1.1 Renal Allograft Rejection

1.2 Aplastic Anemia

ATGAM is indicated for the treatment of moderate to severe aplastic anemia in patients unsuitable for bone marrow transplantation [see Clinical Studies (14.2)].

The usefulness of ATGAM has not been demonstrated in patients with aplastic anemia who are suitable candidates for bone marrow transplantation or in patients with aplastic anemia secondary to neoplastic disease, storage disease, myelofibrosis, Fanconi's syndrome, or in patients known to have been exposed to myelotoxic agents or radiation.

2.1 Dosing Information

2.2 Preparation and Administration Instructions

5.1 Anaphylaxis

Anaphylaxis has been reported with the use of ATGAM. Anaphylaxis is potentially life-threatening. Discontinue ATGAM if anaphylaxis occurs. Generalized rash, tachycardia, dyspnea, and hypotension can be signs of an anaphylactic reaction.

Skin Testing

To identify those at greatest risk of systemic anaphylaxis, skin testing potential recipients is strongly recommended before commencing treatment. Consult an allergist for epicutaneous (prick) and intradermal testing and interpretation. Positive skin testing to ATGAM suggests clinical hypersensitivity and increased risk of a systemic allergic reaction (including anaphylaxis) should the drug be dosed intravenously. In the event of a positive skin test, seriously consider alternative forms of therapy. The predictive value of this test has not been proven clinically, and allergic reactions such as anaphylaxis have occurred in patients whose skin tests were negative. It is important to note that skin testing does not inform risk of delayed hypersensitivity reactions such as serum sickness.

Monitoring and Management of Anaphylaxis

Administer ATGAM in a healthcare facility where a physician familiar with the treatment of potentially life-threatening allergic reactions is in attendance. Monitor patients for signs and symptoms of anaphylaxis during infusion and for at least 24 hours after infusion of ATGAM. Have epinephrine and emergency equipment available for treatment of acute allergic symptoms, should they occur.

5.2 Cytokine Release Syndrome

Cytokine release syndrome has been reported with the use of ATGAM. Cytokine release syndrome can be fatal. Clinical signs may include fever, chills, headache, chest pain, hypotension, dyspnea, tachypnea, and edema. Monitor patients for signs and symptoms of cytokine release syndrome and manage according to relevant clinical guidelines.

5.3 Infusion-Associated Reactions

Serious infusion-associated reactions have been reported with the use of ATGAM. Clinical signs associated with infusion-associated reactions include generalized rash, tachycardia, dyspnea, and hypotension. Monitor patients for signs and symptoms of infusion-associated reactions and manage according to relevant clinical guidelines.

5.4 Serum Sickness

Serum sickness is a delayed hypersensitivity/immune reaction. Symptoms of serum sickness including rash, arthralgia, pyrexia, chills, and pain have been reported. Monitor patients for signs and symptoms of serum sickness and manage according to relevant clinical guidelines.

5.5 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 the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens.

Report any infection suspected to have been transmitted by this product to Pfizer Inc. at 1-800-438-1985.

5.6 Infections

Due to the immunosuppressive effects of ATGAM, opportunistic infections (viral, bacterial and fungal) have been reported. Sepsis has also been reported. There is an increased risk of viral reactivation (e.g., cytomegalovirus [CMV], Epstein–Barr virus [EBV] infection, herpes simplex virus [HSV]). Monitor patients carefully for concurrent infection.

5.7 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.

5.8 Thrombocytopenia and Neutropenia

Thrombocytopenia and neutropenia have been reported with the use of ATGAM. If thrombocytopenia occurs, consider platelet transfusions to maintain platelets at clinically acceptable levels. Consider discontinuing ATGAM if severe and unremitting thrombocytopenia or neutropenia occurs.

5.9 Hepatic and Renal Function Tests

In patients with aplastic anemia and other hematologic abnormalities who have received ATGAM, abnormal test results of liver function (SGOT, SGPT, alkaline phosphatase) and renal function (serum creatinine) have been observed. Monitor liver and renal functions as clinically indicated and manage according to relevant clinical guidelines.

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 allograft rejection and 109 patients with aplastic anemia.

The renal allograft rejection 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ATGAM. Because these 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: Sepsis, Hepatitis viral, Localized infection, Systemic infection (bacterial, viral, fungal).

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

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies in pregnant women. There is a limited amount of data from the use of ATGAM 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. The outcome of pregnancies cannot be determined. Use ATGAM during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcome. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

In embryo-fetal toxicity studies, ATGAM was administered to rats and cynomolgus monkeys for 11 and 16 days, respectively during organogenesis. In rats, hypoplastic cervical vertebrae, a finding consistent with delayed skeletal development, were observed in fetuses whose dams received ATGAM at doses of 100 mg/kg/day during organogenesis. In monkey reproduction studies, maternal toxicity (vaginal bleeding, decreased body weight and loss of appetite) was observed with ATGAM doses ≥20 mg/kg/day after 16 days of dosing. Fetal deaths occurred in dams treated with 20 mg/kg/day ATGAM earlier in organogenesis (days 20‑35), but not when treatment was given at a later part of organogenesis (days 35-50). The maternal and fetal deaths were attributed to maternal anemia due to red blood cell antigen that humans do not share. Therefore, this toxicity is not considered relevant to human fetal development.

8.2 Lactation

Risk Summary

It is not known if ATGAM is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in breast-feeding neonates and infants from ATGAM, a decision should be made whether to discontinue breast-feeding or to discontinue the drug taking into account the importance of the drug to the mother.

Data

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.

8.3 Females and Males of Reproductive Potential

Contraception

Females

It is not known if ATGAM can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ATGAM and for at least 10 weeks after cessation of therapy.

Males

Advise males with a female partner of reproductive potential to use effective contraception during treatment with ATGAM and for at least 10 weeks after cessation of therapy.

Infertility

In fertility studies, ATGAM at doses 10, 20 and 40 mg/kg/day was administered to cynomolgus monkeys (Macaca fascicularis) for 14 days either before (male monkeys) or before and after (female monkeys) cohabitation with untreated mates. ATGAM treatment was not associated with male or female hormonal or copulation behavior changes. A decrease in fertility index in female monkeys receiving ATGAM was seen. Female toxicity, including death, was observed with ATGAM doses of ≥20 mg/kg/day. While the etiology of this toxicity is uncertain, it may be attributed to hemolytic anemia due to cross-reactivity of ATGAM to a monkey red blood antigen.

8.4 Pediatric Use

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.

8.5 Geriatric Use

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. Select the dose for an elderly patient with caution, starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of comorbidities or other drug therapy in this age group.

12.1 Mechanism of Action

ATGAM is composed of antibodies that bind a wide variety of proteins on the surface of lymphocytes. In addition, ATGAM binds to granulocytes, platelets, bone marrow cells, and other cell types. The mechanism of ATGAM-induced immunosuppression has not been determined. Published data indicate that the primary mechanism is the depletion of circulating lymphocytes, with greatest effect on T lymphocytes. Lymphocyte depletion may be caused by complement dependent lysis and/or activation-induced apoptosis. In addition, immunosuppression may be mediated by the binding of antibodies to lymphocytes which results in partial activation and induction of T lymphocyte anergy.

The mechanism of ATGAM therapy for aplastic anemia is attributed to its immunosuppressive actions. In addition, ATGAM directly stimulates the growth of hematopoietic stem cells and release of hematopoietic growth factors such as interleukin-3 and granulocyte/macrophage colony stimulating factor.

12.3 Pharmacokinetics

13.1 Carcinogenesis and Mutagenesis

Carcinogenicity and pre-/post-natal development studies have not been conducted on ATGAM.

14.1 Renal Allograft Rejection

14.2 Aplastic Anemia

The use of ATGAM for the treatment of moderate to severe aplastic anemia in patients unsuitable for bone marrow transplantation is based on data from three controlled studies.

The effectiveness of the ATGAM therapy in the studies described below was evaluated by the hematological response and survival rates (Table 3).

Store in a refrigerator at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Store in the original carton to protect from light.

For storage conditions of diluted solution, see Dosage and Administration (2.2).

Anaphylaxis

Advise the patient that ATGAM may be discontinued and immediate medical attention will be provided if any signs/symptoms of anaphylaxis occur [see Warnings and Precautions (5.1)].

Cytokine Release Syndrome

Advise the patient on the risk of cytokine release syndrome [see Warnings and Precautions (5.2)].

Infusion-Associated Reactions

Advise the patient on the clinical signs associated with infusion-associated reactions [see Warnings and Precautions (5.3)].

Serum Sickness

Advise the patient on the clinical signs associated with serum sickness [see Warnings and Precautions (5.4)].

Transmissible Infectious Agents

Despite screening and testing, products manufactured using components of human blood such as ATGAM may carry a risk of transmitting infectious agents (e.g., viruses). Discuss the risks and benefits of therapy with patients before initiating treatment [see Warnings and Precautions (5.5)].

Infections

Advise the patient to report any signs and symptoms of infection (e.g., fever, sweating, chills, muscle aches, cough, shortness of breath, diarrhea, or stomach pain) [see Warnings and Precautions (5.6)].

Thrombocytopenia and Neutropenia

Advise the patient to report any signs and symptoms of thrombocytopenia and/or neutropenia (e.g., unusual bleeding, bruising, rash of dark red spots under the skin, fever, sweating, chills, muscle aches, cough, shortness of breath, diarrhea, or stomach pain) [see Warnings and Precautions (5.8)].

Hepatic and Renal Function Tests

Advise the patient that monitoring of liver and renal function will occur. Advise the patient of abnormal liver and renal function test results [see Warnings and Precautions (5.9)].