Select safety information of LEMTRADA

Because of the risk of autoimmunity, infusion reactions, and malignancies, LEMTRADA is available only through restricted distribution under a Risk Evaluation and Mitigation Strategy (REMS) Program to help ensure safe use1

Infusion Reactions

Occurred in 92% of LEMTRADA-treated patients in the MS clinical trials1

  • Some infusion reactions were reported more than 24 hours after LEMTRADA infusion
  • Serious reactions occurred in 3% of patients
  • Infusion reactions were generally highest on day 1 of each course2

Monitoring for infusion reactions1

  • Monitor vital signs before the infusion and periodically during the infusion
  • Observe patients for infusion reactions during and for at least 2 hours after each LEMTRADA infusion
  • Advise patients to report symptoms during and after each infusion because prompt medical intervention may be needed
  • Consider additional monitoring in patients with medical conditions which predispose them to cardiovascular or pulmonary compromise

Provide appropriate symptomatic treatment for infusion reactions as needed1

  • Consider stopping the LEMTRADA infusion if severe infusion reactions occur

LEMTRADA causes cytokine release syndrome resulting in infusion reactions, some of which may be serious and life-threatening.1

Learn more about cytokine release syndrome

Immune thrombocytopenia (ITP)

2% of LEMTRADA-treated patients experienced ITP in the MS clinical trials1

Diagnosis and clinical presentation

  • A normal platelet count is generally between 150-450 × 109/L
  • The international working group recommends that a platelet count below 100 × 109/L with exclusion of other causes of thrombocytopenia be required for diagnosis4
  • Symptoms may include: easy bruising, petechiae, spontaneous mucocutaneous bleeding (e.g., epistaxis, hemoptysis), and heavier than normal or irregular menstrual bleeding1

Monitoring may help detect early signs of potentially serious adverse events1

  • Complete blood counts with differential should be obtained prior to initiation of treatment and at monthly intervals until 48 months after the last infusion, or longer if clinically indicated
  • One patient developed ITP that went unrecognized before monthly monitoring was required and died from intracerebral hemorrhage
  • ITP has been diagnosed more than 3 years after the last LEMTRADA dose

If ITP is suspected, appropriate medical intervention should be promptly initiated, including immediate referral to a specialist. Severe or widespread bleeding is life-threatening and demands immediate care5

  • The goal of therapy in ITP is to achieve a platelet count that is associated with adequate hemostasis, rather than a normal platelet count6

Learn about potential treatment strategies for ITP

No ITP-related fatalities were observed since the Phase II study after implementation of required monthly monitoring2

Nephropathies

Glomerular nephropathies occurred in 0.3% of LEMTRADA-treated patients in the MS clinical trials, including 3 cases of membranous glomerulonephritis and 2 cases of anti-GBM disease1

  • There were no cases of Goodpasture’s Syndrome observed in LEMTRADA-treated patients2

Diagnosis and clinical presentation

  • Elevated serum creatinine levels, hematuria, or proteinuria1
    • Patients with anti-GBM may report dark urine7
    • Development of oliguria is a poor prognostic sign for anti-GBM8
  • Membranous nephropathy presentation varies based on severity of proteinuria and includes9:
    • Ranges from proteinuria picked up incidentally to nephrotic syndrome (edema + hypoalbuminemia + proteinuria >3 g/day)
    • Microscopic hematuria is common, but macroscopic hematuria is rare
    • Renal function may be normal at presentation

Monitoring may help detect early signs of potentially serious adverse events1

  • Serum creatinine levels and urinalysis with cell counts should be obtained prior to the first infusion of LEMTRADA and at monthly intervals thereafter until 48 months after the patient’s last infusion, or longer if clinically indicated
  • Anti-GBM disease was reported in LEMTRADA patients and was diagnosed up to 40 months after the last dose of LEMTRADA
  • Urgent evaluation and treatment is required because anti-GBM disease can lead to end-stage renal disease requiring transplantation or dialysis and can be life-threatening if left untreated. Such cases have been reported outside of clinical trials

Anti-GBM disease is life-threatening if not treated and therefore demands immediate care. Without prompt treatment, patients can rapidly develop renal failure requiring dialysis and/or kidney transplantation, and this may lead to death6

  • Immediate referral to a specialist for further assessment for patients with suspected nephropathy is strongly recommended6
Thyroid disorders

34% of LEMTRADA-treated patients had thyroid disorders in the MS clinical trials1

Hyperthyroidism: diagnosis and clinical presentation

  • Thyroid function tests: suppressed thyroid stimulating hormone (TSH), elevated serum thyroxine (T4), and triiodothyronine (T3)10
  • Symptoms may include: irritability, nervousness, muscle weakness, unexplained weight loss, sleep disturbances, vision problems, eye swelling, excessive sweating and fast heartbeat11,12

Hypothyroidism: diagnosis and clinical presentation

  • Thyroid function tests: elevated TSH, suppressed T4 and T32,13
  • Symptoms may include: worsening fatigue, depression, feeling cold, constipation, forgetfulness, unexplained weight gain11,12

Monitoring may help detect early signs of potentially serious adverse events1

  • Thyroid function tests such as TSH levels should be obtained prior to the first infusion of LEMTRADA and then every 3 months thereafter continuing until 48 months following the last infusion, or longer if clinically indicated
  • Newly diagnosed thyroid disorders occurred throughout the uncontrolled clinical study follow-up period, more than 7 years after the first LEMTRADA dose
  • Serious events occurred in 2% of patients and included cardiac and psychiatric events. Of all LEMTRADA-treated patients, 3% underwent thyroidectomy
  • A case of transplacental transfer of anti-thyrotropin receptor antibodies resulting in neonatal Graves’ disease occurred after LEMTRADA treatment of the mother
  • Administer LEMTRADA in patients with ongoing thyroid disorder only if the potential benefit justifies the potential risks

Treatment for thyroid disorders

Learn about potential treatment strategies for thyroid disorders

In the LEMTRADA clinical trials, the annual incidence of thyroid events following treatment peaked in Year 3, but declined in Year 42

Other serious adverse reactions Malignancies

LEMTRADA may cause an increased risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders1

  • 0.3% of LEMTRADA-treated patients developed thyroid cancer vs 0% of interferon beta-1a patients in controlled clinical studies
    • In uncontrolled studies, 2 additional cases occurred in LEMTRADA-treated patients
  • In uncontrolled studies, 0.3% of LEMTRADA-treated patients developed melanoma or melanoma in situ, one of which had evidence of locally advanced disease
  • Cases of lymphoproliferative disorders and lymphoma have occurred in LEMTRADA-treated patients with MS, including a MALT lymphoma, Castleman’s Disease, and a fatality from Burkitt’s lymphoma

Monitoring for malignancies1

  • Healthcare providers should monitor and patients should self-monitor for symptoms of malignancies
  • Monitor for symptoms of thyroid cancer
  • Perform baseline and yearly skin exams to monitor for melanoma

Because LEMTRADA is an immunomodulatory therapy, caution should be exercised in initiating LEMTRADA in patients with pre-existing or ongoing malignancies.1

Other autoimmune cytopenias

Occurred in LEMTRADA-treated patients (e.g., neutropenia [0.1%], hemolytic anemia [0.2%], and pancytopenia [0.2%])

  • One LEMTRADA patient with autoimmune pancytopenia died from sepsis

Monitoring may help detect early signs of potentially serious adverse events

  • Use CBC results to monitor for cytopenias, and use prompt medical intervention if a cytopenia is confirmed
Common adverse reactions

In clinical trials, the most common adverse reactions (incidence ≥10% and >interferon beta-1a) with LEMTRADA vs interferon beta-1a were: rash (53% vs 6%), headache (52% vs 23%), pyrexia (29% vs 9%), nasopharyngitis (25% vs 19%), nausea (21% vs 9%), urinary tract infection (19% vs 8%), fatigue (18% vs 13%), insomnia (16% vs 15%), upper respiratory tract infection (16% vs 13%), herpes viral infection (16% vs 3%), urticaria (16% vs 2%), pruritus (14% vs 2%), thyroid gland disorders (13% vs 3%), fungal infection (13% vs 4%), arthralgia (12% vs 9%), pain in extremity (12% vs 9%), back pain (12% vs 8%), diarrhea (12% vs 6%), sinusitis (11% vs 8%), oropharyngeal pain (11% vs 5%), paresthesia (10% vs 8%), dizziness (10% vs 5%), abdominal pain (10% vs 5%), flushing (10% vs 4%), and vomiting (10% vs 3%).1

Prescribers, healthcare facilities, and pharmacies must be enrolled in the LEMTRADA REMS Program to prescribe, dispense, and administer LEMTRADA for patients with relapsing multiple sclerosis.1

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The LEMTRADA REMS Program

Because of the risk of autoimmunity, infusion reactions, and malignancies, LEMTRADA is available only through restricted distribution under a Risk Evaluation and Mitigation Strategy (REMS) Program.

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IMPORTANT SAFETY INFORMATION

WARNING: AUTOIMMUNITY, INFUSION REACTIONS, AND MALIGNANCIES

  • LEMTRADA causes serious, sometimes fatal, autoimmune conditions such as immune thrombocytopenia and anti-glomerular basement membrane disease. Monitor complete blood counts with differential, serum creatinine levels, and urinalysis with urine cell counts at periodic intervals for 48 months after the last dose of LEMTRADA.
  • LEMTRADA causes serious and life-threatening infusion reactions. LEMTRADA must be administered in a setting with appropriate equipment and personnel to manage anaphylaxis or serious infusion reactions. Monitor patients for two hours after each infusion. Make patients aware that serious infusion reactions can also occur after the 2-hour monitoring period.
  • LEMTRADA may cause an increased risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders. Perform baseline and yearly skin exams.
  • Because of the risk of autoimmunity, infusion reactions, and malignancies, LEMTRADA is available only through restricted distribution under a Risk Evaluation and Mitigation Strategy (REMS) Program. Call 1-855-676-6326 to enroll in the LEMTRADA REMS Program.

WARNINGS AND PRECAUTIONS

  • Autoimmunity: Treatment with LEMTRADA can result in the formation of autoantibodies and increase the risk of serious autoimmune mediated conditions, and may increase the risk of other autoimmune conditions because of the broad range of autoantibody formation. Obtain complete blood counts (CBC) with differential, serum creatinine levels, and urinalysis with cell counts before starting treatment and then at monthly intervals for 48 months after the last dose of LEMTRADA, or longer, if clinically indicated.
  • Infusion Reactions: LEMTRADA causes cytokine release syndrome resulting in infusion reactions. In clinical studies, 92% of LEMTRADA-treated patients experienced infusion reactions. Serious reactions occurred in 3% of these 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. In some patients, infusion reactions were reported more than 24 hours after LEMTRADA infusion. Premedicate patients with corticosteroids immediately prior to LEMTRADA infusion for the first 3 days of each treatment course. Consider pretreatment with antihistamines and/or antipyretics. Infusion reactions may occur despite pretreatment.
  • Malignancies: Monitor for symptoms of thyroid cancer. Because LEMTRADA is an immunomodulatory therapy, caution should be exercised in initiating LEMTRADA in patients with pre-existing or ongoing malignancies.
  • LEMTRADA REMS Program: Only prescribers, patients, pharmacies and healthcare facilities certified and enrolled in the REMS program can prescribe, receive, dispense or administer LEMTRADA. Healthcare facilities must have on-site access to equipment and personnel trained to manage infusion reactions (including anaphylaxis and cardiac and respiratory emergencies).
  • Immune thrombocytopenia (ITP) occurred in 2% of LEMTRADA-treated patients in clinical studies in MS. One LEMTRADA-treated patient developed ITP that went unrecognized prior to the implementation of monthly monitoring requirements, and died from an intracerebral hemorrhage. ITP has been diagnosed more than 3 years after the last LEMTRADA dose. If ITP is confirmed, promptly initiate medical intervention.
  • Glomerular nephropathies occurred in 0.3% of LEMTRADA-treated patients in MS clinical trials and have been diagnosed up to 40 months after the last dose of LEMTRADA. Anti-glomerular basement membrane (anti-GBM) disease can lead to renal failure requiring dialysis and transplantation and has in post-marketing cases of MS patients treated with alemtuzumab. Anti-GBM disease can be life threatening if untreated; early detection and treatment may decrease the risk of poor outcomes.
  • Autoimmune thyroid disorders occurred in 34% of LEMTRADA-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 LEMTRADA dose. Serious thyroid events occurred in 2% of patients, including cardiac and psychiatric events. In LEMTRADA-treated patients, 3% underwent thyroidectomy. In patients with an ongoing thyroid disorder, LEMTRADA should be administered only if the potential benefit justifies the potential risks. Obtain thyroid function tests prior to initiation of treatment and every 3 months until 48 months after the last infusion, or longer, if clinically indicated. Thyroid disease poses special risks in women who are pregnant.
  • Autoimmune cytopenias occurred in LEMTRADA-treated MS patients in clinical trials. One LEMTRADA-treated patient with autoimmune pancytopenia died from sepsis. Prompt medical intervention is indicated if a cytopenia is confirmed.
  • Infections occurred in 71% of LEMTRADA-treated patients compared to 53% of patients treated with interferon beta-1a. Serious infections occurred in 3% of patients treated with LEMTRADA and 1% of patients treated with interferon beta-1a and included: appendicitis, gastroenteritis, pneumonia, herpes zoster, and tooth infection. Consider delaying LEMTRADA administration in patients with active infection until the infection is fully controlled.
    • Do not administer live viral vaccines following a course of LEMTRADA, as patients may be at increased risk of infection.
    • Concomitant use of antineoplastic or immunosuppressive therapies could increase the risk of immunosuppression.
    • Herpes viral infection developed in 16% of LEMTRADA-treated patients compared to 3% of interferon beta-1a patients. Administer antiviral prophylaxis for herpetic viral infections starting on the first day of each treatment course and continue for a minimum of two months following treatment with LEMTRADA or until CD4+ lymphocyte count is ≥200 cells per microliter, whichever occurs later.
    • Cervical human papilloma virus (HPV) infection occurred in 2% of LEMTRADA-treated patients. Annual screening is recommended for female patients.
    • Active and latent tuberculosis cases occurred in 0.3% of LEMTRADA-treated patients, most often in endemic regions.
    • Fungal infections, especially oral and vaginal candidiasis, occurred in 12% of LEMTRADA-treated patients compared to 3% of interferon beta-1a patients.
    • Cases of listeria meningitis occurred within 1 month of LEMTRADA dosing. Advise patients to avoid or adequately heat foods that are potential sources for Listeria monocytogenes.
    • Before initiating LEMTRADA, consider screening patients at high risk of Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infection. Carriers of HBV and/or HCV who receive LEMTRADA may be at risk of irreversible liver damage relative to a potential virus reactivation.
  • Pneumonitis, including hypersensitivity pneumonitis and pneumonitis with fibrosis, occurred in 6 of 1217 (0.5%) LEMTRADA-treated patients in clinical studies. Advise patients to report symptoms of pneumonitis (e.g., shortness of breath, cough, wheezing, chest pain or tightness, and hemoptysis).
  • Drug Products with Same Active Ingredient: LEMTRADA contains the same active ingredient (alemtuzumab) found in CAMPATH®. If LEMTRADA is considered for use in a patient who has previously received CAMPATH, exercise increased vigilance for additive and long-lasting effects on the immune system.

Adverse Reactions

In clinical trials, the most common adverse reactions (incidence ≥10% and >interferon beta-1a) with LEMTRADA vs interferon beta-1a were: rash (53% vs 6%), headache (52% vs 23%), pyrexia (29% vs 9%), nasopharyngitis (25% vs 19%), nausea (21% vs 9%), urinary tract infection (19% vs 8%), fatigue (18% vs 13%), insomnia (16% vs 15%), upper respiratory tract infection (16% vs 13%), herpes viral infection (16% vs 3%), urticaria (16% vs 2%), pruritus (14% vs 2%), thyroid gland disorders (13% vs 3%), fungal infection (13% vs 4%), arthralgia (12% vs 9%), pain in extremity (12% vs 9%), back pain (12% vs 8%), diarrhea (12% vs 6%), sinusitis (11% vs 8%), oropharyngeal pain (11% vs 5%), paresthesia (10% vs 8%), dizziness (10% vs 5%), abdominal pain (10% vs 5%), flushing (10% vs 4%), and vomiting (10% vs 3%).

Use in Specific Populations

LEMTRADA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Autoantibodies may be transferred from the mother to the fetus during pregnancy. Placental transfer of anti-thyroid antibodies resulted in a case of neonatal Graves’ disease. Safety and effectiveness in pediatric patients less than 17 years of age have not been established. Use of LEMTRADA is not recommended in pediatric patients due to the risks of autoimmunity and infusion reactions, and because it may increase the risk of malignancies.

Please see full Prescribing Information, including boxed WARNING, for additional Important Safety Information.

References:
1. LEMTRADA [prescribing information]. Cambridge, MA: Genzyme Corporation; 2016.
2. Data on file. Genzyme Corporation; 2012.
3. Immune thrombocytopenic purpura. Johns Hopkins Medicine website. http://www.hopkinsmedicine.org/healthlibrary/​conditions/adult/hematology_and_blood_disorders/​idiopathic_thrombocytopenic_purpura_85,p00096. Accessed June 3, 2016.
4. Cuker A, Cines DB. Immune thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2010;2010:377-384.
5. LEMTRADA REMS Program website. LEMTRADA REMS education program for prescribers. https://www.lemtradarems.com/Docs/Pdf/​LEMTRADA_REMS_Education_Program_for_​Prescribers.pdf. Accessed June 3, 2016.
6. American Society of Hematology 2011. Clinical Practice Guideline on the Evaluation and Management of Immune Thrombocytopenia (ITP) Quick Reference. American Society of Hematology; 2011. Available at http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Reference.aspx. Accessed June 3, 2016.
7. Phelps RG, Turner AN. Antiglomerular basement membrane disease and Goodpasture’s disease. In: Phelps RG, Turner AN, eds. Comp Clin Nephrol. 4th ed. Elsevier Inc; 2010.
8. Kluth DC, Rees AJ. Anti-glomerular basement membrane disease. J Am Soc Nephrol. 1999;10:2446-2453.
9. Fervenza F, Sethi S, Specks U. Idiopathic membranous nephropathy: diagnosis and treatment. Clin J Am Soc Nephrol. 2008;3:905-919.
10. Brent G. Graves’ Disease. N Engl J Med. 2008;358:2594-2605.
11. LEMTRADA Medication Guide. Cambridge, MA: Genzyme Corporation; 2016.
12. General Information/press room. American Thyroid Association website. http://www.thyroid.org/media-main-about-hypothyroidism. Accessed February 16, 2015.
13. Garber JR, Cobin RH, Gharib H, et al. ATA/AACE Guidelines: clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocrin Pract. 2012;18:998-1028.