Зенапакс

General characteristics. Structure:

Active agent: даклизумаб - 25 mg

Fillers: polysorbate 80, sodium chloride, sodium phosphate monosubstituted (sodium hydrophosphate), sodium phosphate disubstituted (sodium dihydrophosphate), Acidum hydrochloricum, a sodium hydroxide, water for injections.

Pharmacological properties:

Daklizumab - recombinant humanized (90% of the amino-acid sequence in a molecule correspond to IgG of the person, 10% - IgG of a mouse) IgG antibodies 1 (Anti-Tas) operating as antagonists of receptors to interleykinu-2 (IL-2). Daklizumab with high specificity contacts alpha subunit (Tas) of the high-affine receptor SILT-2 complex (which expresses on the activated T-cells). Zenapaks's appointment oppresses the activation of lymphocytes mediated by SILT-2 - extremely important link of a pathogeny of the immune response which is the cornerstone of graft rejection.
In the recommended doses даклизумаб Tas for the term of about 90 days at most of patients sates receptor subunit. In clinical trials of an antibody to a daklizumab they appeared approximately at 9% of the patients receiving Zenapaks, however did not change efficiency, safety, serumal concentration of a daklizumab or any other clinically significant parameters.
The expressed changes of number of the circulating lymphocytes or phenotypes of cells, except for quite expected tranzitorny reduction of Tas-polozhitelnykh of cells, were not found. Зенапакс authentically reduces the frequency of the acute rejection of renal allotransplant confirmed histologically for 6 months after change. It also considerably extends time to the first episode of rejection. Increase in frequency of rejection after drug withdrawal ("rebaund-syndrome") was not noted.
Survival of the patients receiving Zenapaks in 6 and 12 months after transplantation is significantly higher in comparison with that in the group receiving placebo.
Need for anti-lymphocytic therapy concerning acute graft rejection at treatment by Zenapaks arose at smaller number of patients.

Pharmacokinetics. At the patients who transferred allogenic renal transplantation and receiving Zenapaks in a dose of 1 mg/kg every 14 days (only 5 infusions), at the last (fifth) administration of drug increase in average maximum concentration in serum (a standard deviation) (32 22 mkg/ml) in comparison with those after the first introduction (21 14 mkg/ml) was noted. The minimum concentration in serum (a devirage standard deviation) before the fifth administration of drug made 7.6 4.0 mkg/ml. For full saturation of receptors to SILT-2 serumal concentration of drug from 0.5 to 0.9 mkg/ml, and are necessary for suppression of the mediated SILT-2 of biological activity - from 5 to 10 mkg/ml. At most of patients the recommended mode of dosing of a daklizumab allows to maintain the serumal concentration sufficient for saturation of alpha receptors to SILT-2 within more than 90 days after transplantation, that is at a stage of the post-transplant period, important concerning acute rejection.
The elimination half-life of a daklizumab at patients with renal allotransplant fluctuates from 270 to 919 hours (average - 480 hours) that is equivalent to an elimination half-life of IgG of the person. It is caused by a protein humanization, i.e. a combination, the regions defining a complementarity mouse Anti-Tas of antibodies with frame and constant regions of IgG of 1 person.
The system clearance of a daklizumab is influenced by the body weight, age, sex, race and existence of a proteinuria. As, it is established that the system clearance of drug depends on body weight, its dosing should be carried out at the rate of "mg on body weight kg". The recommended mode of dosing provides exposure of drug within 30% of standard exposure in groups of patients with the most different demographic characteristics. At patients with a renal transplant it is not required to adjust Zenapaks's dose depending on other revealed factors (a floor, a proteinuria, race and age).

Pharmacokinetics in special groups. Children. Preliminary results of a pharmacokinetic research at 30 children indicate that concentration of a daklizumab in serum at children are comparable to those at the adult patients who transferred transplantation, and receiving drug in the same mode of dosing. Tas-subjedinitsy receptors to SILT-2 were sated at once after the first administration of drug in a dose of 1.0 mg/kg and there were in a condition of saturation not less three first months after transplantation. Saturation of Tas-subjedinits of a receptor to SILT-2 was same, as at adult patients at the same mode of dosing.

Indications to use:

Prevention of acute rejection of body at the patients who transferred transplantation of a kidney. Drug is used within immunosuppressive therapy together with cyclosporine and glucocorticosteroids.

Route of administration and doses:

The recommended Zenapaks's dose makes 1 mg/kg. Zenapaks's solution in the volume containing the necessary dose is carried to 50 ml of sterile 0.9% by solution of sodium of chloride and is entered intravenously in 15 minutes. The drug can be administered in a peripheral or central vein.
The first introduction of Zenapaks has to be carried out in 24 hours prior to transplantation. The second and everyone the subsequent doses of drug are entered bucketed 14 days, in total - 5 doses. Time of introduction of the subsequent doses should not deviate from planned more, than for one day in this or that party.

Special instructions on dosing
Dose adjustment with a heavy renal failure is not required from patients.
Patients with severe damage of a liver have no data on dosing.
Preliminary results of a research on safety and pharmacokinetics at children testify to efficiency and good tolerance of Zenapaks at children at his introduction in the set dosing mode.
Experience of use of Zenapaks for patients of advanced and senile age (65 years are more senior) is limited because of a small amount of the changes which are carried out to patients of this age group.

Instructions on the treatment of drug
Зенапакс it is not intended for introduction in not divorced look. Before intravenous administration it should be parted in 50 ml sterile 0.9% of solution of sodium of chloride. Mixing solutions, it is impossible to stir up a bottle in order to avoid foaming; for its dissolution it is necessary to overturn carefully. It is necessary to take measures for ensuring sterility of the prepared divorced solution as drug does not contain antimicrobic preservatives or bakteriostatik. Зенапакс, prepared for in/in introductions, represents colourless solution in a one-time bottle, the unused rest of drug needs to be poured out. Before introduction parenteral drugs need to be examined regarding presence of mechanical impurities and change of coloring.
After preparation of infusion solution it is necessary to enter it intravenously not later, than in 4 hours. If solution needs to be stored longer, it should be stored in the refrigerator at a temperature of 2-8 about With, but no more than 24 hours.
To add other drugs to the prepared Zenapaks's solution or to enter them at the same time through the same infusional system it is impossible.

Features of use:

Зенапакс as protein with immunodepressive properties, has to be entered only in the conditions of the qualified medical institution. Patients should be informed on potential advantages of therapy and a risk degree, connected with purpose of immunodepressants.
Heavy reactions of hypersensitivity after Zenapaks's appointment develop seldom, however, at administration of drug on call it is necessary to have all necessary for their stopping.
At the patients receiving immunodepressants after organ transplantation the risk of limfoproliferativny diseases and opportunistic infections is increased. Though Zenapaks is also an immunosuppressant, so far increase in frequency of limfoproliferativny diseases or opportunistic infections at its use was not noted.
It is necessary to be careful at purpose of immunosuppressive drugs the patient of senile age.
There is no experience of appointment repeated or the subsequent courses of therapy Zenapaksy post-transplant patients.

Pregnancy and lactation
Reproductibility researches on animals using Zenapaks were not conducted. Whether Zenapaks can have the damaging effect on a fruit at appointment to his pregnant woman or influence reproductive function, it is unknown. As IgG can pass through a placental barrier, it is necessary to compare the individual risk interfaced to Zenapaks's appointment to the woman of childbearing age with potential advantages of use of this drug. Women of childbearing age have to apply contraception measures at treatment by Zenapaks and for 4 months after his last introduction.
Whether Zenapaks gets to breast milk, it is unknown. As with breast milk many drugs are excreted, and also because of possible side reactions the decision on the feeding termination or the termination of treatment by Zenapaks has to be accepted by a breast taking into account importance of drug for mother.

Side effects:

Зенапакс has no explicit toxicity. A profile of toxicity of other immunodepressants (cyclosporine and corticosteroids, including, with connection of Azathioprinum or mofetil of a mikofenolat) at simultaneous use of Zenapaks same, as at placebo co-administration.
Data on Zenapaks's safety in comparison with placebo and against the background of reception of cyclosporine and corticosteroids are given below.
The undesirable phenomena were noted at 95% of patients from group of placebo and 96% of patients from the group receiving Zenapaks. The undesirable phenomena served as the elimination reason from researches at 8.5% of patients from groups of placebo and at 8.6% of patients from Zenapaks's groups.
The heavy undesirable phenomena were registered at 44% of patients in groups of placebo and at 40% of patients in Zenapaks's group.
Lethal outcomes in the first 6 months after transplantation took place at 3.41% of the patients receiving placebo and at 0.6% of the patients receiving Zenapaks. Mortality in 12 months made 4.4% in group of placebo and 1.5% in Zenapaks's group.
Disturbances from digestive tract which with an identical frequency were noted as in Zenapaks's group (67%), and in group of placebo (68%) were the most widespread undesirable phenomena.
Frequency and types of the undesirable phenomena in groups of placebo and Zenapaks were identical.
The phenomena noted at treatment by Zenapaks at ≥ 5% of patients are included below.
Digestive tract: a lock, nausea, diarrhea, vomiting, abdominal pains, dyspepsia, abdominal distention, pains in epigastriums.
Central and peripheral nervous system: tremor, headaches, dizziness, sleeplessness.
Urinary tract: oliguria, dysuria, necrosis of tubules of kidneys.
Organism in general: thorax pains, fever, weakness, hypostases.
Cardiovascular system: increase and decrease in the ABP, tachycardia, bleedings, thrombosis.
Respiratory organs: asthma, fluid lungs, cough.
Skin and its appendages: bad healing of wounds, acne.
Musculoskeletal system: ostealgia and muscles, back pain.
System of a hemopoiesis and lymphatic: to a limfotsela.
The undesirable phenomena which were noted at 2-5% of the patients receiving Zenapaks.
Digestive tract: meteorism, gastritis, hemorrhoids.
Disbolism and food: liquid delay, diabetes mellitus, dehydration.
Urinary tract: damage of kidneys, a hydronephrosis, bleedings from uric ways, a renal failure, an ischuria.
Organism in general: fever, general weakness, anaphylactoid reactions.
Central and peripheral nervous system: spasms in legs, feeling of a pricking, a depression, alarm.
Respiratory organs: an atelectasis, developments of stagnation in lungs, pharyngitis, rhinitis, a hypoxia, rattles, a pleural exudate.
Skin and its appendages: itch, hirsutism, rash, perspiration; reactions in the place of an injection.
Musculoskeletal system: joint pains.
Sense bodys: vision disorder.
Malignant new growths: in a year the frequency of malignant new growths in group of placebo made 2.7%, in Zenapaks's group - 1.5%. Zenapaks's inclusion in the scheme of therapy did not increase number of post-transplant lymphoma which frequency made less than 1% both in group of placebo, and in Zenapaks's group.
Hyperglycemia: deviations generally and biochemical analysis of blood when using placebo and Zenapaks met identical frequency, except for glycemia level on an empty stomach (it was measured at a small number of patients). Increase in concentration of glucose in blood was noted at 16% (10 of 64) patients on placebo and at 32% (28 of 88) on Zenapaksa. The majority of cases of a hyperglycemia arose or in the first day after transplantation when patients received high doses of glucocorticosteroids, or at patients with already available diabetes mellitus.
Infectious incidence: the general frequency of infections, including, virus, fungal, bacteremia and a septicaemia, and also pneumonia, when using Zenapaks's was no more, than on placebo. Types of infections in Zenapaks's groups and placebo were identical. The Cytomegaloviral infection developed at 16% of the patients receiving placebo and at 13% of the patients receiving Zenapaks. One exception was made by pyoinflammatory diseases of a hypodermic fatty tissue and wound fevers which were noted at 4.1% of patients in groups of placebo and at 8,4% of patients in Zenapaks's groups. In 1 year after change 7 patients receiving placebos and only 1 patient receiving Zenapaks died from infectious diseases.
Children. Arterial hypertension (53%), postoperative pains (45%), diarrhea (43%) and vomiting (32%) were the most frequent undesirable phenomena. Frequency of hypertensia and dehydration at children was higher, than at adult patients.

Interaction with other medicines:

In clinical trials along with Zenapaks appointed the following drugs: cyclosporine, mofetit микофенолат, ганцикловир, an acyclovir, такролимус, Azathioprinum, antithymocyte immunoglobulin, muromonab-CD3 (OKT3) and glucocorticosteroids. Any interactions at the same time were not noted.

Contraindications:

Hypersensitivity to a daklizumab or any of drug components.

Overdose:

The most tolerable dose at patients was not defined; at Zenapaks's appointment animals of such dose did not manage to reach. After bone marrow transplantation the drug was administered in a dose 1.5 mg/kg without any undesirable phenomena. In a toxicological research with one-time administration of drug to mice in a dose of 125 mg/kg no signs of toxicity were observed.
In a toxicological research with repeated intravenous administration of Zenapaks in a dose of 1.5, 5.0 and 15 mg/kg a day within 28 days to monkeys of Cynomolgus no phenomena of toxicity were observed.

Storage conditions:

In the place protected from light at a temperature of 2-8 °C. Not to freeze.
The prepared divorced solution is stable within 24 hours at 2-8 °C or within 4 hours at the room temperature. After preparation of infusion solution it needs to be entered intravenously no later than in 4 hours. If solution has to be stored longer, it should be placed in the refrigerator (at 2-8 °C), but no more than 24 hours.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 5 ml of drug in a bottle. 1 or 3 bottles together with an instuktion on use place in a cardboard pack.