Alemtuzumab (Alemtuzumabum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Antineoplastic agents - monoclonal antibodies

Included in the formulation
  • Lemtrada®
    concentrate d / infusion 
    Genzyme Europe BV     Netherlands
    • АТХ:

    L.01.X.C   Monoclonal antibodies

    L.04.A.A.34   Alemtuzumab

    Pharmacodynamics:

    Genetically engineered humanized κ-monoclonal antibodies (IgG1). Binding to the glycoprotein CD52, not susceptible to modulation and expressed on the surface of normal and malignant B and T lymphocytes, most monocytes, macrophages, NK cells, some subpopulations (less than 5%) of granulocytes and bone marrow cells (including some CD34+cells) that express CD52 in varying degrees. Antibody-mediated lymphocyte lysis, due to complement fixation and antibody-dependent cellular cytotoxic effect. Connection with cells of lymphoid tissue and the system of mononuclear phagocytes. Does not damage stem hematopoietic cells and progenitor cells.

    Pharmacokinetics:

    With a single intravenous administration of the drug at a dose of 7.5, 24 and 75 mg Cmax and AUC are proportional to the dose. The half-life is 23-30 hours. When intravenously administered at a dose of 30 mg 3 times a week, the peak and subsequent levels of the drug increase in the first weeks of treatment, and then, approximately to the 6th week, reach the equilibrium concentration. The increase in serum content corresponds to a significant decrease in lymphocytosis due to the tumor process. In patients with a baseline number of lymphocytes more than 30 × 109/ l peak and subsequent concentration of the drug in the first 4-5 weeks of treatment is significantly lower than in patients with a lymphocyte count of less than 30 × 109/ l, which indicates the accumulation of the drug in malignantized lymphocytes. With a decrease in the degree of lymphocytosis, this pool is eliminated, which leads to an increase in Cmin and Cmax drug in the plasma. Individual variability of pharmacokinetic properties is probably due to the difference in tumor mass.

    Indications:

    Chronic lymphoblastic leukemia (B-cell, resistant to alkylating agents and fludarabine, as third-line therapy).

    ICD-10

    II.C81-C96.C91.1   Chronic lymphocytic leukemia

    Contraindications:

    Acute systemic infections (before recovery, after which it is possible to resume alemtuzumab treatment).

    Immunodeficiency conditions (increased risk of opportunistic infections in patients with AIDS).

    Hypersensitivity (type I) or anaphylactic reactions to alemtuzumab, other monoclonal antibodies or any of its components in the anamnesis.

    Concomitant oncological diseases requiring treatment.

    Pregnancy, breast-feeding.

    Carefully:

    In autoimmune cytopenia or aplasia of bone marrow, myelosuppression, chickenpox or herpes zoster, ischemic heart disease, cytotoxic or radiation therapy in history, simultaneous administration of antihypertensive agents, renal and hepatic insufficiency.

    Pregnancy and lactation:

    Contraindicated during pregnancy and lactation. It is recommended to stop breastfeeding during treatment with alemtuzumab and within 3 months after its last administration. Pregnant is prohibited from working with the drug!

    Women and men of reproductive age are recommended to use contraceptives during treatment with the drug and within 6 months after stopping it.

    Dosing and Administration:

    Chronic lymphoblastic leukemia (B-cell, resistant to alkylating agents and fludarabine, as third-line therapy).

    Initial therapy: intravenously as a 2-hour infusion of 3 mg / day. With good tolerance (toxicity less than II degree), the daily dose can be increased to 10 mg. With a good dose tolerance of 10 mg / day, maintenance therapy can be started.

    Supportive therapy: intravenously at 30 mg / day every other day 3 times a week for 12 weeks (no more).

    In most patients, increasing the dose takes 3-7 days. It is necessary to increase the dose to the maintenance dose.

    If chronic lymphoblastic leukemia is used alemtuzumab (30 mg twice a week for 12 weeks) during consolidation of remission achieved by the use of fludarabine or its combination with cyclophosphamide, the probability of molecular remission in the peripheral blood increases compared with observation (p = 0.048) and the disease-free survival rate increases to 24 , 7 months (p = 0.036), with a significant increase in severe infections (life-threatening pulmonary aspergillosis - 9.1%, recurrence of CMV infection - 36.4%, pulmonary tuberculosis - 9.1% and herpes zoster - 9, 1%).

    Side effects:

    Occur in 80% of patients and more, most often - during the 1 st week of treatment; the development of severe toxicity requires the abolition of alemtuzumab.

    The blood system (severe haematological toxicity requires the abolition of alemtuzumab): anemia, neutropenia, thrombocytopenia, pancytopenia, granulocytopenia, leukopenia, lymphopenia, purpura, bone marrow aplasia, DIC syndrome, autoimmune anemia.

    There are reports of the development of idiopathic thrombocytopenic purpura with a fatal outcome in one patient.

    Transient neutropenia of III-IV degree (less than 1 × 109/ l) very often occurs at 5-8 weeks after the start of treatment.

    Transient thrombocytopenia of III-IV degree (less than 50 × 109/ l) very often occurs during the first 2 weeks of treatment, regressing later in the majority of patients.

    The likelihood of fatal myelosuppression is low when used at recommended doses and increases with increasing doses.

    The expressed decrease in the number of lymphocytes with the use of the drug can be prolonged and occurs in all patients. Number of CD4+- and CD8+lymphocytes begins to increase after discontinuation of treatment, but may not return to the baseline within a year or more.

    Cardiovascular system: hypertension, hypotension, tachycardia, angiospasm, face hyperemia, palpitations, peripheral vascular ischemia, bradycardia.

    Respiratory system: rhinitis, dyspnoea, cough, hypoxia, hemoptysis, pharyngeal irritation, pleural effusion, weakening of breathing, difficulty breathing.

    Digestive system: nausea, vomiting, abdominal pain, anorexia, stomatitis, ulcerative stomatitis, mucositis, pharyngitis, diarrhea, indigestion, constipation, gastrointestinal bleeding, impaired liver function, flatulence, gastroenteritis, dry mouth, ulcerative lesions of the mucous membranes of the gastrointestinal tract.

    Urinary system: impaired renal function.

    Nervous system: asthenia, dizziness, dysesthesia, insomnia, depression, drowsiness, changes in temperature sensitivity, tremor, hypoesthesia, hyperkinesia, anxiety, gait disturbance, dystonia, hyperesthesia, increased intracranial pressure, hearing loss, ringing in the ears, neuropathy, nervousness, violation thinking, depersonalization, personality disorders, impotence.

    Body of vision: conjunctivitis, enophthalmos.

    Skin: local reactions, erythematous, bullous rash, hemorrhage, dermatitis and pain at the injection site.

    Allergic reactions: anaphylaxis, the formation of antibodies to alemtuzumab with the development of an immune response to its administration.

    Infections (cases of fatal infections are described, severe infections require the elimination of alemtuzumab): bacterial, fungal, viral infections, herpes simplex, bronchitis, pneumonitis, pneumonia, sinusitis, upper respiratory and urinary tract infections, candidiasis, sepsis.

    There are a few reports on the development of rhinocerebral mucomycosis. Infections caused by Pneumocystis carinii and Herpes zoster, occurred only in patients who did not receive preventive antibiotic therapy.

    Reproductive system: animal and human studies were not conducted. Women and men of reproductive age during treatment and for at least 6 months after it should resort to reliable methods of contraception.

    Carcinogenicity (mutagenicity): long-term studies of the carcinogenicity of alemtuzumab have not been conducted.

    Other: infusion reactions, peripheral and periorbital edema, back pain, myalgia, ossalgia, increased sweating, epistaxis, flu-like syndrome, hyponatremia, hypocalcemia, hypokalemia, dehydration, thirst, exacerbated course of diabetes mellitus, lymphoma-like syndrome.

    Infusion reactions most often occur at the beginning of treatment, which requires a gradual increase in the dose. At the termination of treatment for 7 days and more, the therapy should be resumed from the starting dose. With the development of acute infusion reactions, the duration of the infusion can be increased to 8 hours after the preparation of the solution.

    Overdose:No data.
    Interaction:

    Antihypertensives - you need careful monitoring of blood pressure and signs of hypotension with simultaneous application.

    Incompatible with any other drugs when administered via a single intravenous access.

    Special instructions:

    Monitoring peripheral blood, platelet count (weekly during treatment often - the amplification of anemia, neutropenia or thrombocytopenia), number of CD4-cells (after cessation of treatment to restore the contents of more than 200 cells in 1 l), blood pressure (during treatment) , infusion reactions.

    Distinctive characteristics

    It is necessary to gradually increase the dose. Before the first administration, each dose escalation alemtuzumab and if clinically indicated that infusion reactions occurred less frequently required to hold premedication (paracetamol in a dose of 650 mg and diphenhydramine in a dose of 50 mg for 30 minutes before the infusion). To stop severe infusion reactions, you can assign hydrocortisone (in a dose of 200 mg).

    Prior to intravenous administration, the required dose of alemtuzumab is taken with a syringe, filtered through a sterile, fibrous membrane with a pore size of 5 μm and a low binding capacity of proteins, after which 100 ml of 0.9% sodium chloride solution or 5% dextrose solution are diluted, carefully turning the container.You can not shake! Unused residues are to be disposed of.

    Alemtuzumab is administered intravenously drip for 2 hours or more. You can not enter alemtuzumab intravenously.

    To reduce the risk of developing severe opportunistic infections, antibacterial therapy is needed in all cases during treatment and for 2 months after discontinuation (or until the number of CD4 cells exceeds 200 in 1 μl). In one study, a combination of trimethoprim and sulfamethoxazole (2 times a day, 3 times a week) and famciclovir (250 mg twice daily) or its equivalent was used for this purpose.

    Immediately, as soon as the amount of neutrophils becomes less than 0.25 × 109/ l and / or the number of platelets - less than 25 × 109/ l, temporarily canceled alemtuzumab, until the neutrophil count exceeds 0.5 × 109/ l, and the number of platelets - 50 × 109/ l, then continue treatment at the previous dose. At a break more than 7 days, the treatment is resumed with a dose of 3 mg, gradually increasing it to 10 and 30 mg (as tolerated).

    In the secondary case, the decrease in the number of neutrophils is less than 0.25 × 109/ l and / or platelets less than 25 × 109/ l - temporarily canceled alemtuzumab, until the neutrophil count exceeds 0.5 × 109/ l, and the number of platelets - 50 × 109/ l, then continue treatment at a dose of 10 mg. If the break lasts more than 7 days, resume treatment with a dose of 3 mg, gradually increasing it to no more than 10 mg.

    If the number of neutrophils and / or platelets decreases again to the same numbers, alemtuzumab treatment is discontinued.

    If the number of neutrophils and / or platelets decreases by less than 50% compared to the baseline, with neutrophil counts less than 0.5 × 109/ l and / or platelets less than 25 × 109/ l is temporarily canceled alemtuzumab, until the neutrophil count exceeds 0.5 × 109/ l, and the number of platelets does not return to the initial index, and then continue therapy. If the break lasts more than 7 days, the treatment is renewed with a dose of 3 mg, gradually increasing it to 10 and 30 mg (as tolerated).

    Maximum doses of alemtuzumab for adults: the initial dose is 3 mg, the single dose is 30 mg, the total weekly dose is 90 mg; their excess increases the likelihood of development of pancytopenia.

    The recommended interval between the administration of alemtuzumab and other chemotherapeutic agents is at least 3 weeks.

    Alemtuzumab causes pronounced lymphopenia,increasing the risk of "graft versus host" reactions; It is recommended to irradiate any blood components before administration to a patient who has undergone lymphopenia.

    In most cases, the maximum response to treatment is noted within 4-12 weeks. After all laboratory and clinical signs of complete remission have been reached, with the development of partial remission or stabilization of the process and further achievement of the plateau without signs of improvement for 4 weeks or more, treatment is discontinued if the patient's condition continues to be monitored and signs of disease progression.

    In routine clinical practice, there is no regular systematic control over the expression of CD52, but when deciding whether to repeat treatment it is advisable to confirm the presence of CD52 expression.

    Alemtuzumab causes myelosuppression, which contributes to the more frequent occurrence of bacterial infections, slows the healing of wounds and increases bleeding gums. It is necessary, if possible, to complete all dental procedures before the beginning of antitumor therapy and they can be renewed only after the resolution of myelosuppression.You should observe oral hygiene and caution when using toothbrushes, threads and toothpicks.

    Although studies that examined the tolerability of alemtuzumab in the elderly did not include a sufficient number of patients, the factors limiting its use in this category of patients have not been established.

    The drug can modify the results of tests based on the definition of antibodies.

    To prevent the risk of exposure to the body, if the vial is destroyed and / or the solution is spilled, it is recommended to use latex gloves and goggles.

    The rules for the use and destruction of the drug should be observed. The unused product can be disposed of by burning.

    How treatment affects the ability of patients to drive a car or work with complex mechanisms has not been studied. Care should be taken in connection with the occurrence of confusion and drowsiness.

    Attempts to use alemtuzumab as an immunosuppressant that prevents the rejection of a kidney transplant: a combination of alemtuzumab with cyclosporine, which is administered at low doses,compared to the standard combination of cyclosporine, azathioprine and glucocorticoids ensures the same probability of occurrence of morphologically confirmed acute graft rejection reaction, is 25% (versus 20% in the control group, p > 0.05) and the need to maintain remission via input glucocorticoids in 88% of patients (95% CI 53-97%) compared to 100% with standard therapy; and allotransplantation cadaveric liver, providing in combination with tacrolimus compared with the standard combination of tacrolimus and corticosteroids smaller transplant rejection frequency in the first 2 months (p = 0.002) equal to a period of 12 months (46-55%), increase the median time to transplant rejection (2.76 months vs. 0.34 months, p = 0.0007), reduced need for maintenance therapy with glucocorticoids during the first 3 months (p < 0.05) and nephrotoxicity (p = 0.004).

    Alemtuzumab diluted solution is stable for 8 hours at a temperature of 15-30 ° C and storage in the dark place, or frozen. Does not contain preservatives.

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