Atgam - instructions for use, doses, side effects, contraindications

Transparent or slightly opalescent liquid, colorless or with a pinkish or brownish tinge. During storage, a small granular or flocculent deposit may form, which does not affect the activity.

Pharmacotherapeutic group:Immunosuppressive agent - immunoglobulin

ATX: & nbsp

L.04.A.A.04 Immunoglobulin antitimotsitarny (rabbit)

Pharmacodynamics:

The preparation is a purified concentrated sterile solution of immunoglobulin (gamma globulin) antitimotsitarnogo, mainly monomeric IgG, obtained from hyperimmune serum of horses immunized with human T-lymphocytes.

Immunological properties

ATGAM® is a selective immunosuppressant that reduces the number of circulating thymus-dependent lymphocytes forming rosettes with erythrocytes of a ram. It is believed that this antilymphocytic action reflects a change in the function of T-lymphocytes responsible for cellular immunity and participating in the humoral immune response. In addition to anti-lymphocyte activity, ATGAM contains a small concentration of antibodies against other blood elements. In the monkeys rhesus and cynomolgus ATGAM® reduces the number of lymphocytes in the thymus-dependent zones of the spleen and lymph nodes. When the drug is used together with other immunosuppressive agents, such as antimetabolites and glucocorticosteroids, the formation of antibodies to the gamma globulin of the horse is insignificant.

Pharmacodynamics

The composition of the drug ATGAM® includes antibodies that bind to a wide range of proteins on the surface of lymphocytes. In addition, ATGAM® binds to granulocytes, platelets and bone marrow cells. The mechanism of drug-induced ATGAM® immunosuppression is not established. Published data show,that the mechanism of action of the drug is based on the elimination of circulating lymphocytes, with the greatest reduction in the number of T-lymphocytes. Elimination of lymphocytes may be due to complement-dependent lysis and / or induced apoptosis. In addition, immunosuppression may be mediated by binding of antibodies to lymphocytes, which leads to partial activation and induction of T-lymphocyte anergy. The mechanism of medicinal action of the drug ATGAM® in aplastic anemia is explained by its immunosuppressive action. In addition, antitimotsitarny horse globulin directly stimulates the growth of hematopoietic stem cells and the secretion of hematopoietic growth factors, such as interleukin-3 and granulocyte-monocyte colony-stimulating factor.

Pharmacokinetics:

Distribution

When infusion of the drug ATGAM ® at a dose of 10-15 mg / kg / day, it was found that the average maximum concentration of antitumocyte immunoglobulin in the blood plasma (n= 27 patients with a transplanted kidney) was 727 ± 310 μg / ml.

Metabolism and excretion

Half-life of horse IgG from the blood plasma is 5.7 ± 3 days.The parameters of the half-life of the drug are in the range of 1.5 to 13 days.

Indications:

Kidney transplantation: ATGAM® is shown to adults and children with kidney transplantation to prevent and treat a transplant rejection reaction.

Aplastic anemia: ATGAM® is shown to adults and children for the treatment of aplastic anemia, which does not show a bone marrow transplant. When used in addition to standard maintenance therapy, ATGAM® can cause complete or partial hematologic remission, as well as an improvement in survival in cases of proven or suspected immune etiology of the disease.

Contraindications:

Do not administer the drug ATGAM® patients who have had severe systemic reactions (eg, anaphylactic reactions) during the previous administration of antitumocyte immunoglobulin or any other preparations of horse serum in the anamnesis.

Pregnancy and lactation:

Pregnancy

The safety category of the drug during pregnancy is C.

Adequate and strictly controlled studies of the use of the drug in pregnant women have not been conducted. ATGAM® should be used during pregnancy only if the potential benefit of using it justifies the potential risk to the fetus.

Breastfeeding period

The ability of ATGAM® to penetrate into breast milk is not established. Because many drugs are excreted in human breast milk, and because of the potential risk of developing serious adverse reactions to ATGAM® in newborns and infants who are breastfeeding, a decision should be made either to stop breastfeeding or stop taking the drug, taking attention to the importance of this medication for the mother.

Dosing and Administration:

ATGAM® IS INTENDED FOR INTRAVENOUS INTRODUCTION

The drug is not suitable for use in ampoules with broken integrity, lack of marking, changing physical properties (discoloration, presence of foreign particles), expired shelf life, improper storage.

Breeding instructions

The parenteral form of the drug should be visually checked for suspended particles and the color change before administration, whenever the solution and vial permit.However, since ATGAM® is a gamma globulin preparation, it can be a clear or slightly opalescent liquid, colorless or with a pale pink or brownish tinge, and may form a slightly grainy or flocculent deposit during storage.

For intravenous infusion, the total daily dose of ATGAM® is added to the dilution solution in accordance with aseptic rules. The sterile solution of the ATGAM® preparation should be diluted for intravenous infusion in an inverted bottle with a sterile liquid such that the undiluted ATGAM® does not come into contact with the air inside. The concentration should not exceed 4 mg / ml. Stir the solution by gently rocking or rotating the bottle. The drug (diluted or undiluted) should not be shaken, as the foaming and / or denaturation of the protein may occur. The resulting solution retains its physical and chemical stability for up to 24 hours provided the following solvents are used: 0.9% sodium chloride solution for injection; injection for 5% dextrose and 0.225% sodium chloride; injection for 5% dextrose and 0.45% sodium chloride.Addition of ATGAM® to the solution of dextrose for injection is not recommended, since a low salt concentration may cause precipitation. Solutions for infusions with a pronounced acidic reaction of the environment can also lead after some time to physical instability. If the solution of ATGAM® can not be used immediately after dilution, it is recommended that it be stored in a refrigerator, The total storage time of the solution should not exceed 24 hours (including the infusion time). Before administration, dilute the drug should be heated to room temperature. Unused residues of the preparation or waste materials should be disposed of in accordance with local requirements.

Skin tests

To identify patients with the highest risk of developing an anaphylactic reaction before beginning therapy, skin tests are strongly recommended. In the framework of the conservative traditional approach, it is recommended first of all to carry out a skin test (a test with piercing): on the inner side of the forearm, a retraction to the skin at a depth of 1-1.5 mm through a drop of undiluted preparation is carried out at a distance of 5 cm from the wrist joint.To do this, use injection needles for IV infusions having a depth stop, or a lancet for obtaining capillary blood, as well as special prick-lancets.

If the papule or blister does not form after 20 minutes after puncture of the skin, the test should be continued by intradermal injection: the skin of the flexor surface of the forearm or on the back is treated with 70% alcohol, after which 0.02 ml of the preparation ATGAM® diluted in 0 with a tubulin or insulin syringe , 9% solution of sodium chloride for injection at a concentration of 1: 1000 (v / v) with a simultaneous control injection of 0.9% solution of sodium chloride for injection in the same volume at a distance of 5 cm. The results are evaluated after 20 minutes. Formation of the blister at the site of administration of the ATGAM® preparation, a diameter exceeding by 3 mm or more the diameter of the blister at the site of the control injection with 0.9% solution of sodium chloride, as well as a positive cutaneous test indicate an increased sensitivity to the drug and the likelihood of developing a systemic allergic reaction with intravenous administration of the drug.

The sensitivity and specificity of this test are not clinically proven.Allergic reactions, such as anaphylactic shock, also occurred in patients with negative skin tests. In case of a positive local reaction to ATGAM®, the possibility of alternative treatment should be seriously considered. The potential benefits of using the drug and the potential risks should be carefully weighed. If, in the presence of a positive skin test, a decision is made to perform therapy with ATGAM®, the treatment should be carried out under conditions that provide for the intensive treatment of allergic reactions of immediate type.

Systemic reactions, such as generalized rash, tachycardia, dyspnoea, hypotension or anaphylaxis, exclude further use of the drug ATGAM® (see sections "Special instructions", "Side effect").

Administration of the drug

ATTENTION! The preparation may contain granular or flaky inclusions.

To prevent them from entering the bloodstream, the introduction always (ie, regardless of their availability) should be carried out by the infusion system through a filter with a pore diameter of 0.2 to 1.0 microns. The most convenient place of administration is arterio-venous anastomosis or shunt, arteriovenous fistula or central vein with high blood flow velocity.The introduction of a vein with a high blood flow velocity minimizes the possibility of developing phlebitis and thrombosis. The duration of administration of the dose of ATGAM® should be at least 4 hours. During the infusion of the drug near the patient's bed, you should always have the necessary reanimation equipment. You should constantly monitor the patient for possible allergic reactions during the infusion (see section "Side effect").

Recipients of renal transplants

Preventing (preventing) graft rejection reaction: the recommended dose is 10 to 15 mg / kg per day daily for 14 days, then every other day for 14 days, just 21 doses for 28 days. The first dose is administered no earlier than 24 hours before or no later than 24 hours after transplantation.

Treatment of rejection: the introduction of the first dose with the appearance of signs of the first attack of rejection. The recommended dose is 10-15 mg / kg daily for 14 days. In the future, the drug can be administered every other day until the total number of doses is equal to 21.

Typically, ATGAM® is used in combination with azithioprine and glucocorticosteroids, which are most often used to suppress the immune response.When repeated use of the drug ATGAM ® should be particularly careful and carefully examine the patient in relation to the symptoms of allergic reactions.

In a few studies, a dose of 5 to 25 mg / kg per day was used in children.

Aplastic anemia

The recommended dose is 10-20 mg / kg per day daily for 8-14 days. In addition, the drug can be given every other day for 14 days until the total number of doses is reached. Since the administration of ATGAM® can lead to thrombocytopenia, patients receiving this drug for aplastic anemia may require platelet transfusion.

Elderly patients (aged 65 and over)

Select the dose of ATGAM® in elderly patients with caution, starting with the lowest recommended dose.

Side effects:

The most common side effects (recorded in more than 10% of patients) are thrombocytopenia, leukopenia, rash, arthralgia, fever and chills.

In the table below, the side effects are classified according to the "system-organ-class" categories and by categories of terms of the preferred use of the dictionary MedDRA. In each group of frequency of occurrence, side effects are presented in order of decreasing severity.

Frequency according to categories CIOMS III (Council of International Medical Scientific Organizations): very often (≥ 1/10), often (≥ 1/100 or <1/10), infrequently (≥ 1/1 000 or <1/100), rarely (≥ 1 / 10 000 or <1/1 000), very rarely (<1/10 000), it is not known - for terms denoting side effects found during the post-marketing use of the drug.

Table of adverse reactions

System-Organ-Class	Category frequencies	Undesirable effects
Infectious and parasitic diseases	Often	Infection
	Infrequently	Herpes simplex
	Unknown	Viral hepatitis, generalized infection, local infection
Violations of the blood and lymphatic system	Often	Thrombocytopenia, leukopenia
	Often	Lymphadenopathy
	Unknown	Anemia, aplasia, granulocytopenia, hemolysis, hemolytic anemia, neutropenia, pancytopenia, eosinophilia
Immune system disorders	Infrequently	Serum sickness, anaphylactic reaction
Immune system disorders	Unknown	Vasculitis
Metabolic and alimentary disorders	Infrequently	Hyperglycaemia
Mental disorders	Infrequently	Anxious excitement
Disturbances from the nervous system	Often	Headache, dizziness
	Infrequently	Convulsions, encephalitis, paresthesia
	Unknown	Confused consciousness, disorientation, dyskinesia, tremor, fainting *
Heart Disease	Often	Bradycardia, tachycardia
Heart Disease	Unknown	Congestive heart failure, angina pectoris
Vascular disorders	Often	Thrombophlebitis, arterial hypertension, arterial hypotension
	Infrequently	Thrombosis of the renal artery, occlusal iliac vein
	Unknown	Deep vein thrombosis, gastrointestinal hemorrhage
Disturbances from the respiratory, thoracic and mediastinal organs	Often	Dyspnea
	Infrequently	Pleural effusion, spasm of the larynx, pulmonary edema
	Unknown	Apnea, cough, nosebleeds, bilateral exudative pleurisy
Disturbances from the skin and subcutaneous tissues	Often	Rash
	Often	Hives^**, itchy skin
	Infrequently	Night sweats, allergic dermatitis, periorbital edema, toxic epidermal necrolysis
Disturbances from musculoskeletal system and connective tissue	Often	Arthralgia
	Often	Backache ^**
	Unknown	Pain in the side, muscle rigidity, myalgia, pain in the limbs
Disorders from the kidneys and urinary tract	Infrequently	Proteinuria
Disorders from the kidneys and urinary tract	Unknown	Renal hypertrophy, acute renal failure, renal rupture
General disorders and reactions at the site of administration	Often	Fever, chills
	Often	Chest pain^**, pain in place of infusion, swelling
	Infrequently	General weakness, discomfort
	Unknown	Erythema at the site of infusion, edema at the site of infusion, increased sweating, pain
Additional research methods	Infrequently	Deviation from the norm of biochemical parameters of kidney function, deviation from the norm of biochemical parameters of liver function
Trauma, intoxication and complications of manipulation	Often	Thrombosis of arteriovenous fistula
Trauma, intoxication and complications of manipulation	Infrequently	Divergence of the edges of the wound

* The frequency of occurrence was taken as unknown.

** For those side effects (**) that were considered as a separate reaction, the number of cases of each side effect was established on the basis that each phenomenon occurred at the same frequency, so the total number of events was divided by the number of reported side effects.

With the development of side effects, the following treatment is recommended:

1. Anaphylaxis (not a frequent but serious complication, may develop at any time during treatment with ATT AM®): Immediately stop the drug infusion; inject 0.3-1.0 ml of an adrenaline solution (1: 1,000) intramuscularly, apply steroids, assisted ventilation, and carry out other resuscitation measures; DO NOT RENEVE the treatment with ATGAM®.

2. Hemolysis (usually determined only laboratory, clinically pronounced manifestations of hemolysis are rare): it is recommended to transfuse the erythrocyte mass, if necessary, intravenously inject mannitol, furosemide, sodium bicarbonate and other infusion solutions; pronounced and uninterrupted hemolysis requires discontinuation of treatment with ATT AM®.

3. Thrombocytopenia: in patients with transplanted kidney transient, the number of platelets usually returns to the original without discontinuing treatment with ATGAM®; patients with aplastic anemia may need a transfusion of platelet mass.

4. Respiratory distress syndrome (may be a manifestation of anaphylactoid reaction): stop the infusion of ATGAM®; ifsymptoms persist, enter antihistamines, adrenaline, glucocorticosteroids or a combination of these drugs.

5. Pain in the chest, side, back (may be a manifestation of anaphylaxis or hemolysis): treatment is carried out as indicated above for hemolysis and anaphylaxis.

6. Hypotension (may indicate anaphylaxis): should stop the infusion of the drug ATGAM® and, if necessary, stabilize blood pressure with special medications.

7. Chills and fever (the most common phenomena): ATGAM ® can lead to the release of endogenous leukocyte pyrogens. It is recommended preventive and / or therapeutic use of antihistamines, antipyretics or glucocorticosteroids.

8. Phlebitis (may be caused by the infusion of ATGAM® into the peripheral veins): infusion solution should be injected into veins with a high blood flow velocity, for example arteriovenous anastomosis.

9. Itching and hyperemia of the skin (possibly due to the effect of ATGAM® on blood elements): antihistamines are used.

10. Symptoms similar to serum sickness: patients with aplastic anemia are given glucocorticosteroids orally or intravenously; usually these transient symptoms are resolved and long-term complications are not observed; preventive use of glucocorticosteroids can reduce the frequency of these reactions.

Overdose:

Expected maximum tolerated dose of the drug ATDAM® is individual in connection with the biological origin of the preparation. To date, the largest single daily dose administered to a patient with a transplanted kidney is 7000 mg, with a concentration of about 10 mg / ml in saline. The introduction of the drug ATGAM® to this patient was not accompanied by any signs of acute intoxication or the development of late complications. The greatest number of doses (from 10 to 20 mg / kg per day) that can be administered to a patient has not yet been determined. Some patients received up to 50 doses after a kidney transplant for 4 months, others received a 28-day course of 21 doses, and three or more treatment courses were required to treat an acute rejection reaction. The number of cases of toxic manifestations did not increase with any of the schemes used,However, it is recommended that patients be carefully monitored.

Interaction:

Not installed.

Since patients receiving ATGAM® are simultaneously assigned glucocorticosteroids or other immunosuppressants, a decrease in their dosage may reveal some previously hidden reactions to ATGAM®. In this case, patients need careful monitoring.

Special instructions:

Only for use in a hospital!

Treatment with ATGAM® should be performed by physicians with experience in conducting immunosuppressive therapy for kidney transplantation or in patients with aplastic anemia. Patients receiving ATGAM® should be treated in departments equipped with appropriate laboratory and medical equipment and staffed by qualified personnel.

Treatment with ATGAM® should be discontinued if one of the following symptoms develops:

1. Anaphylaxis (see the sections "Side effect" and "Method of administration and dose" subsection "Skin tests").

2. Strong and persistent thrombocytopenia (platelets - below 70 000 / mm).

3. Strong and persistent leukopenia (leukocytes - below 1,000 / mm).

Just as with the use of drugs obtained from human blood, there is the possibility of transmission of infectious agents.

Because the ATDAM®, as an immunosuppressive drug, usually used in combination with glucocorticosteroids and antimetabolites, patients should be carefully examined for leukopenia, thrombocytopenia or concomitant infection. In some studies, there was an increase in the incidence of cytomegalovirus infection in patients treated with ATGAM®. This risk can be reduced by lowering the doses of other immunosuppressive drugs prescribed with the drug ATDAM®.

In case of infection, the appropriate treatment is immediately given. Taking into account the clinical circumstances, the doctor must decide whether in this case it is worth continuing treatment with the drug ATDAM®.

Patients who received ATGAM® patients with aplastic anemia and other hematological pathologies showed deviations from the norm of biochemical parameters of liver and kidney function.

When a vaccine is administered after an immunoglobulin, insufficiently active viral replication of live viral vaccines and a weakening of the humoral immune response may be observed.Live viral vaccines should be administered six months after completion of therapy with intramuscular immunoglobulins and six months after completion of immunoglobulin therapy for intravenous administration.

Immuno-mediated reactions

In some cases, against the background of antitimotsitarnogo immunoglobulin reported on the development of serious immuno-mediated reactions. Clinical symptoms of anaphylaxis, other reactions associated with infusions, as well as symptoms of serum sickness were noted. Given the mechanism of action of antitimotsitarnogo immunoglobulin, there is a potential risk of the syndrome of cytokine release. With the development of systemic reactions, such as generalized rash, tachycardia, dyspnoea, arterial hypotension or anaphylactic reactions, subsequent administration of antitumocyte immunoglobulin is impossible.

Application in elderly patients

Limited clinical experience with ATGAM® does not give an idea of the possible differences in response in elderly patients (aged 65 years and older) and younger. In general, the dose of the drug should be selected with caution in elderly patients, starting with the lowest recommended,taking into account a higher incidence of liver, kidney or heart failure, as well as other concomitant diseases or other drugs at this age.

Use in Pediatrics

The experience of using ATGAM® in children is limited. There are data on the use of the drug in a small number of children with kidney transplantation and in patients with aplastic anemia in doses comparable to those for adults.

Effect on the ability to drive transp. cf. and fur:

Studies on the effect of the drug on the ability to drive vehicles or work with mechanisms have not been conducted. At the time of taking the drug ATDAM® care should be taken when managing vehicles and working with mechanisms in connection with the possibility of developing such adverse reactions as dizziness, convulsions, confusion, fainting, etc.

Form release / dosage:Concentrate for solution for infusion, 50 mg / ml.

Packaging:

To 5 ml in ampoules of colorless glass class I (Hebrew Pharm.), 1 or 5 ampoules together with instructions for use in a cardboard bundle.

Storage conditions:

Store at a temperature of 2 ° C to 8 ° C in a dark place. Do not freeze.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N013104 / 01

Date of registration:01.07.2008

Expiration Date:Unlimited

The owner of the registration certificate:Pharmacy and Upjohn CampaniPharmacy and Upjohn Campani USA

Manufacturer: & nbsp

PHARMACIA & UPJOHN COMPANY USA

Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation

Information update date: & nbsp28.09.2017

Illustrated instructions

Instructions

Atgam® (Atgam®)