ATGAM Concentrate for solution for infusion Ref.[10752] Active ingredients: Antithymocyte immunoglobulin

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.

The most clinically significant adverse reactions are anaphylaxis, infection, thrombocytopenia, leukopenia, arthralgia, edema, bradycardia, and abnormal renal and liver function tests.

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:

^* Percentages are treatment-emergent all-causality events
^† Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms

Table 2. Adverse Reactions Occurring in <1% of Patients who Received ATGAM:

^* Percentages are treatment-emergent all-causality events
^† Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms

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

Previously masked reactions to ATGAM may appear when the dose of corticosteroids and other immunosuppressants is being reduced.

ATGAM was not teratogenic in rats or monkeys at a dose up to 20 mg/kg. However, 20 mg/kg/day ATGAM for 16 days during organogenesis in cynomolgus monkeys was fetotoxic. No fetal or maternal toxicity was seen with 10 mg/kg/day ATGAM administered for 16 days during organogenesis [see Nonclinical Toxicology (13.1)].

There are no adequate and well-controlled studies in pregnant women. It is also not known whether ATGAM can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

ATGAM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In animal studies, a single dose of ATGAM up to 40 mg/kg was not detected at the limit of quantification in the milk of lactating cynomolgus monkeys. It is not known whether ATGAM is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing neonates and infants from ATGAM, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.

Experience with children has been limited. ATGAM has been administered safely to a small number of pediatric renal allograft recipients and pediatric aplastic anemia patients at dosage levels comparable to those in adults.

Clinical experience in a limited number of elderly patients (≥65 years of age) has not identified differences in responses between the elderly and younger patients. The dose for an elderly patient should be selected with caution, starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this age group.