LEMTRADA® (alemtuzumab) injection
Alemtuzumab is a recombinant humanized IgG1 kappa monoclonal antibody directed against the cell surface glycoprotein, CD52. Alemtuzumab has an approximate molecular weight of 150 kD. Alemtuzumab is produced in mammalian cell (Chinese hamster ovary) suspension culture in a nutrient medium containing neomycin. Neomycin is not detectable in the final product.
LEMTRADA (alemtuzumab) injection is a sterile, clear and colorless to slightly yellow, solution (pH 7.2 ± 0.2) for intravenous infusion.
Each 1 mL of solution contains 10 mg alemtuzumab, dibasic sodium phosphate (1.15 mg), disodium edetate dihydrate (0.0187 mg), polysorbate 80 (0.1 mg), potassium chloride (0.2 mg), potassium dihydrogen phosphate (0.2 mg), sodium chloride (8 mg), and Water for Injection, USP.
Indications and usage
LEMTRADA is a CD52-directed cytolytic monoclonal antibody indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, the use of LEMTRADA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.
Limitations of Use: LEMTRADA is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile.
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.
Absorption: 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.
Distribution: LEMTRADA is largely confined to the blood and interstitial space with a central volume of distribution of 14.1 L.
Elimination: 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.
Dosage and administration
- Baseline laboratory tests are required prior to treatment with LEMTRADA
- complete any necessary immunizations at least 6 weeks prior to treatment.
- determine whether patients have a history of varicella or have been vaccinated for varicella zoster virus (VZV). If not, test the patient for antibodies to VZV and consider vaccination for those who are antibody-negative. Postpone treatment with LEMTRADA until 6 weeks after VZV vaccination.
- perform tuberculosis screening according to local guidelines
- instruct patients to avoid potential sources of Listeria monocytogenes
Premedicate patients with high dose corticosteroids (1,000 mg methylprednisolone or equivalent) immediately prior to LEMTRADA infusion and for the first 3 days of each treatment course
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 the CD4+ lymphocyte count is at least 200 cells per microliter, whichever occurs later
- The recommended dosage of LEMTRADA is 12 mg/day administered by intravenous infusion for 2 treatment courses: First Treatment Course: 12 mg/day on 5 consecutive days (60 mg total dose).
- Second Treatment Course: 12 mg/day on 3 consecutive days (36 mg total dose) administered 12 months after the first treatment course.
Following the second treatment course, subsequent treatment courses of 12 mg per day on 3 consecutive days (36 mg total dose) may be administered, as needed, at least 12 months after the last dose of any prior treatment courses.
LEMTRADA is contraindicated in patients:
- with known hypersensitivity or anaphylactic reactions to alemtuzumab or any of the excipients in LEMTRADA
- who are infected with human immunodeficiency virus (HIV) because LEMTRADA causes prolonged reductions of CD4+ lymphocyte counts
- with active infection
Warnings and precautions
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 monthly until 48 months after the last dose.
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.
Serious and life-threatening stroke has been reported within 3 days of LEMTRADA administration. Instruct patients to seek immediate medical attention if symptoms of stroke occur.
LEMTRADA may cause an increased risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders. Perform baseline and yearly skin exams.
LEMTRADA is available only through a restricted distribution program.
Immune Thrombocytopenia: Obtain complete blood counts (CBCs) with differential prior to initiation of treatment and at monthly intervals thereafter until 48 months after the last infusion.
Glomerular Nephropathies: Obtain serum creatinine levels, urinalysis with cell counts and urine protein to creatinine ratio prior to initiation of treatment. Monitor serum creatinine levels and urinalysis with cell counts at monthly intervals thereafter until 48 months after the last infusion.
Thyroid Disorders: Obtain thyroid function tests prior to initiation of treatment and every 3 months until 48 months after the last infusion.
Other Autoimmune Cytopenias: Monitor CBCs monthly until 48 months after the last infusion.
Autoimmune Hepatitis: If signs of hepatic dysfunction occur, promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment.
Hemophagocytic Lymphohistiocytosis: Consider this diagnosis and evaluate patients immediately if they develop signs or symptoms of systemic inflammation. Discontinue LEMTRADA if an alternative etiology is not established.
Thrombotic Thrombocytopenic Purpura (TTP): Evaluate patients immediately if they develop clinical symptoms or laboratory findings consistent with TTP. Discontinue LEMTRADA if TTP is confirmed or if an alternative etiology is not established.
Acquired Hemophilia A: Obtain a coagulopathy panel including aPTT in patients who present with signs such as spontaneous subcutaneous hematomas, extensive bruising, hematuria, epistaxis, or gastrointestinal or other types of bleeding.
Infections: Administration is contraindicated in patients with active infection. Do not administer live viral vaccines following a course of LEMTRADA.
Progressive Multifocal Leukoencephalopathy (PML): Withhold LEMTRADA at the first sign or symptom suggestive of PML.
Most common adverse reactions (incidence ≥10% and > interferon beta-1a): 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.
Use in specific populations
Pregnancy: There are no adequate data on the developmental risk associated with the use of LEMTRADA in pregnant women. LEMTRADA was embryolethal in pregnant huCD52 transgenic mice when administered during organogenesis. Auto-antibodies may develop after administration of LEMTRADA. Placental transfer of anti-thyroid antibodies resulting in neonatal Graves’ disease has been reported
LEMTRADA 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
Lactation: There are no data on the presence of alemtuzumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Alemtuzumab was detected in the milk of lactating huCD52 transgenic mice administered LEMTRADA.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LEMTRADA and any potential adverse effects on the breastfed child from LEMTRADA or from the underlying maternal conditions.
Contraception: Before initiation of LEMTRADA treatment, women of childbearing potential should be counselled on the potential for a serious risk to the fetus. To avoid in utero exposure to LEMTRADA, women of childbearing potential should use effective contraceptive measures when receiving a course of treatment with LEMTRADA and for 4 months following that course of treatment.
Infertility: In huCD52 transgenic mice, administration of LEMTRADA prior to and during the mating period resulted in adverse effects on sperm parameters in males and reduced number of corpora lutea and implantations in females
Pediatric Use: 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, infusion reactions, and stroke, and because it may increase the risk of malignancies (thyroid, melanoma, lymphoproliferative disorders, and lymphoma)
Geriatric Use: Clinical studies of LEMTRADA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.
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.
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.