Alemtuzumab Injection for Intravenous Infusion

Dosage Forms And Strengths

Injection: 12 mg/1.2 mL (10 mg/mL) in a single-use vial. LEMTRADA is a clear and colorless to slightly yellow solution that requires dilution prior to intravenous infusion.

Each LEMTRADA carton (NDC: 58468-0200-1) contains 1 single-use vial that delivers 12 mg/1.2 mL (10 mg/mL). The vial stopper is not made with natural rubber latex.

LEMTRADA is a sterile, clear and colorless to slightly yellow solution for infusion, containing no antimicrobial preservatives.

Storage And Handling

Store LEMTRADA vials at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Store in original carton to protect from light.

Manufactured and distributed by: Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142. Issued: November 2014

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

• Autoimmunity [see BOXED WARNINGand WARNINGS AND PRECAUTIONS]
• Infusion reactions [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
• Malignancies [see WARNINGS AND PRECAUTIONS]
• Immune Thrombocytopenia [see WARNINGS AND PRECAUTIONS]
• Glomerular Nephropathies [see WARNINGS AND PRECAUTIONS]
• Thyroid Disorder [see WARNINGS AND PRECAUTIONS]
• Other Autoimmune Cytopenias [see WARNINGS AND PRECAUTIONS]
• Infections [see WARNINGS AND PRECAUTIONS]
• Pneumonitis [see WARNINGS AND PRECAUTIONS]

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. 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 1855 years of age, 65% were female, and 92% were Caucasian.

In 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 109L (range 0.02-2.30 x 109L) and 0.32 (0.02-1.81 x 109L) 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 [see CLINICAL PHARMACOLOGY].

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. Using an enzymelinked immunosorbent assay (ELISA) and a competitive binding assay, anti-alemtuzumab binding antibodies were detected in 62%, 67%, and 29% of LEMTRADA-treated patients, at months 1, 3, 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, 12 (Course 1) as well as 94%, 88%, and 42% of positive binding antibody patients at months 13, 15, and 24 (Course 2). Antialemtuzumab 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 LEMTRADA with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions, not described elsewhere, were identified during postapproval use of alemtuzumab (CAMPATH) for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), as well as for the treatment of other disorders, generally at higher and more frequent doses (e.g., 30 mg) than that recommended in the treatment of MS. 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.

Congestive heart failure, cardiomyopathy, and decreased ejection fraction in non-MS patients previously treated with potentially cardiotoxic agents.

Included as part of the PRECAUTIONS section.

Two MS patients experienced serious reactions (headache, rash, and either hypotension or sinus tachycardia) after a single accidental infusion up to 60 mg of LEMTRADA. Doses of LEMTRADA 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.

Mechanism Of Action

The precise mechanism by which alemtuzumab exerts its therapeutic effects in multiple sclerosis is unknown but is presumed to involve binding to CD52, a cell surface antigen present on T and B lymphocytes, and on natural killer cells, monocytes, and macrophages. Following cell surface binding to T and B lymphocytes, alemtuzumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.

Pharmacodynamics

LEMTRADA depletes circulating T and B lymphocytes after each treatment course. In clinical trials, the lowest cell counts occurred 1 month after a course of treatment at the time of the first post-treatment blood count. Lymphocyte counts then increased over time: B cell counts usually recovered within 6 months; T cell counts increased more slowly and usually remained below baseline 12 months after treatment. Approximately 60% of patients had total lymphocyte counts below the lower limit of normal 6 months after each treatment course and 20% had counts below the lower limit of normal after 12 months.

Reconstitution of the lymphocyte population varies for the different lymphocyte subtypes. At Month 1 in clinical trials, the mean CD4+ lymphocyte count was 40 cells per microliter, and, at Month 12, 270 cells per microliter. At 30 months, approximately half of patients had CD4+ lymphocyte counts that remained below the lower limit of normal.

In a study of 53 MS patients, alemtuzumab 12 mg per day for 5 days caused no changes in the QTc interval greater than 20ms. An average 22 to 26 beats-per-minute increase in heart rate was observed for at least 2 hours after the first but not subsequent infusions.

Pharmacokinetics

The pharmacokinetics of LEMTRADA were evaluated in a total of 148 patients with relapsing forms of MS who received 12 mg/day on 5 consecutive days, followed by 12 mg/day on 3 consecutive days 12 months following the first treatment course.

Serum concentrations increased with each consecutive dose within a treatment course, with the highest observed concentrations occurring following the last infusion of a treatment course. The mean maximum concentration was 3014 ng/mL on Day 5 of the first treatment course, and 2276 ng/mL on Day 3 of the second treatment course.

LEMTRADA is largely confined to the blood and interstitial space with a central volume of distribution of 14.1 L.

The elimination half-life was approximately 2 weeks and was comparable between courses. The serum concentrations were generally undetectable ( < 60 ng/mL) within approximately 30 days following each treatment course.

Specific Populations

Age, race, or gender had no effect on the pharmacokinetics of LEMTRADA.

Clinical Studies

The efficacy of LEMTRADA was demonstrated in two studies (Study 1 and 2) that evaluated LEMTRADA 12 mg in patients with relapsing-remitting multiple sclerosis (RRMS). LEMTRADA was administered by intravenous infusion once daily over a 5- day course, followed one year later by intravenous infusion once daily over a 3-day course. Both studies included patients who had experienced at least 2 relapses during the 2 years prior to trial entry and at least 1 relapse during the year prior to trial entry. Neurological examinations were performed every 12 weeks and at the time of suspected relapse. Magnetic resonance imaging (MRI) evaluations were performed annually.

Study 1 was a 2 year randomized, open-label, rater-blinded, active comparator (interferon beta-1a 44 micrograms administered subcutaneously three times a week) controlled study in patients with RRMS. Patients entering Study 1 had Expanded Disability Status Scale (EDSS) scores of 5 or less and had to have experienced at least one relapse while on interferon beta or glatiramer acetate therapy.

Patients were randomized to receive LEMTRADA (n=426) or interferon beta-1a (n=202).  At baseline, the mean age was 35 years, the mean disease duration was 4.5 years, and the mean EDSS score was 2.7.

The clinical outcome measures were the annualized relapse rate (ARR) over 2 years and the time to confirmed disability progression. Confirmed disability progression was defined as at least a 1 point increase above baseline EDSS (1.5 point increase for patients with baseline EDSS of 0) sustained for 6 months. The MRI outcome measure was the change in T2 lesion volume.

The annualized relapse rate was significantly lower in patients treated with LEMTRADA than in patients who received interferon beta-1a. Time to onset of 6-month confirmed disability progression was significantly delayed with LEMTRADA treatment compared to interferon beta-1a. There was no significant difference between the treatment groups for the change in T2 lesion volume. The results of Study 1 are shown in Table 2 and Figure 1.

Table 2: Clinical and MRI Results of Study 1

Figure 1: Time to 6-month Confirmed Disability Progression (Study 1)

Study 2 was a 2-year randomized, open-label, rater-blinded, active comparator (interferon beta-1a 44 micrograms administered subcutaneously three times a week) controlled study in patients with RRMS. Patients entering Study 2 had EDSS scores of 3 or less and no prior treatment for multiple sclerosis.

Patients were randomized to receive LEMTRADA (n=376) or interferon beta-1a (n=187). At baseline, the mean age was 33 years, the mean disease duration was 2 years, and the mean EDSS score was 2.

The clinical outcome measures were the annualized relapse rate (ARR) over 2 years and the time to confirmed disability progression, as defined in Study 1. The MRI outcome measure was the change in T2 lesion volume.

The annualized relapse rate was significantly lower in patients treated with LEMTRADA than in patients who received interferon beta-1a. There was no significant difference between the treatment groups for the time to confirmed disability progression and for the primary MRI endpoint (change in T2 lesion volume). The results for Study 2 are shown in Table 3.

Table 3: Clinical and MRI Results of Study 2