentrationen stiegen mit jeder aufeinanderfolgenden Dosis innerhalb eines Behandlungsverlaufs an, wobei die höchsten beobachteten Konzentrationen nach der letzten Infusion eines Behandlungsverlaufs auftraten. Die mittlere maximale Konzentration betrug am Tag 5 des ersten Behandlungsverlaufs 3014 ng / ml und am Tag 3 des zweiten Behandlungsverlaufs 2276 ng / ml.
Verteilung
MabCampath ist weitgehend auf das Blut und den interstitiellen Raum mit einem zentralen Verteilungsvolumen von 14,1 l beschränkt
Beseitigung
Die Eliminationshalbwertszeit betrug ungefähr 2 Wochen und war zwischen den Kursen vergleichbar. Die Serumkonzentrationen waren im Allgemeinen innerhalb von ungefähr 30 Tagen nach jedem Behandlungsverlauf nicht nachweisbar (<60 ng / ml).