Kempas

General characteristics. Structure:

Active ingredient: 30 mg of an alemtuzumab.

Excipients: dinatrium эдетат, the phosphatic salt buffer (potassium chloride, potassium dihydrophosphate, sodium chloride, sodium phosphate double-base, polysorbate 80, water for and).

Pharmacological properties:

Pharmacodynamics. Antineoplastic drug, the kappa - the monoclones which are specifically contacting a glycoprotein of CD52 which expresses on a surface normal and malignizirovanny In - and blood T lymphocytes represents the genetically engineered humanized IgG1. Alemtuzumab is received as a result of inclusion of 6 regions of a rat monoclone of IgG2a defining a complementarity in a molecule of human IgG1. Alemtuzumab causes a lysis of lymphocytes due to interaction with CD52 antigen which is not subject to modulation and expresses on a surface of all In - and T lymphocytes, and also monocytes, thymocytes and macrophages. The lysis of lymphocytes mediated by antibodies is caused by complement deflection and an antibody - dependent cellular cytotoxic effect. This antigen is found on a surface of an insignificant part (<5%) granulocytes and is absent on erythrocytes and thrombocytes. Alemtuzumab does not damage stem hemopoietic cells and progenitors.

Pharmacokinetics. The pharmacokinetics of various doses of an alemtuzumab was studied in a multicenter research which included the patients with nekhodzhkinsky lymphoma (NHL) and a chronic lymphoid leukosis (HLL) receiving Kempas 1 time/week no more than 12 weeks. At single in infusions in a dose of 7.5 mg, 24 mg and 75 mg of the drug Cmax and AUC in proportion depended on a dose. Average T1/2 values were in limits of 23-30 h.

The pharmacokinetic and pharmakodinamichesky profile of Kempas which 3 times a week entered in a dose 30 mg in a look into infusions was estimated in a multicenter research at the sick NHL and HLL receiving treatment no more than 12 weeks. At sick HLL peak and the subsequent levels of Kempas increased during the several first weeks of treatment, and then approximately by 6th week reached steady indicators. Increase in concentration of drug in serum corresponded to considerable reduction of expressiveness of the lymphocytosis caused by tumoral process. At patients with initial number of lymphocytes in blood ≥30 000/mkl maximum and the subsequent levels of Kempas during the first 4-5 weeks of treatment were significantly lower in comparison with patients with number of lymphocytes ≤ 30 000/mkl. The specified data demonstrate that the raised number of malignizirovanny lymphocytes, represents a pool of blood cells in which Kempas collects. At decrease in a lymphocytosis this pool eliminirutsya that leads to increase in the minimum and maximum concentration of drug in serum.

Individual variability of pharmacokinetic properties of Kempas is probably partly caused by distinction in tumoral weight.

Kempas's pharmacokinetics was described at the patients with the V-cellular chronic lymphoid leukosis (V-HLL) who were earlier not receiving therapy by this drug at whom treatment failure was noted by purine analogs. Kempas was entered in the form of 2-hour into infusions, according to the recommended dosing mode, in the form of an initial dose of 3 mg with further increase up to 30 mg 3 times a week lasting treatment up to 12 weeks. Kempas's pharmacokinetics is described by 2-phase model and characterized by nonlinear kinetics in an elimination phase. After introduction of the last dose equal of 30 mg, Vd median at Css made 0.15 l/kg (limits of fluctuations of 0.1-0.4 l/kg) that indicates preferential distribution of drug in extracellular liquid and in plasma. The system clearance at repeated introductions decreased owing to reduction a receptor - the mediated clearance (i.e. losses of receptors to CD52 on cells of peripheral blood). At repeated administration and the subsequent cumulation of drug in plasma, the speed of elimination approached kinetics of a zero order. Thus, after introduction of the first dose equal of 30 mg, T1/2 made 8 h (limits of fluctuations of 2-32 h), and after introduction of the last dose of 30 mg - 6 days (limits of fluctuations of 1-14 days). Concentration of a steady state were reached, approximately, in 6 weeks of treatment. Essential distinction in drug pharmacokinetics at men and women was not noted. Also explicit influence on pharmacokinetics of age of patients was not observed.

Indications to use:

— chronic lymphoid leukosis (HLL).

Route of administration and doses:

Kempas it is necessary to apply under control of the doctor having experience of performing antineoplastic therapy.

The drug in any recommended dose has to be administered in a look in/in infusion lasting not less than 2 h. Patients should carry out premedication by the corresponding antihistaminic drugs and analgetics before introduction of the first dose, at each increase in a dose and according to clinical indications at the subsequent infusions. It is necessary to appoint antibiotics and antiviral drugs in a planned order all patient in time and after the end of treatment.

Adults during the first week of treatment Kempas should appoint in the increasing doses: 3 mg in the 1st day, 10 mg - in the 2nd day and 30 mg - in the 3rd day on condition of good tolerance of each dose. Further the dose recommended for use makes 30 mg/days 3 times a week every other day (for example, Monday-Wednesday-Friday or Tuesday-Thursday-Saturday). The maximum duration of treatment makes 12 weeks. At most of patients increase in a dose of drug up to 30 mg can be carried out within 3-7 days. However at development of moderate or heavy acute side reactions as a result of release of cytokines (especially hypotensions, a fever, fever, an asthma, rash or a bronchospasm) as at a dose of 3 mg, and and at a dose of 10 mg, the following daily dose of drug has to be same and should not increase until portability of drug does not become satisfactory.

In most cases the maximum response to treatment is reached at Kempas's use within 4-12 weeks.

After achievement of all laboratory and clinical signs of full remission therapy by Kempas has to be stopped at the continuing observation of a condition of the patient.

At improvement of a condition of the patient (i.e. at achievement of partial remission or stabilization) and further achievement of the plateau without improvement signs within 4 weeks and more therapy by Kempas has to be stopped at the continuing observation of a condition of the patient. Treatment also has to be stopped in the presence of signs of progressing of a disease.

At development of a heavy infection or the expressed signs of hematologic toxicity treatment by Kempas has to be stopped before their disappearance. It is recommended to interrupt therapy by Kempas at patients with decrease in number of thrombocytes <25 000/mkl or with decrease in the absolute number of neutrophils (ANN) <250/mkl. Therapy by Kempas can be continued after elimination of an infection or the toxic phenomena. At development of the autoimmune anemia or autoimmune thrombocytopenia connected with treatment by Kempas, use of drug has to be completely stopped. In the table the recommended actions for change of a dose of drug at development in the course of therapy of hematologic toxicity are specified.

Hematologic toxicity, thrombocytes <25 000/mkl and/or AChN <250/mkl	Dose for therapy resuming
1 case of emergence	after disappearance to continue in a dose 30 mg *
2 case of emergence	after disappearance to continue in a dose 10 mg *
3 case of emergence	complete cessation

* at the therapy termination more than for 7 days resuming of introduction of Kempas has to be carried out in the mode of gradual increase in a dose.

Drug use studies at children and teenagers (17 years are younger) were not carried out.

Correction of the mode of dosing is not required from elderly people (65 years are more senior), but this category of patients has to be under careful observation.

Drug use studies Kempas at patients with diseases of kidneys and a liver were not carried out.

Rules of preparation of solution for in/in introductions. Before use contents of an ampoule should be checked regarding lack of visible particles, contents of an ampoule have to be transparent. The ampoule cannot be used during the coloring of a concentrate or existence in it of visible particles.

Drug does not contain preservatives in this connection preparation of solution should be carried out in aseptic conditions.

The prepared solution should be used directly or during 8 h after its preparation. The necessary quantity of contents of an ampoule should be added to 100 ml 0.9% of solution of sodium of chloride or 5% of solution of a dextrose via the sterile bezvolokonny filter which is not detaining squirrels with a size of time of 5 microns. For hashing of the prepared solution it is necessary to turn a bottle carefully. Other solutions, in addition to specified in the present section should not be applied to preparation of solution of this drug. Compatibility with other drugs is unknown. It is impossible to add other drugs to the prepared Kempas's solution and along with Kempas to enter them through one system for infusion.

The prepared solution can be stored at the room temperature (15-30 °C) or in the refrigerator. The specified characteristics of drug are valid only at preparation of solution in sterile conditions and its protection against light.

Features of use:

Use at pregnancy and feeding by a breast. Kempas's use is contraindicated at pregnancy. It is known that human IgG get through a placental barrier. Kempas can also get through a placental barrier in this connection can potentially reduce level B - and fruit T lymphocytes. The research of influence of drug on reproductive function at laboratory animals was not conducted. It is unknown whether drug makes harmful effects on a fruit at its use for pregnant women and whether its reception influences reproductive function.

In need of drug use Kempas in the period of a lactation breastfeeding has to be stopped during therapy and within 4 weeks after drug withdrawal. It is unknown whether it is allocated алемтузумаб with breast milk.

The pregnant women and women planning pregnancy in the nearest future are forbidden to work with Kempas.

Men and women of childbearing age need to use effective remedies of contraception during treatment and within 6 months after the end of therapy by Kempas.

Use at abnormal liver functions. Drug use studies Kempas at patients with diseases of a liver were not conducted.

Use at renal failures. Drug use studies Kempas at patients with diseases of kidneys were not conducted.

At use of drug it is necessary to consider that during initial increase in a dose sharply developing side reactions (arterial hypotension, a fever, fever, an asthma and rash) can result from release of cytokines. If they are expressed moderately or considerably, administration of drug should be continued in the dose preceding its increase, with carrying out necessary premedication to satisfactory portability of each entered dose. At the therapy termination more than for 7 days, resuming of introduction of Kempas has to be carried out in the mode of gradual increase in a dose.

At the patients receiving treatment by Kempas passing arterial hypotension was observed. At an ischemic heart disease and when performing the accompanying anti-hypertensive therapy it is necessary to be careful. At this category of patients at treatment by Kempas it was reported about a myocardial infarction and a cardiac standstill. At the patients who were earlier receiving treatment by potential cardiotoxic drugs assessment and control of function of heart is necessary (for example, an echocardiography, calculation of ChSS, measurement of body weight).

Premedication is recommended to be carried out by corticosteroid drugs for intake or for to introductions in 30-60 min. prior to each infusion of Kempas during increase in a dose, and also according to clinical indications. The recommended premedication - a hydrocortisone in a dose of 100-200 mg (or its equivalent). Its dose can be reduced at achievement of the recommended Kempas's dose. Besides, perhaps additional use of antihistaminic drugs for intake (for example, 50 mg of diphenhydramine) and not opioid analgetics (for example, 1 g of paracetamol). In case of the remaining acute reactions connected with infusion, duration of time of infusion can be increased to 8 h from the moment of preparation of solution of Kempas for infusion.

The expressed decrease in number of lymphocytes as the expected pharmacological effect of Kempas, can be long and is observed at all patients. The number of CD4+ and CD8 + lymphocytes begins to increase on 8-12 week of treatment and continues to be recovered within several months after the treatment termination. Time median before achievement of level of 200 cells / мкл makes 2 months after infusion of the last dose of Kempas, however the period of recovery of initial level can proceed 6 months and more. This effect can contribute to development of opportunistic infections. In this regard performing prevention of an infection, for example, by Trimethoprimum/sulfamethoxazole on 1 таб is strongly recommended. 2 times/days 3 times a week or other drugs for prevention of the pneumonia caused by Pneumocystis carinii and also effective peroral drugs for treatment of herpes, for example, famtsikloviry on 250 mg of 2 times/days which begins during therapy and proceeds not less than 4 months after the termination of treatment by Kempas or before achievement of the CD4+ level of lymphocytes of 200 cells / мкл and more. At development of the expressed and hard proceeding infection it is necessary to stop Kempas's use before disappearance of this complication. Continuation of therapy after elimination of this complication is possible.

As at patients with the expressed lymphopenia development of reaction of the transplant-against-owner is possible, blood components before their use should be subjected to radiation throughout the lymphopenia period, especially, so far the quantity of T lymphocytes will not be recovered to the level of 200 cells / мкл above.

The passing neutropenia 3 and 4 degrees (<1000/mkl) is observed very often on 5-8 week from an initiation of treatment. Passing thrombocytopenia 3 and 4 degrees (<50 000/mkl) is noted very often within the first 2 weeks of therapy, further at most of patients its weight decreases. At development of the expressed hematologic toxicity treatment by Kempas should be stopped until disappearance of this complication. Treatment by Kempas can be continued after disappearance of signs of hematologic toxicity. At development of the autoimmune anemia or an autoimmune trombotsitoneniya connected with treatment by Kempas, therapy by Kempas has to be completely stopped.

During therapy by Kempas it is regularly necessary to carry out full calculation of a blood count and number of thrombocytes, it is especially frequent - at patients with the developed cytopenia.

Treatment needs to be stopped in the presence of signs of progressing of a disease.

In daily clinical practice regular systematic control of an expression of CD52 is not provided. However at the solution of a question of performing repeated treatment it is reasonable to confirm existence of an expression of CD52.

Patients can have allergic reactions or reactions of hypersensitivity to Kempas, mouse or himerny monoclones.

Special researches of influence of age on efficiency and Kempas's toxicity were not conducted. Elderly people (65 years are more senior) transfer cytotoxic therapy worse in comparison with persons of young age. Because HLL meets preferential at advanced age, patients of this age group have to be under careful observation.

Researches of efficiency and safety of use of Kempas at diseases of kidneys and a liver were not conducted.

At preparation and use of solution of Kempas it is necessary to be careful. For prevention of risk of impact of drug on an organism in case of dissecting of a bottle or a spill of solution use of latex gloves and goggles is recommended.

It is necessary to follow necessary rules of use and destruction of drug. Unused drug can be utilized (is burned). Pregnant medical employees are forbidden to work with Kempas.

Use in pediatrics. Data on safety and efficiency of use of drug for children are absent.

Influence on ability to driving of motor transport and to control of mechanisms. Influence of therapy by Kempas on ability of patients to be engaged in potentially dangerous types of activity was not studied. However it is necessary to be careful in connection with the described cases of emergence of confusion of consciousness and drowsiness.

Side effects:

More than at 80% of patients side reactions can develop; the most frequent known side reactions are observed within the first week of therapy.

At the description of side effects the following criteria of frequency of occurrence are used: very often (≥1/10), it is frequent (≥ 1/100, but <1/10), infrequently (≥1/1000, but <1/100); are revealed in clinical trial of sick HLL (149 patients).

Infusional reactions: very often - fever, a fever, nausea, vomiting, arterial hypotension, increased fatigue, rash, a small tortoiseshell, диспноэ, a headache, an itch and diarrhea. The majority of the listed reactions is expressed poorly and moderately. Due to the syndrome of release of cytokines heavy reactions, such as a syncope, a bronchospasm, a hypoxia, pulmonary infiltrates, a respiratory distress syndrome at adults, an apnoea, a myocardial infarction, arrhythmias, an acute heart failure and a cardiac standstill were observed. In rare instances these reactions led to a lethal outcome. Sharply developing reactions connected with infusion usually arise within the first week of therapy and in the subsequent almost completely disappear. Heavy reactions to administration of drug (3 and 4 degrees on gradation of National Institute of cancer/NCI/) after the first week of therapy are observed infrequently. These symptoms can be prevented or their expressiveness can be reduced due to carrying out premedication and the ordered mode of increase in a dose of drug.

Infections: very often - heavy infections (3 and 4 degrees on gradation of NCI), including pneumonia with development of a sepis and a generalized herpes infection. Often opportunistic infections, including the pneumocystic and aspergillosis pneumonia and infections caused by a cytomegalovirus and the Varicella zoster virus develop. There are not numerous messages on development of a rinotserebralny mukormikoz. Also other heavy viral infections, sometimes from the deaths (an adenoviral infection, a parainfluenza, hepatitis B, the progressing multifocal leukoencephalopathy), bacterial infections (tuberculosis, atypical mikobakterialny infections, a nocardiosis), protozoan infections (for example, the caused Toxoplasma gondi) and fungal infections, including reactivation of their latent forms were observed. Preventive therapy, apparently, reduces risk of development of the infections caused by Pneumocystis carinii and Varicella zoster. Long decrease in number of T lymphocytes, as a result of treatment by Kempas, can increase risk of reactivation of the Epstein-Barre's virus (EBV). In rare instances at immunokomprometirovanny patients development of the WEB associated limfoproliferativny disease was observed.

Hematologic reactions: often - the expressed bleeding. The pancytopenia is observed often and can reach 3 and 4 degrees of manifestation (hemoglobin <80g/l, leukocytes <2000/mkl, thrombocytes <50 000/mkl). Autoimmune complications (autoimmune hemolitic anemia, autoimmune thrombocytopenia, aplastic anemia, a syndrome to Giyena-Barra, a chronic inflammatory demyelinating poliradikulonevropatiya) in time and after treatment by Kempas meet infrequently.

From a metabolism: seldom - a syndrome of a lysis of a tumor from the death.

From TsNS: seldom - intracraneal hemorrhages from the death (it is observed at patients with thrombocytopenia).

From cardiovascular system: infrequently - congestive heart failure, a cardiomyopathy and decrease in fraction of emission (at the patients who were earlier receiving therapy by potentially cardiotoxic drugs).

In the table given below by-effects from various systems of an organism as reduction of their expressiveness are specified.

Very often	Often	Infrequently
Local reactions
	reactions in an injection site	hemorrhages, dermatitis, pain in the place of an injection
From an organism in general
fever, fever, increased fatigue, anorexia	pain of various localization, pain behind a breast, the dorsodynia, oral cavity hypostasis, an adynamy, an indisposition, a grippopodobny symptom, change of body temperature, hypostases, mukozit	peripheral hypostases, periorbital hypostasis, allergic reactions, lower extremity pain
From cardiovascular system
hypotension	hypertensia, tachycardia, vasomotor spasm, hyperemia of the person, heartbeat	cardiac standstill, myocardial infarction, fibrillation of auricles, disturbances on an ECG, arrhythmia, bradycardia, peripheral ischemia, a syncope, supraventricular tachycardia
From TsNS and peripheral nervous system
headache	taste loss, tremor, hypesthesia, dizziness, hyperkinesia, conjunctivitis, paresthesias	gait disturbance, entophthalmia, dystonia, hyperesthesia, hyper tone, hearing loss, sonitus, food faddism, neuropathy
From the alimentary system
vomiting, nausea, diarrhea	anorexia, abdominal pains, bleedings in a GIT, stomatitis, abnormal liver functions, locks, dyspepsia, a stomacace, a meteorism	gastroenteritis, ulitis, eructation, hiccups, dryness in a mouth, a canker of a mucous membrane of an oral cavity, a language canker
From system of a hemopoiesis
granulocytopenia, thrombocytopenia, anemia,	pancytopenia, leukopenia, lymphopenia, purpura, neytropenichesky fever	marrow aplasia, IDCS, decrease in level of a gaptoglobin, hemolitic anemia, oppression of a marrowy hemopoiesis, nasal bleedings, bleeding of gums, deviations in the general blood test
From a metabolism
	hyponatremia, dehydration, decrease in body weight, hypocalcemia, thirst	aggravation of a current of a diabetes mellitus, hypopotassemia
From a musculoskeletal system
	ostealgias, arthralgias, mialgiya
Tumors, high-quality, malignant and nonspecific (including cysts and polyps)
		limfomopodobny state
From the mental sphere
	confusion of consciousness, uneasiness, drowsiness, depression, sleeplessness	nervousness, disturbance of thinking, depersonalization, impotence, frustration of the personality
Infections
sepsis, Herpes simplex	Cytomegaloviral infection, the infection caused by Pneumocystis carinii, Varicella zoster, a fungal infection, a candidiasis, abscess	viral infection, bacterial infection
From respiratory system
pneumonia, диспноэ	pneumonitis, bronchospasm, sinusitis, cough, hypoxia, infections of upper parts of respiratory tracts, bronchitis, pharyngitis, pneumorrhagia	stridor, breath disturbance, breath difficulty, infiltration of pulmonary fabric, respiratory diseases, weakening of breath, laryngitis, rhinitis, feeling of a prelum of a throat, exudate in a pleural cavity, a fluid lungs
Dermatological reactions
urticaria, rash, itch, the increased sweating	erythematic rash, violent rash	disturbances of integuments, makulo-papular rash, fungal dermatitis, onychomycosis
From an urinary system
	infections of urinary tract	renal failures, polyuria, hamaturia, urine incontience, decrease in a diuresis

Interaction with other medicines:

Researches of interaction of Kempas with medicines were not conducted. Clinically significant interactions of Kempas with other medicines are unknown. The recommended interval between Kempas's introduction and use of other chemotherapeutic drugs makes not less than 3 weeks.

Despite the lack of the corresponding researches use of live virus vaccines within, at least, 12 months after therapy by Kempas is not recommended to patients. The possibility of formation of primary or secondary humoral response after use of vaccines was not investigated.

Pharmaceutical interaction. Kempas's incompatibility and bottles from polyvinylchloride (PVC), systems for administration of drugs from PVC or polyethylene, and also filters, not detaining protein, is unknown.

Contraindications:

— acute or exacerbation of a chronic general infectious disease;

— HIV infection;

— the accompanying tumors demanding therapy;

— pregnancy;

— lactation (breastfeeding);

— hypersensitivity and anaphylactic reactions in the anamnesis on алемтузумаб, the mouse proteins or any substances which are a part of drug.

Overdose:

Patients received the repeating introductions of single doses of Kempas to a total dose of 240 mg; at the same time the frequency of hypotension, fever, anemia 3 and 4 degrees on gradation of NCI can be higher.

Treatment: the specific antidote is unknown; administration of drug has to be stopped, if necessary carry out a maintenance therapy.

Storage conditions:

Drug should be stored in protected from light, the place, unavailable to children, at a temperature from 2 °C to 8 °C; not to freeze. Period of validity 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 1 ml of solution in bottles, on 3 bottles in a cardboard pack.