LEMTRADA SIDE EFFECTS

SIDE EFFECTS

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

• Autoimmunity
• Infusion Reactions
• Stroke and Cervicocephalic Arterial Dissection
• Malignancies
• Immune Thrombocytopenia
• Glomerular Nephropathies Including Anti-glomerular Basement Membrane Disease
• Thyroid Disorders
• Other Autoimmune Cytopenias
• Autoimmune Hepatitis
• Hemophagocytic Lymphohistiocytosis
• Adult Onset Still’s Disease
• Thrombotic Thrombocytopenic Purpura (TTP)
• Autoimmune Encephalitis (AIE)
• Acquired Hemophilia A
• Infections
• Progressive Multifocal Leukoencephalopathy (PML)
• 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 LEMTRADA. The population was 18 to 55 years of age, 65% were female, and 92% were Caucasian. 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.

In MS clinical studies (controlled and open-label extension), overall, a total of 1217 patients received LEMTRADA. Approximately 60% of patients received a total of 2 treatment courses and approximately 24% of patients received a total of 3 treatment courses; others received a total of 4 or more treatment courses, although data beyond 3 treatment courses are limited. The overall follow-up was 6858 person-years. Patients had a median of 6 years of follow-up from the first LEMTRADA dose, with approximately 14% having at least 7 years of follow-up.

Most Common Adverse Reactions

In controlled clinical trials, the most common adverse reactions with LEMTRADA (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 LEMTRADA-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

Lymphopenia

Nearly all (99.9%) patients treated with LEMTRADA 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 LEMTRADA 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 LEMTRADA 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 LEMTRADA and interferon beta-1a groups had events of attempted suicide or suicidal ideation. There were no completed suicides in either clinical study treatment group. Suicidal behavior or ideation occurred in patients with or without a history of a psychiatric or thyroid disorder. Advise patients to report immediately any symptoms of depression or suicidal ideation to the prescribing physician.

Immunogenicity

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

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

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 LEMTRADA

Blood and Lymphatic System Disorders: Acquired hemophilia A neutropenia, thrombocytopenia.

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

Gastrointestinal System Disorders: Cholecystitis, including acalculous cholecystitis and acute acalculous cholecystitis.

Hepatobiliary Disorders: Autoimmune hepatitis, viral hepatitis.

Infections and Infestations: Opportunistic infections , Progressive multifocal leukoencephalopathy.

Immune System Disorders: Autoimmune hepatitis, vasculitis, Guillain-Barre syndrome, hemophagocytic lymphohistiocytosis, sarcoidosis

Musculoskeletal and Connective Tissue Disorders: Adult Onset Still’s Disease

Nervous System Disorders: Autoimmune encephalitisvmyasthenia gravis, Lambert-Eaton myasthenic syndrome

Pulmonary System Disorders: Pulmonary alveolar hemorrhage

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.

SRC: NLM .