Zenapax - instructions for use, dose, side effects, contraindications

Active substanceDaclizumabDaclizumab

Similar drugsTo uncover

solution d / infusion

Dosage form: & nbspconcentrate for solution for infusion

Composition:

One bottle with 5 ml of concentrate contains: daclizumab 25 mg

Fillers: polysorbate 80, sodium chloride, sodium phosphate monosodium (sodium hydrophosphate), sodium phosphate disubstituted (sodium dihydrogen phosphate), hydrochloric acid, sodium hydroxide, water for injection

Description:

Transparent or slightly opalescent colorless or slightly yellowish liquid.

Pharmacotherapeutic group:Immunosuppressive remedy

ATX: & nbsp

L.04.A.C.01 Daclizumab

Pharmacodynamics:

Daclizumab - recombinant humanized (90% of the amino acid sequence in the molecule corresponds to IgG human, 10% - IgG mouse) of antibody IgGi (anti-Tas), acting as interleukin-2 receptor antagonists (IL-2). Daclizumab with high specificity binds to the alpha-subunit (Tas) of the high-affinity IL-2 receptor complex (which is expressed on activated T-cells). Zenapax administration inhibits IL-2-mediated activation of lymphocytes - an extremely important link in the pathogenesis of the immune response underlying transplant rejection.

In recommended doses daclizumab saturates the Tas receptor subunit for a period of about 90 days in most patients. In clinical studies, antibodies to daclizumab appeared in about 9% of patients receiving Zenapax, but they did not change efficacy, safety, serum concentrations of daclizumab, or any other clinically relevant parameters.

Expressed changes in the number of circulating lymphocytes or cell phenotypes, with the exception of the quite expected transient decrease in Tas-positive cells, were not detected. Zenapax reliably reduces the frequency of confirmed histologically acute rejection of the renal allograft for 6 months after transplantation. He also significantly lengthens the time to the first episode of rejection. An increase in the incidence of rejection after withdrawal of the drug ("rebound syndrome") was not noted.

Survival of patients who received Zenapax at 6 and 12 months after transplantation was significantly higher than that in the placebo group.

The need for antilymphocyte therapy for acute graft rejection in the treatment of Zenapaks arose in fewer patients.

Pharmacokinetics:

In patients who underwent allogeneic kidney transplantation and received Zenapaks at a dose of 1 mg / kg every 14 days (total 5 infusions), the last (fifth) injection of the drug showed an increase in mean maximum concentrations in the serum (± standard deviation) (32 ± 22 μg / ml) compared with those after the first administration (21 + 14 μg / ml). The minimum serum concentrations (mean ± standard deviation) before the fifth injection of the drug were 7.6 ± 4.0 μg / ml. To completely saturate the receptors to IL-2, serum drug concentrations of 0.5 to 0.9 μg / ml are required, and 5 to 10 μg / ml for suppression of IL-2 mediated biological activity. In most patients, the recommended daclizumab dosing regimen allows maintaining serum concentrations sufficient to saturate alpha receptors for IL-2 for more than 90 days after transplantation, that is, in an important post-transplantation period for acute rejection.

The half-life period of daclizumab in patients with renal allograft varies from 270 to 919 hours (average - 480 hours), which is equivalent to the half-life IgG rights.This is due to the humanization of the protein, i.e. combination, determining the complementarity of regions of mouse anti-TAS antibodies with frame and constant regions IgGi rights.

The systemic clearance of daclizumab is affected by body weight, age, sex, race and the presence of proteinuria. Since the system clearance of the drug depends on the body weight, it should be dosed at the rate of "mg per kg of body weight." The recommended dosage regimen provides exposure to the drug within 30% of the standard exposure in groups of patients with very different demographic characteristics. patients with a renal transplant to adjust the dose of Zenapax according to other identified factors (sex, proteinuria, race and age) is not required.

Pharmacokinetics in special groups

Children. Preliminary results of a pharmacokinetic study in 30 children indicate that the concentrations of daclizumab in serum in children are comparable to those in adult patients who underwent transplantation and who receive the drug in the same dosing regimen. The Tas subunit of IL-2 receptors was saturated immediately after the first administration of the drug at a dose of 1.0 mg / kg and remained in saturation state for at least the first three months after transplantation.Saturation of the Tas subunits of the receptor to IL-2 was the same as in adult patients with the same dosing regimen.

Indications:

Prevention of acute organ rejection in patients after kidney transplantation. The drug is used as part of immunosuppressive therapy together with cyclosporine and glucocorticosteroids.

Contraindications:Hypersensitivity to daclizumab or any of the components of the drug.

Carefully:

Pregnancy and lactation:

Studies of reproductive performance in animals with the use of Zenapax were not carried out. Can Zenapax have a damaging effect on the fetus when given to a pregnant woman or affect reproductive function is unknown. Because the IgG can pass through the placental barrier, it is necessary to compare the individual risk associated with the appointment of Zenapax to a woman of childbearing age, with the potential benefits of using this drug. Women of childbearing age should apply contraceptive measures in the treatment of Zenapax and for 4 months after its last administration.

Whether Zenapax enters into breast milk is not known.Since many drugs are excreted in breast milk, and also because of possible side reactions, the decision to stop breastfeeding or stop treatment with Zenapax should be made taking into account the importance of the drug for the mother.

Dosing and Administration:

The recommended dose of Zenapax is 1 mg / kg. The Zenapax solution in a volume containing the desired dose is adjusted to 50 ml with a sterile 0.9% solution of sodium chloride and administered intravenously in 15 minutes. The drug can be injected into the peripheral or central vein.

The first administration of Zenapax should be performed 24 hours before transplantation. The second and each subsequent dose of the drug is administered at intervals of 14 days, a total of 5 doses. The time of administration of subsequent doses should not deviate from the planned one for more than one day in one direction or the other.

Special instructions for dosing

Dose adjustments in patients with severe renal insufficiency not required.

Data on dosing in patients with severe liver damage no.

Preliminary results of a study on the safety and pharmacokinetics in children testify to the efficacy and good tolerability of Zenapax in children when it is administered in the prescribed dosing regime.

The experience of using Zenapax in elderly and senile patients (over 65 years) is limited due to the small number of transplants performed by patients in this age group.

Instructions for handling the drug

Zenapax is not intended for administration in undiluted form. Before intravenous administration, it should be diluted in 50 ml of sterile 0.9% sodium chloride solution. When mixing solutions, do not shake the bottle to avoid foaming; To dissolve it, it is necessary to turn it gently. It is necessary to take measures to ensure the sterility of the prepared diluted solution, since the preparation does not contain antimicrobial preservatives or bacteriostats.

Zenapax, prepared for IV administration, is a colorless solution in a disposable vial, the unused remnant of the drug should be poured. Before administration, parenteral preparations should be examined for mechanical impurities and discoloration.

After preparation of the infusion solution, it must be administered intravenously no later than 4 hours later.If the solution needs to be stored longer, it should be stored in the refrigerator at a temperature of 2-8 ° C, but not more than 24 hours.

Add to the prepared Zenapax solution other drugs or enter them simultaneously through the same infusion system can not.

Side effects:

Zenapax does not show any obvious toxicity. The toxicity profile of other immunosuppressants (cyclosporine and corticosteroids, including the addition of azathioprine or mycophenolate mofetil) with simultaneous application of Zenapax is the same as with the simultaneous appointment of a placebo.

Data on the safety of Zenapax compared with placebo and against the administration of cyclosporine and corticosteroids are given below.

Adverse events occurred in 95% of patients in the placebo group and 96% in the Zenapax group. Undesirable effects caused drop-out from studies in 8.5% of patients in the placebo group and in 8.6% of patients in the Zenapax groups.

Severe adverse events were reported in 44% of patients in placebo groups and in 40% of patients in the Zenapax group.

Lethal outcomes in the first 6 months after transplantation occurred in 3.41% patients who received placebo, and 0.6% patients who received Zenapax. Mortality after 12 months was 4.4% in the placebo group and 1.5% in the Zenapax group.

The most common adverse events were disorders of the gastrointestinal tract, which were observed with equal frequency in the Zenapax group (67%) and in the placebo group (68%).

The frequency and types of adverse events in the placebo and Zenapax groups were the same.

The following are the phenomena noted in the treatment of Zenapax in> 5% of patients.

Gastrointestinal tract: constipation, nausea, diarrhea, vomiting, abdominal pain, indigestion, bloating, epigastric pain.

Central and peripheral nervous system: tremor, headaches, dizziness, insomnia.

Urinary tract: oliguria, dysuria, necrosis of renal tubules.

Organism as a whole: pain in the chest, fever, weakness, swelling.

The cardiovascular system: increase and decrease in blood pressure, tachycardia, bleeding, thrombosis.

Respiratory system: shortness of breath, pulmonary edema, cough.

Skin and its appendages: poor wound healing, acne.

Musculoskeletal system: pain in the bones and muscles, pain in the lower back.

The system of hematopoiesis and lymphatic: lymphocele.

Adverse events that occurred in 2-5% of patients who received Zenapax.

Gastrointestinal tract: flatulence, gastritis, hemorrhoids. Metabolic and nutritional disorders: fluid retention, diabetes, dehydration.

Urinary tract: kidney damage, hydronephrosis, bleeding from the urinary tract, renal failure, urinary retention.

Organism as a whole: chills, general weakness, anaphylactoid reactions.

Central and peripheral nervous system: cramps in the legs, tingling sensation, depression, anxiety.

Respiratory system: atelectasis, congestion in the lungs, pharyngitis, rhinitis, hypoxia, wheezing, pleural effusion.

Skin and its appendages: itching, hirsutism, rash, sweating; reactions at the injection site.

Musculoskeletal system: pain in the joints. Sense organs: impaired vision.

Malignant neoplasms: a year later, the incidence of malignant neoplasm in the placebo group was 2.7%, in the Zenapax group, 1.5%. Zenapax's inclusion in the therapy regimen did not increase the number of posttransplantation lymphomas, whose frequency was less than 1% in both the placebo group and the Zenapax group.

Hyperglycemia: abnormalities in the general and biochemical blood analysis with placebo and Zenapax were met with the same frequency, with the exception of fasting blood glucose (measured in a small number of patients). An increase in blood glucose was noted in 16% (10 of 64) of patients on placebo and 32% (28 of 88) in Zenapax. Most cases of hyperglycemia occurred either on the first day after transplantation, when patients received large doses of glucocorticosteroids, or in patients with existing diabetes mellitus.

Infectious morbidity: the total incidence of infections, including viral, fungal, bacteremia and septicemia, as well as pneumonia, with Zenapax was no more than on placebo. The types of infections in the Zenapax and placebo groups were the same. Cytomegalovirus infection developed in 16% of patients who received placebo and 13% of patients who received Zenapax. One exception was purulent-inflammatory diseases of subcutaneous fat and wound infections, which were noted in 4.1% of patients in placebo groups and in 8.4% of patients in Zenapax groups. In 1 year after transplantation from infectious diseases, 7 patients who received placebo died and only 1 patient who received Zenapax.

Children. The most frequent adverse events were arterial hypertension (53%), postoperative pain (45%), diarrhea (43%) and vomiting (32%). The frequency of hypertension and dehydration in children was higher than in adult patients.

Overdose:

The maximum tolerated dose in patients was not determined; When Zenapax was prescribed to animals, such a dose could not be achieved. After a bone marrow transplant, the drug was administered at a dose of 1.5 mg / kg without any undesirable effects. In a toxicological study with a single injection of the drug in mice at a dose of 125 mg / kg, no signs of toxicity were observed.

In a toxicological study with multiple intravenous administration of Zenapax at a dose of 1.5, 5.0 and 15 mg / kg per day for 28 days to monkeys Cynomolgus no toxicity was observed.

Interaction:In clinical trials, the following drugs were prescribed simultaneously with Zenapax: ciclosporin, mycophenolate mofetil, ganciclovir, acyclovir, tacrolimus, azathioprine, antitimocyte immunoglobulin, muromonab-CD3 (OKT3) and glucocorticosteroids. There were no interactions at all.

Special instructions:

Zenapax, as a protein with immunosuppressive properties, should be administered only in conditions of a qualified medical institution. Patients should be informed about the potential benefits of therapy and the degree of risk associated with the appointment of immunosuppressants.

Severe hypersensitivity reactions after Zenapax appointment are rare, however, when the drug is ready, you need to have everything you need to stop them.

In patients receiving immunosuppressants after organ transplantation, the risk of lymphoproliferative diseases and opportunistic infections is increased. Although Zenapax is an immunosuppressant, no increase in the incidence of lymphoproliferative diseases or opportunistic infections has been reported to date.

Care must be taken when prescribing immunosuppressive medications for elderly patients.

Experience in the appointment of repeated or subsequent courses of Zenapax therapy for post-transplant patients does not.

Form release / dosage:

Concentrate for the preparation of solution for infusion.

Packaging:5 ml of the drug per bottle. 1 or 3 bottles together with the instructions for use are placed in a cardboard box.

Storage conditions:

In the dark place at a temperature of 2-8 ° C. Do not freeze.

The prepared diluted solution is stable for 24 hours at 2-8 ° C or for 4 hours at room temperature. After the preparation of the infusion solution, it must be administered intravenously no later than 4 hours later. If the solution has to be stored longer, it should be placed in the refrigerator (at 2-8 ° C), but not more than 24 hours.

Keep out of the reach of children.

Shelf life:3 years. Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N013169 / 01

Date of registration:10.10.2003

Expiration Date:10.10.2009

Date of cancellation:2009-11-01

The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland

Manufacturer: & nbsp

F.Hoffmann-La Roche, Ltd. Switzerland

Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland

Information update date: & nbsp11.10.2017

Illustrated instructions

Instructions

Zenapax (Zenapax)