Lemtrada^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Genzyme Europe B.V. (Netherlands)

Manufactured By

Boehringer Ingelheim Pharma, GmbH & Co. KG (Germany)

Quality Control Release

GENZYME, Ltd. (United Kingdom)

Or

GENZYME IRELAND Limited (Ireland)

Or

SANOFI-AVENTIS EAST, CJSC (Russia)

ATC Code

L04AA34 (Alemtuzumab)

Active Substance

Alemtuzumab (Rec.INN registered by WHO)

Dosage Form

Lemtrada®

Concentrate for solution for infusion 10 mg/1 ml: fl. 1.2 ml

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion colorless or light yellow, clear or opalescent.

Excipients: disodium edetate dihydrate – 0.0187 mg, phosphate buffered saline pH 7.2 (potassium chloride – 0.2 mg, potassium dihydrogen phosphate – 0.2 mg, sodium chloride – 8 mg, anhydrous disodium hydrogen phosphate – 1.15 mg (equivalent to 1.44 mg disodium hydrogen phosphate dihydrate), polysorbate 80 – 0.1 mg, water for injections – up to 1 ml).

1.2 ml – colorless glass vials (type I) with a capacity of 2 ml (1) – plastic contour packs (1) – cardboard boxes.

Clinical-Pharmacological Group

Immunomodulator. A drug used for multiple sclerosis

Pharmacotherapeutic Group

Selective immunosuppressant

Pharmacological Action

It is a genetically engineered humanized IgG1 kappa monoclonal antibody that specifically binds to the CD52 glycoprotein, which is expressed on the surface of normal and malignant B- and T-lymphocytes in the blood.

Alemtuzumab is produced by incorporating 6 variable regions (determining complementarity-determining regions) of a rat monoclonal IgG2 antibody into a human IgG1 molecule. The antibodies are produced by a suspension cell culture of a mammalian cell line (Chinese hamster ovary cells) in a nutrient medium.

Alemtuzumab causes lymphocyte lysis through interaction with the CD52 antigen, which is not subject to modulation and is expressed on the surface of all B- and T-lymphocytes, as well as monocytes, thymocytes, and macrophages. Antibody-mediated lymphocyte lysis is due to complement fixation and antibody-dependent cellular cytotoxicity.

This antigen is found on the surface of a small proportion (less than 5%) of granulocytes and is absent on erythrocytes and platelets.

It does not damage hematopoietic stem cells and progenitor cells.

In multiple sclerosis, the mechanism of action may be associated with an immunomodulatory effect following lymphocyte depletion and their subsequent repopulation, including changes in the number, proportion, and properties of some lymphocyte subpopulations after treatment, an increase in the number of regulatory T-lymphocyte subpopulations, an increase in the number of memory T- and B-lymphocytes, and a transient effect on the innate immune system (e.g., on neutrophils, macrophages, and natural killer cells).

The reduction in the number of circulating B- and T-lymphocytes and their subsequent repopulation reduces the likelihood of multiple sclerosis relapses, which ultimately slows the progression of the disease.

Pharmacokinetics

In multiple sclerosis, administration of alemtuzumab at a dose of 12 mg/day achieved a C_max of 3014 ng/ml on day 5 of the initial treatment course and 2276 ng/ml on day 3 of the second treatment course. T_1/2 was approximately 2 days and its values did not differ significantly during the initial and subsequent treatment courses; serum concentrations for approximately 30 days after each treatment course were low or undetectable.

Indications

Active relapsing-remitting multiple sclerosis in adult patients who have experienced two or more relapses in the last two years.

ICD codes

Dosage Regimen

Administer by intravenous infusion only. The recommended dose is 12 mg per day.

Conduct the initial treatment course over five consecutive days.

Conduct the second treatment course over three consecutive days, administered 12 months after the initial course.

Administer subsequent treatment courses only if disease activity recurs. Each subsequent course consists of 12 mg per day for three consecutive days, separated by at least 12 months from the last dose of any prior course.

Premedicate with corticosteroids immediately before infusion during the first three days of any treatment course to reduce the incidence and severity of infusion reactions.

Administer prophylactic anti-herpes viral therapy starting on the first day of each treatment course and continue for a minimum of two months following treatment completion or until the CD4+ lymphocyte count is ≥200 cells/µL, whichever occurs later.

Dilute the concentrate in 100 mL of sterile 0.9% sodium chloride solution or 5% dextrose solution prior to administration.

Infuse the total daily dose over a period of four hours. Do not administer as an intravenous push or bolus.

Monitor patients during and for at least two hours after each infusion for signs and symptoms of infusion-associated reactions.

Discontinue treatment permanently in patients with autoimmune disorders, such as immune thrombocytopenia or anti-glomerular basement membrane disease.

Adverse Reactions

Infections and infestations very common – upper respiratory tract infections, urinary tract infections, infections caused by Herpes simplex viruses types 1 and 2; common – infections caused by Varicella zoster virus, lower respiratory tract infections, gastroenteritis, oral candidiasis, vulvovaginal candidiasis, influenza, ear infections, pneumonia, vaginal infections, dental infections; uncommon – onychomycosis, gingivitis, skin mycosis, tonsillitis, acute sinusitis, cellulitis, pneumonitis, tuberculosis, cytomegalovirus infection; frequency unknown – listeriosis/listeria meningitis.

Neoplasms benign, malignant and unspecified (including cysts and polyps) common – skin papilloma.

Blood and lymphatic system disorders very common – lymphopenia, leukopenia, including neutropenia; common – lymphadenopathy, immune thrombocytopenic purpura, thrombocytopenia, decreased hematocrit due to anemia, leukocytosis; uncommon – pancytopenia, hemolytic anemia; rare – hemophagocytic lymphohistiocytosis.

Immune system disorders common – cytokine release syndrome, hypersensitivity, including anaphylaxis.

Endocrine system disorders very common – diffuse toxic goiter (Graves’ disease), hyperthyroidism, hypothyroidism; common – autoimmune thyroiditis, including subacute thyroiditis, goiter, positive test for antithyroid antibodies.

Metabolism and nutrition disorders uncommon – decreased appetite.

Psychiatric disorders common – insomnia, anxiety, depression.

Nervous system disorders very common – headache; common – multiple sclerosis relapse, dizziness, hypoesthesia, paresthesia, tremor, dysgeusia, migraine; uncommon – sensory disturbance, hyperesthesia, tension headache; frequency unknown – stroke (ischemic and hemorrhagic), cervicocephalic artery dissection.

Eye disorders common – conjunctivitis, endocrine ophthalmopathy, blurred vision; uncommon – diplopia.

Ear and labyrinth disorders common – vertigo; uncommon – ear pain.

Cardiac disorders very common – tachycardia, flushing; common – bradycardia, palpitations; uncommon – atrial fibrillation; frequency unknown – myocardial infarction.

Respiratory, thoracic and mediastinal disorders common – dyspnea, cough, epistaxis, hiccups, oropharyngeal pain, bronchial asthma; uncommon – throat tightness, pharyngeal irritation; frequency unknown – pulmonary alveolar hemorrhage.

Gastrointestinal disorders very common – nausea; common – abdominal pain, vomiting, diarrhea, dyspepsia, stomatitis; uncommon – constipation, gastroesophageal reflux disease, gingival bleeding, dry mouth, dysphagia, gastrointestinal disorders, hematochezia (blood in stool).

Hepatobiliary disorders: common – increased AST, ALT; uncommon – cholecystitis, including acalculous cholecystitis and acute acalculous cholecystitis.

Skin and subcutaneous tissue disorders very common – urticaria, rash, pruritus, generalized rash; common – erythema, bruising, alopecia, hyperhidrosis, acne, skin lesion, dermatitis; uncommon – blisters, night sweats, facial swelling, eczema.

Musculoskeletal and connective tissue disorders: common – myalgia, muscle weakness, arthralgia, back pain, limb pain, muscle spasms, neck pain, musculoskeletal pain; uncommon – musculoskeletal stiffness, limb discomfort.

Renal and urinary disorders common – proteinuria, hematuria; uncommon – nephrolithiasis, ketonuria, nephropathies, including anti-GBM (glomerulonephritis due to antibodies to glomerular basement membrane) disease.

Reproductive system and breast disorders common – menorrhagia, irregular menstruation; uncommon – cervical dysplasia, amenorrhea.

General disorders and administration site conditions very common – pyrexia, fatigue, chills; common – chest discomfort, pain, peripheral edema, asthenia, influenza-like illness, general discomfort (malaise).

Investigations common – increased blood creatinine; uncommon – decreased weight, increased weight, decreased red blood cell count, positive bacterial test, increased blood glucose, increased cell volume.

Injury, poisoning and procedural complications common – contusion, infusion reactions.

Contraindications

Acute or exacerbation of a chronic systemic infectious process; HIV infection; pregnancy, lactation period; age under 18 years; hypersensitivity to alemtuzumab.

Use in Pregnancy and Lactation

Use during pregnancy and breastfeeding is contraindicated.

Breastfeeding should be discontinued during treatment and for 4 months after the last infusion in any treatment course.

Use in Hepatic Impairment

Use of alemtuzumab in patients with liver diseases is not recommended, except when the expected benefit of therapy outweighs the potential risk of adverse effects.

Use in Renal Impairment

Use of alemtuzumab in patients with kidney diseases is not recommended, except when the expected benefit of therapy outweighs the potential risk of adverse effects.

Pediatric Use

The safety and efficacy of alemtuzumab in children have not been studied.

Geriatric Use

The clinical condition of elderly patients should be carefully monitored during treatment.

Special Precautions

Use with caution in patients with coronary artery disease and those receiving antihypertensive drugs.

Premedication with antihistamines and non-opioid analgesics should be performed before the first administration of alemtuzumab, with each subsequent administration of an increased dose of the drug, and as clinically indicated.

During therapy and for at least 2 months after its completion, prophylaxis of infections should be carried out. In case of severe infectious complications, the use of alemtuzumab should be discontinued until they resolve.

During treatment, a complete blood count should be performed regularly. If severe hematotoxicity develops, the use of alemtuzumab should be discontinued until it completely resolves.

The clinical condition of elderly patients should be carefully monitored during treatment.

The safety and efficacy of alemtuzumab in children, patients with liver and kidney diseases have not been studied.

Use of alemtuzumab in patients with liver and kidney diseases is not recommended, except when the expected benefit of therapy outweighs the potential risk of adverse effects.

It is recommended to complete the immunization course in accordance with national vaccination requirements at least 6 weeks before starting alemtuzumab.

Effect on ability to drive vehicles and operate machinery

Dizziness may develop during or within 24 hours after alemtuzumab infusion, which may temporarily affect the ability to drive vehicles and engage in other potentially hazardous activities.

Drug Interactions

When alemtuzumab is used concomitantly or sequentially with immunosuppressants or anticancer drugs, the possibility of enhanced immunosuppression should be considered.

Discontinuation of interferon beta and glatiramer acetate preparations should be done 28 days before starting alemtuzumab.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.