Atgam^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Pfizer, Inc. (USA)

Manufactured By

Pharmacia & Upjohn Company, LLC (USA)

ATC Code

L04AA03 (Antilymphocyte immunoglobulin (equine))

Active Substance

Anti-T lymphocyte immunoglobulin for human use, animal (Ph.Eur. European Pharmacopoeia)

Dosage Form

Atgam®

Concentrate for solution for infusion 50 mg/1 ml: amp. 5 pcs.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion is a clear or slightly opalescent solution, colorless or with a pinkish or brownish tint; during storage, a small granular or flaky precipitate may form, which does not affect the activity.

Excipients: glycine – 22.5 mg, water for injections – q.s. to 1 ml.

5 ml – ampoules of colorless glass (5) – cardboard packs.

Clinical-Pharmacological Group

Antithymocyte immunoglobulin

Pharmacotherapeutic Group

Immunosuppressants, selective immunosuppressants

Pharmacological Action

Immunosuppressive drug. Atgam^® is a selective immunosuppressant that reduces the number of circulating thymus-dependent lymphocytes forming rosettes with sheep erythrocytes. It is believed that this antilymphocytic action reflects an alteration in the function of T-lymphocytes responsible for cellular immunity and involved in the humoral immune response. In addition to antilymphocytic activity, Atgam^® contains a low concentration of antibodies against other blood cells. In rhesus and cynomolgus monkeys, Atgam^® reduces the number of lymphocytes in the thymus-dependent areas of the spleen and lymph nodes. When the drug is administered together with other immunosuppressive agents, such as antimetabolites and corticosteroids, the formation of antibodies to equine gamma-globulin in the patient is not significant.

Pharmacokinetics

When Atgam^® is administered in combination with other immunosuppressive agents, the half-life of equine IgG in plasma is 5.7±3 days.

Indications

• For the prevention of transplant rejection in kidney transplantation (when administered simultaneously with conventional therapy, it increases the frequency of favorable outcomes during the rejection period);
• To delay the first episode of transplant rejection in kidney transplantation (as an addition to other methods of immunosuppressive therapy);
• Treatment of aplastic anemia in the absence of indications for bone marrow transplantation (when administered in addition to standard supportive therapy, Atgam^® may induce complete or partial hematological remission, improving survival in cases with proven or suspected immune etiology of the disease).

To date, the efficacy and safety of the drug in cases other than kidney transplantation and aplastic anemia have not been evaluated.

ICD codes

Dosage Regimen

Atgam^® is intended for intravenous administration only.

The drug in ampoules with damaged integrity, lack of labeling, changes in physical properties (color change, presence of foreign particles), expired shelf life, or improper storage is not suitable for use.

Dilution Instructions

For intravenous infusion, the daily dose of Atgam^® is added to the dilution solution under aseptic conditions. The concentration should not exceed 4 mg/ml. Mix the solution by gently tilting or rotating the vial. The drug (diluted or undiluted) should not be shaken, as this may cause foaming and/or protein denaturation.

The resulting solution remains physically and chemically stable for up to 24 hours when using the following solvents: sodium chloride injection solution; injection solution containing 5% dextrose and 0.225% sodium chloride; injection solution containing 5% dextrose and 0.45% sodium chloride.

Adding Atgam^® to a dextrose injection solution is not recommended, as the low salt concentration may cause precipitate formation. Infusion solutions with a pronounced acidic pH may also lead to physical instability over time. If the Atgam^® solution cannot be used immediately after dilution, it is recommended to store it in the refrigerator, with the total storage time of the solution not exceeding 24 hours (including infusion time). Before administration, the diluted drug should be warmed to room temperature.

Skin Tests

To identify patients at high risk of developing an anaphylactic reaction, skin tests must be performed before starting therapy. As part of a conservative traditional approach, a prick test is first recommended: on the inner side of the forearm, 5 cm from the wrist joint, a prick is made into the skin to a depth of 1-1.5 mm through a drop of undiluted drug. For this, injection needles for intradermal infusions with a depth limiter, or a lancet for obtaining capillary blood, or special prick lancets are used.

If no papule or wheal forms within 20 minutes after the skin prick, testing should be continued by intradermal injection: the skin of the flexor surface of the forearm or back is treated with 70% alcohol, after which 0.02 ml of Atgam^® diluted with 0.9% sodium chloride injection solution to a concentration of 1:1000 (by volume) is injected with a tuberculin or insulin syringe, with a simultaneous control injection of 0.9% sodium chloride injection solution in the same volume at a distance of 5 cm. Results are evaluated after 20 minutes.

The formation of a wheal at the Atgam^® injection site with a diameter exceeding the diameter of the wheal at the control injection site with 0.9% sodium chloride by 3 mm or more, as well as a positive prick test, indicate increased sensitivity to the drug and the likelihood of developing a systemic allergic reaction upon intravenous administration of the drug.

The sensitivity and specificity of this test have not been clinically proven. Allergic reactions, such as anaphylactic shock, have also occurred in patients with negative skin tests. In the case of a positive local reaction to Atgam^®, the possibility of alternative treatment should be considered.

The potential benefits of using the drug and the possible risk must be carefully weighed. If a decision is made to conduct therapy with Atgam^® in the presence of a positive skin test, treatment should be carried out in conditions that ensure intensive care for immediate-type allergic reactions. Systemic reactions such as generalized rash, tachycardia, dyspnea, arterial hypotension, or anaphylaxis preclude further use of Atgam^®.

Drug Administration

The drug may contain granular or flaky inclusions. To prevent their entry into the bloodstream, administration should always (regardless of their presence) be carried out through an infusion system with a filter having a pore size from 0.2 to 1.0 microns. The most convenient site for administration is an arteriovenous anastomosis or shunt, or a central vein with high blood flow velocity. Administration into a vein with high blood flow velocity minimizes the possibility of phlebitis and thrombosis. The duration of administration of a dose of Atgam^® should be at least 4 hours. During the infusion of the drug, the necessary resuscitation equipment should always be available near the patient’s bed. The patient should be constantly monitored for possible allergic reactions during the infusion.

Kidney Transplant Recipients

Delay of transplant rejection the recommended dose of the drug is from 10 to 15 mg/kg/day daily for 14 days, then every other day for 14 days. A total of 21 doses over 28 days. The first dose is administered no earlier than 24 hours before or no later than 24 hours after transplantation.

Treatment of transplant rejection: administration of the first dose upon appearance of signs of the first rejection episode. Subsequently, the drug may be administered every other day until a total number of doses equal to 21 is reached.

Atgam^® is usually used in combination with azathioprine and corticosteroids, which are most commonly used to suppress the immune response. When the drug Atgam^® is repeatedly prescribed, special attention should be paid and the patient should be thoroughly examined for symptoms of allergic reactions.

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

Aplastic Anemia

The recommended dose is 10-20 mg/kg/day daily for 8-14 days. Additionally, the drug may be administered every other day for 14 days until a total number of doses equal to 21 is reached. Since thrombocytopenia may develop during the administration of Atgam^®, patients receiving the drug for aplastic anemia may require platelet transfusion.

In controlled studies in patients with aplastic anemia receiving Atgam^®, a statistically significant higher frequency of improvement was recorded at 3 months compared to standard supportive treatment. Improvement was characterized by a stable increase in peripheral blood counts and a decrease in the need for hemotransfusions.

Adverse Reactions

The main experience with the use of Atgam^® has been accumulated in patients after kidney transplantation receiving standard immunosuppressive treatment (azathioprine, corticosteroids). Most frequently: fever, chills, leukopenia, thrombocytopenia, rash, urticaria, diffuse skin redness, itching.

The frequency of adverse reactions was higher in the treatment of aplastic anemia. Frequently: fever, chills, rash, arthralgia, thrombocytopenia. In patients with aplastic anemia and other hematological diseases receiving Atgam^®, a slight increase in liver function parameters (AST, ALT, ALP) and renal function (serum creatinine) was noted. In some studies, clinical and laboratory (including leukopenia with relative lymphocytosis, decreased ESR, albuminuria) signs of serum sickness were recorded.

The following adverse reactions have been reported in patients with a transplanted kidney or aplastic anemia receiving Atgam^®: headache, nausea, vomiting, diarrhea, dyspnea, hypotension, night sweats, stomatitis, chest pain, back pain, infusion site pain, arteriovenous shunt thrombosis, peripheral thrombophlebitis.

Rarely angioedema, agitation, dizziness, lethargy or weakness, malaise, epigastric pain or hiccups, laryngospasm, paresthesia, lymphadenopathy, infections, encephalitis, Herpes simplex reactivation, wound dehiscence, hyperglycemia, arterial hypertension, pulmonary edema, bilateral exudative pleurisy, tachycardia, seizures, anaphylactic reaction, iliac vein occlusion, renal artery thrombosis, proteinuria, toxic epidermal necrolysis.

Post-marketing studies

Within 5 years after the drug entered the market, the frequency of reported adverse reactions was: fever – 51%; chills -16%; thrombocytopenia – 30%; leukopenia -14%; rash – 27%; generalized infection -13%.

In 5-10% of cases, the following were noted: deviations in renal function parameters; symptoms similar to serum sickness; dyspnea/apnea; arthralgia; chest, flank, back pain; diarrhea; nausea and/or vomiting.

Adverse reactions noted with a frequency of < 5%

Cardiovascular system: arterial hypertension, arterial hypotension, tachycardia, pulmonary edema, decompensated heart failure, deep vein thrombosis, thrombophlebitis, vasculitis, renal artery thrombosis, epistaxis.

Central and peripheral nervous system: headache, weakness, seizures, paresthesia, confusion, disorientation, coordination disorders, tremor, dizziness, muscle rigidity, sweating.

Digestive system: gastrointestinal bleeding/perforation, epigastric pain, stomach and abdominal pain, deviations in liver function parameters.

Metabolism: hyperglycemia.

Urinary system: acute renal failure, kidney enlargement/rupture.

Respiratory system: cough, laryngospasm, laryngeal edema, sore throat, stomatitis.

Hematopoietic system: neutropenia, granulocytopenia, aplasia, pancytopenia, hemolysis/hemolytic anemia, anemia, eosinophilia, lymphadenopathy.

Other: anaphylaxis, swelling/redness at the infusion site, infection at the injection site, myalgia/leg pain, viral hepatitis, Herpes simplex reactivation.

Contraindications

• Hypersensitivity to the components of the drug;
• Hypersensitivity to other equine serum preparations.

Use in Pregnancy and Lactation

Atgam^® has not been used in pregnant or breastfeeding women. The effect of the drug on fetal development has not been established. It is not known whether Atgam^® is excreted in breast milk.

Use of the drug during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus. In nursing mothers, Atgam^® should be used with great caution.

Pediatric Use

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

Special Precautions

The drug is intended for use in a hospital setting only!

Atgam^® should be used by physicians experienced 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.
2. Severe and persistent thrombocytopenia (platelets – below 70,000/µl) in patients with a transplanted kidney.
3. Severe and persistent leukopenia (leukocytes – below 1000/µl) in patients with a transplanted kidney.

As with the use of drugs derived from human blood, there is a possibility of transmission of infectious agents.

Since Atgam^®, as an immunosuppressive drug, is usually used in combination with corticosteroids and antimetabolites, patients should be carefully examined for leukopenia, thrombocytopenia, or concomitant infection. In some studies, an increased incidence of cytomegalovirus infection was noted in patients receiving Atgam^®. This risk can be reduced by lowering the doses of other immunosuppressive drugs prescribed together with Atgam^®. In case of infection, appropriate treatment should be promptly prescribed. Taking into account the clinical circumstances, the physician should decide whether to continue treatment with Atgam^® in this case.

If adverse effects develop, the following treatment is recommended

1. Anaphylaxis (an infrequent but serious complication, can develop at any time during treatment with the drug) – immediately stop the infusion of the drug, administer 0.3 – 1.0 ml of epinephrine solution (adrenaline; 1:1000) intramuscularly, apply corticosteroids, assisted ventilation, and perform other resuscitation measures. Treatment with Atgam^® should not be resumed.
2. Hemolysis (usually determined only by laboratory tests, clinically pronounced manifestations of hemolysis are rare) – transfusion of red blood cells is recommended, if necessary, administer mannitol, furosemide, sodium bicarbonate and other infusion solutions intravenously. Severe and continuous hemolysis requires discontinuation of treatment with Atgam^®.
3. Thrombocytopenia – in patients with a transplanted kidney, it is transient, the platelet count usually returns to baseline without discontinuing treatment with Atgam^®. Patients with aplastic anemia may require platelet transfusion.
4. Respiratory distress syndrome (may be a manifestation of an anaphylactoid reaction) – stop the infusion of the drug. If distress continues, administer epinephrine (adrenaline), corticosteroids, or a combination of these drugs.
5. Chest, flank, back pain (may be a manifestation of anaphylaxis or hemolysis) – treat as indicated above for hemolysis and anaphylaxis.
6. Arterial hypotension/collapse (may indicate anaphylaxis) – stop the infusion of Atgam^® and, if necessary, stabilize blood pressure with hypertensive drugs.
7. Chills and fever (the most common occurrences) – prophylactic and/or therapeutic use of antihistamines, antipyretics, or corticosteroids is recommended.
8. Phlebitis (may be caused by infusion of Atgam^® into peripheral veins) – the infusion solution should be administered into veins with high blood flow velocity, for example, an arteriovenous anastomosis.
9. Skin itching and redness – antihistamines are prescribed.
10. Symptoms similar to serum sickness – patients with aplastic anemia are prescribed corticosteroids orally or intravenously. Usually, these transient symptoms resolve and no long-term complications are observed. Prophylactic administration of corticosteroids may reduce the frequency of these reactions.

Use in Pediatrics

Atgam^® has been safely used in pediatrics for kidney transplantation and in patients with aplastic anemia at doses comparable to those for adults.

Overdose

The expected maximum tolerated dose of the drug Atgam^® is individual. To date, the highest single daily dose used in a patient with a transplanted kidney was 7 g, administered at a concentration of 10 mg/ml in sodium chloride injection solution, with no symptoms of acute intoxication noted. The maximum number of doses (from 10 to 20 mg/kg/day) that can be administered to a patient has not yet been determined. Some patients after kidney transplantation received up to 50 doses over 4 months, others received a 28-day course of 21 doses, and three or more courses of treatment were required to treat an acute rejection reaction. The number of cases of toxic manifestations did not increase with any of the used regimens.

Drug Interactions

Since patients receiving Atgam^® are also administered corticosteroids or other immunosuppressants, a reduction in their dose may reveal some previously hidden reactions to Atgam^®.

In this case, patients receiving Atgam^® require careful monitoring.

Storage Conditions

The drug should be stored and transported at a temperature between 2°C (35.6°F) and 8°C (46.4°F) in a light-protected place, out of reach of children; do not freeze.

Shelf Life

Shelf life – 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.