WARNING: ANAPHYLAXIS Antithymocyte globulins can cause anaphylaxis when injected intravenously. Although ATGAM is processed to reduce the level of antibodies that will react to non-T cells, physicians should be prepared for the potential risk of anaphylaxis and monitor patients for signs and symptoms during infusion. WARNING: ANAPHYLAXIS See full prescribing information for complete boxed warning . Antithymocyte globulins can cause anaphylaxis when injected intravenously. Although ATGAM is processed to reduce the level of antibodies that will react to non-T cells, physicians should be prepared for the potential risk of anaphylaxis and monitor patients for signs and symptoms during infusion.
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Discontinue ATGAM if anaphylaxis occurs. ( 5.1 ) Serious immune-mediated reactions, including anaphylaxis, have been reported. To identify those at greatest risk, skin testing before treatment is strongly recommended. ( 5.1 ) Monitor patients for concurrent infection, including cytomegalovirus. ( 5.2 ) Do not administer live vaccines to patients about to receive, receiving, or after treatment with ATGAM due to a potential of uncontrolled viral replication in the immunosuppressed patient. ( 5.3 ) 5.1 Hypersensitivity Serious immune-mediated reactions have been reported with the use of ATGAM. Clinical signs associated with anaphylaxis, other infusion associated reactions, and serum sickness have been reported. Discontinue ATGAM if anaphylaxis occurs. A systemic reaction such as a generalized rash, tachycardia, dyspnea, hypotension, or anaphylaxis precludes any additional administration of ATGAM. Skin Testing To identify those at greatest risk of systemic anaphylaxis, skin testing potential recipients is strongly recommended before commencing treatment. A conservative, conventional approach would first employ epicutaneous (prick) testing with undiluted ATGAM. If the subject does not show a wheal ten minutes after pricking, proceed to intradermal testing with 0.02 mL of a 1:1000 v/v (volume/volume) saline dilution of ATGAM with a separate saline control injection of similar volume. Read the result at 10 minutes: a wheal at the ATGAM site 3 or more mm larger in diameter than that at the saline control site (or a positive prick test) suggests clinical sensitivity and an increased possibility of a systemic allergic reaction should the drug be dosed intravenously. The predictive value of this test has not been proven clinically. Allergic reactions such as anaphylaxis have occurred in patients whose skin test is negative. Also, skin testing done as described above will not predict for later development of serum sickness. In the presence of a locally positive skin test to ATGAM, serious consideration to alternative forms of therapy should be given. The risk to benefit ratio must be weighed. If therapy with ATGAM is deemed appropriate following a locally positive skin test, treatment should be administered in a setting where intensive life support facilities are immediately available and a physician familiar with the treatment of potentially life threatening allergic reactions is in attendance. 5.2 Transmissible Infectious Agents Because ATGAM is made from equine and human blood components, it may carry a risk of transmitting infectious agents, e.g., viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have been associated with the use of ATGAM. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Pfizer, Inc. at 1-800-438-1985. Monitor patients for concurrent infection. Some studies have suggested an increase in the incidence of cytomegalovirus infection in patients receiving ATGAM. 5.3 Immunizations Do not administer live vaccines to patients about to receive, receiving, or after treatment with ATGAM. Concomitant administration of ATGAM with live virus vaccines carries a potential of uncontrolled viral replication in the immunosuppressed patient. There is insufficient information to fully define the extent of the risk, or the period of time during which the risk exists. If administered, live viruses may interfere with ATGAM treatment. 5.4 Hepatic and Renal Function Tests In patients with aplastic anemia and other hematologic abnormalities who have received ATGAM, abnormal tests of liver function (SGOT, SGPT, alkaline phosphatase) and renal function (serum creatinine) have been observed.
6 ADVERSE REACTIONS The most clinically significant adverse reactions are anaphylaxis, infection, thrombocytopenia, leukopenia, arthralgia, edema, bradycardia, and abnormal renal and liver function tests. The most common (>10%) adverse reactions are pyrexia, chills, rash, thrombocytopenia, leukopenia and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ATGAM has been evaluated in 367 patients with renal transplant and 109 patients with aplastic anemia. The renal transplantation and aplastic anemia patients received a similar dosing regimen, and these data were pooled to obtain the frequencies listed in Tables 1 and 2 below. The most commonly reported adverse reactions (occurring in greater than 10% of patients) are pyrexia, chills, rash, thrombocytopenia, leukopenia and arthralgia. Table 1. Adverse Reactions Occurring in ≥1% of Patients who Received ATGAM Adverse Reaction Percentages are treatment-emergent all-causality events , Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms ATGAM Frequency (%) (N = 476) Pyrexia 39.5 Chills 26.5 Rash 25.6 Thrombocytopenia 21.6 Leukopenia 17.9 Arthralgia 17.2 Urticaria 9.2 Headache 5.3 Pruritus 4.6 Nausea 4.2 Infection 3.4 Vomiting 3.4 Thrombophlebitis 3.2 Hypertension 2.9 Hypotension 2.9 Diarrhea 2.9 Abdominal pain upper 2.7 Chest pain 2.7 Infusion site pain 2.1 Edema 2.1 Bradycardia 1.5 Back pain 1.5 Lymphadenopathy 1.3 Arteriovenous fistula thrombosis 1.3 Dizziness 1.1 Dyspnea 1.1 Tachycardia 1.1 Liver function test abnormal 1.0 Table 2. Adverse Reactions Occurring in <1% of Patients who Received ATGAM Adverse Reaction Percentages are treatment-emergent all-causality events , Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms ATGAM Frequency (%) (N = 476) Convulsion 0.8 Pleural effusion 0.8 Night sweats 0.8 Serum sickness 0.6 Hyperglycemia 0.6 Stomatitis 0.6 Renal function test abnormal 0.6 Herpes simplex 0.4 Agitation 0.4 Hiccups 0.4 Proteinuria 0.4 Asthenia 0.4 Malaise 0.4 Wound dehiscence 0.4 Anaphylactic reaction 0.2 Encephalitis 0.2 Paresthesia 0.2 Renal artery thrombosis 0.2 Iliac vein occlusion 0.2 Laryngospasm 0.2 Pulmonary edema 0.2 Dermatitis allergic 0.2 Periorbital edema 0.2 Toxic epidermal necrolysis 0.2 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of ATGAM. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections and infestations : Hepatitis viral, Localized infection, Systemic infection Blood and lymphatic system disorders : Anemia, Eosinophilia, Granulocytopenia, Hemolysis, Hemolytic anemia, Neutropenia, Pancytopenia Psychiatric disorders : Confusional state, Disorientation Nervous system disorders : Dyskinesia, Syncope, Tremor Cardiac disorders : Cardiac failure congestive Vascular disorders : Deep vein thrombosis, Vasculitis Respiratory, thoracic and mediastinal disorders : Apnea, Cough, Epistaxis, Oropharyngeal pain Gastrointestinal disorders : Abdominal pain, Gastrointestinal hemorrhage, Gastrointestinal perforation, Oral pain Skin and subcutaneous tissue disorders : Hyperhidrosis Musculoskeletal and connective tissue disorders : Flank pain, Muscle rigidity, Myalgia, Pain in extremity Renal and urinary disorders : Kidney enlargement, Kidney rupture, Renal failure acute Congenital, familial and genetic disorders : Aplasia General disorders and administration site conditions : Infusion site erythema, Infusion site swelling, Pain